{ "generated_from": { "pairs.tsv": 21, "phenocopy_links.tsv": 8, "exposure_to_gene.tsv": 12, "curation_overlay.tsv": 4, "verified_citations.tsv": 43 }, "counts": { "pairs": 21, "with_citation": 21, "with_pmid": 21, "with_verified_citation": 21, "with_resolved_mimic": 17, "with_profile": 17, "with_mechanism_edge": 11, "verified": 0, "published": 12, "withheld": 9 }, "records": [ { "pair_id": "TC001", "exposure": "thalidomide", "exposure_id": "CHEBI:9513", "direction": "exposure_mimics_genetic", "embryopathy": "thalidomide embryopathy", "embryopathy_id": "ORPHA:3312", "mimics": [ { "name": "Holt-Oram syndrome", "id": "OMIM:142900", "genes": [ "TBX5" ], "resolved": true, "summary": "Holt-Oram syndrome is an autosomal dominant heart-hand disorder caused by TBX5 variants. The limb defect is preaxial, bilateral and asymmetrical, and it is confined to the upper limbs. Cardiac disease reaches near-complete penetrance in familial cases. Thalidomide embryopathy produces the same radial ray picture, from triphalangeal thumb to phocomelia, and that is where the two meet. The resemblance is phenotypic only, because no perturbation of TBX5 by thalidomide has been demonstrated. Separation rests on the cardiac findings, the lower limbs and the family history.", "shared_count": 2, "overlap_summary": "Both profiles show upper limb defects only, from triphalangeal thumb to phocomelia." }, { "name": "Duane-radial ray syndrome", "id": "OMIM:607323", "genes": [ "SALL4" ], "resolved": true, "summary": "Duane-radial ray syndrome, also called Okihiro syndrome, is an autosomal dominant disorder of SALL4. It combines Duane anomaly with radial ray malformation, and it extends to the acro-renal-ocular end of the spectrum. Thalidomide degrades SALL4 protein through cereblon. This is the one comparison on the entry where the exposure and the disorder share a demonstrated molecular node. Both therefore produce Duane anomaly and a radial ray defect. Separation rests on the facial nerve and lacrimal findings, on inner-ear involvement, and on the molecular result.", "shared_count": 1, "overlap_summary": "Both profiles show triphalangeal thumb, the only shared feature." } ], "genes": [ "SALL4", "TBX5" ], "mechanism_class": "induced_degradation", "teratogenicity": "established", "mechanism_confidence": "definitive", "citations": [ { "pmid": "30067223", "first_author": "Donovan KA", "year": "2018", "journal": "Elife", "volume": "7", "pages": "e38430", "title": "Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome", "level": "title_supports", "checked": "2026-09-17" } ], "notes": "CRBN-dependent degradation of SALL4. Species specificity explained by CRBN/SALL4 sequence. Strongest exemplar in the field.", "targets": [ { "edge_id": "TCE001", "target": "SALL4", "target_type": "gene", "perturbation": "degrades", "mechanism_confidence": "definitive", "window": "gestational days 20-36", "citations": [ { "pmid": "30067223", "first_author": "Donovan KA", "year": "2018", "journal": "Elife", "volume": "7", "pages": "e38430", "title": "Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome", "level": "title_supports", "checked": "2026-09-17" } ], "note": "Cereblon-dependent degradation of SALL4 protein. Lenalidomide and pomalidomide act the same way. Species specificity is explained by cereblon sequence differences.", "verdicts": [ { "mimicked_id": "OMIM:607323", "verdict": "demonstrated", "rationale": "Thalidomide degrades SALL4, the gene disordered in Duane-radial ray syndrome. Both Duane anomaly and radial ray deficiency occur in the embryopathy.", "curator": "agent:claude-opus-5", "date": "2026-09-17" }, { "mimicked_id": "ORPHA:959", "verdict": "unresolved", "rationale": "Acro-renal-ocular syndrome shares the limb and ocular axes and sits in the same MONDO class as Duane-radial ray. Whether it is a distinct mimic or the same entity under another label is unresolved.", "curator": "agent:claude-opus-5", "date": "2026-09-17" } ] }, { "edge_id": "TCE002", "target": "TBX5", "target_type": "gene", "perturbation": "no_demonstrated_action", "mechanism_confidence": "limited", "window": "gestational days 20-36", "citations": [ { "pmid": "27639441", "first_author": "Cassina M", "year": "2017", "journal": "Eur J Med Genet", "volume": "60", "pages": "22-31", "title": "Human teratogens and genetic phenocopies. Understanding pathogenesis through human genes mutation", "level": "title_supports", "checked": "2026-09-17" } ], "note": "No degradation or inhibition of TBX5 by thalidomide has been demonstrated. The resemblance to Holt-Oram is phenotypic only, which is why this edge is graded far below the SALL4 edge from the same exposure.", "verdicts": [ { "mimicked_id": "OMIM:142900", "verdict": "not_demonstrated", "rationale": "The phenotypic overlap with Holt-Oram is real, but no perturbation of TBX5 by thalidomide has been demonstrated. Recorded as a phenotypic resemblance, not a shared mechanism.", "curator": "agent:claude-opus-5", "date": "2026-09-17" } ] } ], "provenance": { "has_citation": true, "has_pmid": true, "citation_verified": true, "mimic_resolved": true, "has_mimic": true, "has_mechanism_edge": true, "verified_against_primary_source": false }, "clinical": { "pair_id": "TC001", "synopsis": [ "Thalidomide damages the embryo only between days 20 and 36 after fertilisation, and one 50 mg tablet inside that window is reported as sufficient (PMID:26043938). The limb defect is bilateral, asymmetric and preaxial, and it progresses thumb, radius, humerus, ulna (PMID:26043938). Lenalidomide and pomalidomide degrade SALL4 protein by the same cereblon route (PMID:30067223)." ], "favours_exposure": [ { "statement": "The limb defect progresses in a fixed proximal order. The order runs thumb, then radius, then humerus, then ulna. Holt-Oram syndrome and Duane-radial ray syndrome involve the same four elements. The order carries the signal, not the parts", "lead": "The limb defect progresses in a fixed proximal order", "detail": "The order runs thumb, then radius, then humerus, then ulna. Holt-Oram syndrome and Duane-radial ray syndrome involve the same four elements. The order carries the signal, not the parts", "weight": "strong", "pmids": [ "26043938", "30067223" ], "mimic": null }, { "statement": "True phocomelia. The proximal long bones are reduced or absent and the hand plate remains. SALL4-related disease runs to radial aplasia, not to intercalary phocomelia. Phocomelia does not separate the embryopathy from Holt-Oram syndrome, which also reports it", "lead": "True phocomelia", "detail": "The proximal long bones are reduced or absent and the hand plate remains. SALL4-related disease runs to radial aplasia, not to intercalary phocomelia. Phocomelia does not separate the embryopathy from Holt-Oram syndrome, which also reports it", "weight": "strong", "pmids": [ "26043938", "20301547" ], "mimic": "OMIM:607323" }, { "statement": "Any lower-limb reduction. In the UK series of 55 Holt-Oram cases, skeletal defects affected the upper limbs only, and every affected case had upper limb involvement. Thalidomide affects the lower limbs less often than the upper limbs, but it does affect them", "lead": "Any lower-limb reduction", "detail": "In the UK series of 55 Holt-Oram cases, skeletal defects affected the upper limbs only, and every affected case had upper limb involvement. Thalidomide affects the lower limbs less often than the upper limbs, but it does affect them", "weight": "strong", "pmids": [ "8730285", "26043938" ], "mimic": "OMIM:142900" }, { "statement": "Facial nerve palsy with the ocular motility defect. 17 of 86 examined survivors had it. Duane anomaly occurs in both conditions, so the facial palsy does the work, not the eye movement", "lead": "Facial nerve palsy with the ocular motility defect", "detail": "17 of 86 examined survivors had it. Duane anomaly occurs in both conditions, so the facial palsy does the work, not the eye movement", "weight": "strong", "pmids": [ "8333272" ], "mimic": "OMIM:607323" }, { "statement": "Abnormal or absent lacrimation with the ocular motility defect. 17 of 86 examined survivors had it. Ear and facial nerve palsies follow ingestion early in the sensitive period, about days 21 to 26 after conception", "lead": "Abnormal or absent lacrimation with the ocular motility defect", "detail": "17 of 86 examined survivors had it. Ear and facial nerve palsies follow ingestion early in the sensitive period, about days 21 to 26 after conception", "weight": "strong", "pmids": [ "8333272", "2019959" ], "mimic": "OMIM:607323" }, { "statement": "Inner-ear involvement. Hypoplasia of the vestibular labyrinth is the typical lesion, with oculomotor and vestibular dysfunction on formal neuro-otological testing across an 18-patient series. Deafness and abnormal pinnae occur in both conditions. The vestibular-oculomotor pairing discriminates, not the hearing loss", "lead": "Inner-ear involvement", "detail": "Hypoplasia of the vestibular labyrinth is the typical lesion, with oculomotor and vestibular dysfunction on formal neuro-otological testing across an 18-patient series. Deafness and abnormal pinnae occur in both conditions. The vestibular-oculomotor pairing discriminates, not the hearing loss", "weight": "strong", "pmids": [ "180947", "30067223" ], "mimic": "OMIM:607323" }, { "statement": "Facial capillary haemangioma present at birth. It fades over the first two to three years, and the source calls it a stork mark and a key hallmark of the embryopathy. Neither lookalike carries it", "lead": "Facial capillary haemangioma present at birth", "detail": "It fades over the first two to three years, and the source calls it a stork mark and a key hallmark of the embryopathy. Neither lookalike carries it", "weight": "strong", "pmids": [ "26043938" ], "mimic": null }, { "statement": "Maternal ingestion dated between days 20 and 36 after fertilisation. This is 34 to 50 days after the last menstrual period. Exposure outside the window is thought not to damage the embryo, so a dated history can exclude as well as include", "lead": "Maternal ingestion dated between days 20 and 36 after fertilisation", "detail": "This is 34 to 50 days after the last menstrual period. Exposure outside the window is thought not to damage the embryo, so a dated history can exclude as well as include", "weight": "strong", "pmids": [ "26043938" ], "mimic": null }, { "statement": "A brief or single exposure inside the window. One 50 mg tablet is reported to cause birth defects in up to half of exposed pregnancies. Duration of therapy does not filter cases", "lead": "A brief or single exposure inside the window", "detail": "One 50 mg tablet is reported to cause birth defects in up to half of exposed pregnancies. Duration of therapy does not filter cases", "weight": "strong", "pmids": [ "26043938" ], "mimic": null }, { "statement": "Lenalidomide or pomalidomide rather than thalidomide. All three drugs produce a dose-dependent, CRBN-dependent fall in SALL4 protein in human embryonic stem cells", "lead": "Lenalidomide or pomalidomide rather than thalidomide", "detail": "All three drugs produce a dose-dependent, CRBN-dependent fall in SALL4 protein in human embryonic stem cells", "weight": "strong", "pmids": [ "30067223" ], "mimic": null }, { "statement": "Left limb long bones more severely affected than the right. Both lookalikes also produce bilateral asymmetric limb defects, so asymmetry alone separates nothing. The left-sided direction is the thalidomide-specific bias", "lead": "Left limb long bones more severely affected than the right", "detail": "Both lookalikes also produce bilateral asymmetric limb defects, so asymmetry alone separates nothing. The left-sided direction is the thalidomide-specific bias", "weight": "suggestive", "pmids": [ "40198353", "8730285" ], "mimic": null }, { "statement": "A denied drug history where thalidomide is widely available. In Brazilian proactive surveillance, both mothers of suspected cases denied use. A denial does not exclude the exposure", "lead": "A denied drug history where thalidomide is widely available", "detail": "In Brazilian proactive surveillance, both mothers of suspected cases denied use. A denial does not exclude the exposure", "weight": "suggestive", "pmids": [ "21754997" ], "mimic": null } ], "favours_gene": [ { "statement": "A pathogenic TBX5 variant. This is the only categorical discriminator against Holt-Oram syndrome. Every other item shifts probability", "lead": "A pathogenic TBX5 variant", "detail": "This is the only categorical discriminator against Holt-Oram syndrome. Every other item shifts probability", "weight": "categorical", "pmids": [ "16183809" ], "mimic": "OMIM:142900" }, { "statement": "A pathogenic SALL4 variant. This is the only categorical discriminator against Duane-radial ray syndrome. Every other item shifts probability", "lead": "A pathogenic SALL4 variant", "detail": "This is the only categorical discriminator against Duane-radial ray syndrome. Every other item shifts probability", "weight": "categorical", "pmids": [ "20301547" ], "mimic": "OMIM:607323" }, { "statement": "Cardiac involvement at near-complete penetrance. Cardiac defects occurred in 95% of familial cases in the UK series of 55. Atrial septal defect occurred in 34% and ventricular septal defect in 25%", "lead": "Cardiac involvement at near-complete penetrance", "detail": "Cardiac defects occurred in 95% of familial cases in the UK series of 55. Atrial septal defect occurred in 34% and ventricular septal defect in 25%", "weight": "strong", "pmids": [ "8730285" ], "mimic": "OMIM:142900" }, { "statement": "Conduction disease as the only cardiac finding. 39% of the same UK series had ECG changes alone, and heart block caused sudden death. The thalidomide literature describes no counterpart to an isolated conduction abnormality with a radial ray defect", "lead": "Conduction disease as the only cardiac finding", "detail": "39% of the same UK series had ECG changes alone, and heart block caused sudden death. The thalidomide literature describes no counterpart to an isolated conduction abnormality with a radial ray defect", "weight": "strong", "pmids": [ "8730285", "26043938" ], "mimic": "OMIM:142900" }, { "statement": "Skeletal defects confined to the upper limbs. They are bilateral and asymmetrical, and the radial ray is predominantly affected. This was the pattern across all 55 cases of the UK series", "lead": "Skeletal defects confined to the upper limbs", "detail": "They are bilateral and asymmetrical, and the radial ray is predominantly affected. This was the pattern across all 55 cases of the UK series", "weight": "strong", "pmids": [ "8730285" ], "mimic": "OMIM:142900" }, { "statement": "A preaxial radial ray malformation, as an entry requirement. Among 54 consecutively referred individuals with a clinical diagnosis of Holt-Oram syndrome, TBX5 mutations were found in 74% of those who met strict criteria. They were found in none of those who did not", "lead": "A preaxial radial ray malformation, as an entry requirement", "detail": "Among 54 consecutively referred individuals with a clinical diagnosis of Holt-Oram syndrome, TBX5 mutations were found in 74% of those who met strict criteria. They were found in none of those who did not", "weight": "strong", "pmids": [ "16183809" ], "mimic": "OMIM:142900" }, { "statement": "Autosomal dominant inheritance with 100% penetrance. The UK series recorded no reduced fitness. Examine the parents, and record an ECG where possible", "lead": "Autosomal dominant inheritance with 100% penetrance", "detail": "The UK series recorded no reduced fitness. Examine the parents, and record an ECG where possible", "weight": "strong", "pmids": [ "8730285" ], "mimic": "OMIM:142900" }, { "statement": "Increasing severity in succeeding generations. The source reports this as consistent with anticipation. A single-pregnancy exposure cannot produce a multigenerational severity gradient", "lead": "Increasing severity in succeeding generations", "detail": "The source reports this as consistent with anticipation. A single-pregnancy exposure cannot produce a multigenerational severity gradient", "weight": "strong", "pmids": [ "8730285" ], "mimic": "OMIM:142900" }, { "statement": "Thrombocytopenia or leukocytosis. Growth deficiency with pituitary hypoplasia counts the same way. These are SALL4 surveillance items. The thalidomide embryopathy literature reviewed here describes none of them", "lead": "Thrombocytopenia or leukocytosis", "detail": "Growth deficiency with pituitary hypoplasia counts the same way. These are SALL4 surveillance items. The thalidomide embryopathy literature reviewed here describes none of them", "weight": "strong", "pmids": [ "20301547", "26043938" ], "mimic": "OMIM:607323" }, { "statement": "A parent with isolated Duane anomaly. Thenar hypoplasia or a triphalangeal thumb on examination counts the same way. SALL4-related disorders are autosomal dominant. About 40% to 50% of cases are de novo, so a negative family history does not exclude the disorder", "lead": "A parent with isolated Duane anomaly", "detail": "Thenar hypoplasia or a triphalangeal thumb on examination counts the same way. SALL4-related disorders are autosomal dominant. About 40% to 50% of cases are de novo, so a negative family history does not exclude the disorder", "weight": "suggestive", "pmids": [ "20301547" ], "mimic": "OMIM:607323" }, { "statement": "Radial ray malformation with renal anomalies and coloboma. This is the acro-renal-ocular end of the spectrum: malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesicoureteral reflux and bladder diverticula. Thalidomide damages the same kidneys and also causes coloboma. The finding points to SALL4 only where the exposure cannot be documented", "lead": "Radial ray malformation with renal anomalies and coloboma", "detail": "This is the acro-renal-ocular end of the spectrum: malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesicoureteral reflux and bladder diverticula. Thalidomide damages the same kidneys and also causes coloboma. The finding points to SALL4 only where the exposure cannot be documented", "weight": "suggestive", "pmids": [ "20301547", "26043938", "8333272" ], "mimic": "OMIM:607323" }, { "statement": "Phocomelia occurs in Holt-Oram syndrome. Family B of Basson's two kindreds had 18 affected members with moderate-to-severe deformity, including phocomelia. 12 of those 18 had no cardiac defect at all. Neither phocomelia nor absent heart disease rules Holt-Oram syndrome out", "lead": "Phocomelia occurs in Holt-Oram syndrome", "detail": "Family B of Basson's two kindreds had 18 affected members with moderate-to-severe deformity, including phocomelia. 12 of those 18 had no cardiac defect at all. Neither phocomelia nor absent heart disease rules Holt-Oram syndrome out", "weight": "caveat", "pmids": [ "8114858" ], "mimic": "OMIM:142900" } ], "not_discriminating": [], "gaps": [ "The diagnostic algorithm for thalidomide embryopathy (DATE). PMID:30253685 introduces a scored algorithm for exactly the question this entry asks, and its abstract states that inadequate proof of ingestion, phenotypic variation and alternative genetic diagnoses hinder the diagnosis. The scoring rules are in the body of the paper, which is not open access and was not read. No weighting, threshold or feature list from DATE is reproduced here.", "Smithells & Newman 1992, \"Recognition of thalidomide defects\" (PMID:1433232). The primary clinical description and the source most of the above ultimately rests on via review. Its PMC record (PMC1016130) holds scanned images only, with no machine-readable body and no abstract. Everything attributed to it here is attributed instead to PMID:26043938, which cites it.", "Newbury-Ecob 1996 denominators. The 95%, 34%, 25% and 39% figures are quoted as the abstract states them. The abstract gives the whole study as 55 cases but does not state the size of the familial subset that the 95% is computed over, and the full text is a scanned PMC record with no machine-readable body. The cohort is named wherever a figure is used; the familial denominator is not recoverable from what was read.", "Whether thalidomide perturbs TBX5. Not demonstrated either way in the sources read. PMID:26043938 notes only that zebrafish Cul4a may bind Tbx5a. PMID:30067223 identifies SALL4 by mass spectrometry and reports ESCO2, ZNF143, SALL1, SALL2 and SALL3 unchanged, but does not test TBX5. The Holt-Oram arm of TC001 is therefore a phenotypic pair, and `data/pairs/curation_overlay.tsv` records TCE002 with assessment `not_demonstrated` on that basis. That vocabulary describes the state of the evidence, not a ruling on the claim.", "Quantified laterality. PMID:40198353 states the left-worse-than-right bias as a proposal from its reanalysis; no n/m is available from the abstract, and the full text is not open access. Written as a direction of effect, not a frequency.", "Frequency of Duane anomaly specifically, as opposed to incomitant strabismus. PMID:8333272 gives 43/86 with ocular motility defects, \"mostly incomitant strabismus\", and PMID:2019959 reports Duane type as the most noteworthy finding in 21 individuals. Neither states a Duane numerator. No figure is given here.", "Facial palsy and aberrant lacrimation in SALL4-related disorders. Neither is mentioned in PMID:20301547. That is absence of mention, not a reported absence, so the synopsis says these findings carry the discriminating weight rather than claiming SALL4 disease does not produce them.", "Any HPO-coded profile for thalidomide embryopathy. TC001 has no curated `.hpoa` in `curation/output/`. The above is prose grounded in literature only; it has not been reconciled against `ORPHA:3312`, which carries 17 P-terms and no ocular term at all." ], "caveat": [], "lookalikes": { "OMIM:142900": "Holt-Oram syndrome is an autosomal dominant heart-hand disorder caused by TBX5 variants. The limb defect is preaxial, bilateral and asymmetrical, and it is confined to the upper limbs. Cardiac disease reaches near-complete penetrance in familial cases. Thalidomide embryopathy produces the same radial ray picture, from triphalangeal thumb to phocomelia, and that is where the two meet. The resemblance is phenotypic only, because no perturbation of TBX5 by thalidomide has been demonstrated. Separation rests on the cardiac findings, the lower limbs and the family history.", "OMIM:607323": "Duane-radial ray syndrome, also called Okihiro syndrome, is an autosomal dominant disorder of SALL4. It combines Duane anomaly with radial ray malformation, and it extends to the acro-renal-ocular end of the spectrum. Thalidomide degrades SALL4 protein through cereblon. This is the one comparison on the entry where the exposure and the disorder share a demonstrated molecular node. Both therefore produce Duane anomaly and a radial ray defect. Separation rests on the facial nerve and lacrimal findings, on inner-ear involvement, and on the molecular result." }, "untagged": 7 }, "phenotype": { "embryopathy_id": "ORPHA:3312", "profile": [ { "hpo_id": "HP:0030680", "label": "Abnormal cardiovascular system morphology", "system": "HP:0001626", "system_label": "Abnormality of the cardiovascular system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3312", "origin": "release" }, { "hpo_id": "HP:0002991", "label": "Abnormal fibula morphology", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3312", "origin": "release" }, { "hpo_id": "HP:0009601", "label": "Aplasia/Hypoplasia of the thumb", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3312", "origin": "release" }, { "hpo_id": "HP:0006495", "label": "Aplasia/Hypoplasia of the ulna", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3312", "origin": "release" }, { "hpo_id": "HP:0005613", "label": "Aplasia/hypoplasia of the femur", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3312", "origin": "release" }, { "hpo_id": "HP:0006507", "label": "Aplasia/hypoplasia of the humerus", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3312", "origin": "release" }, { "hpo_id": "HP:0001177", "label": "Preaxial hand polydactyly", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3312", "origin": "release" }, { "hpo_id": "HP:0006433", "label": "Radial ray deficiency", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3312", "origin": "release" }, { "hpo_id": "HP:0004322", "label": "Short stature", "system": "HP:0001507", "system_label": "Growth abnormality", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3312", "origin": "release" }, { "hpo_id": "HP:0001171", "label": "Split hand", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3312", "origin": "release" }, { "hpo_id": "HP:0001199", "label": "Triphalangeal thumb", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3312", "origin": "release" }, { "hpo_id": "HP:0009813", "label": "Upper limb phocomelia", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3312", "origin": "release" }, { "hpo_id": "HP:0000356", "label": "Abnormality of the outer ear", "system": "HP:0000598", "system_label": "Abnormality of the ear", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3312", "origin": "release" }, { "hpo_id": "HP:0009892", "label": "Anotia", "system": "HP:0000598", "system_label": "Abnormality of the ear", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3312", "origin": "release" }, { "hpo_id": "HP:0002257", "label": "Chronic rhinitis", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3312", "origin": "release" }, { "hpo_id": "HP:0000365", "label": "Hearing impairment", "system": "HP:0000598", "system_label": "Abnormality of the ear", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3312", "origin": "release" }, { "hpo_id": "HP:0000855", "label": "Insulin resistance", "system": "HP:0001939", "system_label": "Abnormality of metabolism/homeostasis", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3312", "origin": "release" } ], "profile_source": "phenotype.hpoa 2026-09-02", "profile_references": [ "ORPHA:3312" ], "profile_evidence_codes": [ "TAS" ], "excluded_features": [], "mimics": [ { "id": "OMIM:142900", "name": "Holt-Oram syndrome", "profile_size": 98, "only_in_exposure": [ { "hpo_id": "HP:0002991", "label": "Abnormal fibula morphology", "frequency": "frequent" }, { "hpo_id": "HP:0005613", "label": "Aplasia/hypoplasia of the femur", "frequency": "frequent" }, { "hpo_id": "HP:0004322", "label": "Short stature", "frequency": "frequent" }, { "hpo_id": "HP:0001171", "label": "Split hand", "frequency": "frequent" }, { "hpo_id": "HP:0000356", "label": "Abnormality of the outer ear", "frequency": "occasional" }, { "hpo_id": "HP:0009892", "label": "Anotia", "frequency": "occasional" }, { "hpo_id": "HP:0002257", "label": "Chronic rhinitis", "frequency": "occasional" }, { "hpo_id": "HP:0000365", "label": "Hearing impairment", "frequency": "occasional" }, { "hpo_id": "HP:0000855", "label": "Insulin resistance", "frequency": "occasional" } ], "only_in_mimic": [ { "hpo_id": "HP:0010704", "label": "1-2 finger cutaneous syndactyly", "frequency": "5/5" }, { "hpo_id": "HP:0000878", "label": "11 pairs of ribs", "frequency": "2/2" }, { "hpo_id": "HP:0001233", "label": "2-3 finger cutaneous syndactyly", "frequency": "1/1" }, { "hpo_id": "HP:0011939", "label": "3-4 finger cutaneous syndactyly", "frequency": "1/3" }, { "hpo_id": "HP:0003363", "label": "Abdominal situs inversus", "frequency": "1/1" }, { "hpo_id": "HP:0001191", "label": "Abnormal carpal morphology", "frequency": "40/42" }, { "hpo_id": "HP:0011636", "label": "Abnormal coronary artery origin", "frequency": "1/1" }, { "hpo_id": "HP:0009812", "label": "Amelia involving the upper limbs", "frequency": "1/151" }, { "hpo_id": "HP:0100379", "label": "Aplasia of the distal phalanx of the 4th toe", "frequency": "1/1" }, { "hpo_id": "HP:0009751", "label": "Aplasia of the pectoralis major muscle", "frequency": "34/55" }, { "hpo_id": "HP:0001631", "label": "Atrial septal defect", "frequency": "50/52" }, { "hpo_id": "HP:0011995", "label": "Atrial septal dilatation", "frequency": "4/4" } ], "shared": [ "HP:0001199", "HP:0009813" ], "overlap_summary": "Both profiles show upper limb defects only, from triphalangeal thumb to phocomelia.", "comparable": true }, { "id": "OMIM:607323", "name": "Duane-radial ray syndrome", "profile_size": 53, "only_in_exposure": [ { "hpo_id": "HP:0002991", "label": "Abnormal fibula morphology", "frequency": "frequent" }, { "hpo_id": "HP:0005613", "label": "Aplasia/hypoplasia of the femur", "frequency": "frequent" }, { "hpo_id": "HP:0004322", "label": "Short stature", "frequency": "frequent" }, { "hpo_id": "HP:0001171", "label": "Split hand", "frequency": "frequent" }, { "hpo_id": "HP:0009813", "label": "Upper limb phocomelia", "frequency": "frequent" }, { "hpo_id": "HP:0009892", "label": "Anotia", "frequency": "occasional" }, { "hpo_id": "HP:0002257", "label": "Chronic rhinitis", "frequency": "occasional" }, { "hpo_id": "HP:0000855", "label": "Insulin resistance", "frequency": "occasional" } ], "only_in_mimic": [ { "hpo_id": "HP:0008588", "label": "Slit-like opening of the exterior auditory meatus", "frequency": "occasional" }, { "hpo_id": "HP:0001739", "label": "Abnormal nasopharynx morphology", "frequency": null }, { "hpo_id": "HP:0002251", "label": "Aganglionic megacolon", "frequency": "1/13" }, { "hpo_id": "HP:0002023", "label": "Anal atresia", "frequency": null }, { "hpo_id": "HP:0002025", "label": "Anal stenosis", "frequency": null }, { "hpo_id": "HP:0010048", "label": "Aplasia of metacarpal bones", "frequency": null }, { "hpo_id": "HP:0001631", "label": "Atrial septal defect", "frequency": null }, { "hpo_id": "HP:0000518", "label": "Cataract", "frequency": null }, { "hpo_id": "HP:0000453", "label": "Choanal atresia", "frequency": null }, { "hpo_id": "HP:0000452", "label": "Choanal stenosis", "frequency": null }, { "hpo_id": "HP:0004736", "label": "Crossed fused renal ectopia", "frequency": null }, { "hpo_id": "HP:0009921", "label": "Duane anomaly", "frequency": "12/13" } ], "shared": [ "HP:0001199" ], "overlap_summary": "Both profiles show triphalangeal thumb, the only shared feature.", "comparable": true } ] }, "publish": true, "withheld_because": [] }, { "pair_id": "TC002", "exposure": "warfarin", "exposure_id": "CHEBI:10033", "direction": "exposure_mimics_genetic", "embryopathy": "vitamin K antagonist embryofetopathy", "embryopathy_id": "ORPHA:1914", "mimics": [ { "name": "Chondrodysplasia punctata 1, X-linked recessive (CDPX1)", "id": "OMIM:302950", "genes": [ "ARSL" ], "resolved": true, "summary": "CDPX1 is an X-linked recessive disorder of ARSL, a gene formerly called ARSE. Affected males show epiphyseal stippling, a depressed nasal bridge, a short nose and short distal phalanges. Warfarin inhibits the same enzyme, arylsulfatase E, which is why the skeletal and midface picture is close enough to be mistaken. The exposure adds a haemorrhagic arm that a sulfatase deficiency cannot produce, and it has no sex restriction.", "shared_count": 6, "overlap_summary": "Both profiles show depressed nasal bridge, short nose, epiphyseal stippling, and short distal phalanges." } ], "genes": [ "ARSL" ], "mechanism_class": "direct_target_inhibition", "teratogenicity": "established", "mechanism_confidence": "strong", "citations": [ { "pmid": "7720070", "first_author": "Franco B", "year": "1995", "journal": "Cell", "volume": "81", "pages": "15-25", "title": "A cluster of sulfatase genes on Xp22.3: mutations in chondrodysplasia punctata (CDPX) and implications for warfarin embryopathy", "level": "title_supports", "checked": "2026-09-17" } ], "notes": "Gene renamed ARSE -> ARSL (HGNC). Warfarin inhibits arylsulfatase L activity.", "targets": [ { "edge_id": "TCE003", "target": "ARSL", "target_type": "gene", "perturbation": "inhibits", "mechanism_confidence": "strong", "window": "first trimester", "citations": [ { "pmid": "7720070", "first_author": "Franco B", "year": "1995", "journal": "Cell", "volume": "81", "pages": "15-25", "title": "A cluster of sulfatase genes on Xp22.3: mutations in chondrodysplasia punctata (CDPX) and implications for warfarin embryopathy", "level": "title_supports", "checked": "2026-09-17" } ], "note": "Inhibits arylsulfatase E, the enzyme deficient in CDPX1. Note the gene was renamed from ARSE; searches under the old symbol return nothing.", "verdicts": [ { "mimicked_id": "OMIM:302950", "verdict": "unresolved", "rationale": "Warfarin inhibits arylsulfatase E, the enzyme deficient in CDPX1. The embryopathy profile used here was curated from warfarin case series without reference to CDPX1, so the resemblance is not an artifact of the curation.", "curator": "agent:claude-opus-5", "date": "2026-09-17" } ] } ], "provenance": { "has_citation": true, "has_pmid": true, "citation_verified": true, "mimic_resolved": true, "has_mimic": true, "has_mechanism_edge": true, "verified_against_primary_source": false }, "clinical": { "pair_id": "TC002", "synopsis": [ "Vitamin K antagonist exposure in weeks six to twelve produces nasal hypoplasia with epiphyseal stippling and short distal phalanges (PMID:20922410; PMID:988645). A change to heparin across that window removed the embryopathy in the reported cohort (PMID:10647757). A second arm is haemorrhagic and mechanically separate: cerebral haemorrhage was found in 8 of 13 autopsied fetuses (PMID:20922410)." ], "favours_exposure": [ { "statement": "Intracranial haemorrhage, or a CNS lesion consequent on it. Cerebral haemorrhage was found in 8 of 13 autopsied fetuses, spread across gestation: 2 before 20 weeks, 4 between 21 and 30, and 2 between 31 and 40. White matter necrosis occurred in 2 of 13, and hydrocephalus in 2 of 13, one of them haematohydrocephalus. The denominators come from an autopsy series of stillbirths and intrauterine deaths, not livebirths", "lead": "Intracranial haemorrhage, or a CNS lesion consequent on it", "detail": "Cerebral haemorrhage was found in 8 of 13 autopsied fetuses, spread across gestation: 2 before 20 weeks, 4 between 21 and 30, and 2 between 31 and 40. White matter necrosis occurred in 2 of 13, and hydrocephalus in 2 of 13, one of them haematohydrocephalus. The denominators come from an autopsy series of stillbirths and intrauterine deaths, not livebirths", "weight": "strong", "pmids": [ "20922410" ], "mimic": "OMIM:302950" }, { "statement": "Subependymal intraventricular haemorrhage on ultrasound. Reported in a liveborn infant whose mother took warfarin alone", "lead": "Subependymal intraventricular haemorrhage on ultrasound", "detail": "Reported in a liveborn infant whose mother took warfarin alone", "weight": "strong", "pmids": [ "8418652" ], "mimic": "OMIM:302950" }, { "statement": "The haemorrhagic arm is mechanically separate from the skeletal arm. Warfarin inhibits VKOR. Sources attribute the CNS anomalies to fetal haemorrhage, with later scarring and impaired brain development, mostly after second-trimester and third-trimester exposure. A sulfatase deficiency gives no route to this", "lead": "The haemorrhagic arm is mechanically separate from the skeletal arm", "detail": "Warfarin inhibits VKOR. Sources attribute the CNS anomalies to fetal haemorrhage, with later scarring and impaired brain development, mostly after second-trimester and third-trimester exposure. A sulfatase deficiency gives no route to this", "weight": "strong", "pmids": [ "42647228" ], "mimic": "OMIM:302950" }, { "statement": "Maternal vitamin K antagonist in weeks six to twelve. Weeks six to nine carry most of the risk. In a systematic review of anticoagulation for mechanical heart valves, a change to heparin at or before six weeks, continued to twelve weeks, removed the embryopathy. The pooled risk with oral anticoagulants throughout was 6.4% of livebirths (95% CI 4.6 to 8.9). This is a pooled review estimate, not a single-cohort count", "lead": "Maternal vitamin K antagonist in weeks six to twelve", "detail": "Weeks six to nine carry most of the risk. In a systematic review of anticoagulation for mechanical heart valves, a change to heparin at or before six weeks, continued to twelve weeks, removed the embryopathy. The pooled risk with oral anticoagulants throughout was 6.4% of livebirths (95% CI 4.6 to 8.9). This is a pooled review estimate, not a single-cohort count", "weight": "strong", "pmids": [ "10647757", "42647228" ], "mimic": "OMIM:302950" }, { "statement": "Exposure at or below 5 mg/day does not argue against the diagnosis. Full fetal warfarin syndrome with skeletal abnormality and ventricular septal defect is reported at 5 mg/day. In that pregnancy the drug was also withheld between weeks 8 and 10. A low dose lowers fetopathic risk but apparently not embryopathic risk. The commonly cited 5 mg/day threshold rests mainly on one small mechanical-valve cohort", "lead": "Exposure at or below 5 mg/day does not argue against the diagnosis", "detail": "Full fetal warfarin syndrome with skeletal abnormality and ventricular septal defect is reported at 5 mg/day. In that pregnancy the drug was also withheld between weeks 8 and 10. A low dose lowers fetopathic risk but apparently not embryopathic risk. The commonly cited 5 mg/day threshold rests mainly on one small mechanical-valve cohort", "weight": "strong", "pmids": [ "29627779", "42647228" ], "mimic": "OMIM:302950" }, { "statement": "An indication that mandates anticoagulation through organogenesis. Prosthetic valve replacement after acute rheumatic fever and valvular damage was the setting for the whole Cape Town series", "lead": "An indication that mandates anticoagulation through organogenesis", "detail": "Prosthetic valve replacement after acute rheumatic fever and valvular damage was the setting for the whole Cape Town series", "weight": "strong", "pmids": [ "20922410" ], "mimic": "OMIM:302950" }, { "statement": "Findings outside the chondro-osseous axis. A cartilage lesion does not explain them. The autopsy series of 13 recorded pelviureteric junction obstruction in 2, and single instances of premature closure of the ductus arteriosus, macroglossia, anal agenesis, testicular Leydig cell hyperplasia and optic nerve neuroma", "lead": "Findings outside the chondro-osseous axis", "detail": "A cartilage lesion does not explain them. The autopsy series of 13 recorded pelviureteric junction obstruction in 2, and single instances of premature closure of the ductus arteriosus, macroglossia, anal agenesis, testicular Leydig cell hyperplasia and optic nerve neuroma", "weight": "strong", "pmids": [ "20922410" ], "mimic": "OMIM:302950" }, { "statement": "Structural cardiac malformation. Warfarin-exposed case reports describe atrial septal defect, ventricular septal defect, patent ductus arteriosus and coarctation of the aorta", "lead": "Structural cardiac malformation", "detail": "Warfarin-exposed case reports describe atrial septal defect, ventricular septal defect, patent ductus arteriosus and coarctation of the aorta", "weight": "strong", "pmids": [ "15605910", "14692224", "41158910" ], "mimic": "OMIM:302950" }, { "statement": "Anterior nasal airway obstruction on fibrobronchoscopy. The obstruction follows narrowing of the nasal cavities and the piriform aperture, not posterior choanal atresia. The exposure literature documents anterior narrowing, so this entry records upper airway obstruction rather than choanal atresia", "lead": "Anterior nasal airway obstruction on fibrobronchoscopy", "detail": "The obstruction follows narrowing of the nasal cavities and the piriform aperture, not posterior choanal atresia. The exposure literature documents anterior narrowing, so this entry records upper airway obstruction rather than choanal atresia", "weight": "strong", "pmids": [ "25899236", "29627779", "7426582" ], "mimic": "OMIM:302950" }, { "statement": "Epiphora with a distended lacrimal sac. It follows nasolacrimal duct obstruction caused by the nasal malformation, and is a mechanical consequence of the midface lesion. The same case had healthy eyes, clear lenses and normal optic discs", "lead": "Epiphora with a distended lacrimal sac", "detail": "It follows nasolacrimal duct obstruction caused by the nasal malformation, and is a mechanical consequence of the midface lesion. The same case had healthy eyes, clear lenses and normal optic discs", "weight": "strong", "pmids": [ "7426582" ], "mimic": "OMIM:302950" } ], "favours_gene": [ { "statement": "A hemizygous pathogenic ARSL variant. This is the only categorical discriminator. ARSL enzymatic activity testing is not clinically available, so the molecular result is the test", "lead": "A hemizygous pathogenic ARSL variant", "detail": "This is the only categorical discriminator. ARSL enzymatic activity testing is not clinically available, so the molecular result is the test", "weight": "categorical", "pmids": [ "20301713" ], "mimic": "OMIM:302950" }, { "statement": "Male sex, with unaffected parents. Affected males may also appear in the maternal line. CDPX1 maps to Xp22.3, and females who inherit the pathogenic ARSL variant are carriers who have not been affected to date. FISH across 23 boys with Xp22.3 phenotypes found nullisomy in 9 male patients and hemizygosity in all female carriers. Warfarin embryopathy has no sex restriction, and both sexes appear in the Cape Town autopsy series and in the 18-child liveborn series", "lead": "Male sex, with unaffected parents", "detail": "Affected males may also appear in the maternal line. CDPX1 maps to Xp22.3, and females who inherit the pathogenic ARSL variant are carriers who have not been affected to date. FISH across 23 boys with Xp22.3 phenotypes found nullisomy in 9 male patients and hemizygosity in all female carriers. Warfarin embryopathy has no sex restriction, and both sexes appear in the Cape Town autopsy series and in the 18-child liveborn series", "weight": "strong", "pmids": [ "16323556", "7720070", "20301713", "20922410", "8418652" ], "mimic": "OMIM:302950" }, { "statement": "Cervical spine stenosis or instability. This is a recognised CDPX1 complication with explicit surveillance and anaesthetic implications. They are flexion-extension radiographs every six to twelve months until growth is complete, cervical spine imaging before general anaesthesia, and avoidance of contact sports. The warfarin autopsy series and the warfarin case reports curated here do not tabulate it", "lead": "Cervical spine stenosis or instability", "detail": "This is a recognised CDPX1 complication with explicit surveillance and anaesthetic implications. They are flexion-extension radiographs every six to twelve months until growth is complete, cervical spine imaging before general anaesthesia, and avoidance of contact sports. The warfarin autopsy series and the warfarin case reports curated here do not tabulate it", "weight": "strong", "pmids": [ "20301713", "20922410" ], "mimic": "OMIM:302950" }, { "statement": "Additional Xp22.3 phenotypes in the same male. These are ichthyosis, anosmia with hypogonadotropic hypogonadism, ocular albinism and intellectual disability. Together they indicate a contiguous gene deletion across STS, KAL1/ANOS1 and neighbouring loci rather than an isolated ARSL lesion. Two or more of these distinct entities in one individual is the signature", "lead": "Additional Xp22.3 phenotypes in the same male", "detail": "These are ichthyosis, anosmia with hypogonadotropic hypogonadism, ocular albinism and intellectual disability. Together they indicate a contiguous gene deletion across STS, KAL1/ANOS1 and neighbouring loci rather than an isolated ARSL lesion. Two or more of these distinct entities in one individual is the signature", "weight": "strong", "pmids": [ "16323556", "20301713" ], "mimic": "OMIM:302950" }, { "statement": "No vitamin K antagonist anywhere in the pregnancy. The mother must also have no indication for one. The exposure window is narrow and specific, so a documented clean first trimester carries real weight here", "lead": "No vitamin K antagonist anywhere in the pregnancy", "detail": "The mother must also have no indication for one. The exposure window is narrow and specific, so a documented clean first trimester carries real weight here", "weight": "strong", "pmids": [ "10647757", "42647228" ], "mimic": "OMIM:302950" }, { "statement": "Mixed conductive and sensorineural hearing loss. It is a defined component of CDPX1. Treat it with care as a discriminator. The warfarin literature records one case with functional change in the cortical auditory pathways on long-latency auditory evoked potentials, so the axis is not wholly absent from the exposure side", "lead": "Mixed conductive and sensorineural hearing loss", "detail": "It is a defined component of CDPX1. Treat it with care as a discriminator. The warfarin literature records one case with functional change in the cortical auditory pathways on long-latency auditory evoked potentials, so the axis is not wholly absent from the exposure side", "weight": "suggestive", "pmids": [ "20301713", "25899236" ], "mimic": "OMIM:302950" } ], "not_discriminating": [], "gaps": [ "Any ocular exclusion. PMID:7426582 examined its case's eyes and found them healthy, which would license an explicit negative. It is not written, because the same paper reports second-hand that Shaul & Hall 1977 (PMID:831501) found ophthalmic abnormalities in 5 of 14 anticoagulant-exposed infants and optic atrophy in 2. PMID:831501 has no abstract and no PMC record and remains the single highest-value outstanding document for this entry; it is the only systematic ocular denominator in the warfarin literature.", "Any liveborn denominator for the warfarin phenotype. Every frequency available to this entry is from an autopsy series of 13 stillbirths and intrauterine deaths. The largest liveborn series read here (PMID:8418652) gives 18 warfarin-only children with narrative findings, not systematic organ-by-organ denominators. The distribution of features among surviving children is therefore not known from these sources.", "Exposure window for most individual features. The autopsy series states plainly that no information was available on dose or timing. The embryopathy/fetopathy split proposed while curating this entry is a hypothesis under test, not a settled partition, and no shipped file records it; the haemorrhages were spread across gestation rather than confined to the third trimester.", "Whether the ARSL mechanism is the whole skeletal story. PMID:7720070 supports warfarin inhibition of the Xp22.3 sulfatase in its title, but PMID:42647228 attributes the chondrodysplasia punctata, nasal hypoplasia and distal skeletal changes to impaired \u03b3-carboxylation of matrix Gla protein and osteocalcin, and notes that GGCX mutations produce a phenotype resembling fetal warfarin syndrome. Two live mechanistic accounts of the same lesion. The `mechanism_class` column in `data/annotations/evidence.tsv` partitions terms on the ARSL hypothesis and is flagged in that file's header as curator judgement, not grounded evidence. No causal attribution beyond \"both are proposed\" is made here.", "Whether `ORPHA:1914` is independent of CDPX1. Its `reference` column is self-referential with evidence code TAS, so its underlying source is not visible in the release. Nothing in this document is sourced from `ORPHA:1914`.", "Frequency of cervical spine involvement in CDPX1, and its true absence in warfarin embryopathy. Neither is quantified in the sources read. The discriminator above is stated as \"described in CDPX1, not tabulated in the warfarin series read here\", which is an asymmetry of evidence and not a demonstrated absence." ], "caveat": [ "Not part of the synopsis. Read it before quoting any n/13 above.", "Every n/13 comes from PMID:20922410. That is an autopsy series of 13 fresh or macerated stillbirths and intrauterine deaths at 17\u201337 weeks. It is not a liveborn cohort. The paper says its own denominators describe the severe end of the spectrum. The 8/13 cerebral haemorrhage figure is not a liveborn rate. It must never be presented as one. The series also records that no information was available on the dose or timing of warfarin administration, so nothing in it can be assigned to an exposure window." ], "lookalikes": { "OMIM:302950": "CDPX1 is an X-linked recessive disorder of ARSL, a gene formerly called ARSE. Affected males show epiphyseal stippling, a depressed nasal bridge, a short nose and short distal phalanges. Warfarin inhibits the same enzyme, arylsulfatase E, which is why the skeletal and midface picture is close enough to be mistaken. The exposure adds a haemorrhagic arm that a sulfatase deficiency cannot produce, and it has no sex restriction." }, "untagged": 0 }, "phenotype": { "embryopathy_id": "ORPHA:1914", "profile": [ { "hpo_id": "HP:0000463", "label": "Anteverted nares", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1914", "origin": "release" }, { "hpo_id": "HP:0005280", "label": "Depressed nasal bridge", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1914", "origin": "release" }, { "hpo_id": "HP:0010655", "label": "Epiphyseal stippling", "system": "HP:0033127", "system_label": "Abnormality of the musculoskeletal system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1914", "origin": "release" }, { "hpo_id": "HP:0008420", "label": "Punctate vertebral calcifications", "system": "HP:0033127", "system_label": "Abnormality of the musculoskeletal system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1914", "origin": "release" }, { "hpo_id": "HP:0003196", "label": "Short nose", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1914", "origin": "release" }, { "hpo_id": "HP:0001156", "label": "Brachydactyly", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1914", "origin": "release" }, { "hpo_id": "HP:0001249", "label": "Intellectual disability", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1914", "origin": "release" }, { "hpo_id": "HP:0001511", "label": "Intrauterine growth retardation", "system": "HP:0001507", "system_label": "Growth abnormality", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1914", "origin": "release" }, { "hpo_id": "HP:0002093", "label": "Respiratory insufficiency", "system": "HP:0002086", "system_label": "Abnormality of the respiratory system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1914", "origin": "release" }, { "hpo_id": "HP:0009882", "label": "Short distal phalanx of finger", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "frequent", 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"origin": "release" }, { "hpo_id": "HP:0000518", "label": "Cataract", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1914", "origin": "release" }, { "hpo_id": "HP:0000453", "label": "Choanal atresia", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1914", "origin": "release" }, { "hpo_id": "HP:0000365", "label": "Hearing impairment", "system": "HP:0000598", "system_label": "Abnormality of the ear", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1914", "origin": "release" }, { "hpo_id": "HP:0000238", "label": "Hydrocephalus", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": 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"hpo_id": "HP:0001342", "label": "Cerebral hemorrhage", "system": "HP:0001871", "system_label": "Abnormality of blood and blood-forming tissues", "frequency": "8/13", "frequency_range": "8/13", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:20922410", "origin": "teracopy" }, { "hpo_id": "HP:0001680", "label": "Coarctation of aorta", "system": "HP:0001626", "system_label": "Abnormality of the cardiovascular system", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:14692224", "origin": "teracopy" }, { "hpo_id": "HP:0011120", "label": "Concave nasal ridge", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:41158910", "origin": "teracopy" }, { "hpo_id": "HP:0030752", "label": "Dacryocystocele", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:7426582", "origin": "teracopy" }, { "hpo_id": "HP:0000684", "label": "Delayed eruption of teeth", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:25899236", "origin": "teracopy" }, { "hpo_id": "HP:0002750", "label": "Delayed skeletal maturation", "system": "HP:0033127", "system_label": "Abnormality of the musculoskeletal system", "frequency": "1/13", "frequency_range": "1/13", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:20922410", "origin": "teracopy" }, { "hpo_id": "HP:0011968", "label": "Feeding difficulties", "system": "HP:0025031", "system_label": "Abnormality of the digestive system", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:29627779", "origin": "teracopy" }, { "hpo_id": "HP:0001510", "label": "Growth delay", "system": "HP:0001507", "system_label": "Growth abnormality", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:15605910", "origin": "teracopy" }, { "hpo_id": "HP:0010791", "label": "Hyperplasia of the Leydig cells", "system": "HP:0000119", "system_label": "Abnormality of the genitourinary system", "frequency": "1/13", "frequency_range": "1/13", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:20922410", "origin": "teracopy" }, { "hpo_id": "HP:0030746", "label": "Intraventricular hemorrhage", "system": "HP:0001871", "system_label": "Abnormality of blood and blood-forming tissues", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:8418652", "origin": "teracopy" }, { "hpo_id": "HP:0001601", "label": "Laryngomalacia", "system": "HP:0002086", "system_label": "Abnormality of the respiratory system", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:15605910", "origin": "teracopy" }, { "hpo_id": "HP:0011800", "label": "Midface retrusion", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:988645", "origin": "teracopy" }, { "hpo_id": "HP:0002643", "label": "Neonatal respiratory distress", "system": "HP:0002086", "system_label": "Abnormality of the respiratory system", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:41158910", "origin": "teracopy" }, { "hpo_id": "HP:0001643", "label": "Patent ductus arteriosus", "system": "HP:0001626", "system_label": "Abnormality of the cardiovascular system", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:15605910", "origin": "teracopy" }, { "hpo_id": "HP:0000767", "label": "Pectus excavatum", "system": "HP:0033127", "system_label": "Abnormality of the musculoskeletal system", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:26078896", "origin": "teracopy" }, { "hpo_id": "HP:0025675", "label": "Premature closure of the ductus arteriosus", "system": "HP:0001197", "system_label": "Abnormality of prenatal development or birth", "frequency": "1/13", "frequency_range": "1/13", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:20922410", "origin": "teracopy" }, { "hpo_id": "HP:0000879", "label": "Short sternum", "system": "HP:0033127", "system_label": "Abnormality of the musculoskeletal system", "frequency": "1/13", "frequency_range": "1/13", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:20922410", "origin": "teracopy" }, { "hpo_id": "HP:0001518", "label": "Small for gestational age", "system": "HP:0001507", "system_label": "Growth abnormality", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:8418652", "origin": "teracopy" }, { "hpo_id": "HP:0001792", "label": "Small nail", "system": "HP:0001574", "system_label": "Abnormality of the integument", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:16856447", "origin": "teracopy" }, { "hpo_id": "HP:0000506", "label": "Telecanthus", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:988645", "origin": "teracopy" }, { "hpo_id": "HP:0002781", "label": "Upper airway obstruction", "system": "HP:0002086", "system_label": "Abnormality of the respiratory system", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:25899236", "origin": "teracopy" }, { "hpo_id": "HP:0000074", "label": "Ureteropelvic junction obstruction", "system": "HP:0000119", "system_label": "Abnormality of the genitourinary system", "frequency": "2/13", "frequency_range": "2/13", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:20922410", "origin": "teracopy" }, { "hpo_id": "HP:0001629", "label": "Ventricular septal defect", "system": "HP:0001626", "system_label": "Abnormality of the cardiovascular system", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:14692224", "origin": "teracopy" }, { "hpo_id": "HP:0002119", "label": "Ventriculomegaly", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:15605910", "origin": "teracopy" }, { "hpo_id": "HP:0000445", "label": "Wide nose", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:988645", "origin": "teracopy" } ], "profile_source": "phenotype.hpoa 2026-09-02", "profile_references": [ "ORPHA:1914", "PMID:14692224", "PMID:15605910", "PMID:16856447", "PMID:20922410", "PMID:25899236", "PMID:26078896", "PMID:29627779", "PMID:41158910", "PMID:7426582", "PMID:8418652", "PMID:988645" ], "profile_evidence_codes": [ "IEA", "TAS" ], "excluded_features": [], "mimics": [ { "id": "OMIM:302950", "name": "Chondrodysplasia punctata 1, X-linked recessive (CDPX1)", "profile_size": 14, "only_in_exposure": [ { "hpo_id": "HP:0000463", "label": "Anteverted nares", "frequency": "very frequent" }, { "hpo_id": "HP:0008420", "label": "Punctate vertebral calcifications", "frequency": "very frequent" }, { "hpo_id": "HP:0002093", "label": "Respiratory insufficiency", "frequency": "frequent" }, { "hpo_id": "HP:0000470", "label": "Short neck", "frequency": "frequent" }, { "hpo_id": "HP:0030680", "label": "Abnormal cardiovascular system morphology", "frequency": "occasional" }, { "hpo_id": "HP:0008056", "label": "Aplasia/Hypoplasia affecting the eye", "frequency": "occasional" }, { "hpo_id": "HP:0000453", "label": "Choanal atresia", "frequency": "occasional" }, { "hpo_id": "HP:0000238", "label": "Hydrocephalus", "frequency": "occasional" }, { "hpo_id": "HP:0000316", "label": "Hypertelorism", "frequency": "occasional" }, { "hpo_id": "HP:0001252", "label": "Hypotonia", "frequency": "occasional" }, { "hpo_id": "HP:0000158", "label": "Macroglossia", "frequency": "occasional" }, { "hpo_id": "HP:0008551", "label": "Microtia", "frequency": "occasional" } ], "only_in_mimic": [ { "hpo_id": "HP:0000458", "label": "Anosmia", "frequency": null }, { "hpo_id": "HP:0000135", "label": "Hypogonadism", "frequency": null }, { "hpo_id": "HP:0008064", "label": "Ichthyosis", "frequency": null }, { "hpo_id": "HP:0000252", "label": "Microcephaly", "frequency": null }, { "hpo_id": "HP:0000420", "label": "Short nasal septum", "frequency": null } ], "shared": [ "HP:0000365", "HP:0000518", "HP:0003196", "HP:0005280", "HP:0009882", "HP:0010655" ], "overlap_summary": "Both profiles show depressed nasal bridge, short nose, epiphyseal stippling, and short distal phalanges.", "comparable": true } ] }, "publish": true, "withheld_because": [] }, { "pair_id": "TC003", "exposure": "fluconazole (high dose, continuous 1st trimester)", "exposure_id": "CHEBI:46081", "direction": "exposure_mimics_genetic", "embryopathy": "fluconazole embryopathy", "embryopathy_id": "TERACOPY:1", "mimics": [ { "name": "Antley-Bixler syndrome with disordered steroidogenesis", "id": "OMIM:201750", "genes": [], "resolved": true, "summary": "This is the POR-deficiency form of Antley-Bixler syndrome, an autosomal recessive disorder of cytochrome P450 oxidoreductase. It combines craniosynostosis and radioulnar synostosis with ambiguous genitalia, disordered steroidogenesis and adrenal insufficiency. One infant exposed to high-dose continuous fluconazole in the first trimester had craniosynostosis and radioulnar synostosis together. That is the whole of the resemblance. The pair is contested. The source case report states that the exposed child did not have the features of Antley-Bixler syndrome. No fluconazole report describes the steroidogenic half of the disorder.", "shared_count": 3, "overlap_summary": "Both profiles show craniosynostosis, radioulnar synostosis, and hypertelorism, each from a single exposed case." } ], "genes": [ "CYP51A1" ], "mechanism_class": "direct_target_inhibition", "teratogenicity": "established", "mechanism_confidence": "moderate", "citations": [ { "pmid": "21705796", "first_author": "Keber R", "year": "2011", "journal": "J Biol Chem", "volume": "286", "pages": "29086-29097", "title": "Mouse knockout of the cholesterogenic cytochrome P450 lanosterol 14alpha-demethylase (Cyp51) resembles Antley-Bixler syndrome", "level": "title_supports", "checked": "2026-09-17" } ], "notes": "Azole inhibits lanosterol 14-alpha-demethylase (CYP51A1); Cyp51 KO mouse resembles ABS. No demonstrated action on POR. POR donates electrons to BOTH the cholesterogenic and steroidogenic arms, so POR deficiency gives skeleton plus ambiguous genitalia; fluconazole hits only the cholesterogenic arm, which predicts the observed absence of a steroidogenic phenotype. Concordance contested: one blind ABS diagnosis re-attributed to exposure (PMID:8838193) against one explicit non-ABS statement (PMID:16265639).", "targets": [ { "edge_id": "TCE004", "target": "CYP51A1", "target_type": "gene", "perturbation": "inhibits", "mechanism_confidence": "moderate", "window": "first trimester, high dose", "citations": [ { "pmid": "23274672", "first_author": "Warrilow AG", "year": "2013", "journal": "Antimicrob Agents Chemother", "volume": "57", "pages": "1352-60", "title": "Azole affinity of sterol 14\u03b1-demethylase (CYP51) enzymes from Candida albicans and Homo sapiens", "level": "title_supports", "checked": "2026-09-20" }, { "pmid": "20149798", "first_author": "Strushkevich N", "year": "2010", "journal": "J Mol Biol", "volume": "397", "pages": "1067-78", "title": "Structural basis of human CYP51 inhibition by antifungal azoles", "level": "title_supports", "checked": "2026-09-20" }, { "pmid": "21705796", "first_author": "Keber R", "year": "2011", "journal": "J Biol Chem", "volume": "286", "pages": "29086-29097", "title": "Mouse knockout of the cholesterogenic cytochrome P450 lanosterol 14alpha-demethylase (Cyp51) resembles Antley-Bixler syndrome", "level": "title_supports", "checked": "2026-09-17" } ], "note": "Inhibits lanosterol 14-alpha-demethylase, which is CYP51A1 itself rather than an orthologue. Inhibition of the human enzyme is measured and not inferred from binding. Fluconazole binds human CYP51 weakly, Kd about 30,500 nM against 10 to 56 nM for the Candida enzyme, which is 540-fold selectivity for the fungal target and the widest gap of the five medical azoles tested, and the IC50 values follow the same order (PMID:23274672). Crystal structures of human CYP51 with azoles bound give the structural basis (PMID:20149798). That is consistent with the embryopathy appearing only after sustained high dose, roughly 400-800 mg/day. Single low-dose exposure is not implicated. PMID:21705796 is a Cyp51 knockout mouse that does not mention fluconazole, so it supports the gene-to-phenotype half and not the drug action. Axis B cannot reach strong whatever is cited, because the disease gene for OMIM:201750 is POR and CYP51A1 is neither POR nor a close orthologue of it. No demonstrated action on POR, so only the cholesterogenic arm of the Antley-Bixler phenotype is predicted, not the steroidogenic arm.", "verdicts": [] } ], "provenance": { "has_citation": true, "has_pmid": true, "citation_verified": true, "mimic_resolved": true, "has_mimic": true, "has_mechanism_edge": true, "verified_against_primary_source": false }, "clinical": { "pair_id": "TC003", "synopsis": [ "The human literature is five infants in four reports (PMID:16265639; PMID:8838193). The described phenotype is multiple synostosis: craniosynostosis with radioulnar synostosis and symphalangism, alongside thin wavy ribs and congenital heart disease (PMID:16265639; PMID:8838193). Every reported case followed sustained treatment at 400 to 800 mg daily through organogenesis, and a single 150 mg dose carried no excess of these defects (PMID:23984730)." ], "favours_exposure": [ { "statement": "Maternal fluconazole 400-800 mg/day in the first trimester. The reported teratogenic effect attaches to that regimen. The index case took 400 mg/day until the fifth month, and again from six months to term", "lead": "Maternal fluconazole 400-800 mg/day in the first trimester", "detail": "The reported teratogenic effect attaches to that regimen. The index case took 400 mg/day until the fifth month, and again from six months to term", "weight": "strong", "pmids": [ "16265639" ], "mimic": "OMIM:201750" }, { "statement": "Radioulnar synostosis (HP:0002974). The same infant also had metacarpophalangeal to proximal interphalangeal symphalangism of D2 to D5, and craniosynostosis (HP:0001363)", "lead": "Radioulnar synostosis (HP:0002974)", "detail": "The same infant also had metacarpophalangeal to proximal interphalangeal symphalangism of D2 to D5, and craniosynostosis (HP:0001363)", "weight": "strong", "pmids": [ "16265639" ], "mimic": "OMIM:201750" }, { "statement": "Thin, wavy ribs with craniofacial ossification defects. This finding matches the animal data. It was the basis for attributing the first case series to the drug", "lead": "Thin, wavy ribs with craniofacial ossification defects", "detail": "This finding matches the animal data. It was the basis for attributing the first case series to the drug", "weight": "strong", "pmids": [ "8838193" ], "mimic": "OMIM:201750" }, { "statement": "Several concurrent exposures, so hold the attribution loosely. The usual setting is several maternal drug exposures at once, with a severe maternal systemic mycosis. The best-described infant carried six other first-trimester drug exposures", "lead": "Several concurrent exposures, so hold the attribution loosely", "detail": "The usual setting is several maternal drug exposures at once, with a severe maternal systemic mycosis. The best-described infant carried six other first-trimester drug exposures", "weight": "caveat", "pmids": [ "16265639" ], "mimic": "OMIM:201750" } ], "favours_gene": [ { "statement": "Ambiguous genitalia, disordered steroidogenesis, adrenal insufficiency. The pattern is undervirilisation in 46,XY and overvirilisation in 46,XX. This finding defines POR deficiency, and no fluconazole case reports it. No fluconazole report states that steroidogenesis was assessed, so the silence is an absent measurement rather than an absent finding", "lead": "Ambiguous genitalia, disordered steroidogenesis, adrenal insufficiency", "detail": "The pattern is undervirilisation in 46,XY and overvirilisation in 46,XX. This finding defines POR deficiency, and no fluconazole case reports it. No fluconazole report states that steroidogenesis was assessed, so the silence is an absent measurement rather than an absent finding", "weight": "strong", "pmids": [ "18493134", "16265639" ], "mimic": "OMIM:201750" }, { "statement": "Maternal virilisation and low urinary oestriol. Sources attribute both to impaired fetal aromatisation", "lead": "Maternal virilisation and low urinary oestriol", "detail": "Sources attribute both to impaired fetal aromatisation", "weight": "strong", "pmids": [ "18493134" ], "mimic": "OMIM:201750" }, { "statement": "An Antley-Bixler-like skeleton with normal steroidogenesis. Among 32 individuals ascertained for Antley-Bixler syndrome or suggestive hormonal findings, 15 carried biallelic POR mutations and 10 carried FGFR2 or FGFR3 mutations. The two groups segregated completely. A normal steroid profile therefore points away from POR, not toward the exposure", "lead": "An Antley-Bixler-like skeleton with normal steroidogenesis", "detail": "Among 32 individuals ascertained for Antley-Bixler syndrome or suggestive hormonal findings, 15 carried biallelic POR mutations and 10 carried FGFR2 or FGFR3 mutations. The two groups segregated completely. A normal steroid profile therefore points away from POR, not toward the exposure", "weight": "strong", "pmids": [ "15793702" ], "mimic": "OMIM:201750" }, { "statement": "The source case report denies Antley-Bixler features. The exposed case states that the child did not have the features of Antley-Bixler syndrome or of other craniosynostosis syndromes. The resemblance this pair asserts is therefore not one the source endorses", "lead": "The source case report denies Antley-Bixler features", "detail": "The exposed case states that the child did not have the features of Antley-Bixler syndrome or of other craniosynostosis syndromes. The resemblance this pair asserts is therefore not one the source endorses", "weight": "caveat", "pmids": [ "16265639" ], "mimic": "OMIM:201750" } ], "not_discriminating": [ { "statement": "Single low-dose fluconazole (150 mg or less). Among 226,599 pregnancies analysed for major congenital malformation, first-trimester fluconazole showed no association with overall major malformation. Only a high dose above 150 mg in the first trimester was associated with cardiac septal closure anomalies, adjusted OR 1.81 (95% CI 1.04 to 3.14) on 13 exposed cases", "lead": "Single low-dose fluconazole (150 mg or less)", "detail": "Among 226,599 pregnancies analysed for major congenital malformation, first-trimester fluconazole showed no association with overall major malformation. Only a high dose above 150 mg in the first trimester was associated with cardiac septal closure anomalies, adjusted OR 1.81 (95% CI 1.04 to 3.14) on 13 exposed cases", "weight": "strong", "pmids": [ "30782643" ], "mimic": "OMIM:201750" }, { "statement": "Craniosynostosis alone. It was one of the 14 azole-associated defects that the Danish cohort specifically did not find raised at typical doses", "lead": "Craniosynostosis alone", "detail": "It was one of the 14 azole-associated defects that the Danish cohort specifically did not find raised at typical doses", "weight": "strong", "pmids": [ "23984730" ], "mimic": "OMIM:201750" }, { "statement": "A normal-looking genital examination. A reader may take \"no ambiguous genitalia\" as evidence for the exposure and against POR deficiency. It is not, because no fluconazole report states that steroidogenesis was assessed. Absence of the finding in the literature is absence of the measurement. A measured normal steroid profile would discriminate. An unremarkable examination recorded without hormonal testing would not", "lead": "A normal-looking genital examination", "detail": "A reader may take \"no ambiguous genitalia\" as evidence for the exposure and against POR deficiency. It is not, because no fluconazole report states that steroidogenesis was assessed. Absence of the finding in the literature is absence of the measurement. A measured normal steroid profile would discriminate. An unremarkable examination recorded without hormonal testing would not", "weight": "strong", "pmids": [ "16265639", "8838193" ], "mimic": "OMIM:201750" }, { "statement": "Symphalangism with radioulnar synostosis. This limb pattern is the hallmark of NOG-related symphalangism spectrum disorder, where fusion starts distally and progresses to the radio-ulnar and radio-humeral joints. On its own it points at a Mendelian synostosis disorder at least as readily as at the exposure. Only the accompanying craniosynostosis moves it", "lead": "Symphalangism with radioulnar synostosis", "detail": "This limb pattern is the hallmark of NOG-related symphalangism spectrum disorder, where fusion starts distally and progresses to the radio-ulnar and radio-humeral joints. On its own it points at a Mendelian synostosis disorder at least as readily as at the exposure. Only the accompanying craniosynostosis moves it", "weight": "strong", "pmids": [ "34334433", "21538686" ], "mimic": "OMIM:201750" } ], "gaps": [ "Case count and case identity. Lopez-Rangel 2005 states the embryopathy had been \"previously reported in 4 cases\", making theirs the fifth (PMID:16265639). But the primary reports are Lee 1992 (PMID:1461702, 1 infant), Pursley 1996 (PMID:8838193, 3 infants, one of whom had been previously published as Antley-Bixler syndrome) and Aleck 1997 (PMID:9332650, 1 infant). Those sum to 5 or 6 depending on whether Pursley's re-attributed infant is one of the others. The overlap is unresolved, because PubMed returns no abstract at all for Lee 1992 or Aleck 1997 and neither is open access. Only their titles are readable. The count \"five infants in four reports\" is therefore a reasonable summary, and it is not independently verifiable.", "Dose in the Pursley infants. The abstract says only \"through or beyond the first trimester\". The 400\u2013800 mg/day figure is grounded solely in Lopez-Rangel 2005. Not asserted for Pursley.", "Fluconazole exposure in Antley-Bixler cases ascertained genetically. No source examined whether the Huang 2005 ABS cohort (PMID:15793702) was screened for azole exposure, so the frequency with which exposure explains gene-negative ABS is unknown.", "CYP51A1 as a human disease gene for this phenotype. The pair record lists CYP51A1 alongside POR. No human case links a CYP51A1 variant to an Antley-Bixler phenotype. The CYP51 evidence is the mouse knockout (PMID:21705796). Mark CYP51A1 as mouse-only." ], "caveat": [], "lookalikes": { "OMIM:201750": "This is the POR-deficiency form of Antley-Bixler syndrome, an autosomal recessive disorder of cytochrome P450 oxidoreductase. It combines craniosynostosis and radioulnar synostosis with ambiguous genitalia, disordered steroidogenesis and adrenal insufficiency. One infant exposed to high-dose continuous fluconazole in the first trimester had craniosynostosis and radioulnar synostosis together. That is the whole of the resemblance. The pair is contested. The source case report states that the exposed child did not have the features of Antley-Bixler syndrome. No fluconazole report describes the steroidogenic half of the disorder." }, "untagged": 0 }, "phenotype": { "embryopathy_id": "TERACOPY:1", "profile": [ { "hpo_id": "HP:0001999", "label": "Abnormal facial shape", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "1/1", "frequency_range": "1/1", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:16265639", "origin": "teracopy" }, { "hpo_id": "HP:0001627", "label": "Abnormal heart morphology", "system": "HP:0001626", "system_label": "Abnormality of the cardiovascular system", "frequency": "1/1", "frequency_range": "1/1", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:16265639", "origin": "teracopy" }, { "hpo_id": "HP:0011314", "label": "Abnormal long bone morphology", "system": "HP:0033127", "system_label": "Abnormality of the musculoskeletal system", "frequency": "1/1", "frequency_range": "1/1", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:16265639", "origin": "teracopy" }, { "hpo_id": "HP:0004440", "label": "Coronal craniosynostosis", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "1/1", "frequency_range": "1/1", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:16265639", "origin": "teracopy" }, { "hpo_id": "HP:0001363", "label": "Craniosynostosis", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "1/1", "frequency_range": "1/1", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:16265639", "origin": "teracopy" }, { "hpo_id": "HP:0000316", "label": "Hypertelorism", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "1/1", "frequency_range": "1/1", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:16265639", "origin": "teracopy" }, { "hpo_id": "HP:0004443", "label": "Lambdoidal craniosynostosis", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "1/1", "frequency_range": "1/1", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:16265639", "origin": "teracopy" }, { "hpo_id": "HP:0006152", "label": "Proximal finger symphalangism", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "1/1", "frequency_range": "1/1", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:16265639", "origin": "teracopy" }, { "hpo_id": "HP:0000508", "label": "Ptosis", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "1/1", "frequency_range": "1/1", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:16265639", "origin": "teracopy" }, { "hpo_id": "HP:0002974", "label": "Radioulnar synostosis", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "1/1", "frequency_range": "1/1", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:16265639", "origin": "teracopy" }, { "hpo_id": "HP:0000586", "label": "Shallow orbits", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "1/1", "frequency_range": "1/1", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:16265639", "origin": "teracopy" }, { "hpo_id": "HP:0000883", "label": "Thin ribs", "system": "HP:0033127", "system_label": "Abnormality of the musculoskeletal system", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:8838193", "origin": "teracopy" }, { "hpo_id": "HP:0009891", "label": "Underdeveloped supraorbital ridges", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "1/1", "frequency_range": "1/1", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:16265639", "origin": "teracopy" }, { "hpo_id": "HP:0010561", "label": "Undulate ribs", "system": "HP:0033127", "system_label": "Abnormality of the musculoskeletal system", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:8838193", "origin": "teracopy" } ], "profile_source": "phenotype.hpoa 2026-09-02", "profile_references": [ "PMID:16265639", "PMID:8838193" ], "profile_evidence_codes": [ "IEA" ], "excluded_features": [], "mimics": [ { "id": "OMIM:201750", "name": "Antley-Bixler syndrome with disordered steroidogenesis", "profile_size": 71, "only_in_exposure": [ { "hpo_id": "HP:0001999", "label": "Abnormal facial shape", "frequency": "1/1" }, { "hpo_id": "HP:0001627", "label": "Abnormal heart morphology", "frequency": "1/1" }, { "hpo_id": "HP:0000508", "label": "Ptosis", "frequency": "1/1" }, { "hpo_id": "HP:0000883", "label": "Thin ribs", "frequency": null }, { "hpo_id": "HP:0009891", "label": "Underdeveloped supraorbital ridges", "frequency": "1/1" }, { "hpo_id": "HP:0010561", "label": "Undulate ribs", "frequency": null } ], "only_in_mimic": [ { "hpo_id": "HP:0000062", "label": "Ambiguous genitalia", "frequency": "occasional" }, { "hpo_id": "HP:0000846", "label": "Adrenal insufficiency", "frequency": "1/3" }, { "hpo_id": "HP:0001545", "label": "Anteriorly placed anus", "frequency": null }, { "hpo_id": "HP:0001166", "label": "Arachnodactyly", "frequency": "2/3" }, { "hpo_id": "HP:0000048", "label": "Bifid scrotum", "frequency": null }, { "hpo_id": "HP:0001623", "label": "Breech presentation", "frequency": "1/3" }, { "hpo_id": "HP:0001769", "label": "Broad foot", "frequency": "1/3" }, { "hpo_id": "HP:0002780", "label": "Bronchomalacia", "frequency": null }, { "hpo_id": "HP:0011410", "label": "Caesarean section", "frequency": "1/3" }, { "hpo_id": "HP:0012385", "label": "Camptodactyly", "frequency": null }, { "hpo_id": "HP:0002308", "label": "Chiari malformation", "frequency": null }, { "hpo_id": "HP:0000453", "label": "Choanal atresia", "frequency": null } ], "shared": [ "HP:0000316", "HP:0001363", "HP:0002974" ], "overlap_summary": "Both profiles show craniosynostosis, radioulnar synostosis, and hypertelorism, each from a single exposed case.", "comparable": true } ] }, "publish": true, "withheld_because": [] }, { "pair_id": "TC004", "exposure": "vismodegib; sonidegib; cyclopamine", "exposure_id": "CHEBI:90878", "direction": "exposure_mimics_genetic", "embryopathy": "Hedgehog-inhibitor embryopathy", "embryopathy_id": null, "mimics": [ { "name": "holoprosencephaly spectrum", "id": "ORPHA:2162", "genes": [], "resolved": true, "summary": null, "shared_count": 0, "overlap_summary": null } ], "genes": [ "SMO", "SHH", "PTCH1" ], "mechanism_class": "direct_target_inhibition", "teratogenicity": "established", "mechanism_confidence": "definitive", "citations": [ { "pmid": "25793997", "first_author": "Heyne GW", "year": "2015", "journal": "PLoS One", "volume": "10", "pages": "e0120517", "title": "Definition of critical periods for Hedgehog pathway antagonist-induced holoprosencephaly, cleft lip, and cleft palate", "level": "title_supports", "checked": "2026-09-17" }, { "pmid": "9716521", "first_author": "Incardona JP", "year": "1998", "journal": "Development", "volume": "125", "pages": "3553-62", "title": "The teratogenic Veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction", "level": "title_supports", "checked": "2026-09-17" } ], "notes": "Live clinical example of a targeted therapy against a developmental pathway gene. Stage-dependent HPE, cleft lip/palate in mouse.", "targets": [ { "edge_id": "TCE005", "target": "SMO", "target_type": "gene", "perturbation": "antagonises", "mechanism_confidence": "definitive", "window": "first trimester", "citations": [ { "pmid": "25793997", "first_author": "Heyne GW", "year": "2015", "journal": "PLoS One", "volume": "10", "pages": "e0120517", "title": "Definition of critical periods for Hedgehog pathway antagonist-induced holoprosencephaly, cleft lip, and cleft palate", "level": "title_supports", "checked": "2026-09-17" } ], "note": "Live example of a targeted therapy against a developmental pathway gene.", "verdicts": [] } ], "provenance": { "has_citation": true, "has_pmid": true, "citation_verified": true, "mimic_resolved": true, "has_mimic": true, "has_mechanism_edge": true, "verified_against_primary_source": false }, "clinical": null, "phenotype": { "embryopathy_id": null, "profile": [], "profile_source": null, "profile_references": [], "profile_evidence_codes": [], "excluded_features": [], "mimics": [ { "id": "ORPHA:2162", "name": "holoprosencephaly spectrum", "profile_size": 93, "only_in_exposure": [], "only_in_mimic": [], "shared": [], "overlap_summary": null, "comparable": false } ] }, "publish": false, "withheld_because": [ "no phenotype profile", "no clinical synopsis written" ] }, { "pair_id": "TC005", "exposure": "isotretinoin; all-trans retinoic acid", "exposure_id": "CHEBI:6067", "direction": "exposure_mimics_genetic", "embryopathy": "retinoic acid embryopathy", "embryopathy_id": "ORPHA:2305", "mimics": [ { "name": "22q11.2 deletion / DiGeorge syndrome", "id": "ORPHA:567", "genes": [], "resolved": true, "summary": null, "shared_count": 3, "overlap_summary": null } ], "genes": [ "TBX1" ], "mechanism_class": "pathway_convergence", "teratogenicity": "established", "mechanism_confidence": "moderate", "citations": [ { "pmid": "12563036", "first_author": "Vermot J", "year": "2003", "journal": "Proc Natl Acad Sci U S A", "volume": "100", "pages": "1763-8", "title": "Decreased embryonic retinoic acid synthesis results in a DiGeorge syndrome phenotype in newborn mice", "level": "title_supports", "checked": "2026-09-17" }, { "pmid": "3162101", "first_author": "Lammer EJ", "year": "1985", "journal": "N Engl J Med", "volume": "313", "pages": "837-41", "title": "Retinoic acid embryopathy", "level": "title_supports", "checked": "2026-09-17" } ], "notes": "RA represses TBX1. Bidirectional: reduced Raldh2 also yields DGS-like phenotype. Cephalic neural crest.", "targets": [ { "edge_id": "TCE006", "target": "TBX1", "target_type": "gene", "perturbation": "represses", "mechanism_confidence": "moderate", "window": "first trimester", "citations": [ { "pmid": "12563036", "first_author": "Vermot J", "year": "2003", "journal": "Proc Natl Acad Sci U S A", "volume": "100", "pages": "1763-8", "title": "Decreased embryonic retinoic acid synthesis results in a DiGeorge syndrome phenotype in newborn mice", "level": "title_supports", "checked": "2026-09-17" } ], "note": "Bidirectional: reduced Raldh2 also yields a DiGeorge-like phenotype.", "verdicts": [] } ], "provenance": { "has_citation": true, "has_pmid": true, "citation_verified": true, "mimic_resolved": true, "has_mimic": true, "has_mechanism_edge": true, "verified_against_primary_source": false }, "clinical": null, "phenotype": { "embryopathy_id": "ORPHA:2305", "profile": [ { "hpo_id": "HP:0000356", "label": "Abnormality of the outer ear", "system": "HP:0000598", "system_label": "Abnormality of the ear", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2305", "origin": "release" }, { "hpo_id": "HP:0001315", "label": "Diminished deep tendon reflex", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2305", "origin": "release" }, { "hpo_id": "HP:0001252", "label": "Hypotonia", "system": "HP:0033127", "system_label": "Abnormality of the musculoskeletal system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2305", "origin": "release" }, { "hpo_id": "HP:0008551", "label": "Microtia", "system": "HP:0000598", "system_label": "Abnormality of the ear", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2305", "origin": "release" }, { "hpo_id": "HP:0004422", "label": "Biparietal narrowing", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2305", "origin": "release" }, { "hpo_id": "HP:0000175", "label": "Cleft palate", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2305", "origin": "release" }, { "hpo_id": "HP:0100543", "label": "Cognitive impairment", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2305", "origin": "release" }, { "hpo_id": "HP:0005280", "label": "Depressed nasal bridge", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2305", "origin": "release" }, { "hpo_id": "HP:0001800", "label": "Hypoplastic toenails", "system": "HP:0001574", "system_label": "Abnormality of the integument", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2305", "origin": "release" }, { "hpo_id": "HP:0000347", "label": "Micrognathia", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2305", "origin": "release" }, { "hpo_id": "HP:0000960", "label": "Sacral dimple", "system": "HP:0001574", "system_label": "Abnormality of the integument", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2305", "origin": "release" }, { "hpo_id": "HP:0003298", "label": "Spina bifida occulta", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2305", "origin": "release" } ], "profile_source": "phenotype.hpoa 2026-09-02", "profile_references": [ "ORPHA:2305" ], "profile_evidence_codes": [ "TAS" ], "excluded_features": [], "mimics": [ { "id": "ORPHA:567", "name": "22q11.2 deletion / DiGeorge syndrome", "profile_size": 131, "only_in_exposure": [ { "hpo_id": "HP:0001315", "label": "Diminished deep tendon reflex", "frequency": "very frequent" }, { "hpo_id": "HP:0008551", "label": "Microtia", "frequency": "very frequent" }, { "hpo_id": "HP:0001800", "label": "Hypoplastic toenails", "frequency": "frequent" }, { "hpo_id": "HP:0000960", "label": "Sacral dimple", "frequency": "occasional" } ], "only_in_mimic": [ { "hpo_id": "HP:0012303", "label": "Abnormal aortic arch morphology", "frequency": "very frequent" }, { "hpo_id": "HP:0030680", "label": "Abnormal cardiovascular system morphology", "frequency": "very frequent" }, { "hpo_id": "HP:0001999", "label": "Abnormal facial shape", "frequency": "very frequent" }, { "hpo_id": "HP:0001641", "label": "Abnormal pulmonary valve morphology", "frequency": "very frequent" }, { "hpo_id": "HP:0000600", "label": "Abnormality of the pharynx", "frequency": "very frequent" }, { "hpo_id": "HP:0002381", "label": "Aphasia", "frequency": "very frequent" }, { "hpo_id": "HP:0001631", "label": "Atrial septal defect", "frequency": "very frequent" }, { "hpo_id": "HP:0000414", "label": "Bulbous nose", "frequency": "very frequent" }, { "hpo_id": "HP:0000405", "label": "Conductive hearing impairment", "frequency": "very frequent" }, { "hpo_id": "HP:0000286", "label": "Epicanthus", "frequency": "very frequent" }, { "hpo_id": "HP:0001611", "label": "Hypernasal speech", "frequency": "very frequent" }, { "hpo_id": "HP:0000778", "label": "Hypoplasia of the thymus", "frequency": "very frequent" } ], "shared": [ "HP:0000175", "HP:0000347", "HP:0001252" ], "overlap_summary": null, "comparable": true } ] }, "publish": false, "withheld_because": [ "no clinical synopsis written" ] }, { "pair_id": "TC006", "exposure": "ACE inhibitors; angiotensin receptor blockers", "exposure_id": null, "direction": "exposure_mimics_genetic", "embryopathy": "RAS-blockade fetopathy", "embryopathy_id": "ORPHA:3033", "mimics": [ { "name": "Renal tubular dysgenesis (genetic form)", "id": "OMIM:267430", "genes": [ "REN", "AGT", "ACE", "AGTR1" ], "resolved": true, "summary": "Autosomal recessive renal tubular dysgenesis follows biallelic defects in REN, AGT, ACE or AGTR1, the genes of the renin-angiotensin system. The kidney forms absent or poorly differentiated proximal tubules, and the fetus develops anuria, oligohydramnios, Potter sequence and a skull ossification defect. ACE inhibitors and angiotensin receptor blockers block the same pathway in the second and third trimesters and produce the same lesion. The overlap is near-total, and the outcome separates them rather than the phenotype. All 29 fetuses and neonates in the defining genetic series died perinatally, while about half of exposed newborns have no complications.", "shared_count": 4, "overlap_summary": "Both profiles show renotubular dysgenesis with the oligohydramnios and pulmonary hypoplasia that follow it, plus microcephaly." } ], "genes": [ "REN", "AGT", "ACE", "AGTR1" ], "mechanism_class": "direct_target_inhibition", "teratogenicity": "established", "mechanism_confidence": "definitive", "citations": [ { "pmid": "16116425", "first_author": "Gribouval O", "year": "2005", "journal": "Nat Genet", "volume": "37", "pages": "964-8", "title": "Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis", "level": "title_supports", "checked": "2026-09-17" } ], "notes": "Near-exact phenocopy. Anuria-oligohydramnios, hypocalvaria, tubular dysgenesis.", "targets": [ { "edge_id": "TCE009", "target": "AGTR1", "target_type": "gene", "perturbation": "blocks", "mechanism_confidence": "definitive", "window": "second and third trimester", "citations": [ { "pmid": "16116425", "first_author": "Gribouval O", "year": "2005", "journal": "Nat Genet", "volume": "37", "pages": "964-8", "title": "Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis", "level": "title_supports", "checked": "2026-09-17" } ], "note": "Blocks the angiotensin II type 1 receptor. The same axis is encoded by REN, AGT, ACE and AGTR1, biallelic loss of any of which causes the genetic form.", "verdicts": [] } ], "provenance": { "has_citation": true, "has_pmid": true, "citation_verified": true, "mimic_resolved": true, "has_mimic": true, "has_mechanism_edge": true, "verified_against_primary_source": false }, "clinical": { "pair_id": "TC006", "synopsis": [ "Exposure in the second or third trimester produces fetal anuria and oligohydramnios after a normal mid-trimester scan, then Potter sequence, pulmonary hypoplasia and a poorly ossified calvarium (PMID:24477978; PMID:8507813). The renal lesion is the same one the genes produce, and Orphanet describes both aetiologies under a single term. The outcomes differ: the genetic form killed all 29 fetuses and neonates in its defining series, while 52% of 118 ACE-inhibitor-exposed newborns had no complications (PMID:16790508; PMID:22753220)." ], "favours_exposure": [ { "statement": "Maternal ACE inhibitor or ARB in the second or third trimester. This is the window in which the fetopathy arises", "lead": "Maternal ACE inhibitor or ARB in the second or third trimester", "detail": "This is the window in which the fetopathy arises", "weight": "strong", "pmids": [ "24477978" ], "mimic": "OMIM:267430" }, { "statement": "Severe renal outcome concentrated in post-first-trimester exposure. Chronic dialysis or kidney transplantation followed in 8 of 17 children exposed after the first trimester, against 0 of 7 exposed in the first trimester only", "lead": "Severe renal outcome concentrated in post-first-trimester exposure", "detail": "Chronic dialysis or kidney transplantation followed in 8 of 17 children exposed after the first trimester, against 0 of 7 exposed in the first trimester only", "weight": "strong", "pmids": [ "26130112" ], "mimic": "OMIM:267430" }, { "statement": "Survival past the neonatal period without complications. This is common after exposure. Of 118 well-documented published ACE-inhibitor-exposed newborns, 52% had no complications, as did 13% of 68 ARB-exposed newborns", "lead": "Survival past the neonatal period without complications", "detail": "This is common after exposure. Of 118 well-documented published ACE-inhibitor-exposed newborns, 52% had no complications, as did 13% of 68 ARB-exposed newborns", "weight": "strong", "pmids": [ "22753220" ], "mimic": "OMIM:267430" }, { "statement": "Proximal tubular differentiation recovers once the drug stops. A 5-case autopsy series was compared with 5 gestational-age-matched controls. The single case with cessation in utero had a proximal convoluted tubule density of 34.2%, against a median 19.0% across the exposed cases and 52.8% in the controls", "lead": "Proximal tubular differentiation recovers once the drug stops", "detail": "A 5-case autopsy series was compared with 5 gestational-age-matched controls. The single case with cessation in utero had a proximal convoluted tubule density of 34.2%, against a median 19.0% across the exposed cases and 52.8% in the controls", "weight": "strong", "pmids": [ "34082612" ], "mimic": "OMIM:267430" }, { "statement": "Exposure in an unrecognised or unbooked pregnancy. Seek the history from the prescribing and dispensing record rather than the booking notes", "lead": "Exposure in an unrecognised or unbooked pregnancy", "detail": "Seek the history from the prescribing and dispensing record rather than the booking notes", "weight": "strong", "pmids": [ "26130112" ], "mimic": "OMIM:267430" }, { "statement": "First-trimester-only exposure without tubular dysgenesis. First-trimester ACE inhibitor exposure was associated with major congenital malformations, RR 2.71 (95% CI 1.72 to 4.27). These were mostly cardiovascular and central nervous system defects, a signal distinct from the renal fetopathy", "lead": "First-trimester-only exposure without tubular dysgenesis", "detail": "First-trimester ACE inhibitor exposure was associated with major congenital malformations, RR 2.71 (95% CI 1.72 to 4.27). These were mostly cardiovascular and central nervous system defects, a signal distinct from the renal fetopathy", "weight": "strong", "pmids": [ "16760444" ], "mimic": "OMIM:267430" }, { "statement": "Extra-renal findings reported in exposed children. These are cystic encephalomalacia, cortical blindness, sensorineural hearing loss, arachnoid cysts, pneumothorax and pneumomediastinum. The series had no comparison group, and prematurity is a plausible alternative cause for several of them", "lead": "Extra-renal findings reported in exposed children", "detail": "These are cystic encephalomalacia, cortical blindness, sensorineural hearing loss, arachnoid cysts, pneumothorax and pneumomediastinum. The series had no comparison group, and prematurity is a plausible alternative cause for several of them", "weight": "strong", "pmids": [ "26130112" ], "mimic": "OMIM:267430" } ], "favours_gene": [ { "statement": "Perinatal death. All 29 fetuses and neonates from 18 unrelated families in the defining clinical series died perinatally, from persistent anuria and hypoxia related to pulmonary hypoplasia", "lead": "Perinatal death", "detail": "All 29 fetuses and neonates from 18 unrelated families in the defining clinical series died perinatally, from persistent anuria and hypoxia related to pulmonary hypoplasia", "weight": "strong", "pmids": [ "16790508" ], "mimic": "OMIM:267430" }, { "statement": "Consanguinity, or a previously affected sibling or fetus. The disorder is autosomal recessive. Sources report 54 distinct mutations across 48 unrelated families", "lead": "Consanguinity, or a previously affected sibling or fetus", "detail": "The disorder is autosomal recessive. Sources report 54 distinct mutations across 48 unrelated families", "weight": "strong", "pmids": [ "16116425", "22095942" ], "mimic": "OMIM:267430" }, { "statement": "Severe proximal tubular defects established by 18 weeks. Every fetus examined from 18 gestational weeks onward showed them. The lesion therefore predates the window in which a late-gestation drug insult would act", "lead": "Severe proximal tubular defects established by 18 weeks", "detail": "Every fetus examined from 18 gestational weeks onward showed them. The lesion therefore predates the window in which a late-gestation drug insult would act", "weight": "strong", "pmids": [ "16790508" ], "mimic": "OMIM:267430" }, { "statement": "Absent renal renin immunostaining on fetal kidney. This indicates a biallelic REN defect. Renin was undetectable in 4 of 24 patients studied, from 3 of 13 families, and strikingly increased in 19 of 24", "lead": "Absent renal renin immunostaining on fetal kidney", "detail": "This indicates a biallelic REN defect. Renin was undetectable in 4 of 24 patients studied, from 3 of 13 families, and strikingly increased in 19 of 24", "weight": "strong", "pmids": [ "16790508" ], "mimic": "OMIM:267430" }, { "statement": "ACE is the most frequently mutated gene. It accounts for 64.6% of 48 families. Clinical severity does not differ by which RAS gene is mutated, so the phenotype does not predict the gene", "lead": "ACE is the most frequently mutated gene", "detail": "It accounts for 64.6% of 48 families. Clinical severity does not differ by which RAS gene is mutated, so the phenotype does not predict the gene", "weight": "suggestive", "pmids": [ "22095942" ], "mimic": "OMIM:267430" } ], "not_discriminating": [ { "statement": "Renal tubular dysgenesis itself. Absent or poorly developed proximal tubules are definitional on both sides", "lead": "Renal tubular dysgenesis itself", "detail": "Absent or poorly developed proximal tubules are definitional on both sides", "weight": "strong", "pmids": [ "16790508", "34082612" ], "mimic": "OMIM:267430" }, { "statement": "Skull ossification defect. Hypocalvaria occurred in 4 of 5 exposed autopsy cases, and skull ossification defects are part of the description of the genetic disorder", "lead": "Skull ossification defect", "detail": "Hypocalvaria occurred in 4 of 5 exposed autopsy cases, and skull ossification defects are part of the description of the genetic disorder", "weight": "strong", "pmids": [ "34082612", "16790508", "22095942" ], "mimic": "OMIM:267430" }, { "statement": "Thickening of the renal arterial and arteriolar wall. It was found in 14 fetuses and neonates who died after RAS blocker exposure, and in the genetic series from the arcuate to the afferent arteries", "lead": "Thickening of the renal arterial and arteriolar wall", "detail": "It was found in 14 fetuses and neonates who died after RAS blocker exposure, and in the genetic series from the arcuate to the afferent arteries", "weight": "strong", "pmids": [ "24477978", "16790508" ], "mimic": "OMIM:267430" }, { "statement": "Oligohydramnios and anuria leading to Potter sequence. Pulmonary hypoplasia and refractory arterial hypotension follow", "lead": "Oligohydramnios and anuria leading to Potter sequence", "detail": "Pulmonary hypoplasia and refractory arterial hypotension follow", "weight": "strong", "pmids": [ "8507813", "7778045", "24477978", "22095942" ], "mimic": "OMIM:267430" } ], "gaps": [ "All eleven sources below were retrievable as abstracts only through EuropePMC; no full text was obtained. Every claim above is grounded in abstract text, and the frequencies quoted are the ones the abstracts state.", "No exposure-side renal renin immunostaining data were located. The renin discriminator is therefore grounded on the gene side only; what renin staining looks like in RAS-blockade fetopathy is unrecorded here, and the discriminator should not be read as implying a contrast that has not been measured.", "No source was located that compares gestational age at onset of oligohydramnios between exposed and genetic cases. \"From 18 gestational weeks onward\" is grounded for the genetic disorder (PMID 16790508); there is no matched figure for the exposure.", "No n/m frequency for skull ossification defect in genetic renal tubular dysgenesis was located; the sources describe it as a feature of the disorder without a denominator.", "Survival and renal recovery among exposed fetuses are reported from published case reports and series (PMID 22753220), which are subject to reporting bias in both directions. The absolute risk of fetopathy per exposed pregnancy remains undetermined.", "Whether Cooper 2006's first-trimester malformation signal survives adjustment for confounding by indication is not adjudicated here; the literature testing that question was not retrieved." ], "caveat": [], "lookalikes": { "OMIM:267430": "Autosomal recessive renal tubular dysgenesis follows biallelic defects in REN, AGT, ACE or AGTR1, the genes of the renin-angiotensin system. The kidney forms absent or poorly differentiated proximal tubules, and the fetus develops anuria, oligohydramnios, Potter sequence and a skull ossification defect. ACE inhibitors and angiotensin receptor blockers block the same pathway in the second and third trimesters and produce the same lesion. The overlap is near-total, and the outcome separates them rather than the phenotype. All 29 fetuses and neonates in the defining genetic series died perinatally, while about half of exposed newborns have no complications." }, "untagged": 0 }, "phenotype": { "embryopathy_id": "ORPHA:3033", "profile": [ { "hpo_id": "HP:0000316", "label": "Hypertelorism", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3033", "origin": "release" }, { "hpo_id": "HP:0001382", "label": "Joint hypermobility", "system": "HP:0033127", "system_label": "Abnormality of the musculoskeletal system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3033", "origin": "release" }, { "hpo_id": "HP:0005562", "label": "Multiple renal cysts", "system": "HP:0000119", "system_label": "Abnormality of the genitourinary system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3033", "origin": "release" }, { "hpo_id": "HP:0001561", "label": "Polyhydramnios", "system": "HP:0001197", "system_label": "Abnormality of prenatal development or birth", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3033", "origin": "release" }, { "hpo_id": "HP:0001622", "label": "Premature birth", "system": "HP:0001197", "system_label": "Abnormality of prenatal development or birth", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3033", "origin": "release" }, { "hpo_id": "HP:0000114", "label": "Proximal tubulopathy", "system": "HP:0000119", "system_label": "Abnormality of the genitourinary system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3033", "origin": "release" }, { "hpo_id": "HP:0002089", "label": "Pulmonary hypoplasia", "system": "HP:0002086", "system_label": "Abnormality of the respiratory system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3033", "origin": "release" }, { "hpo_id": "HP:0008660", "label": "Renotubular dysgenesis", "system": "HP:0000119", "system_label": "Abnormality of the genitourinary system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3033", "origin": "release" }, { "hpo_id": "HP:0007598", "label": "Bilateral single transverse palmar creases", "system": "HP:0001574", "system_label": "Abnormality of the integument", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3033", "origin": "release" }, { "hpo_id": "HP:0000252", "label": "Microcephaly", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3033", "origin": "release" }, { "hpo_id": "HP:0000112", "label": "Nephropathy", "system": "HP:0000119", "system_label": "Abnormality of the genitourinary system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3033", "origin": "release" }, { "hpo_id": "HP:0001562", "label": "Oligohydramnios", "system": "HP:0001197", "system_label": "Abnormality of prenatal development or birth", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3033", "origin": "release" }, { "hpo_id": "HP:0001636", "label": "Tetralogy of Fallot", "system": "HP:0001626", "system_label": "Abnormality of the cardiovascular system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:3033", "origin": "release" } ], "profile_source": "phenotype.hpoa 2026-09-02", "profile_references": [ "ORPHA:3033" ], "profile_evidence_codes": [ "TAS" ], "excluded_features": [], "mimics": [ { "id": "OMIM:267430", "name": "Renal tubular dysgenesis (genetic form)", "profile_size": 10, "only_in_exposure": [ { "hpo_id": "HP:0000316", "label": "Hypertelorism", "frequency": "very frequent" }, { "hpo_id": "HP:0001382", "label": "Joint hypermobility", "frequency": "very frequent" }, { "hpo_id": "HP:0005562", "label": "Multiple renal cysts", "frequency": "very frequent" }, { "hpo_id": "HP:0001622", "label": "Premature birth", "frequency": "very frequent" }, { "hpo_id": "HP:0000114", "label": "Proximal tubulopathy", "frequency": "very frequent" }, { "hpo_id": "HP:0007598", "label": "Bilateral single transverse palmar creases", "frequency": "occasional" }, { "hpo_id": "HP:0000112", "label": "Nephropathy", "frequency": "occasional" }, { "hpo_id": "HP:0001636", "label": "Tetralogy of Fallot", "frequency": "occasional" } ], "only_in_mimic": [ { "hpo_id": "HP:0100519", "label": "Anuria", "frequency": null }, { "hpo_id": "HP:0002615", "label": "Hypotension", "frequency": null }, { "hpo_id": "HP:0002009", "label": "Potter facies", "frequency": null }, { "hpo_id": "HP:0002093", "label": "Respiratory insufficiency", "frequency": null }, { "hpo_id": "HP:0004492", "label": "Widely patent fontanelles and sutures", "frequency": null } ], "shared": [ "HP:0000252", "HP:0001562", "HP:0002089", "HP:0008660" ], "overlap_summary": "Both profiles show renotubular dysgenesis with the oligohydramnios and pulmonary hypoplasia that follow it, plus microcephaly.", "comparable": true } ] }, "publish": true, "withheld_because": [] }, { "pair_id": "TC007", "exposure": "mycophenolate mofetil", "exposure_id": "CHEBI:8764", "direction": "exposure_mimics_genetic", "embryopathy": "MMF embryopathy", "embryopathy_id": "ORPHA:268249", "mimics": [ { "name": "CHARGE syndrome", "id": "OMIM:214800", "genes": [ "CHD7" ], "resolved": true, "summary": "CHARGE syndrome is caused by CHD7 variants, usually de novo. It brings coloboma, choanal atresia, external ear anomalies and, in nearly every imaged patient, semicircular canal hypoplasia or aplasia. Mycophenolate embryopathy produces microtia with external auditory canal atresia and uveal coloboma, so the two overlap across the ear and the eye. Phenotype alone does not separate them. The maternal prescribing record and CHD7 sequencing decide it.", "shared_count": 7, "overlap_summary": "Both profiles show most of the CHARGE core, including microtia, iris coloboma, microphthalmia, tracheoesophageal fistula, and ventricular septal defect." }, { "name": "Treacher Collins syndrome 1", "id": "OMIM:154500", "genes": [], "resolved": true, "summary": "Treacher Collins syndrome is a mandibulofacial dysostosis, most often autosomal dominant through TCOF1, and 55% to 61% of cases are de novo. It produces symmetric hypoplasia of the zygomatic bones, maxilla and mandible, ear anomalies with canal atresia, and conductive hearing loss, with normal intellect. The shared ground with mycophenolate embryopathy is the ear, because microtia or anotia with external auditory canal atresia occurs in both. The trap is the coloboma, which is of the lower eyelid here and uveal or chorioretinal after the exposure.", "shared_count": 5, "overlap_summary": "Both profiles show microtia, aural atresia, micrognathia, visual loss, and hydrocephalus." }, { "name": "Fryns syndrome", "id": "OMIM:229850", "genes": [], "resolved": true, "summary": "Fryns syndrome is autosomal recessive, and biallelic truncating PIGN variants account for part of it. The defining combination is a diaphragmatic defect with significant pulmonary hypoplasia, alongside coarse facies, short distal phalanges and developmental delay. Clinicians re-attributed one mycophenolate-exposed infant from Fryns syndrome to the drug, on aural atresia with digital anomalies. That is how the two came to be paired. Only one human case of diaphragmatic hernia after mycophenolate has been reported, so the diaphragm is what separates them.", "shared_count": 4, "overlap_summary": "Both profiles show hypertelorism, microphthalmia, agenesis of the corpus callosum, and ventricular septal defect." } ], "genes": [ "CHD7" ], "mechanism_class": "pathway_convergence", "teratogenicity": "established", "mechanism_confidence": "limited", "citations": [ { "pmid": "19449404", "first_author": "Parisi MA", "year": "2009", "journal": "Am J Med Genet A", "volume": "149A", "pages": "1237-40", "title": "Congenital diaphragmatic hernia and microtia in a newborn with mycophenolate mofetil (MMF) exposure: phenocopy for Fryns syndrome or broad spectrum of teratogenic effects?", "level": "title_supports", "checked": "2026-09-17" } ], "notes": "Microtia/anotia, EAC atresia, cleft, coloboma. One case initially diagnosed as Fryns. Mechanism not established.", "targets": [ { "edge_id": "TCE008", "target": "CHD7", "target_type": "gene", "perturbation": "no_demonstrated_action", "mechanism_confidence": "limited", "window": "first trimester", "citations": [ { "pmid": "19449404", "first_author": "Parisi MA", "year": "2009", "journal": "Am J Med Genet A", "volume": "149A", "pages": "1237-40", "title": "Congenital diaphragmatic hernia and microtia in a newborn with mycophenolate mofetil (MMF) exposure: phenocopy for Fryns syndrome or broad spectrum of teratogenic effects?", "level": "title_supports", "checked": "2026-09-17" } ], "note": "Phenotypic overlap only. No action of mycophenolate on CHD7 has been demonstrated.", "verdicts": [] } ], "provenance": { "has_citation": true, "has_pmid": true, "citation_verified": true, "mimic_resolved": true, "has_mimic": true, "has_mechanism_edge": true, "verified_against_primary_source": false }, "clinical": { "pair_id": "TC007", "synopsis": [ "The reported pattern is microtia or anotia with an atretic external auditory canal, cleft lip and ocular coloboma, usually with micrognathia and hypertelorism (PMID:19491002; PMID:27639443). Among twelve collated exposed newborns, microtia occurred in 11, canal atresia in 8, cleft lip and palate in 6 and coloboma in 3 (PMID:19491002). Four days of exposure in the seventh post-menstrual week, with no other immunosuppressant, preceded the full phenotype (PMID:18570296)." ], "favours_exposure": [ { "statement": "Documented maternal mycophenolate through early organogenesis. Ask for it first, because it separates this entry from every lookalike and is the item least often sought. An exposure as short as four days in the seventh post-menstrual week, with no other immunosuppressant, produced the full ear-and-coloboma phenotype", "lead": "Documented maternal mycophenolate through early organogenesis", "detail": "Ask for it first, because it separates this entry from every lookalike and is the item least often sought. An exposure as short as four days in the seventh post-menstrual week, with no other immunosuppressant, produced the full ear-and-coloboma phenotype", "weight": "strong", "pmids": [ "18570296" ], "mimic": null }, { "statement": "High concurrent fetal loss in the same pregnancies. Among 57 prospectively ascertained pregnancies there were 16 spontaneous abortions and 12 terminations. 6 of 29 liveborns were malformed", "lead": "High concurrent fetal loss in the same pregnancies", "detail": "Among 57 prospectively ascertained pregnancies there were 16 spontaneous abortions and 12 terminations. 6 of 29 liveborns were malformed", "weight": "strong", "pmids": [ "22319001" ], "mimic": null }, { "statement": "The ear lesion is outer, not inner. Microtia or anotia with external auditory canal atresia dominates, at 11 of 12 and 8 of 12. The near-universal CHARGE ear lesion is a semicircular canal anomaly, found in 18 of 18 imaged", "lead": "The ear lesion is outer, not inner", "detail": "Microtia or anotia with external auditory canal atresia dominates, at 11 of 12 and 8 of 12. The near-universal CHARGE ear lesion is a semicircular canal anomaly, found in 18 of 18 imaged", "weight": "strong", "pmids": [ "19491002", "27832265" ], "mimic": "OMIM:214800" }, { "statement": "Iris and chorioretinal coloboma without choanal atresia. Choanal atresia is a CHARGE criterion. Neither mycophenolate review enumerates it", "lead": "Iris and chorioretinal coloboma without choanal atresia", "detail": "Choanal atresia is a CHARGE criterion. Neither mycophenolate review enumerates it", "weight": "strong", "pmids": [ "27639443", "19491002", "27832265" ], "mimic": "OMIM:214800" }, { "statement": "The coloboma is uveal or retinal, not of the eyelid. It is an iris and chorioretinal lesion", "lead": "The coloboma is uveal or retinal, not of the eyelid", "detail": "It is an iris and chorioretinal lesion", "weight": "strong", "pmids": [ "27639443", "18570296" ], "mimic": "OMIM:154500" }, { "statement": "Cleft lip, with or without cleft palate, in 6 of 12 exposed newborns. Treacher Collins syndrome involves cleft palate as a less common feature, and not cleft lip", "lead": "Cleft lip, with or without cleft palate, in 6 of 12 exposed newborns", "detail": "Treacher Collins syndrome involves cleft palate as a less common feature, and not cleft lip", "weight": "strong", "pmids": [ "19491002", "20301704" ], "mimic": "OMIM:154500" }, { "statement": "Aural atresia with digital anomalies and dysmorphic features. These are the features that prompted re-attribution of an infant from Fryns syndrome to the drug", "lead": "Aural atresia with digital anomalies and dysmorphic features", "detail": "These are the features that prompted re-attribution of an infant from Fryns syndrome to the drug", "weight": "strong", "pmids": [ "19449404" ], "mimic": "OMIM:229850" }, { "statement": "Diaphragmatic hernia absent, or present without pulmonary hypoplasia. Only one human case of diaphragmatic hernia after mycophenolate has been reported", "lead": "Diaphragmatic hernia absent, or present without pulmonary hypoplasia", "detail": "Only one human case of diaphragmatic hernia after mycophenolate has been reported", "weight": "strong", "pmids": [ "19449404", "20301632" ], "mimic": "OMIM:229850" } ], "favours_gene": [ { "statement": "A pathogenic CHD7 variant. Mutations were found in 69 of 107 index patients screened, with broad variability and no genotype to phenotype correlation. A negative examination does not exclude the syndrome. A positive test decides it", "lead": "A pathogenic CHD7 variant", "detail": "Mutations were found in 69 of 107 index patients screened, with broad variability and no genotype to phenotype correlation. A negative examination does not exclude the syndrome. A positive test decides it", "weight": "categorical", "pmids": [ "16155193" ], "mimic": "OMIM:214800" }, { "statement": "A heterozygous TCOF1, POLR1B or POLR1D variant, or biallelic POLR1C or POLR1D. Between 55% and 61% of autosomal dominant cases are de novo, so an absent family history does not exclude the syndrome", "lead": "A heterozygous TCOF1, POLR1B or POLR1D variant, or biallelic POLR1C or POLR1D", "detail": "Between 55% and 61% of autosomal dominant cases are de novo, so an absent family history does not exclude the syndrome", "weight": "categorical", "pmids": [ "20301704" ], "mimic": "OMIM:154500" }, { "statement": "Biallelic truncating PIGN variants, autosomal recessive. Of 16 cases with biallelic truncating variants, 10 had Fryns syndrome. Diaphragmatic hernia and abdominal wall defects were almost absent from the missense and mixed-genotype group", "lead": "Biallelic truncating PIGN variants, autosomal recessive", "detail": "Of 16 cases with biallelic truncating variants, 10 had Fryns syndrome. Diaphragmatic hernia and abdominal wall defects were almost absent from the missense and mixed-genotype group", "weight": "categorical", "pmids": [ "36322149" ], "mimic": "OMIM:229850" }, { "statement": "Semicircular canal hypoplasia or aplasia on temporal bone imaging. It was present in 18 of 18 CHARGE patients imaged, and is more consistent than coloboma at 13 of 18 or choanal atresia at 5 of 18. It produces vestibular areflexia. No mycophenolate-exposed infant has been imaged, so the exposure literature can neither report it nor exclude it", "lead": "Semicircular canal hypoplasia or aplasia on temporal bone imaging", "detail": "It was present in 18 of 18 CHARGE patients imaged, and is more consistent than coloboma at 13 of 18 or choanal atresia at 5 of 18. It produces vestibular areflexia. No mycophenolate-exposed infant has been imaged, so the exposure literature can neither report it nor exclude it", "weight": "strong", "pmids": [ "27832265", "16155193" ], "mimic": "OMIM:214800" }, { "statement": "Coloboma of the lower eyelid, not of iris or retina. Treacher Collins ocular involvement is of the lid. Mycophenolate colobomas are uveal and chorioretinal. The same word covers two different structures, which is the specific trap on this pair", "lead": "Coloboma of the lower eyelid, not of iris or retina", "detail": "Treacher Collins ocular involvement is of the lid. Mycophenolate colobomas are uveal and chorioretinal. The same word covers two different structures, which is the specific trap on this pair", "weight": "strong", "pmids": [ "20301704", "27639443" ], "mimic": "OMIM:154500" }, { "statement": "Symmetric hypoplasia of the zygomatic bones, maxilla and mandible. Downslanted palpebral fissures and malar hypoplasia accompany it", "lead": "Symmetric hypoplasia of the zygomatic bones, maxilla and mandible", "detail": "Downslanted palpebral fissures and malar hypoplasia accompany it", "weight": "strong", "pmids": [ "20301704" ], "mimic": "OMIM:154500" }, { "statement": "Conductive hearing loss in 40% to 50%. It follows ossicular malformation and middle-ear hypoplasia, with normal inner ear structures. The normal inner ear also separates Treacher Collins syndrome from CHARGE syndrome", "lead": "Conductive hearing loss in 40% to 50%", "detail": "It follows ossicular malformation and middle-ear hypoplasia, with normal inner ear structures. The normal inner ear also separates Treacher Collins syndrome from CHARGE syndrome", "weight": "strong", "pmids": [ "20301704" ], "mimic": "OMIM:154500" }, { "statement": "Typically normal intellect", "lead": "Typically normal intellect", "detail": null, "weight": "strong", "pmids": [ "20301704" ], "mimic": "OMIM:154500" }, { "statement": "Diaphragmatic defect with significant pulmonary hypoplasia. This is the defining combination, and the reason survival beyond the neonatal period is rare", "lead": "Diaphragmatic defect with significant pulmonary hypoplasia", "detail": "This is the defining combination, and the reason survival beyond the neonatal period is rare", "weight": "strong", "pmids": [ "20301632" ], "mimic": "OMIM:229850" }, { "statement": "Short distal phalanges of fingers and toes with small nails", "lead": "Short distal phalanges of fingers and toes with small nails", "detail": null, "weight": "strong", "pmids": [ "20301632" ], "mimic": "OMIM:229850" }, { "statement": "Coarse facies. The pattern is wide-set eyes, a wide depressed nasal bridge with a broad tip, a long philtrum, tented vermilion of the upper lip, a wide mouth and a small jaw", "lead": "Coarse facies", "detail": "The pattern is wide-set eyes, a wide depressed nasal bridge with a broad tip, a long philtrum, tented vermilion of the upper lip, a wide mouth and a small jaw", "weight": "strong", "pmids": [ "20301632" ], "mimic": "OMIM:229850" }, { "statement": "Cloudy corneas or microphthalmia, with renal dysplasia or cortical cysts", "lead": "Cloudy corneas or microphthalmia, with renal dysplasia or cortical cysts", "detail": null, "weight": "strong", "pmids": [ "20301632" ], "mimic": "OMIM:229850" }, { "statement": "Cardiovascular malformation. It occurred in 42 of 82 narrowly-defined Fryns patients, or 51%, most often an atrial or ventricular septal defect at 23 of 42", "lead": "Cardiovascular malformation", "detail": "It occurred in 42 of 82 narrowly-defined Fryns patients, or 51%, most often an atrial or ventricular septal defect at 23 of 42", "weight": "strong", "pmids": [ "16283673" ], "mimic": "OMIM:229850" }, { "statement": "Developmental delay. It was completely penetrant across all PIGN genotypes in patients who survived the neonatal period", "lead": "Developmental delay", "detail": "It was completely penetrant across all PIGN genotypes in patients who survived the neonatal period", "weight": "strong", "pmids": [ "36322149" ], "mimic": "OMIM:229850" }, { "statement": "Choanal atresia. It occurred in 5 of 18 in that series, and neither mycophenolate review enumerates it. It is also a Treacher Collins feature, so it argues against the exposure without separating CHARGE from Treacher Collins syndrome", "lead": "Choanal atresia", "detail": "It occurred in 5 of 18 in that series, and neither mycophenolate review enumerates it. It is also a Treacher Collins feature, so it argues against the exposure without separating CHARGE from Treacher Collins syndrome", "weight": "suggestive", "pmids": [ "27832265", "27639443", "20301704" ], "mimic": "OMIM:214800" } ], "not_discriminating": [ { "statement": "Microtia or anotia with external auditory canal atresia. Treacher Collins syndrome includes absent, small, malformed or posteriorly rotated ears with atresia or stenosis of the external auditory canals. The mycophenolate signature feature therefore separates the exposure from CHARGE syndrome and from Fryns syndrome, but not from Treacher Collins syndrome", "lead": "Microtia or anotia with external auditory canal atresia", "detail": "Treacher Collins syndrome includes absent, small, malformed or posteriorly rotated ears with atresia or stenosis of the external auditory canals. The mycophenolate signature feature therefore separates the exposure from CHARGE syndrome and from Fryns syndrome, but not from Treacher Collins syndrome", "weight": "strong", "pmids": [ "20301704" ], "mimic": "OMIM:154500" }, { "statement": "Ocular coloboma. It occurred in 13 of 18 in the CHARGE series and in 3 of 12 collated exposed newborns. The denominators are not comparable, because an imaged tertiary cohort is set against a collation of published case reports. The apparent frequency gap therefore does not apply to an individual patient", "lead": "Ocular coloboma", "detail": "It occurred in 13 of 18 in the CHARGE series and in 3 of 12 collated exposed newborns. The denominators are not comparable, because an imaged tertiary cohort is set against a collation of published case reports. The apparent frequency gap therefore does not apply to an individual patient", "weight": "strong", "pmids": [ "27832265", "19491002" ], "mimic": "OMIM:214800" }, { "statement": "Cleft lip or cleft palate, or both. It occurred in 6 of 14 CHARGE patients without choanal atresia and in 6 of 12 exposed newborns", "lead": "Cleft lip or cleft palate, or both", "detail": "It occurred in 6 of 14 CHARGE patients without choanal atresia and in 6 of 12 exposed newborns", "weight": "strong", "pmids": [ "27832265", "19491002" ], "mimic": "OMIM:214800" }, { "statement": "Developmental delay. It was present in all patients in the CHARGE series and completely penetrant in PIGN-related Fryns survivors. It is typically absent in Treacher Collins syndrome, and generally favourable but occasionally deficient after mycophenolate. It sorts out Treacher Collins syndrome and nothing else", "lead": "Developmental delay", "detail": "It was present in all patients in the CHARGE series and completely penetrant in PIGN-related Fryns survivors. It is typically absent in Treacher Collins syndrome, and generally favourable but occasionally deficient after mycophenolate. It sorts out Treacher Collins syndrome and nothing else", "weight": "strong", "pmids": [ "27832265", "36322149", "20301704", "27639443" ], "mimic": null } ], "gaps": [ "Whether semicircular canals have ever been imaged in a mycophenolate-exposed infant. No report exists either way. Targeted PubMed queries for mycophenolate with semicircular canal or temporal bone imaging return nothing. The discriminator above is therefore \"not reported in the exposure literature\", which is weaker than \"absent in the exposure\". Stated that way throughout. This is the single highest-value experiment this pair suggests and it is cheap.", "Whether choanal atresia has ever been reported after mycophenolate. Same status: a targeted query returned nothing, so the claim is that it is not enumerated in the two review feature lists, not that it never occurs.", "Treacher Collins (OMIM:154500) is defended from its own literature, not the exposure's. The GeneReviews entry supplies a clean, clinically usable set of discriminators. It also shows that Treacher Collins is the closest of the three mimics on ear morphology, because it shares microtia with external auditory canal atresia with the exposure, which CHARGE and Fryns do not (PMID:20301704). Keep OMIM:154500. It is the mimic most likely to be confused on examination alone, and the lid-versus-uveal coloboma distinction is the single most useful line on this page.", "Mechanism. No molecular link between mycophenolate and CHD7 or its pathway was found. The one mechanistic paper retrieved concerns TP53-associated ribosome stress in mycophenolic acid-induced microtia (PMID:34537545, title only, which is why it is not cited above). It does not implicate CHD7. `mechanism_class` in `data/pairs/pairs.tsv` currently reads `pathway_convergence`, which overstates it. `phenotypic_overlap_only` would be accurate.", "Frequency of the full phenotype among all exposed pregnancies. The 11/12, 8/12 figures come from a collation of published cases and are ascertainment-biased upward. The only unbiased denominator available is 6/29 liveborns with any major defect (PMID:22319001), and only 4 of those had a phenotype the authors called consistent with the embryopathy." ], "caveat": [], "lookalikes": { "OMIM:214800": "CHARGE syndrome is caused by CHD7 variants, usually de novo. It brings coloboma, choanal atresia, external ear anomalies and, in nearly every imaged patient, semicircular canal hypoplasia or aplasia. Mycophenolate embryopathy produces microtia with external auditory canal atresia and uveal coloboma, so the two overlap across the ear and the eye. Phenotype alone does not separate them. The maternal prescribing record and CHD7 sequencing decide it.", "OMIM:154500": "Treacher Collins syndrome is a mandibulofacial dysostosis, most often autosomal dominant through TCOF1, and 55% to 61% of cases are de novo. It produces symmetric hypoplasia of the zygomatic bones, maxilla and mandible, ear anomalies with canal atresia, and conductive hearing loss, with normal intellect. The shared ground with mycophenolate embryopathy is the ear, because microtia or anotia with external auditory canal atresia occurs in both. The trap is the coloboma, which is of the lower eyelid here and uveal or chorioretinal after the exposure.", "OMIM:229850": "Fryns syndrome is autosomal recessive, and biallelic truncating PIGN variants account for part of it. The defining combination is a diaphragmatic defect with significant pulmonary hypoplasia, alongside coarse facies, short distal phalanges and developmental delay. Clinicians re-attributed one mycophenolate-exposed infant from Fryns syndrome to the drug, on aural atresia with digital anomalies. That is how the two came to be paired. Only one human case of diaphragmatic hernia after mycophenolate has been reported, so the diaphragm is what separates them." }, "untagged": 2 }, "phenotype": { "embryopathy_id": "ORPHA:268249", "profile": [ { "hpo_id": "HP:0009892", "label": "Anotia", "system": "HP:0000598", "system_label": "Abnormality of the ear", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:268249", "origin": "release" }, { "hpo_id": "HP:0000413", "label": "Atresia of the external auditory canal", "system": "HP:0000598", "system_label": "Abnormality of the ear", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:268249", "origin": "release" }, { "hpo_id": "HP:0008551", "label": "Microtia", "system": "HP:0000598", "system_label": "Abnormality of the ear", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:268249", "origin": "release" }, { "hpo_id": "HP:0000567", "label": "Chorioretinal coloboma", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:268249", "origin": "release" }, { "hpo_id": "HP:0000365", "label": "Hearing impairment", "system": "HP:0000598", "system_label": "Abnormality of the ear", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:268249", "origin": "release" }, { "hpo_id": "HP:0000316", "label": "Hypertelorism", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:268249", "origin": "release" }, { "hpo_id": "HP:0001800", "label": "Hypoplastic toenails", "system": "HP:0001574", "system_label": "Abnormality of the integument", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:268249", "origin": "release" }, { "hpo_id": "HP:0000612", "label": "Iris coloboma", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:268249", "origin": "release" }, { "hpo_id": "HP:0000347", "label": "Micrognathia", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:268249", "origin": "release" }, { "hpo_id": "HP:0000568", "label": "Microphthalmia", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:268249", "origin": "release" }, { "hpo_id": "HP:0000202", "label": "Orofacial cleft", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:268249", "origin": "release" }, { "hpo_id": "HP:0000572", "label": "Visual loss", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:268249", "origin": "release" }, { "hpo_id": "HP:0001274", "label": "Agenesis of corpus callosum", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:268249", "origin": "release" }, { "hpo_id": "HP:0011803", "label": "Bifid nose", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:268249", "origin": "release" }, { "hpo_id": "HP:0008437", "label": "Bifid thoracic vertebrae", "system": "HP:0033127", "system_label": "Abnormality of the musculoskeletal system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:268249", "origin": "release" }, { "hpo_id": "HP:0001680", "label": "Coarctation of aorta", "system": "HP:0001626", "system_label": "Abnormality of the cardiovascular system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:268249", "origin": "release" }, { "hpo_id": "HP:0000776", "label": "Congenital diaphragmatic hernia", "system": "HP:0033127", "system_label": "Abnormality of the musculoskeletal system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:268249", "origin": "release" }, { "hpo_id": "HP:0000086", "label": "Ectopic kidney", "system": "HP:0000119", "system_label": "Abnormality of the genitourinary system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:268249", "origin": "release" }, { "hpo_id": "HP:0000625", "label": "Eyelid coloboma", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:268249", "origin": "release" }, { "hpo_id": "HP:0001829", "label": "Foot polydactyly", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:268249", "origin": "release" }, { "hpo_id": "HP:0000238", "label": "Hydrocephalus", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:268249", "origin": "release" }, { "hpo_id": "HP:0001789", "label": "Hydrops fetalis", "system": "HP:0001197", "system_label": "Abnormality of prenatal development or birth", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:268249", "origin": "release" }, { "hpo_id": "HP:0001256", "label": "Mild intellectual disability", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:268249", "origin": "release" }, { "hpo_id": "HP:0004279", "label": "Short palm", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:268249", "origin": "release" }, { "hpo_id": "HP:0002006", "label": "Tessier cleft", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:268249", "origin": "release" }, { "hpo_id": "HP:0002575", "label": "Tracheoesophageal fistula", "system": "HP:0002086", "system_label": "Abnormality of the respiratory system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:268249", "origin": "release" }, { "hpo_id": "HP:0002779", "label": "Tracheomalacia", "system": "HP:0002086", "system_label": "Abnormality of the respiratory system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:268249", "origin": "release" }, { "hpo_id": "HP:0001629", "label": "Ventricular septal defect", "system": "HP:0001626", "system_label": "Abnormality of the cardiovascular system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:268249", "origin": "release" } ], "profile_source": "phenotype.hpoa 2026-09-02", "profile_references": [ "ORPHA:268249" ], "profile_evidence_codes": [ "TAS" ], "excluded_features": [], "mimics": [ { "id": "OMIM:214800", "name": "CHARGE syndrome", "profile_size": 89, "only_in_exposure": [ { "hpo_id": "HP:0000413", "label": "Atresia of the external auditory canal", "frequency": "very frequent" }, { "hpo_id": "HP:0001800", "label": "Hypoplastic toenails", "frequency": "frequent" }, { "hpo_id": "HP:0000572", "label": "Visual loss", "frequency": "frequent" }, { "hpo_id": "HP:0011803", "label": "Bifid nose", "frequency": "occasional" }, { "hpo_id": "HP:0000625", "label": "Eyelid coloboma", "frequency": "occasional" }, { "hpo_id": "HP:0000238", "label": "Hydrocephalus", "frequency": "occasional" }, { "hpo_id": "HP:0001789", "label": "Hydrops fetalis", "frequency": "occasional" } ], "only_in_mimic": [ { "hpo_id": "HP:0003974", "label": "Absent radius", "frequency": "occasional" }, { "hpo_id": "HP:0000772", "label": "Abnormal rib morphology", "frequency": null }, { "hpo_id": "HP:0009556", "label": "Absent tibia", "frequency": "2/3" }, { "hpo_id": "HP:0002023", "label": "Anal atresia", "frequency": null }, { "hpo_id": "HP:0002025", "label": "Anal stenosis", "frequency": null }, { "hpo_id": "HP:0000458", "label": "Anosmia", "frequency": null }, { "hpo_id": "HP:0011381", "label": "Aplasia of the semicircular canal", "frequency": "1/2" }, { "hpo_id": "HP:0010515", "label": "Aplasia/Hypoplasia of the thymus", "frequency": null }, { "hpo_id": "HP:0002139", "label": "Arrhinencephaly", "frequency": "11/144" }, { "hpo_id": "HP:0010443", "label": "Bifid femur", "frequency": "1/3" }, { "hpo_id": "HP:0001776", "label": "Bilateral talipes equinovarus", "frequency": "2/3" }, { "hpo_id": "HP:0000518", "label": "Cataract", "frequency": "1/3" } ], "shared": [ "HP:0000316", "HP:0000347", "HP:0000568", "HP:0000612", "HP:0001629", "HP:0002575", "HP:0008551" ], "overlap_summary": "Both profiles show most of the CHARGE core, including microtia, iris coloboma, microphthalmia, tracheoesophageal fistula, and ventricular septal defect.", "comparable": true }, { "id": "OMIM:154500", "name": "Treacher Collins syndrome 1", "profile_size": 32, "only_in_exposure": [ { "hpo_id": "HP:0000567", "label": "Chorioretinal coloboma", "frequency": "frequent" }, { "hpo_id": "HP:0000316", "label": "Hypertelorism", "frequency": "frequent" }, { "hpo_id": "HP:0001800", "label": "Hypoplastic toenails", "frequency": "frequent" }, { "hpo_id": "HP:0000612", "label": "Iris coloboma", "frequency": "frequent" }, { "hpo_id": "HP:0001274", "label": "Agenesis of corpus callosum", "frequency": "occasional" }, { "hpo_id": "HP:0011803", "label": "Bifid nose", "frequency": "occasional" }, { "hpo_id": "HP:0008437", "label": "Bifid thoracic vertebrae", "frequency": "occasional" }, { "hpo_id": "HP:0001680", "label": "Coarctation of aorta", "frequency": "occasional" }, { "hpo_id": "HP:0000776", "label": "Congenital diaphragmatic hernia", "frequency": "occasional" }, { "hpo_id": "HP:0000086", "label": "Ectopic kidney", "frequency": "occasional" }, { "hpo_id": "HP:0001829", "label": "Foot polydactyly", "frequency": "occasional" }, { "hpo_id": "HP:0001789", "label": "Hydrops fetalis", "frequency": "occasional" } ], "only_in_mimic": [ { "hpo_id": "HP:0000197", "label": "Abnormal parotid gland morphology", "frequency": null }, { "hpo_id": "HP:0000561", "label": "Absent eyelashes", "frequency": "3/3" }, { "hpo_id": "HP:0000453", "label": "Choanal atresia", "frequency": "9/60" }, { "hpo_id": "HP:0004440", "label": "Coronal craniosynostosis", "frequency": "1/4" }, { "hpo_id": "HP:0000028", "label": "Cryptorchidism", "frequency": null }, { "hpo_id": "HP:0000494", "label": "Downslanted palpebral fissures", "frequency": "74/74" }, { "hpo_id": "HP:0009555", "label": "Hypoplasia of the pharynx", "frequency": null }, { "hpo_id": "HP:0007678", "label": "Lacrimal duct stenosis", "frequency": null }, { "hpo_id": "HP:0004443", "label": "Lambdoidal craniosynostosis", "frequency": "1/4" }, { "hpo_id": "HP:0000272", "label": "Malar flattening", "frequency": "74/75" }, { "hpo_id": "HP:0000160", "label": "Narrow mouth", "frequency": null }, { "hpo_id": "HP:0009554", "label": "Preauricular hair displacement", "frequency": "24/49" } ], "shared": [ "HP:0000238", "HP:0000347", "HP:0000413", "HP:0000572", "HP:0008551" ], "overlap_summary": "Both profiles show microtia, aural atresia, micrognathia, visual loss, and hydrocephalus.", "comparable": true }, { "id": "OMIM:229850", "name": "Fryns syndrome", "profile_size": 64, "only_in_exposure": [ { "hpo_id": "HP:0009892", "label": "Anotia", "frequency": "very frequent" }, { "hpo_id": "HP:0000413", "label": "Atresia of the external auditory canal", "frequency": "very frequent" }, { "hpo_id": "HP:0008551", "label": "Microtia", "frequency": "very frequent" }, { "hpo_id": "HP:0000567", "label": "Chorioretinal coloboma", "frequency": "frequent" }, { "hpo_id": "HP:0000365", "label": "Hearing impairment", "frequency": "frequent" }, { "hpo_id": "HP:0000612", "label": "Iris coloboma", "frequency": "frequent" }, { "hpo_id": "HP:0000572", "label": "Visual loss", "frequency": "frequent" }, { "hpo_id": "HP:0011803", "label": "Bifid nose", "frequency": "occasional" }, { "hpo_id": "HP:0008437", "label": "Bifid thoracic vertebrae", "frequency": "occasional" }, { "hpo_id": "HP:0001680", "label": "Coarctation of aorta", "frequency": "occasional" }, { "hpo_id": "HP:0000086", "label": "Ectopic kidney", "frequency": "occasional" }, { "hpo_id": "HP:0000625", "label": "Eyelid coloboma", "frequency": "occasional" } ], "only_in_mimic": [ { "hpo_id": "HP:0011039", "label": "Abnormal helix morphology", "frequency": null }, { "hpo_id": "HP:0002251", "label": "Aganglionic megacolon", "frequency": null }, { "hpo_id": "HP:0002023", "label": "Anal atresia", "frequency": null }, { "hpo_id": "HP:0000463", "label": "Anteverted nares", "frequency": null }, { "hpo_id": "HP:0002139", "label": "Arrhinencephaly", "frequency": null }, { "hpo_id": "HP:0000813", "label": "Bicornuate uterus", "frequency": null }, { "hpo_id": "HP:0000048", "label": "Bifid scrotum", "frequency": null }, { "hpo_id": "HP:0000581", "label": "Blepharophimosis", "frequency": null }, { "hpo_id": "HP:0000475", "label": "Broad neck", "frequency": "20/20" }, { "hpo_id": "HP:0000885", "label": "Broad ribs", "frequency": null }, { "hpo_id": "HP:0012385", "label": "Camptodactyly", "frequency": null }, { "hpo_id": "HP:0000204", "label": "Cleft upper lip", "frequency": null } ], "shared": [ "HP:0000316", "HP:0000568", "HP:0001274", "HP:0001629" ], "overlap_summary": "Both profiles show hypertelorism, microphthalmia, agenesis of the corpus callosum, and ventricular septal defect.", "comparable": true } ] }, "publish": true, "withheld_because": [] }, { "pair_id": "TC008", "exposure": "sodium valproate", "exposure_id": "CHEBI:9925", "direction": "exposure_mimics_genetic", "embryopathy": "fetal valproate spectrum disorder", "embryopathy_id": "ORPHA:1906", "mimics": [ { "name": "Kabuki syndrome 1", "id": "OMIM:147920", "genes": [ "KMT2D" ], "resolved": true, "summary": "Kabuki syndrome follows loss of function in KMT2D or in KDM6A, and one of these is present in 70% of individuals. The face is the meeting point. It shows long palpebral fissures with eversion of the lateral third of the lower eyelid, alongside infantile hypotonia and developmental delay. Fetal valproate spectrum disorder also produces a distinctive eyelid finding, an epicanthal fold that runs into an infraorbital groove, with delay and reduced IQ. The two eyelid findings are not the same. Blood DNA methylation carries a separate signature for the exposure and for KMT2D loss of function.", "shared_count": 4, "overlap_summary": "Both profiles show facial features only: short nose, depressed nasal ridge, epicanthus, and thin vermilion border." }, { "name": "CHARGE syndrome", "id": "OMIM:214800", "genes": [], "resolved": true, "summary": "CHARGE syndrome is caused by CHD7 variants and presents with deafness or semicircular canal hypoplasia, pituitary defect, external ear anomalies, coloboma and choanal atresia. It shares little with fetal valproate spectrum disorder on phenotype, and this entry records one feature in common, omphalocele. The pairing is kept for the methylation question rather than for the face. CHD7 loss of function and KMT2D loss of function carry mutually exclusive episignatures, and valproate exposure carries a third. No source read here tests the valproate classifier against CHARGE syndrome directly.", "shared_count": 1, "overlap_summary": "Both profiles show omphalocele, the only shared feature." } ], "genes": [ "KMT2D", "KDM6A", "CHD7" ], "mechanism_class": "pathway_convergence", "teratogenicity": "established", "mechanism_confidence": "moderate", "citations": [ { "pmid": "33959609", "first_author": "Parodi C", "year": "2021", "journal": "Front Cell Dev Biol", "volume": "9", "pages": "654467", "title": "Chromatin Imbalance as the Vertex Between Fetal Valproate Syndrome and Chromatinopathies", "level": "title_supports", "checked": "2026-09-17" } ], "notes": "HDAC inhibition. A valproate-specific peripheral-blood methylation episignature is reported in PMID:39097820; the review formerly cited here for it (PMID:33959609) does not report one, and is a narrative review. Spina bifida aOR 12.7 (7.7-20.7), EUROCAT (PMID:20558369). The absolute NTD risk formerly recorded here could not be traced and a case-control analysis of malformed registrations cannot yield one.", "targets": [ { "edge_id": "TCE007", "target": "GO:0016575", "target_type": "pathway", "perturbation": "inhibits", "mechanism_confidence": "moderate", "window": "first trimester", "citations": [ { "pmid": "33959609", "first_author": "Parodi C", "year": "2021", "journal": "Front Cell Dev Biol", "volume": "9", "pages": "654467", "title": "Chromatin Imbalance as the Vertex Between Fetal Valproate Syndrome and Chromatinopathies", "level": "title_supports", "checked": "2026-09-17" }, { "pmid": "39097820", "first_author": "Haghshenas S", "year": "2024", "journal": "Genet Med", "volume": "26", "pages": "101226", "title": "Discovery of DNA methylation signature in the peripheral blood of individuals with history of antenatal exposure to valproic acid", "level": "title_supports", "checked": "2026-09-18" } ], "note": "HDAC inhibition, not inhibition of any chromatinopathy gene product. Target is deliberately a pathway, not a gene, because valproate does not inhibit any chromatinopathy gene product and writing one here would be a lie.", "verdicts": [] } ], "provenance": { "has_citation": true, "has_pmid": true, "citation_verified": true, "mimic_resolved": true, "has_mimic": true, "has_mechanism_edge": true, "verified_against_primary_source": false }, "clinical": { "pair_id": "TC008", "synopsis": [ "First-trimester valproate monotherapy raised spina bifida at an adjusted odds ratio of 12.7, with craniosynostosis at 6.8 and cleft palate at 5.2 in the same EUROCAT analysis (PMID:20558369). Major congenital malformations occurred in 142 of 1381 EURAP monotherapy pregnancies and rose with dose at conception (PMID:29680205). Mean IQ at age six was 97 after valproate, against 105 to 108 after carbamazepine, lamotrigine or phenytoin (PMID:23352199)." ], "favours_exposure": [ { "statement": "Confirmed valproate exposure during pregnancy, at any dose or duration. This is one of four essential criteria in the ERN-ITHACA consensus definition of fetal valproate spectrum disorder. The others are absence of another recognisable diagnosis, normal array-CGH and Fragile X studies, and exclusion of other teratogenic disorders with clinical overlap, in particular fetal alcohol spectrum disorder", "lead": "Confirmed valproate exposure during pregnancy, at any dose or duration", "detail": "This is one of four essential criteria in the ERN-ITHACA consensus definition of fetal valproate spectrum disorder. The others are absence of another recognisable diagnosis, normal array-CGH and Fragile X studies, and exclusion of other teratogenic disorders with clinical overlap, in particular fetal alcohol spectrum disorder", "weight": "strong", "pmids": [ "31324220" ], "mimic": null }, { "statement": "Spina bifida. It occurred at an adjusted odds ratio of 12.7 (95% CI 7.7 to 20.7) in EUROCAT registrations exposed to first-trimester valproate monotherapy. The comparison group was malformed infants whose anomalies had no previous link to valproate. The data set held 98,075 registrations with malformations among 3.8 million births in 14 European countries from 1995 to 2005, with 180 valproate monotherapy registrations", "lead": "Spina bifida", "detail": "It occurred at an adjusted odds ratio of 12.7 (95% CI 7.7 to 20.7) in EUROCAT registrations exposed to first-trimester valproate monotherapy. The comparison group was malformed infants whose anomalies had no previous link to valproate. The data set held 98,075 registrations with malformations among 3.8 million births in 14 European countries from 1995 to 2005, with 180 valproate monotherapy registrations", "weight": "strong", "pmids": [ "20558369" ], "mimic": null }, { "statement": "Craniosynostosis, cleft palate, hypospadias, atrial septal defect, polydactyly. In the same case-control analysis the adjusted odds ratios were 6.8 for craniosynostosis (95% CI 1.8 to 18.8), 5.2 for cleft palate (2.8 to 9.9), 4.8 for hypospadias (2.9 to 8.1), 2.5 for atrial septal defect (1.4 to 4.4) and 2.2 for polydactyly (1.0 to 4.5)", "lead": "Craniosynostosis, cleft palate, hypospadias, atrial septal defect, polydactyly", "detail": "In the same case-control analysis the adjusted odds ratios were 6.8 for craniosynostosis (95% CI 1.8 to 18.8), 5.2 for cleft palate (2.8 to 9.9), 4.8 for hypospadias (2.9 to 8.1), 2.5 for atrial septal defect (1.4 to 4.4) and 2.2 for polydactyly (1.0 to 4.5)", "weight": "strong", "pmids": [ "20558369" ], "mimic": null }, { "statement": "Malformation rate rising with dose at conception. Major congenital malformations were recorded in 142 of 1381 valproate monotherapy pregnancies in the EURAP prospective registry. The figures were 74 of 2514 for lamotrigine and 17 of 599 for levetiracetam. Prevalence rose with dose at conception (p<0.0001). A de novo variant has no counterpart to a dose-response relationship with a drug", "lead": "Malformation rate rising with dose at conception", "detail": "Major congenital malformations were recorded in 142 of 1381 valproate monotherapy pregnancies in the EURAP prospective registry. The figures were 74 of 2514 for lamotrigine and 17 of 599 for levetiracetam. Prevalence rose with dose at conception (p<0.0001). A de novo variant has no counterpart to a dose-response relationship with a drug", "weight": "strong", "pmids": [ "29680205" ], "mimic": null }, { "statement": "A valproate-specific DNA methylation episignature. Sources have defined a peripheral-blood episignature specific to antenatal valproate exposure, and built a support vector machine classifier from it. The classifier showed high sensitivity and specificity against a large reference data set of unaffected controls and of individuals with syndromic disorders that carry their own episignatures. Gene set enrichment was for cell adhesion terms, with significant overrepresentation of the cadherin superfamily. The sources read here do not name Kabuki syndrome or CHARGE syndrome among the disorders tested, so the classifier is not shown to separate the exposure from these two lookalikes", "lead": "A valproate-specific DNA methylation episignature", "detail": "Sources have defined a peripheral-blood episignature specific to antenatal valproate exposure, and built a support vector machine classifier from it. The classifier showed high sensitivity and specificity against a large reference data set of unaffected controls and of individuals with syndromic disorders that carry their own episignatures. Gene set enrichment was for cell adhesion terms, with significant overrepresentation of the cadherin superfamily. The sources read here do not name Kabuki syndrome or CHARGE syndrome among the disorders tested, so the classifier is not shown to separate the exposure from these two lookalikes", "weight": "strong", "pmids": [ "39097820" ], "mimic": null }, { "statement": "Reduced mean IQ at age 6. It was 97 after fetal valproate exposure (95% CI 94 to 101), against 105 for carbamazepine (102 to 108), 108 for lamotrigine (105 to 110) and 108 for phenytoin (104 to 112). The study covered 311 children of 305 mothers on antiepileptic monotherapy. Dose correlated negatively with IQ (r=-0.56, p<0.0001)", "lead": "Reduced mean IQ at age 6", "detail": "It was 97 after fetal valproate exposure (95% CI 94 to 101), against 105 for carbamazepine (102 to 108), 108 for lamotrigine (105 to 110) and 108 for phenytoin (104 to 112). The study covered 311 children of 305 mothers on antiepileptic monotherapy. Dose correlated negatively with IQ (r=-0.56, p<0.0001)", "weight": "strong", "pmids": [ "23352199" ], "mimic": null }, { "statement": "Autism above the maternal-epilepsy background rate. Among 508 valproate-exposed children in a Danish population cohort of 655,615, the absolute risk was 4.42% for autism spectrum disorder (2.59 to 7.46) and 2.50% for childhood autism (1.30 to 4.81). The whole-cohort figures were 1.53% and 0.48%. Restricted to the 6584 children of women with epilepsy, the adjusted hazard ratio for childhood autism was 2.9 (1.4 to 6.0), so the signal survives adjustment for maternal epilepsy", "lead": "Autism above the maternal-epilepsy background rate", "detail": "Among 508 valproate-exposed children in a Danish population cohort of 655,615, the absolute risk was 4.42% for autism spectrum disorder (2.59 to 7.46) and 2.50% for childhood autism (1.30 to 4.81). The whole-cohort figures were 1.53% and 0.48%. Restricted to the 6584 children of women with epilepsy, the adjusted hazard ratio for childhood autism was 2.9 (1.4 to 6.0), so the signal survives adjustment for maternal epilepsy", "weight": "strong", "pmids": [ "23613074" ], "mimic": null }, { "statement": "The valproate facial pattern. All seven children in the first series showed epicanthal folds that continue inferiorly and laterally into a crease or groove just under the orbit. They also had a flat nasal bridge, a small upturned nose, a long upper lip with a relatively shallow philtrum, a thin upper vermilion border and downturned angles of the mouth. The eyelid finding here is an epicanthal fold that runs into an infraorbital groove", "lead": "The valproate facial pattern", "detail": "All seven children in the first series showed epicanthal folds that continue inferiorly and laterally into a crease or groove just under the orbit. They also had a flat nasal bridge, a small upturned nose, a long upper lip with a relatively shallow philtrum, a thin upper vermilion border and downturned angles of the mouth. The eyelid finding here is an epicanthal fold that runs into an infraorbital groove", "weight": "strong", "pmids": [ "6439041" ], "mimic": "OMIM:147920" } ], "favours_gene": [ { "statement": "A pathogenic or likely pathogenic KMT2D or KDM6A variant. One is present in 70% of individuals with Kabuki syndrome", "lead": "A pathogenic or likely pathogenic KMT2D or KDM6A variant", "detail": "One is present in 70% of individuals with Kabuki syndrome", "weight": "categorical", "pmids": [ "30514738" ], "mimic": "OMIM:147920" }, { "statement": "A pathogenic CHD7 variant. It was found in 83% of typical and 58% of atypical cases in that cohort", "lead": "A pathogenic CHD7 variant", "detail": "It was found in 83% of typical and 58% of atypical cases in that cohort", "weight": "categorical", "pmids": [ "29178447" ], "mimic": "OMIM:214800" }, { "statement": "Long palpebral fissures with everted lower lids. The eversion affects the lateral third of the lower eyelid. Two or more of the following accompany it: arched and broad eyebrows with the lateral third notched or sparse, a short columella with a depressed nasal tip, large, prominent or cupped ears, and persistent fingertip pads. This is the typical dysmorphism in the international consensus criteria, alongside a history of infantile hypotonia and developmental delay or intellectual disability", "lead": "Long palpebral fissures with everted lower lids", "detail": "The eversion affects the lateral third of the lower eyelid. Two or more of the following accompany it: arched and broad eyebrows with the lateral third notched or sparse, a short columella with a depressed nasal tip, large, prominent or cupped ears, and persistent fingertip pads. This is the typical dysmorphism in the international consensus criteria, alongside a history of infantile hypotonia and developmental delay or intellectual disability", "weight": "strong", "pmids": [ "30514738" ], "mimic": "OMIM:147920" }, { "statement": "The commonest CHARGE features, by frequency. In a French national cohort of 119 patients the most frequent were deafness or semicircular canal hypoplasia at 94%, pituitary defect or hypogonadism at 89%, external ear anomalies at 87%, square-shaped face at 81% and arhinencephaly or anosmia at 80%. Coloboma reached 73%, heart defects 65% and choanal atresia 43%", "lead": "The commonest CHARGE features, by frequency", "detail": "In a French national cohort of 119 patients the most frequent were deafness or semicircular canal hypoplasia at 94%, pituitary defect or hypogonadism at 89%, external ear anomalies at 87%, square-shaped face at 81% and arhinencephaly or anosmia at 80%. Coloboma reached 73%, heart defects 65% and choanal atresia 43%", "weight": "strong", "pmids": [ "29178447" ], "mimic": "OMIM:214800" }, { "statement": "CHD7 and KMT2D loss of function carry distinct episignatures. The blood DNA methylation signatures are mutually exclusive, at 75 CpGs and 112 CpGs respectively. No KMT2D LOF individual and no control scored as CHD7 LOF, and no CHD7 LOF individual and no control scored as KMT2D LOF. In a blinded validation cohort the CHD7 model scored all 20 pathogenic or likely pathogenic CHD7 samples high, and the KMT2D model scored all 8 high, at 100% specificity. Methylation therefore separates Kabuki syndrome from CHARGE syndrome, which clinical criteria do poorly in early life", "lead": "CHD7 and KMT2D loss of function carry distinct episignatures", "detail": "The blood DNA methylation signatures are mutually exclusive, at 75 CpGs and 112 CpGs respectively. No KMT2D LOF individual and no control scored as CHD7 LOF, and no CHD7 LOF individual and no control scored as KMT2D LOF. In a blinded validation cohort the CHD7 model scored all 20 pathogenic or likely pathogenic CHD7 samples high, and the KMT2D model scored all 8 high, at 100% specificity. Methylation therefore separates Kabuki syndrome from CHARGE syndrome, which clinical criteria do poorly in early life", "weight": "strong", "pmids": [ "28475860" ], "mimic": null }, { "statement": "A KDM6A variant scored high on the KMT2D LOF classifier. That signature therefore detects both Kabuki genes, not KMT2D alone", "lead": "A KDM6A variant scored high on the KMT2D LOF classifier", "detail": "That signature therefore detects both Kabuki genes, not KMT2D alone", "weight": "strong", "pmids": [ "28475860" ], "mimic": "OMIM:147920" } ], "not_discriminating": [], "gaps": [ "The anchor does not say what the entry record says it says. `data/pairs/pairs.tsv` and `data/pairs/phenocopy_links.tsv` both cite PMID:33959609 (Parodi 2021) for \"shared DNA-methylation episignatures\". Parodi 2021 is a narrative review and contains no methylation data. The strings \"episignature\", \"signature\", \"EPIC array\" and \"450K\" do not occur in its full text (`data/fulltext/PMID33959609.txt`). What it actually offers is a table of shared clinical features between fetal valproate spectrum disorder and six chromatinopathies, and a table of shared pathways from gene-expression work. The real episignature paper for this exposure is PMID:39097820 (Haghshenas 2024, Genet Med). The `notes` on both pair rows now say so, and `data/exposures/exposure_to_gene.tsv` cites it on TCE007. The anchor columns have not moved: `key_reference` in `data/pairs/pairs.tsv` and `reference` in `data/pairs/phenocopy_links.tsv` still name Parodi 2021 alone. Under `curation/curation-protocol.md` \u00a7Sources ranked, Parodi 2021 is a rank-4 narrative review and may not stand as a sole citation.", "The valproate episignature cohort size. PMID:39097820 has no PMC record and no open-access full text (`src/fetch_fulltext.py` returns abstract only, flagged NEEDS A HUMAN). The abstract gives no n for the exposed group, no sensitivity or specificity figure, and does not list the comparison disorders. No n/m is written above for it, and none should be until the full text is obtained. This is the highest-value outstanding document for this entry.", "Absolute neural tube defect risk after valproate. The ~1\u20132% figure recorded in `data/pairs/pairs.tsv` was not traced to a source read here, and the retired annotation row carried 2% citing PMID:20558369, which reports an odds ratio and not an absolute risk. Jentink 2010 is a case-control study of malformed registrations; it cannot yield an absolute risk. No absolute NTD risk is stated above.", "Any head-to-head phenotype comparison. No study read here phenotyped valproate-exposed children and Kabuki or CHARGE patients under one protocol. Every discriminator above is an asymmetry between separately ascertained cohorts, not a demonstrated difference. In particular, the absence of coloboma, choanal atresia and semicircular canal hypoplasia from the valproate sources read here is an absence of evidence: the ERN-ITHACA criteria do list coloboma among supportive ophthalmological anomalies (PMID:31324220), so that axis is not clean.", "Explicit exclusions on the exposure side. Not one `0/n` could be written. No valproate source read here reports systematically looking for and not finding long palpebral fissures with lower lid eversion, persistent fingertip pads, or semicircular canal anomalies. Per `curation/curation-protocol.md` \u00a7Blind then compare, these are recorded as never assessed, not as absent, and the profile must keep the two distinct.", "Frequencies for the facial gestalt. The only denominator is 7/7 from PMID:6439041, a 1984 series of seven children. The ERN-ITHACA statement grades the facial dysmorphism as \"suggestive\" rather than essential, notes it is subtle, age-dependent and hard for non-experts to recognise, and states that individuals can have impaired development from valproate exposure with no dysmorphism at all (PMID:31324220). No modern denominator for the facies was found.", "Whether the ERN-ITHACA \"20 fold risk\" for spina bifida is independent of Jentink 2010. The consensus statement gives that figure in Table 4 without a distinguishable primary citation (PMID:31324220). It is close to the 12.7 odds ratio but not equal to it, and the two are not the same quantity. Neither number is presented above as the other.", "Protocol breach. PMID:31324220 is an expert consensus statement, not a primary series, and it is the sole citation for two items above: the essential diagnostic criteria, and the coloboma caveat in this section. Both are statements about what the consensus says, which is the thing that document uniquely is, but each should acquire a primary co-citation before release." ], "caveat": [], "lookalikes": { "OMIM:147920": "Kabuki syndrome follows loss of function in KMT2D or in KDM6A, and one of these is present in 70% of individuals. The face is the meeting point. It shows long palpebral fissures with eversion of the lateral third of the lower eyelid, alongside infantile hypotonia and developmental delay. Fetal valproate spectrum disorder also produces a distinctive eyelid finding, an epicanthal fold that runs into an infraorbital groove, with delay and reduced IQ. The two eyelid findings are not the same. Blood DNA methylation carries a separate signature for the exposure and for KMT2D loss of function.", "OMIM:214800": "CHARGE syndrome is caused by CHD7 variants and presents with deafness or semicircular canal hypoplasia, pituitary defect, external ear anomalies, coloboma and choanal atresia. It shares little with fetal valproate spectrum disorder on phenotype, and this entry records one feature in common, omphalocele. The pairing is kept for the methylation question rather than for the face. CHD7 loss of function and KMT2D loss of function carry mutually exclusive episignatures, and valproate exposure carries a third. No source read here tests the valproate classifier against CHARGE syndrome directly." }, "untagged": 8 }, "phenotype": { "embryopathy_id": "ORPHA:1906", "profile": [ { "hpo_id": "HP:0000457", "label": "Depressed nasal ridge", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1906", "origin": "release" }, { "hpo_id": "HP:0002714", "label": "Downturned corners of mouth", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1906", "origin": "release" }, { "hpo_id": "HP:0000286", "label": "Epicanthus", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1906", "origin": "release" }, { "hpo_id": "HP:0000343", "label": "Long philtrum", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1906", "origin": "release" }, { "hpo_id": "HP:0000160", "label": "Narrow mouth", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1906", "origin": "release" }, { "hpo_id": "HP:0001539", "label": "Omphalocele", "system": "HP:0025031", "system_label": "Abnormality of the digestive system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1906", "origin": "release" }, { "hpo_id": "HP:0003196", "label": "Short nose", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1906", "origin": "release" }, { "hpo_id": "HP:0000233", "label": "Thin vermilion border", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1906", "origin": "release" } ], "profile_source": "phenotype.hpoa 2026-09-02", "profile_references": [ "ORPHA:1906" ], "profile_evidence_codes": [ "TAS" ], "excluded_features": [], "mimics": [ { "id": "OMIM:147920", "name": "Kabuki syndrome 1", "profile_size": 175, "only_in_exposure": [ { "hpo_id": "HP:0002714", "label": "Downturned corners of mouth", "frequency": "very frequent" }, { "hpo_id": "HP:0000160", "label": "Narrow mouth", "frequency": "very frequent" } ], "only_in_mimic": [ { "hpo_id": "HP:0001633", "label": "Abnormal mitral valve morphology", "frequency": "0/20" }, { "hpo_id": "HP:0000164", "label": "Abnormality of the dentition", "frequency": null }, { "hpo_id": "HP:0002561", "label": "Absent nipple", "frequency": "5/12" }, { "hpo_id": "HP:0006988", "label": "Alobar holoprosencephaly", "frequency": "2/3" }, { "hpo_id": "HP:0002023", "label": "Anal atresia", "frequency": "1/6" }, { "hpo_id": "HP:0002025", "label": "Anal stenosis", "frequency": null }, { "hpo_id": "HP:0005218", "label": "Anoperineal fistula", "frequency": null }, { "hpo_id": "HP:0001545", "label": "Anteriorly placed anus", "frequency": "1/1" }, { "hpo_id": "HP:0001650", "label": "Aortic valve stenosis", "frequency": "1/30" }, { "hpo_id": "HP:0011381", "label": "Aplasia of the semicircular canal", "frequency": "3/4" }, { "hpo_id": "HP:0001631", "label": "Atrial septal defect", "frequency": "6/15" }, { "hpo_id": "HP:0001973", "label": "Autoimmune thrombocytopenia", "frequency": null } ], "shared": [ "HP:0000233", "HP:0000286", "HP:0000457", "HP:0003196" ], "overlap_summary": "Both profiles show facial features only: short nose, depressed nasal ridge, epicanthus, and thin vermilion border.", "comparable": true }, { "id": "OMIM:214800", "name": "CHARGE syndrome", "profile_size": 89, "only_in_exposure": [ { "hpo_id": "HP:0000457", "label": "Depressed nasal ridge", "frequency": "very frequent" }, { "hpo_id": "HP:0002714", "label": "Downturned corners of mouth", "frequency": "very frequent" }, { "hpo_id": "HP:0000286", "label": "Epicanthus", "frequency": "very frequent" }, { "hpo_id": "HP:0000160", "label": "Narrow mouth", "frequency": "very frequent" }, { "hpo_id": "HP:0003196", "label": "Short nose", "frequency": "very frequent" } ], "only_in_mimic": [ { "hpo_id": "HP:0003974", "label": "Absent radius", "frequency": "occasional" }, { "hpo_id": "HP:0001018", "label": "Abnormal palmar dermatoglyphics", "frequency": null }, { "hpo_id": "HP:0000772", "label": "Abnormal rib morphology", "frequency": null }, { "hpo_id": "HP:0009556", "label": "Absent tibia", "frequency": "2/3" }, { "hpo_id": "HP:0002023", "label": "Anal atresia", "frequency": null }, { "hpo_id": "HP:0002025", "label": "Anal stenosis", "frequency": null }, { "hpo_id": "HP:0000528", "label": "Anophthalmia", "frequency": null }, { "hpo_id": "HP:0000458", "label": "Anosmia", "frequency": null }, { "hpo_id": "HP:0011381", "label": "Aplasia of the semicircular canal", "frequency": "1/2" }, { "hpo_id": "HP:0010515", "label": "Aplasia/Hypoplasia of the thymus", "frequency": null }, { "hpo_id": "HP:0002139", "label": "Arrhinencephaly", "frequency": "11/144" }, { "hpo_id": "HP:0001631", "label": "Atrial septal defect", "frequency": null } ], "shared": [ "HP:0001539" ], "overlap_summary": "Both profiles show omphalocele, the only shared feature.", "comparable": true } ] }, "publish": true, "withheld_because": [] }, { "pair_id": "TC009", "exposure": "carbimazole; methimazole", "exposure_id": "CHEBI:50673", "direction": "exposure_mimics_genetic", "embryopathy": "methimazole embryofetopathy", "embryopathy_id": "ORPHA:1923", "mimics": [ { "name": "scalp-ear-nipple syndrome", "id": "OMIM:181270", "genes": [], "resolved": true, "summary": "Scalp-ear-nipple syndrome is autosomal dominant. KCTD1 missense variants in the conserved BTB domain were found in every one of ten families tested. Three features define it: aplasia cutis of the scalp, cupped or folded ears, and athelia or hypothelia. Other ectodermal features and renal anomalies accompany them. Methimazole and carbimazole embryopathy also produces aplasia cutis and athelia, and the founding exposure case report carries athelia in its title. Those shared features carry no directional information. The defect cluster points to the exposure, above all choanal atresia. The scalp nodules, the breast aplasia and the dominant transmission point to the disorder.", "shared_count": 1, "overlap_summary": "Both profiles show the calvarial skull defect, the only shared feature." } ], "genes": [ "KCTD1" ], "mechanism_class": "unknown", "teratogenicity": "established", "mechanism_confidence": "limited", "citations": [ { "pmid": "3688031", "first_author": "Greenberg F", "year": "1987", "journal": "Am J Med Genet", "volume": "28", "pages": "931-4", "title": "Choanal atresia and athelia: methimazole teratogenicity or a new syndrome?", "level": "title_supports", "checked": "2026-09-17" }, { "pmid": "16982979", "first_author": "Wolf D", "year": "2006", "journal": "Arch Otolaryngol Head Neck Surg", "volume": "132", "pages": "1009-11", "title": "Antenatal carbimazole and choanal atresia: a new embryopathy", "level": "title_supports", "checked": "2026-09-17" } ], "notes": "Choanal atresia, athelia/hypothelia, aplasia cutis, normal intellect. Overlap is phenotypic; shared molecular mechanism NOT established. Likely fetal thyroid disruption.", "targets": [ { "edge_id": "TCE011", "target": null, "target_type": "gene", "perturbation": "unknown", "mechanism_confidence": "limited", "window": "first trimester", "citations": [ { "pmid": "3688031", "first_author": "Greenberg F", "year": "1987", "journal": "Am J Med Genet", "volume": "28", "pages": "931-4", "title": "Choanal atresia and athelia: methimazole teratogenicity or a new syndrome?", "level": "title_supports", "checked": "2026-09-17" } ], "note": "Target unresolved. Carbimazole and methimazole block thyroid iodine organification, but the dysmorphic features are not obviously downstream of that.", "verdicts": [] } ], "provenance": { "has_citation": true, "has_pmid": true, "citation_verified": true, "mimic_resolved": true, "has_mimic": true, "has_mechanism_edge": true, "verified_against_primary_source": false }, "clinical": { "pair_id": "TC009", "synopsis": [ "Two arms are reported and they do not occur in the same infant (PMID:27978517). The dysmorphic arm follows exposure in gestational weeks six to ten: choanal atresia, scalp aplasia cutis, athelia, oesophageal atresia with fistula, omphalocele and omphalomesenteric duct anomalies (PMID:16982979; PMID:3688031; PMID:21344626). That specific cluster reaches an odds ratio of 21.8, while overall malformation risk is raised only to 1.66 (PMID:24151287)." ], "favours_exposure": [ { "statement": "The defect cluster, not any single member of it. The cluster is choanal atresia, oesophageal atresia, omphalocele, omphalomesenteric duct anomalies and aplasia cutis together. The combined adjusted OR was 21.8 (95% CI 13.4 to 35.4) in methimazole-exposed or carbimazole-exposed children against non-exposed, in a cohort of 817,093", "lead": "The defect cluster, not any single member of it", "detail": "The cluster is choanal atresia, oesophageal atresia, omphalocele, omphalomesenteric duct anomalies and aplasia cutis together. The combined adjusted OR was 21.8 (95% CI 13.4 to 35.4) in methimazole-exposed or carbimazole-exposed children against non-exposed, in a cohort of 817,093", "weight": "strong", "pmids": [ "24151287" ], "mimic": "OMIM:181270" }, { "statement": "Choanal atresia (HP:0000453) specifically. It is the presenting feature in both founding case reports, and the one that should prompt a drug history", "lead": "Choanal atresia (HP:0000453) specifically", "detail": "It is the presenting feature in both founding case reports, and the one that should prompt a drug history", "weight": "strong", "pmids": [ "3688031", "16982979" ], "mimic": "OMIM:181270" }, { "statement": "Tracheo-oesophageal fistula and patent vitelline duct. The reports describe tracheo-oesophageal fistula (HP:0002575) and a persistent vitelline or patent omphalomesenteric duct. One case had oesophageal atresia with a small omphalocele and ileal prolapse through a patent omphalomesenteric duct after four weeks of exposure", "lead": "Tracheo-oesophageal fistula and patent vitelline duct", "detail": "The reports describe tracheo-oesophageal fistula (HP:0002575) and a persistent vitelline or patent omphalomesenteric duct. One case had oesophageal atresia with a small omphalocele and ileal prolapse through a patent omphalomesenteric duct after four weeks of exposure", "weight": "strong", "pmids": [ "21344626", "23845657" ], "mimic": "OMIM:181270" }, { "statement": "Developmental delay and hearing loss. The embryopathy literature describes both. The index athelia case had mild-to-moderate intellectual disability, the defined phenotype lists delay, and a further patient had developmental delay with radioulnar synostosis. The scalp-ear-nipple side of this comparison is not documented, so use the finding to support the exposure and not to exclude the disorder", "lead": "Developmental delay and hearing loss", "detail": "The embryopathy literature describes both. The index athelia case had mild-to-moderate intellectual disability, the defined phenotype lists delay, and a further patient had developmental delay with radioulnar synostosis. The scalp-ear-nipple side of this comparison is not documented, so use the finding to support the exposure and not to exclude the disorder", "weight": "strong", "pmids": [ "3688031", "16982979", "17218082" ], "mimic": "OMIM:181270" }, { "statement": "Microtia (HP:0008551). Sources report it with increased frequency after prenatal methimazole exposure, and propose it as part of the embryopathy", "lead": "Microtia (HP:0008551)", "detail": "Sources report it with increased frequency after prenatal methimazole exposure, and propose it as part of the embryopathy", "weight": "strong", "pmids": [ "21344626" ], "mimic": "OMIM:181270" }, { "statement": "An enlarged anterior fontanel. Three patients in one series had it, and three had fifth-finger clinodactyly", "lead": "An enlarged anterior fontanel", "detail": "Three patients in one series had it, and three had fifth-finger clinodactyly", "weight": "strong", "pmids": [ "21344626" ], "mimic": "OMIM:181270" }, { "statement": "Fetal goitre with hypothyroidism, the endocrine arm only. It follows a maternal antithyroid dose that suits the mother but is excessive for the fetus. It is distinguishable from TRAb-driven fetal hyperthyroidism, and it is managed by lowering the maternal dose", "lead": "Fetal goitre with hypothyroidism, the endocrine arm only", "detail": "It follows a maternal antithyroid dose that suits the mother but is excessive for the fetus. It is distinguishable from TRAb-driven fetal hyperthyroidism, and it is managed by lowering the maternal dose", "weight": "strong", "pmids": [ "27978517" ], "mimic": "OMIM:181270" } ], "favours_gene": [ { "statement": "Autosomal dominant transmission, with a KCTD1 missense variant. The variants sit in the conserved BTB domain. KCTD1 missense mutations were found in every one of ten scalp-ear-nipple families tested", "lead": "Autosomal dominant transmission, with a KCTD1 missense variant", "detail": "The variants sit in the conserved BTB domain. KCTD1 missense mutations were found in every one of ten scalp-ear-nipple families tested", "weight": "categorical", "pmids": [ "23541344" ], "mimic": "OMIM:181270" }, { "statement": "Hairless posterior scalp nodules with the aplasia cutis. The nodules accompany aplasia cutis congenita of the scalp. They are part of the scalp-ear-nipple description, and the exposure literature does not describe them", "lead": "Hairless posterior scalp nodules with the aplasia cutis", "detail": "The nodules accompany aplasia cutis congenita of the scalp. They are part of the scalp-ear-nipple description, and the exposure literature does not describe them", "weight": "strong", "pmids": [ "34456244" ], "mimic": "OMIM:181270" }, { "statement": "Breast aplasia or amastia, not isolated nipple absence. In one family the women had nearly complete aplasia of the breast, with a small unpigmented skin dimple in place of a nipple", "lead": "Breast aplasia or amastia, not isolated nipple absence", "detail": "In one family the women had nearly complete aplasia of the breast, with a small unpigmented skin dimple in place of a nipple", "weight": "strong", "pmids": [ "8042668" ], "mimic": "OMIM:181270" }, { "statement": "Other ectodermal features. These are widely spaced or missing secondary teeth (HP:0000668), sparse hair, brittle fingernails, and reduced axillary hair and apocrine secretion. Partial syndactyly of the third and fourth fingers and complete cutaneous syndactyly of the second and third toes also occur", "lead": "Other ectodermal features", "detail": "These are widely spaced or missing secondary teeth (HP:0000668), sparse hair, brittle fingernails, and reduced axillary hair and apocrine secretion. Partial syndactyly of the third and fourth fingers and complete cutaneous syndactyly of the second and third toes also occur", "weight": "strong", "pmids": [ "8042668", "34456244" ], "mimic": "OMIM:181270" }, { "statement": "Renal anomalies. In some patients they progress to hypertension and renal insufficiency. One of two reported affected siblings died neonatally of renal failure", "lead": "Renal anomalies", "detail": "In some patients they progress to hypertension and renal insufficiency. One of two reported affected siblings died neonatally of renal failure", "weight": "strong", "pmids": [ "22639454" ], "mimic": "OMIM:181270" } ], "not_discriminating": [ { "statement": "Athelia and hypothelia (HP:0002561, HP:0002557). The finding is in the title of the founding exposure case report and is one of the three defining features of scalp-ear-nipple syndrome. It makes the two conditions look alike and carries no directional information", "lead": "Athelia and hypothelia (HP:0002561, HP:0002557)", "detail": "The finding is in the title of the founding exposure case report and is one of the three defining features of scalp-ear-nipple syndrome. It makes the two conditions look alike and carries no directional information", "weight": "strong", "pmids": [ "3688031", "8042668" ], "mimic": "OMIM:181270" }, { "statement": "Aplasia cutis of the scalp. It is part of the exposure cluster and part of the scalp-ear-nipple definition. It is also non-directional", "lead": "Aplasia cutis of the scalp", "detail": "It is part of the exposure cluster and part of the scalp-ear-nipple definition. It is also non-directional", "weight": "strong", "pmids": [ "24151287", "16982979", "23541344", "34456244" ], "mimic": "OMIM:181270" }, { "statement": "External ear anomaly. Both sides report it, the exposure at PMID:21344626 and the disorder at PMID:34456244. The exposure reports describe microtia, and the disorder reports describe cupped or folded ears that stand out from the head. That is a difference in kind, and it is suggestive rather than sufficient on its own", "lead": "External ear anomaly", "detail": "Both sides report it, the exposure at PMID:21344626 and the disorder at PMID:34456244. The exposure reports describe microtia, and the disorder reports describe cupped or folded ears that stand out from the head. That is a difference in kind, and it is suggestive rather than sufficient on its own", "weight": "strong", "pmids": [ "21344626", "34456244", "8042668" ], "mimic": "OMIM:181270" }, { "statement": "Absence of a positive drug history. It does not exclude the exposure arm, and a positive history does not confirm it. In a Swedish cohort of 684,340 children with 162 methimazole-exposed, the cumulative incidence of birth defects was 6.8% in exposed children against 8.0% in non-exposed, which was not significant, and the severe malformations of the embryopathy were rarely seen. Meta-analysis also indicates that bias inflated earlier estimates, and that part of the apparent risk may attach to untreated hyperthyroidism rather than to the drug. The exposure is real but uncommonly expressed", "lead": "Absence of a positive drug history", "detail": "It does not exclude the exposure arm, and a positive history does not confirm it. In a Swedish cohort of 684,340 children with 162 methimazole-exposed, the cumulative incidence of birth defects was 6.8% in exposed children against 8.0% in non-exposed, which was not significant, and the severe malformations of the embryopathy were rarely seen. Meta-analysis also indicates that bias inflated earlier estimates, and that part of the apparent risk may attach to untreated hyperthyroidism rather than to the drug. The exposure is real but uncommonly expressed", "weight": "strong", "pmids": [ "28780518", "33783857" ], "mimic": "OMIM:181270" } ], "gaps": [ "Normal intellect in scalp-ear-nipple syndrome. This is the candidate discriminator, and it is not grounded. Neither the KCTD1 discovery paper (PMID:23541344), the most recent SEN review (PMID:34456244), the two-sibling report and literature review (PMID:22639454) nor the additional-manifestations report (PMID:8042668) states anything about cognition in their abstracts, and none was retrievable in full text. A targeted query for SEN and intellectual development returns nothing. The exposure half is grounded. The comparison is not, so the entry must not assert it. Resolving this needs full text of PMID:34456244, which tabulates all 13 reported KCTD1 variants and their phenotypes.", "Whether choanal atresia has ever been reported in SEN. Absence from the descriptions read here is not the same as a documented negative. The entry says \"not features of SEN\" only because no SEN source lists it. No source examined for choanal atresia and reported it absent.", "Dose-response for the dysmorphic arm. The critical window is grounded (weeks 6 to 10, PMID:32607131). No source relates dysmorphic risk to methimazole dose, so the entry does not assert one.", "Full text. All TC009 sources here were read as PubMed abstracts only, except PMID:32607131 and PMID:33783857, which were retrieved in full. No row in this entry is at `full_text` verification level as `data/refs/verified_citations.tsv` defines it." ], "caveat": [], "lookalikes": { "OMIM:181270": "Scalp-ear-nipple syndrome is autosomal dominant. KCTD1 missense variants in the conserved BTB domain were found in every one of ten families tested. Three features define it: aplasia cutis of the scalp, cupped or folded ears, and athelia or hypothelia. Other ectodermal features and renal anomalies accompany them. Methimazole and carbimazole embryopathy also produces aplasia cutis and athelia, and the founding exposure case report carries athelia in its title. Those shared features carry no directional information. The defect cluster points to the exposure, above all choanal atresia. The scalp nodules, the breast aplasia and the dominant transmission point to the disorder." }, "untagged": 0 }, "phenotype": { "embryopathy_id": "ORPHA:1923", "profile": [ { "hpo_id": "HP:0002032", "label": "Esophageal atresia", "system": "HP:0025031", "system_label": "Abnormality of the digestive system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1923", "origin": "release" }, { "hpo_id": "HP:0000821", "label": "Hypothyroidism", "system": "HP:0000818", "system_label": "Abnormality of the endocrine system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1923", "origin": "release" }, { "hpo_id": "HP:0001511", "label": "Intrauterine growth retardation", "system": "HP:0001507", "system_label": "Growth abnormality", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1923", "origin": "release" }, { "hpo_id": "HP:0001561", "label": "Polyhydramnios", "system": "HP:0001197", "system_label": "Abnormality of prenatal development or birth", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1923", "origin": "release" }, { "hpo_id": "HP:0002575", "label": "Tracheoesophageal fistula", "system": "HP:0002086", "system_label": "Abnormality of the respiratory system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1923", "origin": "release" }, { "hpo_id": "HP:0001679", "label": "Abnormal aortic morphology", "system": "HP:0001626", "system_label": "Abnormality of the cardiovascular system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1923", "origin": "release" }, { "hpo_id": "HP:0000820", "label": "Abnormality of the thyroid gland", "system": "HP:0000818", "system_label": "Abnormality of the endocrine system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1923", "origin": "release" }, { "hpo_id": "HP:0001362", "label": "Calvarial skull defect", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1923", "origin": "release" }, { "hpo_id": "HP:0000453", "label": "Choanal atresia", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1923", "origin": "release" }, { "hpo_id": "HP:0001680", "label": "Coarctation of aorta", "system": "HP:0001626", "system_label": "Abnormality of the cardiovascular system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1923", "origin": "release" }, { "hpo_id": "HP:0000047", "label": "Hypospadias", "system": "HP:0000119", "system_label": "Abnormality of the genitourinary system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1923", "origin": "release" }, { "hpo_id": "HP:0100589", "label": "Urogenital fistula", "system": "HP:0000119", "system_label": "Abnormality of the genitourinary system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1923", "origin": "release" }, { "hpo_id": "HP:0001629", "label": "Ventricular septal defect", "system": "HP:0001626", "system_label": "Abnormality of the cardiovascular system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1923", "origin": "release" } ], "profile_source": "phenotype.hpoa 2026-09-02", "profile_references": [ "ORPHA:1923" ], "profile_evidence_codes": [ "TAS" ], "excluded_features": [], "mimics": [ { "id": "OMIM:181270", "name": "scalp-ear-nipple syndrome", "profile_size": 58, "only_in_exposure": [ { "hpo_id": "HP:0002032", "label": "Esophageal atresia", "frequency": "very frequent" }, { "hpo_id": "HP:0000821", "label": "Hypothyroidism", "frequency": "very frequent" }, { "hpo_id": "HP:0001561", "label": "Polyhydramnios", "frequency": "very frequent" }, { "hpo_id": "HP:0002575", "label": "Tracheoesophageal fistula", "frequency": "very frequent" }, { "hpo_id": "HP:0001679", "label": "Abnormal aortic morphology", "frequency": "frequent" }, { "hpo_id": "HP:0000820", "label": "Abnormality of the thyroid gland", "frequency": "frequent" }, { "hpo_id": "HP:0000453", "label": "Choanal atresia", "frequency": "frequent" }, { "hpo_id": "HP:0001680", "label": "Coarctation of aorta", "frequency": "frequent" }, { "hpo_id": "HP:0000047", "label": "Hypospadias", "frequency": "frequent" }, { "hpo_id": "HP:0100589", "label": "Urogenital fistula", "frequency": "frequent" }, { "hpo_id": "HP:0001629", "label": "Ventricular septal defect", "frequency": "frequent" } ], "only_in_mimic": [ { "hpo_id": "HP:0000463", "label": "Anteverted nares", "frequency": "occasional" }, { "hpo_id": "HP:0000581", "label": "Blepharophimosis", "frequency": "occasional" }, { "hpo_id": "HP:0000519", "label": "Developmental cataract", "frequency": "occasional" }, { "hpo_id": "HP:0000601", "label": "Hypotelorism", "frequency": "occasional" }, { "hpo_id": "HP:0000303", "label": "Mandibular prognathia", "frequency": "occasional" }, { "hpo_id": "HP:0002000", "label": "Short columella", "frequency": "occasional" }, { "hpo_id": "HP:0008070", "label": "Sparse hair", "frequency": "occasional" }, { "hpo_id": "HP:0045025", "label": "Narrow palpebral fissure", "frequency": "very rare" }, { "hpo_id": "HP:0004691", "label": "2-3 toe syndactyly", "frequency": null }, { "hpo_id": "HP:0011939", "label": "3-4 finger cutaneous syndactyly", "frequency": null }, { "hpo_id": "HP:0006349", "label": "Agenesis of permanent teeth", "frequency": null }, { "hpo_id": "HP:0009916", "label": "Anisocoria", "frequency": "1/17" } ], "shared": [ "HP:0001362" ], "overlap_summary": "Both profiles show the calvarial skull defect, the only shared feature.", "comparable": true } ] }, "publish": true, "withheld_because": [] }, { "pair_id": "TC010", "exposure": "lithium", "exposure_id": "CHEBI:25212", "direction": "exposure_mimics_genetic", "embryopathy": "lithium cardiac teratogenicity", "embryopathy_id": null, "mimics": [ { "name": "Ebstein anomaly", "id": "OMIM:224700", "genes": [], "resolved": true, "summary": null, "shared_count": 0, "overlap_summary": null } ], "genes": [], "mechanism_class": "unknown", "teratogenicity": "disputed", "mechanism_confidence": "not_applicable", "citations": [ { "pmid": "28591541", "first_author": "Patorno E", "year": "2017", "journal": "N Engl J Med", "volume": "376", "pages": "2245-2254", "title": "Lithium Use in Pregnancy and the Risk of Cardiac Malformations", "level": "title_supports", "checked": "2026-09-17" }, { "pmid": "29929874", "first_author": "Munk-Olsen T", "year": "2018", "journal": "Lancet Psychiatry", "volume": "5", "pages": "644-652", "title": "Maternal and infant outcomes associated with lithium use in pregnancy: an international collaborative meta-analysis of six cohort studies", "level": "resolved", "checked": "2026-09-17" } ], "notes": "HISTORICAL PAIR, EVIDENCE ATTENUATED. Original ~400x RR from two cases in a voluntary register. Modern cohort adjusted RR 1.65 (1.02-2.68) for any cardiac defect, dose-dependent; meta-analysis found no significant cardiac-specific excess.", "targets": [], "provenance": { "has_citation": true, "has_pmid": true, "citation_verified": true, "mimic_resolved": true, "has_mimic": true, "has_mechanism_edge": false, "verified_against_primary_source": false }, "clinical": null, "phenotype": { "embryopathy_id": null, "profile": [], "profile_source": null, "profile_references": [], "profile_evidence_codes": [], "excluded_features": [], "mimics": [ { "id": "OMIM:224700", "name": "Ebstein anomaly", "profile_size": 7, "only_in_exposure": [], "only_in_mimic": [], "shared": [], "overlap_summary": null, "comparable": false } ] }, "publish": false, "withheld_because": [ "no phenotype profile", "no clinical synopsis written" ] }, { "pair_id": "TC011", "exposure": "fentanyl; other opioids", "exposure_id": "CHEBI:119915", "direction": "exposure_mimics_genetic", "embryopathy": "fetal fentanyl syndrome", "embryopathy_id": "TERACOPY:2", "mimics": [ { "name": "Smith-Lemli-Opitz syndrome", "id": "OMIM:270400", "genes": [], "resolved": true, "summary": "Smith-Lemli-Opitz syndrome is an autosomal recessive defect of DHCR7, the last enzyme of cholesterol biosynthesis. It gives a recognisable facial gestalt with microcephaly, cleft palate, 2-3 toe syndactyly, postaxial polydactyly, cardiac defects and intellectual disability. Elevated 7-dehydrocholesterol and low cholesterol sit behind it. The ten reported fentanyl-exposed infants resembled it closely enough to prompt DHCR7 testing, which was non-diagnostic in every case tested. Fentanyl disrupts post-lanosterol sterol biosynthesis in vitro, which is the proposed reason. The biochemistry separates them. The elevation after fentanyl normalised on repeat testing, and in the syndrome it persists.", "shared_count": 14, "overlap_summary": "Both profiles show fourteen shared features, including 2-3 toe syndactyly, micrognathia, cleft palate, microcephaly, and short stature." } ], "genes": [ "DHCR7" ], "mechanism_class": "direct_target_inhibition", "teratogenicity": "emerging", "mechanism_confidence": "limited", "citations": [ { "pmid": "39669238", "first_author": "Wadman E", "year": "2023", "journal": "Genet Med Open", "volume": "1", "pages": "100834", "title": "A novel syndrome associated with prenatal fentanyl exposure", "level": "title_supports", "checked": "2026-09-17" } ], "notes": "Elevated 7-DHC/8-DHC that NORMALIZED over time; DHCR7 sequencing negative. Direct proof of fentanyl inhibition of DHCR7 not yet published. 2024-25 replication abstracts exist.", "targets": [], "provenance": { "has_citation": true, "has_pmid": true, "citation_verified": true, "mimic_resolved": true, "has_mimic": true, "has_mechanism_edge": false, "verified_against_primary_source": false }, "clinical": { "pair_id": "TC011", "synopsis": [ "Ten infants were reported whose Smith-Lemli-Opitz-like features prompted DHCR7 testing that proved non-diagnostic, and all followed pregnancies complicated by nonprescription fentanyl use (PMID:39669238). Elevated 7-dehydrocholesterol or 8-dehydrocholesterol was found in 7 of 8 tested soon after birth, and repeat testing was normal in all 6 retested (PMID:39669238). The authors of a larger cohort concluded that further investigation is needed before a fetal fentanyl syndrome is substantiated (PMID:41530901)." ], "favours_exposure": [ { "statement": "Documented nonprescription fentanyl exposure during the pregnancy. All 10 reported infants were born after pregnancies complicated by fentanyl use, each alongside at least one other substance", "lead": "Documented nonprescription fentanyl exposure during the pregnancy", "detail": "All 10 reported infants were born after pregnancies complicated by fentanyl use, each alongside at least one other substance", "weight": "strong", "pmids": [ "39669238" ], "mimic": "OMIM:270400" }, { "statement": "Elevated 7-DHC or 8-DHC after delivery, normal on retest. 7 of 8 tested were elevated at first, and all 6 who had repeat testing were normal. In one infant 7-DHC and 8-DHC were elevated at age 8 days. At 19 days 7-DHC was normal and 8-DHC was less elevated, and both were normal at 5 months", "lead": "Elevated 7-DHC or 8-DHC after delivery, normal on retest", "detail": "7 of 8 tested were elevated at first, and all 6 who had repeat testing were normal. In one infant 7-DHC and 8-DHC were elevated at age 8 days. At 19 days 7-DHC was normal and 8-DHC was less elevated, and both were normal at 5 months", "weight": "strong", "pmids": [ "39669238" ], "mimic": "OMIM:270400" }, { "statement": "Non-diagnostic genomic testing alongside the biochemistry. Chromosome microarray was non-diagnostic in 10 of 10 and exome in 7 of 7. DHCR7 was sequenced in 5 of the 10 and was non-diagnostic in each", "lead": "Non-diagnostic genomic testing alongside the biochemistry", "detail": "Chromosome microarray was non-diagnostic in 10 of 10 and exome in 7 of 7. DHCR7 was sequenced in 5 of the 10 and was non-diagnostic in each", "weight": "strong", "pmids": [ "39669238" ], "mimic": "OMIM:270400" }, { "statement": "Facial gestalt scored as distinct from the lookalike. GestaltMatcher analysis of facial photographs separated the group from Smith-Lemli-Opitz syndrome (n = 9), fetal alcohol syndrome (n = 10) and age-matched typical individuals (n = 10), at P < .00001 after Bonferroni correction", "lead": "Facial gestalt scored as distinct from the lookalike", "detail": "GestaltMatcher analysis of facial photographs separated the group from Smith-Lemli-Opitz syndrome (n = 9), fetal alcohol syndrome (n = 10) and age-matched typical individuals (n = 10), at P < .00001 after Bonferroni correction", "weight": "strong", "pmids": [ "39669238" ], "mimic": "OMIM:270400" }, { "statement": "Sterol biosynthesis disrupted by fentanyl in vitro. Exposure altered most post-lanosterol intermediates, with elevated 7-DHC and decreased desmosterol. The work covered Neuro2a cells, primary mouse neuronal and astrocytic cultures, and human dermal fibroblasts. DHCR7+/- fibroblasts were significantly more susceptible than DHCR7+/+", "lead": "Sterol biosynthesis disrupted by fentanyl in vitro", "detail": "Exposure altered most post-lanosterol intermediates, with elevated 7-DHC and decreased desmosterol. The work covered Neuro2a cells, primary mouse neuronal and astrocytic cultures, and human dermal fibroblasts. DHCR7+/- fibroblasts were significantly more susceptible than DHCR7+/+", "weight": "strong", "pmids": [ "38844533" ], "mimic": "OMIM:270400" }, { "statement": "Concurrent exposure to other substances. In 5053 opioid-use-disorder dyads, prenatal cannabis, sedative, stimulant, nicotine and other nonopioid exposures were all documented more often among dyads with documented fentanyl exposure than without", "lead": "Concurrent exposure to other substances", "detail": "In 5053 opioid-use-disorder dyads, prenatal cannabis, sedative, stimulant, nicotine and other nonopioid exposures were all documented more often among dyads with documented fentanyl exposure than without", "weight": "strong", "pmids": [ "41530901" ], "mimic": "OMIM:270400" }, { "statement": "Late or absent prenatal care in the pregnancy. A first prenatal care appointment in the third trimester was documented in 28.3% of dyads with documented fentanyl exposure (95% CI 24.5 to 32.1), against 15.4% without (95% CI 14.8 to 16.0)", "lead": "Late or absent prenatal care in the pregnancy", "detail": "A first prenatal care appointment in the third trimester was documented in 28.3% of dyads with documented fentanyl exposure (95% CI 24.5 to 32.1), against 15.4% without (95% CI 14.8 to 16.0)", "weight": "strong", "pmids": [ "41530901" ], "mimic": "OMIM:270400" }, { "statement": "Feeding difficulties. They were more common among infants with documented prenatal fentanyl exposure than without. Gestational age, birth weight and length were similar across those groups", "lead": "Feeding difficulties", "detail": "They were more common among infants with documented prenatal fentanyl exposure than without. Gestational age, birth weight and length were similar across those groups", "weight": "strong", "pmids": [ "41530901" ], "mimic": "OMIM:270400" }, { "statement": "The feature set does not separate exposed from unexposed infants. In the same 5053 dyads, 18.9% of infants with at least one of the seven features had documented fentanyl exposure (95% CI 17.1 to 20.8), against 13.0% of those with none (95% CI 12.5 to 13.6, odds ratio 1.6, 95% CI 1.4 to 1.8). Stratified by exposure, feature counts were sparse and no substantial differences in prevalence were detected", "lead": "The feature set does not separate exposed from unexposed infants", "detail": "In the same 5053 dyads, 18.9% of infants with at least one of the seven features had documented fentanyl exposure (95% CI 17.1 to 20.8), against 13.0% of those with none (95% CI 12.5 to 13.6, odds ratio 1.6, 95% CI 1.4 to 1.8). Stratified by exposure, feature counts were sparse and no substantial differences in prevalence were detected", "weight": "caveat", "pmids": [ "41530901" ], "mimic": "OMIM:270400" }, { "statement": "The reported frequency rests on self-report and a small numerator. Of 639 patients enrolled in a substance-use-disorder treatment programme, 103 had neonates with a head circumference below the 10th percentile. 51 of those patients self-reported fentanyl use within the past year, and 6 had confirmatory toxicology. Four neonates showed the described anomalies, which that report states is 7.8% of individuals with self-reported fentanyl use. That cohort did not assess cholesterol metabolism", "lead": "The reported frequency rests on self-report and a small numerator", "detail": "Of 639 patients enrolled in a substance-use-disorder treatment programme, 103 had neonates with a head circumference below the 10th percentile. 51 of those patients self-reported fentanyl use within the past year, and 6 had confirmatory toxicology. Four neonates showed the described anomalies, which that report states is 7.8% of individuals with self-reported fentanyl use. That cohort did not assess cholesterol metabolism", "weight": "caveat", "pmids": [ "41856964" ], "mimic": "OMIM:270400" } ], "favours_gene": [ { "statement": "Biallelic pathogenic variants in DHCR7. With suggestive features and elevated 7-DHC, they establish the diagnosis", "lead": "Biallelic pathogenic variants in DHCR7", "detail": "With suggestive features and elevated 7-DHC, they establish the diagnosis", "weight": "categorical", "pmids": [ "20301322" ], "mimic": "OMIM:270400" }, { "statement": "Persistently elevated serum 7-dehydrocholesterol. Clinicians monitor 7-DHC every three to four months in the first years of life, and twice yearly after that", "lead": "Persistently elevated serum 7-dehydrocholesterol", "detail": "Clinicians monitor 7-DHC every three to four months in the first years of life, and twice yearly after that", "weight": "strong", "pmids": [ "20301322" ], "mimic": "OMIM:270400" }, { "statement": "Low serum cholesterol. This is usual, though it stays within the normal range in about 10% of affected individuals", "lead": "Low serum cholesterol", "detail": "This is usual, though it stays within the normal range in about 10% of affected individuals", "weight": "strong", "pmids": [ "20301322" ], "mimic": "OMIM:270400" }, { "statement": "Moderate-to-severe intellectual disability. It is part of the syndrome definition", "lead": "Moderate-to-severe intellectual disability", "detail": "It is part of the syndrome definition", "weight": "strong", "pmids": [ "20301322" ], "mimic": "OMIM:270400" }, { "statement": "Neonatal cholestatic liver disease. Photosensitivity and adrenal insufficiency belong with it. All three are listed among the manifestations that require treatment and surveillance", "lead": "Neonatal cholestatic liver disease", "detail": "Photosensitivity and adrenal insufficiency belong with it. All three are listed among the manifestations that require treatment and surveillance", "weight": "strong", "pmids": [ "20301322" ], "mimic": "OMIM:270400" }, { "statement": "Postaxial polydactyly. It is among the characterising malformations of the syndrome. The table of findings for the 10 reported fentanyl-exposed infants does not record it, which is weak evidence because the table reports what was seen and not what was sought", "lead": "Postaxial polydactyly", "detail": "It is among the characterising malformations of the syndrome. The table of findings for the 10 reported fentanyl-exposed infants does not record it, which is weak evidence because the table reports what was seen and not what was sought", "weight": "suggestive", "pmids": [ "20301322", "39669238" ], "mimic": "OMIM:270400" }, { "statement": "Cardiac defects. They are among the characterising malformations of the syndrome. The table of findings for the 10 reported infants does not record congenital heart defects, with the same limit as above", "lead": "Cardiac defects", "detail": "They are among the characterising malformations of the syndrome. The table of findings for the 10 reported infants does not record congenital heart defects, with the same limit as above", "weight": "suggestive", "pmids": [ "20301322", "39669238" ], "mimic": "OMIM:270400" } ], "not_discriminating": [], "gaps": [ "Full text was read for PMID 39669238 and PMID 41530901. PMID 42639750, 41856964, 41856958, 38844533 and 20301322 were available as abstracts only; every claim from them is grounded in abstract text.", "Teratogenicity for this pair is graded `emerging` and mechanism confidence `limited` in the pair record. No source located adjudicates causality. PMID 39669238 states that Shepard criteria 1, 3 and 4 may be met, that a biologic gradient is not established, and that no animal model recapitulates the phenotype.", "Direct evidence that fentanyl inhibits DHCR7 in vivo was not located. PMID 38844533 is in vitro and reports disruption across the post-lanosterol pathway that its authors describe as more complex than DHCR7 inhibition alone.", "Independent replication of the 7-DHC/8-DHC elevation is incomplete. PMID 42639750 reports elevated cholesterol precursors in some children tested in the first weeks of life but states no denominator in the abstract; PMID 41856964 did not assess cholesterol metabolism. The elevation reported in PMID 39669238 normalised on repeat testing in all 6 retested.", "No denominator exists for how often the described phenotype occurs among fentanyl-exposed pregnancies. The 8.0% and 0.7% figures in PMID 41530901 are proportions of all 5053 opioid-use-disorder dyads, not of the 667 with documented fentanyl exposure.", "Features in PMID 41530901 were ascertained from EHR data and ICD-9/10-CM codes. That report states that rocker-bottom feet have no specific ICD-9-CM code and that some features may not have been recognised or coded, so its feature counts and the case-series counts are not measured the same way.", "Adulterants in illicitly manufactured fentanyl are not systematically tested for. PMID 39669238 states that a contaminant rather than fentanyl itself cannot be excluded as causal, and PMID 41530901 states that the role of unknown adulterants remains unknown.", "Whether other opioid types affect cholesterol biosynthesis is unknown (PMID 41530901). The entry is titled \"fentanyl and other opioids\", but every case-level source located concerns fentanyl.", "Per-feature frequencies for the 56-child cohort in PMID 42639750 were not obtainable from the abstract; only microcephaly, failure to thrive, feeding difficulties and gastrostomy placement are named as common, without n/m.", "No frequency data for Smith-Lemli-Opitz syndrome features were located with denominators; the gene-side items above are grounded on a clinical-characteristics summary, not a counted series." ], "caveat": [], "lookalikes": { "OMIM:270400": "Smith-Lemli-Opitz syndrome is an autosomal recessive defect of DHCR7, the last enzyme of cholesterol biosynthesis. It gives a recognisable facial gestalt with microcephaly, cleft palate, 2-3 toe syndactyly, postaxial polydactyly, cardiac defects and intellectual disability. Elevated 7-dehydrocholesterol and low cholesterol sit behind it. The ten reported fentanyl-exposed infants resembled it closely enough to prompt DHCR7 testing, which was non-diagnostic in every case tested. Fentanyl disrupts post-lanosterol sterol biosynthesis in vitro, which is the proposed reason. The biochemistry separates them. The elevation after fentanyl normalised on repeat testing, and in the syndrome it persists." }, "untagged": 0 }, "phenotype": { "embryopathy_id": "TERACOPY:2", "profile": [ { "hpo_id": "HP:0004691", "label": "2-3 toe syndactyly", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "8/10", "frequency_range": "8/10", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:39669238", "origin": "teracopy" }, { "hpo_id": "HP:0000811", "label": "Abnormal external genitalia morphology", "system": "HP:0000119", "system_label": "Abnormality of the genitourinary system", "frequency": "6/10", "frequency_range": "6/10", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:39669238", "origin": "teracopy" }, { "hpo_id": "HP:0001181", "label": "Adducted thumb", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "9/10", "frequency_range": "9/10", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:39669238", "origin": "teracopy" }, { "hpo_id": "HP:0000463", "label": "Anteverted nares", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:39669238", "origin": "teracopy" }, { "hpo_id": "HP:0000717", "label": "Autism", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:42639750", "origin": "teracopy" }, { "hpo_id": "HP:0011304", "label": "Broad thumb", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "9/10", "frequency_range": "9/10", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:39669238", "origin": "teracopy" }, { "hpo_id": "HP:0000041", "label": "Chordee", "system": "HP:0000119", "system_label": "Abnormality of the genitourinary system", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:39669238", "origin": "teracopy" }, { "hpo_id": "HP:0000175", "label": "Cleft palate", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "7/10", "frequency_range": "7/10", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:39669238", "origin": "teracopy" }, { "hpo_id": "HP:0001508", "label": "Failure to thrive", "system": "HP:0001507", "system_label": "Growth abnormality", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:42639750", "origin": "teracopy" }, { "hpo_id": "HP:0011968", "label": "Feeding difficulties", "system": "HP:0025031", "system_label": "Abnormality of the digestive system", "frequency": "6/6", "frequency_range": "6/6", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:39669238", "origin": "teracopy" }, { "hpo_id": "HP:0001263", "label": "Global developmental delay", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:42639750", "origin": "teracopy" }, { "hpo_id": "HP:0002079", "label": "Hypoplasia of the corpus callosum", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "5/9", "frequency_range": "5/9", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:39669238", "origin": "teracopy" }, { "hpo_id": "HP:0000047", "label": "Hypospadias", "system": "HP:0000119", "system_label": "Abnormality of the genitourinary system", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:39669238", "origin": "teracopy" }, { "hpo_id": "HP:0001252", "label": "Hypotonia", "system": "HP:0033127", "system_label": "Abnormality of the musculoskeletal system", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:42639750", "origin": "teracopy" }, { "hpo_id": "HP:0000252", "label": "Microcephaly", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "6/6", "frequency_range": "6/6", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:39669238", "origin": "teracopy" }, { "hpo_id": "HP:0000347", "label": "Micrognathia", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "10/10", "frequency_range": "10/10", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:39669238", "origin": "teracopy" }, { "hpo_id": "HP:0000508", "label": "Ptosis", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:39669238", "origin": "teracopy" }, { "hpo_id": "HP:0001838", "label": "Rocker bottom foot", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "3/10", "frequency_range": "3/10", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:39669238", "origin": "teracopy" }, { "hpo_id": "HP:0003196", "label": "Short nose", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "10/10", "frequency_range": "10/10", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:39669238", "origin": "teracopy" }, { "hpo_id": "HP:0004322", "label": "Short stature", "system": "HP:0001507", "system_label": "Growth abnormality", "frequency": "6/6", "frequency_range": "6/6", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:39669238", "origin": "teracopy" }, { "hpo_id": "HP:0000954", "label": "Single transverse palmar crease", "system": "HP:0001574", "system_label": "Abnormality of the integument", "frequency": "10/10", "frequency_range": "10/10", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:39669238", "origin": "teracopy" }, { "hpo_id": "HP:0001518", "label": "Small for gestational age", "system": "HP:0001507", "system_label": "Growth abnormality", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:39669238", "origin": "teracopy" }, { "hpo_id": "HP:0001762", "label": "Talipes equinovarus", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "3/10", "frequency_range": "3/10", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:39669238", "origin": "teracopy" }, { "hpo_id": "HP:0000219", "label": "Thin upper lip vermilion", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "9/10", "frequency_range": "9/10", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:39669238", "origin": "teracopy" } ], "profile_source": "phenotype.hpoa 2026-09-02", "profile_references": [ "PMID:39669238", "PMID:42639750" ], "profile_evidence_codes": [ "IEA" ], "excluded_features": [], "mimics": [ { "id": "OMIM:270400", "name": "Smith-Lemli-Opitz syndrome", "profile_size": 117, "only_in_exposure": [ { "hpo_id": "HP:0001181", "label": "Adducted thumb", "frequency": "9/10" }, { "hpo_id": "HP:0011304", "label": "Broad thumb", "frequency": "9/10" }, { "hpo_id": "HP:0001838", "label": "Rocker bottom foot", "frequency": "3/10" }, { "hpo_id": "HP:0003196", "label": "Short nose", "frequency": "10/10" }, { "hpo_id": "HP:0000954", "label": "Single transverse palmar crease", "frequency": "10/10" } ], "only_in_mimic": [ { "hpo_id": "HP:0002101", "label": "Abnormal lung lobation", "frequency": null }, { "hpo_id": "HP:0002251", "label": "Aganglionic megacolon", "frequency": null }, { "hpo_id": "HP:0000718", "label": "Aggressive behavior", "frequency": null }, { "hpo_id": "HP:0000062", "label": "Ambiguous genitalia", "frequency": "2/5" }, { "hpo_id": "HP:0100702", "label": "Arachnoid cyst", "frequency": "17/55" }, { "hpo_id": "HP:0001631", "label": "Atrial septal defect", "frequency": "1/1" }, { "hpo_id": "HP:0000813", "label": "Bicornuate uterus", "frequency": null }, { "hpo_id": "HP:0000048", "label": "Bifid scrotum", "frequency": null }, { "hpo_id": "HP:0000193", "label": "Bifid uvula", "frequency": "1/3" }, { "hpo_id": "HP:0001623", "label": "Breech presentation", "frequency": null }, { "hpo_id": "HP:0000187", "label": "Broad alveolar ridges", "frequency": null }, { "hpo_id": "HP:0000518", "label": "Cataract", "frequency": null } ], "shared": [ "HP:0000047", "HP:0000175", "HP:0000252", "HP:0000347", "HP:0000463", "HP:0000508", "HP:0000717", "HP:0001252", "HP:0001263", "HP:0001508", "HP:0002079", "HP:0004322", "HP:0004691", "HP:0011968" ], "overlap_summary": "Both profiles show fourteen shared features, including 2-3 toe syndactyly, micrognathia, cleft palate, microcephaly, and short stature.", "comparable": true } ] }, "publish": true, "withheld_because": [] }, { "pair_id": "TC012", "exposure": "exogenous / maternal androgens", "exposure_id": null, "direction": "exposure_mimics_genetic", "embryopathy": "prenatal virilisation of a 46,XX fetus", "embryopathy_id": "TERACOPY:3", "mimics": [ { "name": "21-hydroxylase deficiency congenital adrenal hyperplasia", "id": "OMIM:201910", "genes": [], "resolved": true, "summary": "Classic 21-hydroxylase deficiency is autosomal recessive and follows biallelic CYP21A2 variants. The adrenal cortex cannot make cortisol from cholesterol, adrenal androgens accumulate, and at least 75% of affected individuals also have salt wasting. Exogenous maternal androgens virilise a 46,XX fetus in the same pattern of clitoromegaly, fused labia and urogenital sinus formation. That is the whole of the overlap. The two separate on the course rather than on the appearance. Adrenal biochemistry after an exposure returns to normal, and in the disorder the defect persists.", "shared_count": 0, "overlap_summary": null } ], "genes": [ "CYP21A2" ], "mechanism_class": "endocrine_disruption", "teratogenicity": "established", "mechanism_confidence": "strong", "citations": [ { "pmid": "6720789", "first_author": "Rosa FW", "year": "1984", "journal": "Am J Obstet Gynecol", "volume": "149", "pages": "99-100", "title": "Virilization of the female fetus with maternal danazol exposure", "level": "title_supports", "checked": "2026-09-17" } ], "notes": "Biochemically separable: CAH has elevated 17-OHP.", "targets": [], "provenance": { "has_citation": true, "has_pmid": true, "citation_verified": true, "mimic_resolved": true, "has_mimic": true, "has_mechanism_edge": false, "verified_against_primary_source": false }, "clinical": { "pair_id": "TC012", "synopsis": [ "Danazol taken in pregnancy virilises the female fetus. Across 94 completed pregnancies, 23 of 57 female infants were virilised and the 37 male infants were recorded as normal (PMID:1606119). The pattern is clitoromegaly, fused labia and urogenital sinus formation, and no case is reported where danazol stopped before the eighth week (PMID:1606119)." ], "favours_exposure": [ { "statement": "Maternal danazol at or beyond the eighth completed week. No report describes virilisation where therapy stopped before the eighth week", "lead": "Maternal danazol at or beyond the eighth completed week", "detail": "No report describes virilisation where therapy stopped before the eighth week", "weight": "strong", "pmids": [ "1606119" ], "mimic": "OMIM:201910" }, { "statement": "Effect confined to female fetuses. Of 94 completed pregnancies, 37 produced normal males, 34 produced non-virilised females and 23 produced virilised females", "lead": "Effect confined to female fetuses", "detail": "Of 94 completed pregnancies, 37 produced normal males, 34 produced non-virilised females and 23 produced virilised females", "weight": "strong", "pmids": [ "1606119" ], "mimic": "OMIM:201910" }, { "statement": "Virilisation as the only reported anomaly. The pattern is clitoromegaly, fused labia and urogenital sinus formation", "lead": "Virilisation as the only reported anomaly", "detail": "The pattern is clitoromegaly, fused labia and urogenital sinus formation", "weight": "strong", "pmids": [ "1606119" ], "mimic": "OMIM:201910" }, { "statement": "Dose relation. Virilisation was more common at higher dosages, but one case is reported at 200 mg daily", "lead": "Dose relation", "detail": "Virilisation was more common at higher dosages, but one case is reported at 200 mg daily", "weight": "strong", "pmids": [ "1606119" ], "mimic": "OMIM:201910" }, { "statement": "Adrenal biochemistry that normalises. One exposed newborn had raised 17-hydroxyprogesterone, ACTH, testosterone, androstenedione, 11-deoxycortisol and renin, with low cortisol. The 17-hydroxyprogesterone and 11-deoxycortisol responses to corticotropin were excessive. One year later the basal adrenal steroids and the corticotropin response were normal", "lead": "Adrenal biochemistry that normalises", "detail": "One exposed newborn had raised 17-hydroxyprogesterone, ACTH, testosterone, androstenedione, 11-deoxycortisol and renin, with low cortisol. The 17-hydroxyprogesterone and 11-deoxycortisol responses to corticotropin were excessive. One year later the basal adrenal steroids and the corticotropin response were normal", "weight": "strong", "pmids": [ "6271010" ], "mimic": "OMIM:201910" } ], "favours_gene": [ { "statement": "Biallelic pathogenic variants in CYP21A2. Inheritance is autosomal recessive. Most parents are heterozygous, and about 1% of pathogenic variants arise de novo", "lead": "Biallelic pathogenic variants in CYP21A2", "detail": "Inheritance is autosomal recessive. Most parents are heterozygous, and about 1% of pathogenic variants arise de novo", "weight": "categorical", "pmids": [ "20301350" ], "mimic": "OMIM:201910" }, { "statement": "Salt wasting, with inadequate aldosterone production. It affects at least 75% of individuals with classic 21-hydroxylase deficiency. Newborns with the salt-wasting form risk life-threatening crises", "lead": "Salt wasting, with inadequate aldosterone production", "detail": "It affects at least 75% of individuals with classic 21-hydroxylase deficiency. Newborns with the salt-wasting form risk life-threatening crises", "weight": "strong", "pmids": [ "20301350" ], "mimic": "OMIM:201910" }, { "statement": "Persistently elevated serum 17-hydroxyprogesterone. Elevated adrenal androgens accompany it. Together with the characteristic clinical features they establish the diagnosis in newborns", "lead": "Persistently elevated serum 17-hydroxyprogesterone", "detail": "Elevated adrenal androgens accompany it. Together with the characteristic clinical features they establish the diagnosis in newborns", "weight": "strong", "pmids": [ "20301350" ], "mimic": "OMIM:201910" }, { "statement": "Persistent impairment of cortisol synthesis. The adrenal cortex cannot make cortisol from cholesterol. This is the defining defect of the disorder, and it needs lifelong glucocorticoid replacement", "lead": "Persistent impairment of cortisol synthesis", "detail": "The adrenal cortex cannot make cortisol from cholesterol. This is the defining defect of the disorder, and it needs lifelong glucocorticoid replacement", "weight": "strong", "pmids": [ "20301350" ], "mimic": "OMIM:201910" }, { "statement": "Ascertainment by newborn screening. Screening targets classic 21-hydroxylase deficiency before a salt-wasting crisis occurs", "lead": "Ascertainment by newborn screening", "detail": "Screening targets classic 21-hydroxylase deficiency before a salt-wasting crisis occurs", "weight": "strong", "pmids": [ "20301350" ], "mimic": "OMIM:201910" } ], "not_discriminating": [], "gaps": [ "PMID 6720789 is a two-page clinical communication with no indexed abstract and no accessible full text. Its title is the only text obtained for it; it supports virilisation after maternal danazol exposure and nothing further.", "PMID 1606119 is a retrospective review of reported case histories drawn from case reports, two national adverse-reaction registries and manufacturer reports. It carries no denominator of exposed pregnancies, and reporting bias operates in both directions. The 23/57 figure is of female infants born in that reported series, not a risk per exposed pregnancy.", "The pair record states that the two conditions are \"biochemically separable: CAH has elevated 17-OHP\". PMID 6271010 records a danazol-exposed newborn with elevated 17-hydroxyprogesterone, elevated ACTH, low cortisol and an exaggerated corticotropin response. In that case the two were separated only by repeat testing at one year.", "The single case in PMID 6271010 was a premature infant. Whether the transient adrenal biochemistry it describes is usual after androgen exposure is not established by any source located; no series repeats the measurement.", "Every case-level source located concerns danazol. No source was curated for testosterone, methyltestosterone or virilising progestins, although the entry is titled for exogenous androgens as a class.", "Maternal androgen-secreting tumours are excluded from this entry by scope, and no source concerning them was retrieved or assessed here.", "No Prader stage distribution, and no n/m for which exposed infants required surgery; PMID 1606119 states only that surgery was \"usually, but not always\" required.", "No frequency data with denominators were located for the gene disorder beyond the proportions of the classic form (\u226575% salt-wasting, ~25% simple virilising) given in PMID 20301350; the remaining gene-side items are grounded on a clinical-characteristics summary, not a counted series.", "No source was located that compares degree of virilisation between androgen-exposed and 21-hydroxylase deficient 46,XX newborns." ], "caveat": [], "lookalikes": { "OMIM:201910": "Classic 21-hydroxylase deficiency is autosomal recessive and follows biallelic CYP21A2 variants. The adrenal cortex cannot make cortisol from cholesterol, adrenal androgens accumulate, and at least 75% of affected individuals also have salt wasting. Exogenous maternal androgens virilise a 46,XX fetus in the same pattern of clitoromegaly, fused labia and urogenital sinus formation. That is the whole of the overlap. The two separate on the course rather than on the appearance. Adrenal biochemistry after an exposure returns to normal, and in the disorder the defect persists." }, "untagged": 0 }, "phenotype": { "embryopathy_id": "TERACOPY:3", "profile": [ { "hpo_id": "HP:0000058", "label": "Abnormal labia morphology", "system": "HP:0000119", "system_label": "Abnormality of the genitourinary system", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:1606119", "origin": "teracopy" }, { "hpo_id": "HP:0008665", "label": "Clitoral hypertrophy", "system": "HP:0000119", "system_label": "Abnormality of the genitourinary system", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:1606119", "origin": "teracopy" }, { "hpo_id": "HP:0031213", "label": "Elevated circulating 17-hydroxyprogesterone concentration", "system": "HP:0000818", "system_label": "Abnormality of the endocrine system", "frequency": "1/1", "frequency_range": "1/1", "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:6271010", "origin": "teracopy" }, { "hpo_id": "HP:0031170", "label": "Female fetal virilization", "system": "HP:0001197", "system_label": "Abnormality of prenatal development or birth", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:6720789", "origin": "teracopy" }, { "hpo_id": "HP:0100779", "label": "Urogenital sinus anomaly", "system": "HP:0000119", "system_label": "Abnormality of the genitourinary system", "frequency": null, "frequency_range": null, "rank": -1, "excluded": false, "evidence": "IEA", "reference": "PMID:1606119", "origin": "teracopy" } ], "profile_source": "phenotype.hpoa 2026-09-02", "profile_references": [ "PMID:1606119", "PMID:6271010", "PMID:6720789" ], "profile_evidence_codes": [ "IEA" ], "excluded_features": [], "mimics": [ { "id": "OMIM:201910", "name": "21-hydroxylase deficiency congenital adrenal hyperplasia", "profile_size": 12, "only_in_exposure": [ { "hpo_id": "HP:0000058", "label": "Abnormal labia morphology", "frequency": null }, { "hpo_id": "HP:0008665", "label": "Clitoral hypertrophy", "frequency": null }, { "hpo_id": "HP:0031213", "label": "Elevated circulating 17-hydroxyprogesterone concentration", "frequency": "1/1" }, { "hpo_id": "HP:0031170", "label": "Female fetal virilization", "frequency": null } ], "only_in_mimic": [ { "hpo_id": "HP:0000765", "label": "Abnormal thorax morphology", "frequency": null }, { "hpo_id": "HP:0008221", "label": "Adrenal hyperplasia", "frequency": null }, { "hpo_id": "HP:0000840", "label": "Adrenogenital syndrome", "frequency": null }, { "hpo_id": "HP:6000516", "label": "Elevated circulating 21-deoxycortisol concentration", "frequency": null }, { "hpo_id": "HP:0001945", "label": "Fever", "frequency": null }, { "hpo_id": "HP:0001507", "label": "Growth abnormality", "frequency": null }, { "hpo_id": "HP:0000771", "label": "Gynecomastia", "frequency": null }, { "hpo_id": "HP:0000822", "label": "Hypertension", "frequency": null }, { "hpo_id": "HP:0001943", "label": "Hypoglycemia", "frequency": null }, { "hpo_id": "HP:0001954", "label": "Recurrent fever", "frequency": null }, { "hpo_id": "HP:0000127", "label": "Renal salt wasting", "frequency": null } ], "shared": [], "overlap_summary": null, "comparable": true } ] }, "publish": true, "withheld_because": [] }, { "pair_id": "TC013", "exposure": "aminopterin; methotrexate", "exposure_id": "CHEBI:44185", "direction": "exposure_mimics_genetic", "embryopathy": "aminopterin/methotrexate embryofetopathy", "embryopathy_id": "ORPHA:1908", "mimics": [ { "name": "folate pathway defects", "id": null, "genes": [], "resolved": false, "summary": null, "shared_count": 0, "overlap_summary": null } ], "genes": [ "DHFR" ], "mechanism_class": "nutrient_antagonism", "teratogenicity": "established", "mechanism_confidence": "moderate", "citations": [ { "pmid": "22434686", "first_author": "Hyoun SC", "year": "2012", "journal": "Birth Defects Res A Clin Mol Teratol", "volume": "94", "pages": "187-207", "title": "Teratogen update: methotrexate", "level": "title_supports", "checked": "2026-09-17" } ], "notes": "Aminopterin syndrome sine aminopterin is the descriptive genetic counterpart.", "targets": [], "provenance": { "has_citation": true, "has_pmid": true, "citation_verified": true, "mimic_resolved": false, "has_mimic": true, "has_mechanism_edge": false, "verified_against_primary_source": false }, "clinical": null, "phenotype": { "embryopathy_id": "ORPHA:1908", "profile": [ { "hpo_id": "HP:0002323", "label": "Anencephaly", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0000286", "label": "Epicanthus", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0000238", "label": "Hydrocephalus", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0000316", "label": "Hypertelorism", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0000303", "label": "Mandibular prognathia", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0003027", "label": "Mesomelia", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0002983", "label": "Micromelia", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0000520", "label": "Proptosis", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0004322", "label": "Short stature", "system": "HP:0001507", "system_label": "Growth abnormality", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0002652", "label": "Skeletal dysplasia", "system": "HP:0033127", "system_label": "Abnormality of the musculoskeletal system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0009891", "label": "Underdeveloped supraorbital ridges", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0000431", "label": "Wide nasal bridge", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0000175", "label": "Cleft palate", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0002084", "label": "Encephalocele", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0001511", "label": "Intrauterine growth retardation", "system": "HP:0001507", "system_label": "Growth abnormality", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0002435", "label": "Meningocele", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0000252", "label": "Microcephaly", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0000347", "label": "Micrognathia", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0100335", "label": "Non-midline cleft of the upper lip", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0000358", "label": "Posteriorly rotated ears", "system": "HP:0000598", "system_label": "Abnormality of the ear", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0001883", "label": "Talipes", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0001231", "label": "Abnormal fingernail morphology", "system": "HP:0001574", "system_label": "Abnormality of the integument", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0007360", "label": "Aplasia/Hypoplasia of the cerebellum", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0007370", "label": "Aplasia/Hypoplasia of the corpus callosum", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0009601", "label": "Aplasia/Hypoplasia of the thumb", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0006101", "label": "Finger syndactyly", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0001360", "label": "Holoprosencephaly", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0004935", "label": "Pulmonary artery atresia", "system": "HP:0002086", "system_label": "Abnormality of the respiratory system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0001696", "label": "Situs inversus totalis", "system": "HP:0001626", "system_label": "Abnormality of the cardiovascular system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0001792", "label": "Small nail", "system": "HP:0001574", "system_label": "Abnormality of the integument", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0010301", "label": "Spinal dysraphism", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0001636", "label": "Tetralogy of Fallot", "system": "HP:0001626", "system_label": "Abnormality of the cardiovascular system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" }, { "hpo_id": "HP:0001629", "label": "Ventricular septal defect", "system": "HP:0001626", "system_label": "Abnormality of the cardiovascular system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1908", "origin": "release" } ], "profile_source": "phenotype.hpoa 2026-09-02", "profile_references": [ "ORPHA:1908" ], "profile_evidence_codes": [ "TAS" ], "excluded_features": [], "mimics": [ { "id": null, "name": "folate pathway defects", "profile_size": 0, "only_in_exposure": [], "only_in_mimic": [], "shared": [], "overlap_summary": null, "comparable": false } ] }, "publish": false, "withheld_because": [ "no Mendelian lookalike with an identifier", "no clinical synopsis written" ] }, { "pair_id": "TC014", "exposure": "congenital CMV / rubella / Zika (TORCH)", "exposure_id": null, "direction": "genetic_mimics_exposure", "embryopathy": "congenital infection phenotype (, fetal cytomegalovirus syndrome)", "embryopathy_id": "ORPHA:294", "mimics": [ { "name": "Aicardi-Goutieres syndrome 1", "id": "OMIM:225750", "genes": [], "resolved": true, "summary": null, "shared_count": 7, "overlap_summary": "Both profiles show the full congenital infection presentation: microcephaly, seizures, hepatosplenomegaly, thrombocytopenia, petechiae, and raised transaminases." }, { "name": "pseudo-TORCH syndrome 1", "id": "ORPHA:1229", "genes": [], "resolved": true, "summary": null, "shared_count": 3, "overlap_summary": "Both profiles show the triad that names the condition: microcephaly, cerebral calcification, and seizures." } ], "genes": [ "TREX1", "RNASEH2A", "RNASEH2B", "RNASEH2C", "SAMHD1", "ADAR", "IFIH1", "OCLN", "USP18" ], "mechanism_class": "pathway_convergence", "teratogenicity": "established", "mechanism_confidence": "strong", "citations": [ { "pmid": "18422679", "first_author": "Crow YJ", "year": "2008", "journal": "Dev Med Child Neurol", "volume": "50", "pages": "410-6", "title": "Aicardi-Gouti\u00e8res syndrome: an important Mendelian mimic of congenital infection", "level": "title_supports", "checked": "2026-09-17" } ], "notes": "INVERSE DIRECTION. The mature template for this whole project: a gene-anchored catalogue of genetic conditions mimicking an exposure. Type I interferon axis.", "targets": [], "provenance": { "has_citation": true, "has_pmid": true, "citation_verified": true, "mimic_resolved": true, "has_mimic": true, "has_mechanism_edge": false, "verified_against_primary_source": false }, "clinical": null, "phenotype": { "embryopathy_id": "ORPHA:294", "profile": [ { "hpo_id": "HP:0001928", "label": "Abnormality of coagulation", "system": "HP:0001871", "system_label": "Abnormality of blood and blood-forming tissues", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:294", "origin": "release" }, { "hpo_id": "HP:0001903", "label": "Anemia", "system": "HP:0001871", "system_label": "Abnormality of blood and blood-forming tissues", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:294", "origin": "release" }, { "hpo_id": "HP:0012424", "label": "Chorioretinitis", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:294", "origin": "release" }, { "hpo_id": "HP:0002908", "label": "Conjugated hyperbilirubinemia", "system": "HP:0001939", "system_label": "Abnormality of metabolism/homeostasis", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:294", "origin": "release" }, { "hpo_id": "HP:0002910", "label": "Elevated circulating hepatic transaminase concentration", "system": "HP:0001939", "system_label": "Abnormality of metabolism/homeostasis", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:294", "origin": "release" }, { "hpo_id": "HP:0002240", "label": "Hepatomegaly", "system": "HP:0025031", "system_label": "Abnormality of the digestive system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:294", "origin": "release" }, { "hpo_id": "HP:0001249", "label": "Intellectual disability", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:294", "origin": "release" }, { "hpo_id": "HP:0000407", "label": "Sensorineural hearing impairment", "system": "HP:0000598", "system_label": "Abnormality of the ear", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:294", "origin": "release" }, { "hpo_id": "HP:0001744", "label": "Splenomegaly", "system": "HP:0025031", "system_label": "Abnormality of the digestive system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:294", "origin": "release" }, { "hpo_id": "HP:0001873", "label": "Thrombocytopenia", "system": "HP:0001871", "system_label": "Abnormality of blood and blood-forming tissues", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:294", "origin": "release" }, { "hpo_id": "HP:0002514", "label": "Cerebral calcification", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:294", "origin": "release" }, { "hpo_id": "HP:0012115", "label": "Hepatitis", "system": "HP:0025031", "system_label": "Abnormality of the digestive system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:294", "origin": "release" }, { "hpo_id": "HP:0001511", "label": "Intrauterine growth retardation", "system": "HP:0001507", "system_label": "Growth abnormality", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:294", "origin": "release" }, { "hpo_id": "HP:0000952", "label": "Jaundice", "system": "HP:0025031", "system_label": "Abnormality of the digestive system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:294", "origin": "release" }, { "hpo_id": "HP:0000252", "label": "Microcephaly", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:294", "origin": "release" }, { "hpo_id": "HP:0000648", "label": "Optic atrophy", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:294", "origin": "release" }, { "hpo_id": "HP:0000967", "label": "Petechiae", "system": "HP:0001871", "system_label": "Abnormality of blood and blood-forming tissues", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:294", "origin": "release" }, { "hpo_id": "HP:0000573", "label": "Retinal hemorrhage", "system": "HP:0001871", "system_label": "Abnormality of blood and blood-forming tissues", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:294", "origin": "release" }, { "hpo_id": "HP:0001250", "label": "Seizure", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:294", "origin": "release" }, { "hpo_id": "HP:0002119", "label": "Ventriculomegaly", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:294", "origin": "release" } ], "profile_source": "phenotype.hpoa 2026-09-02", "profile_references": [ "ORPHA:294" ], "profile_evidence_codes": [ "TAS" ], "excluded_features": [], "mimics": [ { "id": "OMIM:225750", "name": "Aicardi-Goutieres syndrome 1", "profile_size": 47, "only_in_exposure": [ { "hpo_id": "HP:0001928", "label": "Abnormality of coagulation", "frequency": "frequent" }, { "hpo_id": "HP:0001903", "label": "Anemia", "frequency": "frequent" }, { "hpo_id": "HP:0012424", "label": "Chorioretinitis", "frequency": "frequent" }, { "hpo_id": "HP:0002908", "label": "Conjugated hyperbilirubinemia", "frequency": "frequent" }, { "hpo_id": "HP:0000407", "label": "Sensorineural hearing impairment", "frequency": "frequent" }, { "hpo_id": "HP:0012115", "label": "Hepatitis", "frequency": "occasional" }, { "hpo_id": "HP:0000648", "label": "Optic atrophy", "frequency": "occasional" }, { "hpo_id": "HP:0000573", "label": "Retinal hemorrhage", "frequency": "occasional" }, { "hpo_id": "HP:0002119", "label": "Ventriculomegaly", "frequency": "occasional" } ], "only_in_mimic": [ { "hpo_id": "HP:0002062", "label": "Abnormal pyramidal tract morphology", "frequency": null }, { "hpo_id": "HP:0002071", "label": "Abnormality of extrapyramidal motor function", "frequency": null }, { "hpo_id": "HP:0001344", "label": "Absent speech", "frequency": "1/1" }, { "hpo_id": "HP:0001063", "label": "Acrocyanosis", "frequency": null }, { "hpo_id": "HP:0003613", "label": "Antiphospholipid antibody positivity", "frequency": "1/79" }, { "hpo_id": "HP:0008936", "label": "Axial hypotonia", "frequency": null }, { "hpo_id": "HP:0007305", "label": "CNS demyelination", "frequency": "1/1" }, { "hpo_id": "HP:0200149", "label": "CSF lymphocytic pleiocytosis", "frequency": "1/1" }, { "hpo_id": "HP:0001638", "label": "Cardiomyopathy", "frequency": "9/79" }, { "hpo_id": "HP:0007352", "label": "Cerebellar calcifications", "frequency": "1/1" }, { "hpo_id": "HP:0009710", "label": "Chilblains", "frequency": "40/90" }, { "hpo_id": "HP:0009704", "label": "Chronic CSF lymphocytosis", "frequency": "23/23" } ], "shared": [ "HP:0000252", "HP:0000967", "HP:0001250", "HP:0001744", "HP:0001873", "HP:0002240", "HP:0002910" ], "overlap_summary": "Both profiles show the full congenital infection presentation: microcephaly, seizures, hepatosplenomegaly, thrombocytopenia, petechiae, and raised transaminases.", "comparable": true }, { "id": "ORPHA:1229", "name": "pseudo-TORCH syndrome 1", "profile_size": 7, "only_in_exposure": [ { "hpo_id": "HP:0001928", "label": "Abnormality of coagulation", "frequency": "frequent" }, { "hpo_id": "HP:0001903", "label": "Anemia", "frequency": "frequent" }, { "hpo_id": "HP:0012424", "label": "Chorioretinitis", "frequency": "frequent" }, { "hpo_id": "HP:0002908", "label": "Conjugated hyperbilirubinemia", "frequency": "frequent" }, { "hpo_id": "HP:0002910", "label": "Elevated circulating hepatic transaminase concentration", "frequency": "frequent" }, { "hpo_id": "HP:0002240", "label": "Hepatomegaly", "frequency": "frequent" }, { "hpo_id": "HP:0001249", "label": "Intellectual disability", "frequency": "frequent" }, { "hpo_id": "HP:0000407", "label": "Sensorineural hearing impairment", "frequency": "frequent" }, { "hpo_id": "HP:0001744", "label": "Splenomegaly", "frequency": "frequent" }, { "hpo_id": "HP:0001873", "label": "Thrombocytopenia", "frequency": "frequent" }, { "hpo_id": "HP:0012115", "label": "Hepatitis", "frequency": "occasional" }, { "hpo_id": "HP:0001511", "label": "Intrauterine growth retardation", "frequency": "occasional" } ], "only_in_mimic": [ { "hpo_id": "HP:0001347", "label": "Hyperreflexia", "frequency": "very frequent" }, { "hpo_id": "HP:0001257", "label": "Spasticity", "frequency": "very frequent" }, { "hpo_id": "HP:0100022", "label": "Abnormality of movement", "frequency": "frequent" }, { "hpo_id": "HP:0002120", "label": "Cerebral cortical atrophy", "frequency": "frequent" } ], "shared": [ "HP:0000252", "HP:0001250", "HP:0002514" ], "overlap_summary": "Both profiles show the triad that names the condition: microcephaly, cerebral calcification, and seizures.", "comparable": true } ] }, "publish": false, "withheld_because": [ "no clinical synopsis written", "direction genetic_mimics_exposure needs its own treatment" ] }, { "pair_id": "TC015", "exposure": "maternal phenylketonuria", "exposure_id": null, "direction": "maternal_genotype_as_exposure", "embryopathy": "maternal PKU embryopathy", "embryopathy_id": "ORPHA:2209", "mimics": [ { "name": "Phenylketonuria", "id": "OMIM:261600", "genes": [ "PAH" ], "resolved": true, "summary": "PAH deficiency is autosomal recessive, and newborn screening normally detects it before symptoms appear. Untreated, a phenylalanine above 360 \u00b5mol/L in the child leads to microcephaly, intellectual disability, seizures and behavioural difficulty. Maternal PKU embryopathy produces the same picture in a child who does not have the disorder, because the damage comes from the mother's phenylalanine crossing the placenta. One measurement separates them. In maternal PKU syndrome the child's own phenylalanine is normal, and the treatment belongs to the mother.", "shared_count": 4, "overlap_summary": "Both profiles show microcephaly, intellectual disability, seizures, and hyperactivity." } ], "genes": [ "PAH" ], "mechanism_class": "metabolite_toxicity", "teratogenicity": "established", "mechanism_confidence": "strong", "citations": [ { "pmid": "7421947", "first_author": "Lenke RR", "year": "1980", "journal": "N Engl J Med", "volume": "303", "pages": "1202-8", "title": "Maternal phenylketonuria and hyperphenylalaninemia. An international survey of the outcome of untreated and treated pregnancies", "level": "title_supports", "checked": "2026-09-17" } ], "notes": "Modelling test case: exposure attaches to the mother, phenotype to a genetically unaffected fetus. Forces resolution of the fetus-as-individual question in GA4GH Pedigree.", "targets": [ { "edge_id": "TCE010", "target": "PAH", "target_type": "gene", "perturbation": "depletes_substrate", "mechanism_confidence": "strong", "window": "all trimesters", "citations": [ { "pmid": "8761885", "first_author": "Levy HL", "year": "1996", "journal": "Teratology", "volume": "53", "pages": "176-84", "title": "Maternal phenylketonuria: a metabolic teratogen", "level": "title_supports", "checked": "2026-09-17" } ], "note": "The exposure is maternal hyperphenylalaninaemia, not a fetal genotype. The fetus is usually PAH-unaffected, so fetal sequencing is uninformative and the maternal phenylalanine level is the relevant measurement.", "verdicts": [] } ], "provenance": { "has_citation": true, "has_pmid": true, "citation_verified": true, "mimic_resolved": true, "has_mimic": true, "has_mechanism_edge": true, "verified_against_primary_source": false }, "clinical": { "pair_id": "TC015", "synopsis": [ "The affected child usually carries no PAH defect, because the causative genotype is the mother's (PMID:3454352). The reported phenotype is congenital microcephaly, growth restriction, congenital heart defect and later developmental delay (PMID:9066890). Risk scales with maternal phenylalanine, no heart defect occurred at maternal levels of 120 to 360 \u00b5mol/L, and the damaging window for the heart is gestational weeks 0 to 8 (PMID:9066890; PMID:10636975)." ], "favours_exposure": [ { "statement": "The child's own serum phenylalanine is normal despite the full syndrome. This is the finding that separates the two conditions outright", "lead": "The child's own serum phenylalanine is normal despite the full syndrome", "detail": "This is the finding that separates the two conditions outright", "weight": "categorical", "pmids": [ "3454352" ], "mimic": "OMIM:261600" }, { "statement": "Elevated maternal plasma phenylalanine. In an untreated pregnancy where the mother has classic PKU the level is 1200 \u00b5mol/L or above, which is 20 mg/dL. The frequency of offspring abnormality falls progressively at lower maternal levels", "lead": "Elevated maternal plasma phenylalanine", "detail": "In an untreated pregnancy where the mother has classic PKU the level is 1200 \u00b5mol/L or above, which is 20 mg/dL. The frequency of offspring abnormality falls progressively at lower maternal levels", "weight": "strong", "pmids": [ "8761885" ], "mimic": "OMIM:261600" }, { "statement": "Mother undiagnosed until the child presents. 11 of 32 women with PKU in a national series were diagnosed in adulthood, after they had an affected child", "lead": "Mother undiagnosed until the child presents", "detail": "11 of 32 women with PKU in a national series were diagnosed in adulthood, after they had an affected child", "weight": "strong", "pmids": [ "31053953" ], "mimic": "OMIM:261600" }, { "statement": "Congenital heart defect in the child. It occurred in 31 of 413 offspring in the Maternal PKU Collaborative Study, and 17 of those children also had microcephaly", "lead": "Congenital heart defect in the child", "detail": "It occurred in 31 of 413 offspring in the Maternal PKU Collaborative Study, and 17 of those children also had microcephaly", "weight": "strong", "pmids": [ "10636975" ], "mimic": "OMIM:261600" }, { "statement": "Heart defects track maternal phenylalanine in weeks 0 to 8. No woman whose offspring had a congenital heart defect held blood phenylalanine in control during the first 8 weeks. Average phenylalanine over weeks 0 to 8 predicted heart defects, at P = .0001 and P = 0.001 in the two reports", "lead": "Heart defects track maternal phenylalanine in weeks 0 to 8", "detail": "No woman whose offspring had a congenital heart defect held blood phenylalanine in control during the first 8 weeks. Average phenylalanine over weeks 0 to 8 predicted heart defects, at P = .0001 and P = 0.001 in the two reports", "weight": "strong", "pmids": [ "10636975", "9066890" ], "mimic": "OMIM:261600" }, { "statement": "Growth and facies track phenylalanine in weeks 8 to 12. The significant associations were with brain, fetal and postnatal growth retardation (P < 0.0005), wide nasal bridge (P < 0.0005) and anteverted nares (P = 0.001)", "lead": "Growth and facies track phenylalanine in weeks 8 to 12", "detail": "The significant associations were with brain, fetal and postnatal growth retardation (P < 0.0005), wide nasal bridge (P < 0.0005) and anteverted nares (P = 0.001)", "weight": "strong", "pmids": [ "9066890" ], "mimic": "OMIM:261600" }, { "statement": "Steep maternal dose-response. Microcephaly and intrauterine and postnatal growth restriction were nearly absent at a maternal phenylalanine of 120 to 360 \u00b5mol/L, and nearly universal above 900 \u00b5mol/L. No congenital heart defect occurred at 120 to 360 \u00b5mol/L", "lead": "Steep maternal dose-response", "detail": "Microcephaly and intrauterine and postnatal growth restriction were nearly absent at a maternal phenylalanine of 120 to 360 \u00b5mol/L, and nearly universal above 900 \u00b5mol/L. No congenital heart defect occurred at 120 to 360 \u00b5mol/L", "weight": "strong", "pmids": [ "9066890" ], "mimic": "OMIM:261600" }, { "statement": "Treated and untreated pregnancies differ in one population. Microcephaly, intellectual disability and dysmorphic facies were all significantly more prevalent in the offspring of untreated classical PKU pregnancies than of treated ones, at P < 0.001, P < 0.001 and P = 0.037", "lead": "Treated and untreated pregnancies differ in one population", "detail": "Microcephaly, intellectual disability and dysmorphic facies were all significantly more prevalent in the offspring of untreated classical PKU pregnancies than of treated ones, at P < 0.001, P < 0.001 and P = 0.037", "weight": "strong", "pmids": [ "31053953" ], "mimic": "OMIM:261600" }, { "statement": "Outcome graded by how late metabolic control was achieved. Across 253 children followed to age 4, the McCarthy General Cognitive Index fell as the weeks to maternal metabolic control increased (r = -0.58, P < .001). Offspring of women in control before pregnancy had a mean index of 99 (SD 13)", "lead": "Outcome graded by how late metabolic control was achieved", "detail": "Across 253 children followed to age 4, the McCarthy General Cognitive Index fell as the weeks to maternal metabolic control increased (r = -0.58, P < .001). Offspring of women in control before pregnancy had a mean index of 99 (SD 13)", "weight": "strong", "pmids": [ "10683054" ], "mimic": "OMIM:261600" }, { "statement": "Prenatal imaging pattern. Among 33 pregnancies with a second-trimester scan, congenital heart disease was identified in 5. Biparietal diameter identified microcephaly in only 1 of 9 fetuses who proved microcephalic at birth, and in 3 of 7 on a third-trimester scan. The scan shows the heart prenatally. It does not show the head", "lead": "Prenatal imaging pattern", "detail": "Among 33 pregnancies with a second-trimester scan, congenital heart disease was identified in 5. Biparietal diameter identified microcephaly in only 1 of 9 fetuses who proved microcephalic at birth, and in 3 of 7 on a third-trimester scan. The scan shows the heart prenatally. It does not show the head", "weight": "strong", "pmids": [ "8843468" ], "mimic": "OMIM:261600" }, { "statement": "Maternal nutritional factors beyond phenylalanine. Among 416 Maternal PKU Collaborative Study live-birth pregnancies, the 28 offspring with congenital heart defects had significantly lower maternal red-cell folate, methionine, proline, valine, isoleucine, leucine, lysine and arginine. Low natural protein and medical food intake was an independent risk factor whatever the blood phenylalanine. A reassuring maternal phenylalanine therefore does not by itself exclude the syndrome", "lead": "Maternal nutritional factors beyond phenylalanine", "detail": "Among 416 Maternal PKU Collaborative Study live-birth pregnancies, the 28 offspring with congenital heart defects had significantly lower maternal red-cell folate, methionine, proline, valine, isoleucine, leucine, lysine and arginine. Low natural protein and medical food intake was an independent risk factor whatever the blood phenylalanine. A reassuring maternal phenylalanine therefore does not by itself exclude the syndrome", "weight": "strong", "pmids": [ "23784316" ], "mimic": "OMIM:261600" }, { "statement": "Maternal PAH genotype is not itself informative. The study found no direct relationship between the mother's PKU mutation and the offspring outcome", "lead": "Maternal PAH genotype is not itself informative", "detail": "The study found no direct relationship between the mother's PKU mutation and the offspring outcome", "weight": "caveat", "pmids": [ "10636975" ], "mimic": "OMIM:261600" } ], "favours_gene": [ { "statement": "Biallelic PAH variants in the child. Guidelines recommend genetic testing for PAH variants at birth, to confirm the diagnosis and guide therapy. A child with the gene disorder is therefore expected to carry a confirmed molecular result", "lead": "Biallelic PAH variants in the child", "detail": "Guidelines recommend genetic testing for PAH variants at birth, to confirm the diagnosis and guide therapy. A child with the gene disorder is therefore expected to carry a confirmed molecular result", "weight": "categorical", "pmids": [ "39630157" ], "mimic": "OMIM:261600" }, { "statement": "Persistently elevated plasma phenylalanine in the child. Test after the neonatal period. Untreated levels above 360 \u00b5mol/L define the group for whom lifelong treatment is indicated", "lead": "Persistently elevated plasma phenylalanine in the child", "detail": "Test after the neonatal period. Untreated levels above 360 \u00b5mol/L define the group for whom lifelong treatment is indicated", "weight": "strong", "pmids": [ "39630157" ], "mimic": "OMIM:261600" }, { "statement": "Ascertainment by newborn screening rather than by dysmorphology. PAH deficiency was the first inborn error of metabolism identified through population screening, and is normally detected before symptoms appear", "lead": "Ascertainment by newborn screening rather than by dysmorphology", "detail": "PAH deficiency was the first inborn error of metabolism identified through population screening, and is normally detected before symptoms appear", "weight": "suggestive", "pmids": [ "24385074" ], "mimic": "OMIM:261600" }, { "statement": "The two conditions need different management. The child with PAH deficiency needs lifelong blood phenylalanine held at 120 to 360 \u00b5mol/L. The child with maternal PKU syndrome needs no metabolic treatment, and it is the mother who requires it before her next pregnancy", "lead": "The two conditions need different management", "detail": "The child with PAH deficiency needs lifelong blood phenylalanine held at 120 to 360 \u00b5mol/L. The child with maternal PKU syndrome needs no metabolic treatment, and it is the mother who requires it before her next pregnancy", "weight": "suggestive", "pmids": [ "24385074", "39630157" ], "mimic": "OMIM:261600" } ], "not_discriminating": [], "gaps": [ "The congenital-versus-acquired microcephaly axis is grounded on one side only. Microcephaly present at birth is established for maternal PKU syndrome (PMID 8843468, PMID 3454352). No retrievable primary source was found stating that head circumference is normal at birth in untreated PAH deficiency and that microcephaly there is postnatally acquired, so that contrast is deliberately not asserted above.", "No explicit negative was located for congenital heart disease in PAH deficiency. The heart-defect discriminator is therefore written as a positive association with maternal first-trimester phenylalanine, not as an exclusion on the gene side.", "Frequencies reported only as stratum percentages. Lenke 1980 (PMID 7421947, 524 pregnancies in 155 women) and Rouse 1997 (PMID 9066890) give their key figures as percentages whose stratum denominators do not appear in the retrievable abstracts, and neither full text was obtainable through EuropePMC. Those findings are recorded qualitatively above rather than as fabricated n/m.", "The classic clinical features of the untreated affected child \u2014 hypopigmentation, eczema, musty body odour \u2014 could not be grounded in a retrievable primary source and are omitted.", "Paternal carrier status is not covered. The residual possibility that a child of a PKU mother is also PAH-deficient, through a carrier father, is not grounded in any source retrieved here, and no figure for how often this occurs is recorded.", "All sources below were retrievable as abstracts only through EuropePMC; no full text was obtained." ], "caveat": [], "lookalikes": { "OMIM:261600": "PAH deficiency is autosomal recessive, and newborn screening normally detects it before symptoms appear. Untreated, a phenylalanine above 360 \u00b5mol/L in the child leads to microcephaly, intellectual disability, seizures and behavioural difficulty. Maternal PKU embryopathy produces the same picture in a child who does not have the disorder, because the damage comes from the mother's phenylalanine crossing the placenta. One measurement separates them. In maternal PKU syndrome the child's own phenylalanine is normal, and the treatment belongs to the mother." }, "untagged": 0 }, "phenotype": { "embryopathy_id": "ORPHA:2209", "profile": [ { "hpo_id": "HP:0001627", "label": "Abnormal heart morphology", "system": "HP:0001626", "system_label": "Abnormality of the cardiovascular system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0001999", "label": "Abnormal facial shape", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0001680", "label": "Coarctation of aorta", "system": "HP:0001626", "system_label": "Abnormality of the cardiovascular system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0001263", "label": "Global developmental delay", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0004383", "label": "Hypoplastic left ventricle", "system": "HP:0001626", "system_label": "Abnormality of the cardiovascular system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0001249", "label": "Intellectual disability", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0001511", "label": "Intrauterine growth retardation", "system": "HP:0001507", "system_label": "Growth abnormality", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0000252", "label": "Microcephaly", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0000463", "label": "Anteverted nares", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0001719", "label": "Double outlet right ventricle", "system": "HP:0001626", "system_label": "Abnormality of the cardiovascular system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0000218", "label": "High palate", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0000752", "label": "Hyperactivity", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0002079", "label": "Hypoplasia of the corpus callosum", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0000343", "label": "Long philtrum", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0000347", "label": "Micrognathia", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0001250", "label": "Seizure", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0001636", "label": "Tetralogy of Fallot", "system": "HP:0001626", "system_label": "Abnormality of the cardiovascular system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0001629", "label": "Ventricular septal defect", "system": "HP:0001626", "system_label": "Abnormality of the cardiovascular system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0000431", "label": "Wide nasal bridge", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0012210", "label": "Abnormal renal morphology", "system": "HP:0000119", "system_label": "Abnormality of the genitourinary system", "frequency": "very rare", "frequency_range": "1-4%", "rank": 2, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0009611", "label": "Bifid distal phalanx of the thumb", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "very rare", "frequency_range": "1-4%", "rank": 2, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0001488", "label": "Bilateral ptosis", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "very rare", "frequency_range": "1-4%", "rank": 2, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0002836", "label": "Bladder exstrophy", "system": "HP:0025031", "system_label": "Abnormality of the digestive system", "frequency": "very rare", "frequency_range": "1-4%", "rank": 2, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0001156", "label": "Brachydactyly", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "very rare", "frequency_range": "1-4%", "rank": 2, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0030084", "label": "Clinodactyly", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "very rare", "frequency_range": "1-4%", "rank": 2, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0004411", "label": "Deviated nasal septum", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "very rare", "frequency_range": "1-4%", "rank": 2, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0000286", "label": "Epicanthus", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "very rare", "frequency_range": "1-4%", "rank": 2, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0002032", "label": "Esophageal atresia", "system": "HP:0025031", "system_label": "Abnormality of the digestive system", "frequency": "very rare", "frequency_range": "1-4%", "rank": 2, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0008589", "label": "Hypoplastic helices", "system": "HP:0000598", "system_label": "Abnormality of the ear", "frequency": "very rare", "frequency_range": "1-4%", "rank": 2, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0000601", "label": "Hypotelorism", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "very rare", "frequency_range": "1-4%", "rank": 2, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0000340", "label": "Sloping forehead", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "very rare", "frequency_range": "1-4%", "rank": 2, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" }, { "hpo_id": "HP:0000486", "label": "Strabismus", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "very rare", "frequency_range": "1-4%", "rank": 2, "excluded": false, "evidence": "TAS", "reference": "ORPHA:2209", "origin": "release" } ], "profile_source": "phenotype.hpoa 2026-09-02", "profile_references": [ "ORPHA:2209" ], "profile_evidence_codes": [ "TAS" ], "excluded_features": [], "mimics": [ { "id": "OMIM:261600", "name": "Phenylketonuria", "profile_size": 27, "only_in_exposure": [ { "hpo_id": "HP:0001627", "label": "Abnormal heart morphology", "frequency": "very frequent" }, { "hpo_id": "HP:0001999", "label": "Abnormal facial shape", "frequency": "frequent" }, { "hpo_id": "HP:0001680", "label": "Coarctation of aorta", "frequency": "frequent" }, { "hpo_id": "HP:0004383", "label": "Hypoplastic left ventricle", "frequency": "frequent" }, { "hpo_id": "HP:0001511", "label": "Intrauterine growth retardation", "frequency": "frequent" }, { "hpo_id": "HP:0000463", "label": "Anteverted nares", "frequency": "occasional" }, { "hpo_id": "HP:0001719", "label": "Double outlet right ventricle", "frequency": "occasional" }, { "hpo_id": "HP:0000218", "label": "High palate", "frequency": "occasional" }, { "hpo_id": "HP:0000343", "label": "Long philtrum", "frequency": "occasional" }, { "hpo_id": "HP:0000347", "label": "Micrognathia", "frequency": "occasional" }, { "hpo_id": "HP:0001636", "label": "Tetralogy of Fallot", "frequency": "occasional" }, { "hpo_id": "HP:0001629", "label": "Ventricular septal defect", "frequency": "occasional" } ], "only_in_mimic": [ { "hpo_id": "HP:0000739", "label": "Anxiety", "frequency": null }, { "hpo_id": "HP:0000635", "label": "Blue irides", "frequency": null }, { "hpo_id": "HP:0000518", "label": "Cataract", "frequency": null }, { "hpo_id": "HP:0002514", "label": "Cerebral calcification", "frequency": null }, { "hpo_id": "HP:0000722", "label": "Compulsive behaviors", "frequency": null }, { "hpo_id": "HP:0000716", "label": "Depression", "frequency": null }, { "hpo_id": "HP:0000958", "label": "Dry skin", "frequency": null }, { "hpo_id": "HP:0000964", "label": "Eczematoid dermatitis", "frequency": null }, { "hpo_id": "HP:6000281", "label": "Elevated urinary gamma-glutamylphenylalanine level", "frequency": "12/12" }, { "hpo_id": "HP:0034458", "label": "Elevated urinary phenylpyruvic acid level", "frequency": null }, { "hpo_id": "HP:0002286", "label": "Fair hair", "frequency": null }, { "hpo_id": "HP:0007513", "label": "Generalized hypopigmentation", "frequency": null } ], "shared": [ "HP:0000252", "HP:0000752", "HP:0001249", "HP:0001250" ], "overlap_summary": "Both profiles show microcephaly, intellectual disability, seizures, and hyperactivity.", "comparable": true } ] }, "publish": true, "withheld_because": [] }, { "pair_id": "TC016", "exposure": "ethanol", "exposure_id": "CHEBI:16236", "direction": "exposure_mimics_genetic", "embryopathy": "fetal alcohol spectrum disorder", "embryopathy_id": "ORPHA:1915", "mimics": [ { "name": "holoprosencephaly spectrum", "id": "ORPHA:2162", "genes": [], "resolved": true, "summary": "Holoprosencephaly is incomplete cleavage of the forebrain, with a midface that reflects it, and it runs from a single ventricle to microform signs alone. Heterozygous SHH variants segregate in dominant pedigrees, often through a mildly affected or unaffected parent. Nearly half of affected patients have a recognised syndrome or single gene defect. Prenatal alcohol produces microcephaly, developmental delay and a midface of short palpebral fissures, epicanthus and anteverted nares, which is where the two meet. The link to holoprosencephaly itself is contested. Two case-control studies found no association, and the strongest human signal is for alcohol and smoking together.", "shared_count": 8, "overlap_summary": "Both profiles show microcephaly, global developmental delay, cognitive impairment, and a midface of epicanthus, ptosis, anteverted nares, and microphthalmia." } ], "genes": [ "SHH" ], "mechanism_class": "pathway_convergence", "teratogenicity": "established", "mechanism_confidence": "limited", "citations": [ { "pmid": "12140368", "first_author": "Ahlgren SC", "year": "2002", "journal": "Proc Natl Acad Sci U S A", "volume": "99", "pages": "10476-81", "title": "Sonic hedgehog rescues cranial neural crest from cell death induced by ethanol exposure", "level": "title_supports", "checked": "2026-09-17" } ], "notes": "Mechanistically diffuse. Gene mirror is weak; include but grade low.", "targets": [], "provenance": { "has_citation": true, "has_pmid": true, "citation_verified": true, "mimic_resolved": true, "has_mimic": true, "has_mechanism_edge": false, "verified_against_primary_source": false }, "clinical": { "pair_id": "TC016", "synopsis": [ "The mechanistic link rests on animal and cell work. Ethanol caused a dramatic loss of Shh transcripts in chick embryos, and applied Shh rescued the craniofacial defect (PMID:12140368). In humans the resemblance is confined to the midline end of the spectrum, and the association with holoprosencephaly itself is contested (PMID:1897567; PMID:20104597)." ], "favours_exposure": [ { "statement": "Documented prenatal alcohol exposure, to the published definition. The current diagnostic guidelines set out that definition, with neurobehavioural criteria for fetal alcohol syndrome, partial fetal alcohol syndrome and alcohol-related neurodevelopmental disorder", "lead": "Documented prenatal alcohol exposure, to the published definition", "detail": "The current diagnostic guidelines set out that definition, with neurobehavioural criteria for fetal alcohol syndrome, partial fetal alcohol syndrome and alcohol-related neurodevelopmental disorder", "weight": "strong", "pmids": [ "27464676" ], "mimic": "ORPHA:2162" }, { "statement": "Midline forebrain dysgenesis together with the fetal alcohol face. An infant exposed to first-trimester binge drinking had, at autopsy, anteriorly fused frontal lobes, absent olfactory bulbs and tracts, a midline-fused thalamus and caudate, and an absent posterior pituitary. The same infant had short palpebral fissures and midfacial hypoplasia", "lead": "Midline forebrain dysgenesis together with the fetal alcohol face", "detail": "An infant exposed to first-trimester binge drinking had, at autopsy, anteriorly fused frontal lobes, absent olfactory bulbs and tracts, a midline-fused thalamus and caudate, and an absent posterior pituitary. The same infant had short palpebral fissures and midfacial hypoplasia", "weight": "strong", "pmids": [ "8323485" ], "mimic": "ORPHA:2162" }, { "statement": "Holoprosencephaly without the fetal alcohol face. Of 3 infants with holoprosencephaly born to mothers who drank heavily in the first trimester, 2 did not show the characteristic facies", "lead": "Holoprosencephaly without the fetal alcohol face", "detail": "Of 3 infants with holoprosencephaly born to mothers who drank heavily in the first trimester, 2 did not show the characteristic facies", "weight": "strong", "pmids": [ "1897567" ], "mimic": "ORPHA:2162" }, { "statement": "Gastrulation-stage timing. Two small ethanol doses at mouse gastrulation, which matches the third week of human pregnancy, produced the fetal alcohol syndrome craniofacial pattern", "lead": "Gastrulation-stage timing", "detail": "Two small ethanol doses at mouse gastrulation, which matches the third week of human pregnancy, produced the fetal alcohol syndrome craniofacial pattern", "weight": "strong", "pmids": [ "6795717" ], "mimic": "ORPHA:2162" }, { "statement": "Non-human primate exposure. A macaque given ethanol 1.8 g/kg once weekly from postconception weeks 2 to 19 delivered a fetus with holoprosencephaly, median cleft lip and palate, and bilateral anophthalmia. The karyotype was normal and there were no extracranial anomalies", "lead": "Non-human primate exposure", "detail": "A macaque given ethanol 1.8 g/kg once weekly from postconception weeks 2 to 19 delivered a fetus with holoprosencephaly, median cleft lip and palate, and bilateral anophthalmia. The karyotype was normal and there were no extracranial anomalies", "weight": "strong", "pmids": [ "1957260" ], "mimic": "ORPHA:2162" }, { "statement": "Co-exposure signal in humans. Periconceptional alcohol gave an odds ratio of 2.0 (95% CI 0.9 to 4.5), smoking 4.1 (1.4 to 12.0) and the two combined 5.4 (1.4 to 20.0). The study covered 58 cases of cytogenetically normal holoprosencephaly against 107 controls", "lead": "Co-exposure signal in humans", "detail": "Periconceptional alcohol gave an odds ratio of 2.0 (95% CI 0.9 to 4.5), smoking 4.1 (1.4 to 12.0) and the two combined 5.4 (1.4 to 20.0). The study covered 58 cases of cytogenetically normal holoprosencephaly against 107 controls", "weight": "strong", "pmids": [ "10710231" ], "mimic": "ORPHA:2162" }, { "statement": "A high base rate for the exposure phenotype. The prevalence of fetal alcohol spectrum disorders exceeds 1% in 76 countries", "lead": "A high base rate for the exposure phenotype", "detail": "The prevalence of fetal alcohol spectrum disorders exceeds 1% in 76 countries", "weight": "strong", "pmids": [ "36823161" ], "mimic": "ORPHA:2162" }, { "statement": "The largest US study found no association with holoprosencephaly. Alcohol was not among the exposures associated with holoprosencephaly in the National Birth Defects Prevention Study, in 74 non-syndromic cases against 5871 controls", "lead": "The largest US study found no association with holoprosencephaly", "detail": "Alcohol was not among the exposures associated with holoprosencephaly in the National Birth Defects Prevention Study, in 74 non-syndromic cases against 5871 controls", "weight": "caveat", "pmids": [ "20104597" ], "mimic": "ORPHA:2162" }, { "statement": "A second case-control study also found none. Alcohol exposure was not significantly associated with non-syndromic holoprosencephaly in a Manitoba case-control study of 23 non-syndromic cases", "lead": "A second case-control study also found none", "detail": "Alcohol exposure was not significantly associated with non-syndromic holoprosencephaly in a Manitoba case-control study of 23 non-syndromic cases", "weight": "caveat", "pmids": [ "22419615" ], "mimic": "ORPHA:2162" } ], "favours_gene": [ { "statement": "Heterozygous SHH mutations segregating in a dominant pedigree. 5 of 30 autosomal dominant holoprosencephaly families carried distinct heterozygous SHH mutations", "lead": "Heterozygous SHH mutations segregating in a dominant pedigree", "detail": "5 of 30 autosomal dominant holoprosencephaly families carried distinct heterozygous SHH mutations", "weight": "categorical", "pmids": [ "8896572" ], "mimic": "ORPHA:2162" }, { "statement": "A mildly affected or unaffected transmitting parent. Across 396 individuals from 157 unrelated kindreds with SHH mutations, 64% had non-holoprosencephaly phenotypes rather than frank holoprosencephaly", "lead": "A mildly affected or unaffected transmitting parent", "detail": "Across 396 individuals from 157 unrelated kindreds with SHH mutations, 64% had non-holoprosencephaly phenotypes rather than frank holoprosencephaly", "weight": "strong", "pmids": [ "22791840" ], "mimic": "ORPHA:2162" }, { "statement": "Family history of a midline facial defect. The odds ratio was 8.2 (95% CI 1.5 to 45.2) in the Manitoba case-control study", "lead": "Family history of a midline facial defect", "detail": "The odds ratio was 8.2 (95% CI 1.5 to 45.2) in the Manitoba case-control study", "weight": "strong", "pmids": [ "22419615" ], "mimic": "ORPHA:2162" }, { "statement": "Truncating versus non-truncating genotype. Frank holoprosencephaly occurred in 49% of individuals with truncating SHH mutations, against 35% with non-truncating mutations (p = 0.012). The study established no genotype-phenotype correlation by mutation location", "lead": "Truncating versus non-truncating genotype", "detail": "Frank holoprosencephaly occurred in 49% of individuals with truncating SHH mutations, against 35% with non-truncating mutations (p = 0.012). The study established no genotype-phenotype correlation by mutation location", "weight": "strong", "pmids": [ "22791840" ], "mimic": "ORPHA:2162" }, { "statement": "Population frequency of the lookalike. Holoprosencephaly occurs in about 1 in 250 conceptuses and 1 in 10,000 to 20,000 live births. Nearly half of affected patients have a recognised syndrome or single gene defect", "lead": "Population frequency of the lookalike", "detail": "Holoprosencephaly occurs in about 1 in 250 conceptuses and 1 in 10,000 to 20,000 live births. Nearly half of affected patients have a recognised syndrome or single gene defect", "weight": "suggestive", "pmids": [ "22419615" ], "mimic": "ORPHA:2162" } ], "not_discriminating": [], "gaps": [ "The gene mirror is not established in humans. Every demonstration that ethanol acts on the Sonic hedgehog pathway is from chick, mouse or cultured cells (PMID 12140368, PMID 23071453, PMID 24586787). No source retrieved here shows ethanol perturbing SHH signalling in a human embryo or in human tissue.", "The two human case-control studies that examined alcohol and holoprosencephaly disagree, and the third did not report it among its associations (PMID 10710231, PMID 22419615, PMID 20104597). None had more than 74 cases. The direction of the human association is unresolved on this evidence.", "Holoprosencephaly is not annotated to the fetal alcohol syndrome profile. The 32 Orphanet terms for `ORPHA:1915` cover the dysmorphic, growth and neurodevelopmental phenotype and contain no holoprosencephaly or midline forebrain term. The resemblance asserted here is to a part of the fetal alcohol spectrum that the structured profile does not currently represent.", "The mouse gene-environment results turn on strain and on a sensitising genotype. The 129S6 Cdon and C57BL/6J Shh/Gli2 results both required a mutant background; wild-type littermates were largely unaffected (PMID 23071453, PMID 24586787). Whether ethanol alone produces holoprosencephaly at human exposures is not settled by these experiments.", "No dose or exposure-pattern threshold for the midline phenotype was located in any human source. The Ronen and Coulter cases describe heavy or binge first-trimester drinking without quantification (PMID 1897567, PMID 8323485).", "No frequency of holoprosencephaly among children with fetal alcohol syndrome was located, and none is asserted. The human evidence retrieved is three case reports and one autopsy.", "Sources marked abstract-only below were retrievable as abstracts through EuropePMC; no full text was obtained for them." ], "caveat": [], "lookalikes": { "ORPHA:2162": "Holoprosencephaly is incomplete cleavage of the forebrain, with a midface that reflects it, and it runs from a single ventricle to microform signs alone. Heterozygous SHH variants segregate in dominant pedigrees, often through a mildly affected or unaffected parent. Nearly half of affected patients have a recognised syndrome or single gene defect. Prenatal alcohol produces microcephaly, developmental delay and a midface of short palpebral fissures, epicanthus and anteverted nares, which is where the two meet. The link to holoprosencephaly itself is contested. Two case-control studies found no association, and the strongest human signal is for alcohol and smoking together." }, "untagged": 0 }, "phenotype": { "embryopathy_id": "ORPHA:1915", "profile": [ { "hpo_id": "HP:0000708", "label": "Atypical behavior", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0100543", "label": "Cognitive impairment", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0001263", "label": "Global developmental delay", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0001249", "label": "Intellectual disability", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0001511", "label": "Intrauterine growth retardation", "system": "HP:0001507", "system_label": "Growth abnormality", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0000252", "label": "Microcephaly", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0000275", "label": "Narrow face", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0004322", "label": "Short stature", "system": "HP:0001507", "system_label": "Growth abnormality", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0001328", "label": "Specific learning disability", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0000506", "label": "Telecanthus", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0007477", "label": "Abnormal dermatoglyphics", "system": "HP:0001574", "system_label": "Abnormality of the integument", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0010978", "label": "Abnormality of immune system physiology", "system": "HP:0002715", "system_label": "Abnormality of the immune system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0000463", "label": "Anteverted nares", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0001631", "label": "Atrial septal defect", "system": "HP:0001626", "system_label": "Abnormality of the cardiovascular system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0004422", "label": "Biparietal narrowing", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0000286", "label": "Epicanthus", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0001387", "label": "Joint stiffness", "system": "HP:0033127", "system_label": "Abnormality of the musculoskeletal system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0000691", "label": "Microdontia", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0000347", "label": "Micrognathia", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0000568", "label": "Microphthalmia", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0100335", "label": "Non-midline cleft of the upper lip", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0000358", "label": "Posteriorly rotated ears", "system": "HP:0000598", "system_label": "Abnormality of the ear", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0000508", "label": "Ptosis", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0003196", "label": "Short nose", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0000319", "label": "Smooth philtrum", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0000486", "label": "Strabismus", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0000219", "label": "Thin upper lip vermilion", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0003422", "label": "Vertebral segmentation defect", "system": "HP:0033127", "system_label": "Abnormality of the musculoskeletal system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0100761", "label": "Visceral angiomatosis", "system": "HP:0002664", "system_label": "Neoplasm", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0000175", "label": "Cleft palate", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0000776", "label": "Congenital diaphragmatic hernia", "system": "HP:0033127", "system_label": "Abnormality of the musculoskeletal system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" }, { "hpo_id": "HP:0002230", "label": "Generalized hirsutism", "system": "HP:0001574", "system_label": "Abnormality of the integument", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1915", "origin": "release" } ], "profile_source": "phenotype.hpoa 2026-09-02", "profile_references": [ "ORPHA:1915" ], "profile_evidence_codes": [ "TAS" ], "excluded_features": [], "mimics": [ { "id": "ORPHA:2162", "name": "holoprosencephaly spectrum", "profile_size": 93, "only_in_exposure": [ { "hpo_id": "HP:0000708", "label": "Atypical behavior", "frequency": "very frequent" }, { "hpo_id": "HP:0001511", "label": "Intrauterine growth retardation", "frequency": "very frequent" }, { "hpo_id": "HP:0004322", "label": "Short stature", "frequency": "very frequent" }, { "hpo_id": "HP:0000506", "label": "Telecanthus", "frequency": "very frequent" }, { "hpo_id": "HP:0007477", "label": "Abnormal dermatoglyphics", "frequency": "frequent" }, { "hpo_id": "HP:0010978", "label": "Abnormality of immune system physiology", "frequency": "frequent" }, { "hpo_id": "HP:0004422", "label": "Biparietal narrowing", "frequency": "frequent" }, { "hpo_id": "HP:0001387", "label": "Joint stiffness", "frequency": "frequent" }, { "hpo_id": "HP:0000691", "label": "Microdontia", "frequency": "frequent" }, { "hpo_id": "HP:0000347", "label": "Micrognathia", "frequency": "frequent" }, { "hpo_id": "HP:0000358", "label": "Posteriorly rotated ears", "frequency": "frequent" }, { "hpo_id": "HP:0003196", "label": "Short nose", "frequency": "frequent" } ], "only_in_mimic": [ { "hpo_id": "HP:0001360", "label": "Holoprosencephaly", "frequency": "very frequent" }, { "hpo_id": "HP:0006315", "label": "Solitary median maxillary central incisor", "frequency": "very frequent" }, { "hpo_id": "HP:0000458", "label": "Anosmia", "frequency": "frequent" }, { "hpo_id": "HP:0000453", "label": "Choanal atresia", "frequency": "frequent" }, { "hpo_id": "HP:0009914", "label": "Cyclopia", "frequency": "frequent" }, { "hpo_id": "HP:0000819", "label": "Diabetes mellitus", "frequency": "frequent" }, { "hpo_id": "HP:0001332", "label": "Dystonia", "frequency": "frequent" }, { "hpo_id": "HP:0002020", "label": "Gastroesophageal reflux", "frequency": "frequent" }, { "hpo_id": "HP:0001943", "label": "Hypoglycemia", "frequency": "frequent" }, { "hpo_id": "HP:0004409", "label": "Hyposmia", "frequency": "frequent" }, { "hpo_id": "HP:0000601", "label": "Hypotelorism", "frequency": "frequent" }, { "hpo_id": "HP:0001252", "label": "Hypotonia", "frequency": "frequent" } ], "shared": [ "HP:0000252", "HP:0000286", "HP:0000463", "HP:0000508", "HP:0000568", "HP:0000776", "HP:0001263", "HP:0100543" ], "overlap_summary": "Both profiles show microcephaly, global developmental delay, cognitive impairment, and a midface of epicanthus, ptosis, anteverted nares, and microphthalmia.", "comparable": true } ] }, "publish": true, "withheld_because": [] }, { "pair_id": "TC017", "exposure": "maternal pregestational diabetes", "exposure_id": null, "direction": "exposure_mimics_genetic", "embryopathy": "diabetic embryopathy", "embryopathy_id": "ORPHA:1926", "mimics": [ { "name": "VACTERL", "id": "ORPHA:887", "genes": [], "resolved": true, "summary": "VACTERL is an association rather than a syndrome. It covers vertebral defects, anal atresia, cardiac malformation, tracheo-oesophageal fistula, renal anomalies and limb defects, and three or more together make the diagnosis. Few familial cases have been identified, and no single gene explains it. Maternal pregestational diabetes was recorded in 4 of 135 VACTERL cases across 15 EUROCAT registries, which is the basis of the pairing. That association is contested, because a Dutch study could neither replicate nor refute it. This is the weakest of the three comparisons on the entry.", "shared_count": 10, "overlap_summary": "Both profiles show most of the VACTERL axis: vertebral and sacral defects, cardiovascular malformation, hydronephrosis, and genital anomalies." }, { "name": "holoprosencephaly", "id": "ORPHA:2162", "genes": [], "resolved": true, "summary": "Holoprosencephaly is incomplete cleavage of the forebrain, with the midline facial pattern that follows it, and heterozygous SHH variants segregate in dominant pedigrees. Maternal pregestational diabetes carries an adjusted odds ratio of 13.1 for it, and the association is stronger where other malformations are present. The shared ground is the midline brain finding together with conotruncal heart disease. A transmitting parent, mildly affected or unaffected, points to the gene. First- trimester glycaemia points to the exposure.", "shared_count": 10, "overlap_summary": "Both profiles show midline brain findings and conotruncal heart defects, including microcephaly, hydrocephalus, callosal hypoplasia, and tetralogy of Fallot." }, { "name": "caudal regression", "id": "ORPHA:3027", "genes": [], "resolved": true, "summary": "Caudal regression is a spectrum of sacral and lower vertebral agenesis, with the anorectal, renal and genital anomalies that accompany it. It carries the strongest exposure signal on this entry. Sacral agenesis had an adjusted odds ratio of 80.2 with maternal pregestational diabetes, the largest of any non-cardiac defect examined. It also carries the weakest genetic one. MNX1 explains Currarino syndrome only, and exome sequencing of 30 non-syndromic cases found no established Mendelian gene. A presacral mass with hemisacrum and anorectal malformation points to Currarino syndrome rather than to the exposure.", "shared_count": 3, "overlap_summary": "Both profiles show cryptorchidism, ureteral duplication, and cardiovascular malformation." } ], "genes": [], "mechanism_class": "unknown", "teratogenicity": "established", "mechanism_confidence": "limited", "citations": [ { "pmid": "18674752", "first_author": "Correa A", "year": "2008", "journal": "Am J Obstet Gynecol", "volume": "199", "pages": "237.e1-9", "title": "Diabetes mellitus and birth defects", "level": "title_supports", "checked": "2026-09-17" } ], "notes": "No clean single-gene mirror. Tests the \"mechanism without a gene mirror\" branch of the model.", "targets": [], "provenance": { "has_citation": true, "has_pmid": true, "citation_verified": true, "mimic_resolved": true, "has_mimic": true, "has_mechanism_edge": false, "verified_against_primary_source": false }, "clinical": { "pair_id": "TC017", "synopsis": [ "No single Mendelian disorder mirrors diabetic embryopathy. The exposure was significantly associated with 7 of 23 non-cardiac and 11 of 16 cardiac isolated defect categories in the National Birth Defects Prevention Study (PMID:18674752). The association is largest at the caudal end, where sacral agenesis gave an adjusted odds ratio of 80.2 and holoprosencephaly 13.1 (PMID:31454511)." ], "favours_exposure": [ { "statement": "Pregestational, not gestational, diabetes carries the signal. Adjusted odds ratios for all isolated and all multiple defects were 3.17 (95% CI 2.20 to 4.99) and 8.62 (5.27 to 14.10) for pregestational diabetes. For gestational diabetes they were 1.42 (1.17 to 1.73) and 1.50 (1.13 to 2.00)", "lead": "Pregestational, not gestational, diabetes carries the signal", "detail": "Adjusted odds ratios for all isolated and all multiple defects were 3.17 (95% CI 2.20 to 4.99) and 8.62 (5.27 to 14.10) for pregestational diabetes. For gestational diabetes they were 1.42 (1.17 to 1.73) and 1.50 (1.13 to 2.00)", "weight": "strong", "pmids": [ "18674752" ], "mimic": null }, { "statement": "Sacral agenesis. It had the largest odds ratio of any non-cardiac defect examined, adjusted 80.2 (95% CI 46.1 to 139.3). 33 of 104 cases had a mother with pregestational diabetes. The corresponding figure for gestational diabetes was 1.7 (0.6 to 4.8)", "lead": "Sacral agenesis", "detail": "It had the largest odds ratio of any non-cardiac defect examined, adjusted 80.2 (95% CI 46.1 to 139.3). 33 of 104 cases had a mother with pregestational diabetes. The corresponding figure for gestational diabetes was 1.7 (0.6 to 4.8)", "weight": "strong", "pmids": [ "31454511" ], "mimic": "ORPHA:3027" }, { "statement": "Isolated sacral agenesis, more than the multiple-defect form. 8 of 12 isolated cases were exposed, at an adjusted odds ratio of 807.1 (95% CI 110.7 to 5884.0). 24 of 89 multiple cases were exposed, at 67.8 (37.0 to 124.2)", "lead": "Isolated sacral agenesis, more than the multiple-defect form", "detail": "8 of 12 isolated cases were exposed, at an adjusted odds ratio of 807.1 (95% CI 110.7 to 5884.0). 24 of 89 multiple cases were exposed, at 67.8 (37.0 to 124.2)", "weight": "strong", "pmids": [ "31454511" ], "mimic": "ORPHA:3027" }, { "statement": "Holoprosencephaly. It carried an adjusted odds ratio of 13.1 with pregestational diabetes (95% CI 7.0 to 24.5), with 15 of 163 cases exposed. With gestational diabetes the figure was 1.2 (0.6 to 2.4)", "lead": "Holoprosencephaly", "detail": "It carried an adjusted odds ratio of 13.1 with pregestational diabetes (95% CI 7.0 to 24.5), with 15 of 163 cases exposed. With gestational diabetes the figure was 1.2 (0.6 to 2.4)", "weight": "strong", "pmids": [ "31454511" ], "mimic": "ORPHA:2162" }, { "statement": "Holoprosencephaly with other malformations. The adjusted odds ratio was 25.4 in 7 exposed multiple cases (95% CI 10.0 to 64.1), against 9.7 in 8 exposed isolated cases (4.3 to 21.6)", "lead": "Holoprosencephaly with other malformations", "detail": "The adjusted odds ratio was 25.4 in 7 exposed multiple cases (95% CI 10.0 to 64.1), against 9.7 in 8 exposed isolated cases (4.3 to 21.6)", "weight": "strong", "pmids": [ "31454511" ], "mimic": "ORPHA:2162" }, { "statement": "Insulin-dependent diabetes, in holoprosencephaly. It gave an odds ratio of 10.2 (95% CI 1.9 to 39.4) for cytogenetically normal holoprosencephaly, in a Californian case-control study of 58 cases and 107 controls", "lead": "Insulin-dependent diabetes, in holoprosencephaly", "detail": "It gave an odds ratio of 10.2 (95% CI 1.9 to 39.4) for cytogenetically normal holoprosencephaly, in a Californian case-control study of 58 cases and 107 controls", "weight": "strong", "pmids": [ "10710231" ], "mimic": "ORPHA:2162" }, { "statement": "Pregestational diabetes in VACTERL. It was recorded in 4 of 135 VACTERL cases against 153 of 17,527 controls across 15 EUROCAT registries, at an adjusted odds ratio of 3.1 (95% CI 1.1 to 8.6)", "lead": "Pregestational diabetes in VACTERL", "detail": "It was recorded in 4 of 135 VACTERL cases against 153 of 17,527 controls across 15 EUROCAT registries, at an adjusted odds ratio of 3.1 (95% CI 1.1 to 8.6)", "weight": "strong", "pmids": [ "32319733" ], "mimic": "ORPHA:887" }, { "statement": "Risk graded with first-trimester glycaemia. Among 303 insulin-requiring gravidas, major malformation occurred in 3.0% at haemoglobin A1 of 9.3% or below, and in 40% above 14.4%. The risk ratio was 13.2 (95% CI 4.3 to 40.4)", "lead": "Risk graded with first-trimester glycaemia", "detail": "Among 303 insulin-requiring gravidas, major malformation occurred in 3.0% at haemoglobin A1 of 9.3% or below, and in 40% above 14.4%. The risk ratio was 13.2 (95% CI 4.3 to 40.4)", "weight": "strong", "pmids": [ "2727930" ], "mimic": null }, { "statement": "Adverse outcome graded by HbA1c quintile. In 573 type 1 diabetic pregnancies it rose from 12% in the lowest quintile (95% CI 7.2 to 17) to 79% in the highest (60 to 91). Risk rose 5.5% in relative terms per 1% of HbA1c (3.8 to 7.3)", "lead": "Adverse outcome graded by HbA1c quintile", "detail": "In 573 type 1 diabetic pregnancies it rose from 12% in the lowest quintile (95% CI 7.2 to 17) to 79% in the highest (60 to 91). Risk rose 5.5% in relative terms per 1% of HbA1c (3.8 to 7.3)", "weight": "strong", "pmids": [ "17130193" ], "mimic": null }, { "statement": "Residual risk at normal glycaemia. In an Israeli cohort of 46,534 children, pre-existing type 2 diabetes was associated with congenital heart defects after accounting for HbA1c and other cardiometabolic comorbidity, at an odds ratio of 1.89 (95% CI 1.18 to 3.03). The association held when restricted to mothers with normal HbA1c and high medication adherence", "lead": "Residual risk at normal glycaemia", "detail": "In an Israeli cohort of 46,534 children, pre-existing type 2 diabetes was associated with congenital heart defects after accounting for HbA1c and other cardiometabolic comorbidity, at an odds ratio of 1.89 (95% CI 1.18 to 3.03). The association held when restricted to mothers with normal HbA1c and high medication adherence", "weight": "strong", "pmids": [ "39406385" ], "mimic": null }, { "statement": "Timing fits a first-trimester insult. The caudal mesoderm develops within the first 4 embryonic weeks. The reported diabetic-embryopathy malformations are blastogenetic, and arise before the end of the fourth week", "lead": "Timing fits a first-trimester insult", "detail": "The caudal mesoderm develops within the first 4 embryonic weeks. The reported diabetic-embryopathy malformations are blastogenetic, and arise before the end of the fourth week", "weight": "strong", "pmids": [ "33158301", "23653578" ], "mimic": null }, { "statement": "A Dutch case-control study did not replicate the VACTERL association. None of 121 VACTERL case mothers had pregestational diabetes, against 7 of 2,126 control mothers. The authors state that the EUROCAT finding could be neither replicated nor refuted", "lead": "A Dutch case-control study did not replicate the VACTERL association", "detail": "None of 121 VACTERL case mothers had pregestational diabetes, against 7 of 2,126 control mothers. The authors state that the EUROCAT finding could be neither replicated nor refuted", "weight": "caveat", "pmids": [ "33179873" ], "mimic": "ORPHA:887" } ], "favours_gene": [ { "statement": "Heterozygous SHH mutations in dominant holoprosencephaly. They segregated in 5 of 30 autosomal dominant holoprosencephaly families", "lead": "Heterozygous SHH mutations in dominant holoprosencephaly", "detail": "They segregated in 5 of 30 autosomal dominant holoprosencephaly families", "weight": "categorical", "pmids": [ "8896572" ], "mimic": "ORPHA:2162" }, { "statement": "A mildly affected or unaffected transmitting parent. Across 396 individuals from 157 unrelated kindreds with SHH mutations, 64% had a non-holoprosencephaly phenotype rather than frank holoprosencephaly", "lead": "A mildly affected or unaffected transmitting parent", "detail": "Across 396 individuals from 157 unrelated kindreds with SHH mutations, 64% had a non-holoprosencephaly phenotype rather than frank holoprosencephaly", "weight": "strong", "pmids": [ "22791840" ], "mimic": "ORPHA:2162" }, { "statement": "A presacral mass with hemisacrum and anorectal malformation. This triad defines Currarino syndrome, for which MNX1 is the major causative gene", "lead": "A presacral mass with hemisacrum and anorectal malformation", "detail": "This triad defines Currarino syndrome, for which MNX1 is the major causative gene", "weight": "strong", "pmids": [ "16498628" ], "mimic": "ORPHA:3027" }, { "statement": "Background frequency of the lookalike. Sacral agenesis occurs in 0.01 to 0.05 per 1,000 live births in the general population", "lead": "Background frequency of the lookalike", "detail": "Sacral agenesis occurs in 0.01 to 0.05 per 1,000 live births in the general population", "weight": "strong", "pmids": [ "35274497" ], "mimic": "ORPHA:3027" }, { "statement": "MNX1 is causative only for Currarino syndrome. No MNX1 or HLXB9 pathogenic variant was found in 48 caudal regression cases without Currarino syndrome, and exon 1 GCC repeat length did not affect risk. Outside Currarino syndrome the gene does not explain the malformation", "lead": "MNX1 is causative only for Currarino syndrome", "detail": "No MNX1 or HLXB9 pathogenic variant was found in 48 caudal regression cases without Currarino syndrome, and exon 1 GCC repeat length did not affect risk. Outside Currarino syndrome the gene does not explain the malformation", "weight": "caveat", "pmids": [ "16498628" ], "mimic": "ORPHA:3027" }, { "statement": "No established Mendelian gene for non-syndromic sacral agenesis. Exome sequencing of 30 children with non-syndromic sacral agenesis, in 28 trios and 2 duos, found rare heterozygous ID1 missense variants in 3, inherited from a parent in each. No established Mendelian gene for the malformation emerged", "lead": "No established Mendelian gene for non-syndromic sacral agenesis", "detail": "Exome sequencing of 30 children with non-syndromic sacral agenesis, in 28 trios and 2 duos, found rare heterozygous ID1 missense variants in 3, inherited from a parent in each. No established Mendelian gene for the malformation emerged", "weight": "caveat", "pmids": [ "35274497" ], "mimic": "ORPHA:3027" }, { "statement": "Few familial VACTERL cases have been identified. The single-gene syndromes that carry VACTERL component malformations usually have additional features that separate them from the association. This column is therefore thin for VACTERL, and the comparison rests mainly on the exposure side", "lead": "Few familial VACTERL cases have been identified", "detail": "The single-gene syndromes that carry VACTERL component malformations usually have additional features that separate them from the association. This column is therefore thin for VACTERL, and the comparison rests mainly on the exposure side", "weight": "caveat", "pmids": [ "23653571" ], "mimic": "ORPHA:887" } ], "not_discriminating": [], "gaps": [ "No gene is shared between the exposure and the three mimics. The only molecular node retrieved is Pax3: maternal diabetes reduced Pax3 expression in mouse embryonic neuroepithelium, and the resulting neural tube defects resembled those of Pax3 loss-of-function Splotch embryos (PMID 32918152). Human PAX3 disorders do not resemble diabetic embryopathy, and no human data on this node were located.", "The mechanism is a metabolic one and has no single-target formulation. The hypothesised pathway is embryonic mitochondrial glucose overload, reactive oxygen species and apoptosis (PMID 32319733, PMID 32918152). This is recorded as hypothesis, not demonstration, in the sources retrieved.", "The VACTERL association is the weakest of the three limbs. It rests on one positive registry study (PMID 32319733), one null study of similar design (PMID 33179873), and case reports (PMID 18181216). No frequency of VACTERL per diabetic pregnancy could be grounded.", "Caudal regression is not annotated as such in the exposure profile. The 32 Orphanet terms for `ORPHA:1926` carry abnormal sacrum morphology and spinal dysraphism, but no caudal regression or holoprosencephaly term. The structured profile therefore under-represents the two resemblances the literature most often names.", "The widely repeated figure of caudal regression in up to 1 in 350 infants of diabetic mothers was located only in a review that cites it secondarily (PMID 33158301). It is recorded here as unverified and is not carried into the synopsis; the grounded figure is the case-exposure proportion 33/104 (PMID 31454511).", "The NBDPS estimates are from overlapping analyses of one study. Correa 2008 covers 1997\u20132003 and Tinker 2020 the same study through 2011 (PMID 18674752, PMID 31454511). They are not independent replications; the two sets of figures come from one overlapping study population.", "Diabetes type is not separated in the older sources. Greene 1989 and Nielsen 2006 concern insulin-requiring and type 1 pregnancies respectively (PMID 2727930, PMID 17130193); how the dose-response applies to type 2 diabetes is not addressed by them.", "Sources marked abstract-only below were retrievable as abstracts through EuropePMC; no full text was obtained for them." ], "caveat": [], "lookalikes": { "ORPHA:887": "VACTERL is an association rather than a syndrome. It covers vertebral defects, anal atresia, cardiac malformation, tracheo-oesophageal fistula, renal anomalies and limb defects, and three or more together make the diagnosis. Few familial cases have been identified, and no single gene explains it. Maternal pregestational diabetes was recorded in 4 of 135 VACTERL cases across 15 EUROCAT registries, which is the basis of the pairing. That association is contested, because a Dutch study could neither replicate nor refute it. This is the weakest of the three comparisons on the entry.", "ORPHA:2162": "Holoprosencephaly is incomplete cleavage of the forebrain, with the midline facial pattern that follows it, and heterozygous SHH variants segregate in dominant pedigrees. Maternal pregestational diabetes carries an adjusted odds ratio of 13.1 for it, and the association is stronger where other malformations are present. The shared ground is the midline brain finding together with conotruncal heart disease. A transmitting parent, mildly affected or unaffected, points to the gene. First- trimester glycaemia points to the exposure.", "ORPHA:3027": "Caudal regression is a spectrum of sacral and lower vertebral agenesis, with the anorectal, renal and genital anomalies that accompany it. It carries the strongest exposure signal on this entry. Sacral agenesis had an adjusted odds ratio of 80.2 with maternal pregestational diabetes, the largest of any non-cardiac defect examined. It also carries the weakest genetic one. MNX1 explains Currarino syndrome only, and exome sequencing of 30 non-syndromic cases found no established Mendelian gene. A presacral mass with hemisacrum and anorectal malformation points to Currarino syndrome rather than to the exposure." }, "untagged": 5 }, "phenotype": { "embryopathy_id": "ORPHA:1926", "profile": [ { "hpo_id": "HP:0001679", "label": "Abnormal aortic morphology", "system": "HP:0001626", "system_label": "Abnormality of the cardiovascular system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0030680", "label": "Abnormal cardiovascular system morphology", "system": "HP:0001626", "system_label": "Abnormality of the cardiovascular system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0000008", "label": "Abnormal morphology of female internal genitalia", "system": "HP:0000119", "system_label": "Abnormality of the genitourinary system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0005107", "label": "Abnormal sacrum morphology", "system": "HP:0033127", "system_label": "Abnormality of the musculoskeletal system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0000464", "label": "Abnormality of the neck", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0004414", "label": "Abnormality of the pulmonary artery", "system": "HP:0002086", "system_label": "Abnormality of the respiratory system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0008056", "label": "Aplasia/Hypoplasia affecting the eye", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0010318", "label": "Aplasia/Hypoplasia of the abdominal wall musculature", "system": "HP:0025031", "system_label": "Abnormality of the digestive system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0000175", "label": "Cleft palate", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0000028", "label": "Cryptorchidism", "system": "HP:0000119", "system_label": "Abnormality of the genitourinary system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0000126", "label": "Hydronephrosis", "system": "HP:0000119", "system_label": "Abnormality of the genitourinary system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0000252", "label": "Microcephaly", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0000054", "label": "Micropenis", "system": "HP:0000119", "system_label": "Abnormality of the genitourinary system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0008551", "label": "Microtia", "system": "HP:0000598", "system_label": "Abnormality of the ear", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0000358", "label": "Posteriorly rotated ears", "system": "HP:0000598", "system_label": "Abnormality of the ear", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0008678", "label": "Renal hypoplasia/aplasia", "system": "HP:0000119", "system_label": "Abnormality of the genitourinary system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0001636", "label": "Tetralogy of Fallot", "system": "HP:0001626", "system_label": "Abnormality of the cardiovascular system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0001669", "label": "Transposition of the great arteries", "system": "HP:0001626", "system_label": "Abnormality of the cardiovascular system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0000073", "label": "Ureteral duplication", "system": "HP:0000119", "system_label": "Abnormality of the genitourinary system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0001629", "label": "Ventricular septal defect", "system": "HP:0001626", "system_label": "Abnormality of the cardiovascular system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0003422", "label": "Vertebral segmentation defect", "system": "HP:0033127", "system_label": "Abnormality of the musculoskeletal system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0000707", "label": "Abnormality of the nervous system", "system": null, "system_label": "Other", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0007360", "label": "Aplasia/Hypoplasia of the cerebellum", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0007370", "label": "Aplasia/Hypoplasia of the corpus callosum", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0002007", "label": "Frontal bossing", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0000365", "label": "Hearing impairment", "system": "HP:0000598", "system_label": "Abnormality of the ear", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0000238", "label": "Hydrocephalus", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0000347", "label": "Micrognathia", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0001195", "label": "Single umbilical artery", "system": "HP:0001197", "system_label": "Abnormality of prenatal development or birth", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0010301", "label": "Spinal dysraphism", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0000098", "label": "Tall stature", "system": "HP:0001507", "system_label": "Growth abnormality", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" }, { "hpo_id": "HP:0001732", "label": "Abnormality of the pancreas", "system": "HP:0025031", "system_label": "Abnormality of the digestive system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1926", "origin": "release" } ], "profile_source": "phenotype.hpoa 2026-09-02", "profile_references": [ "ORPHA:1926" ], "profile_evidence_codes": [ "TAS" ], "excluded_features": [], "mimics": [ { "id": "ORPHA:887", "name": "VACTERL", "profile_size": 41, "only_in_exposure": [ { "hpo_id": "HP:0001679", "label": "Abnormal aortic morphology", "frequency": "very frequent" }, { "hpo_id": "HP:0000464", "label": "Abnormality of the neck", "frequency": "very frequent" }, { "hpo_id": "HP:0004414", "label": "Abnormality of the pulmonary artery", "frequency": "very frequent" }, { "hpo_id": "HP:0008056", "label": "Aplasia/Hypoplasia affecting the eye", "frequency": "very frequent" }, { "hpo_id": "HP:0010318", "label": "Aplasia/Hypoplasia of the abdominal wall musculature", "frequency": "very frequent" }, { "hpo_id": "HP:0008551", "label": "Microtia", "frequency": "very frequent" }, { "hpo_id": "HP:0001636", "label": "Tetralogy of Fallot", "frequency": "very frequent" }, { "hpo_id": "HP:0001669", "label": "Transposition of the great arteries", "frequency": "very frequent" }, { "hpo_id": "HP:0000073", "label": "Ureteral duplication", "frequency": "very frequent" }, { "hpo_id": "HP:0002007", "label": "Frontal bossing", "frequency": "frequent" }, { "hpo_id": "HP:0000365", "label": "Hearing impairment", "frequency": "frequent" }, { "hpo_id": "HP:0000238", "label": "Hydrocephalus", "frequency": "frequent" } ], "only_in_mimic": [ { "hpo_id": "HP:0002023", "label": "Anal atresia", "frequency": "very frequent" }, { "hpo_id": "HP:0006703", "label": "Aplasia/Hypoplasia of the lungs", "frequency": "very frequent" }, { "hpo_id": "HP:0001561", "label": "Polyhydramnios", "frequency": "very frequent" }, { "hpo_id": "HP:0001622", "label": "Premature birth", "frequency": "very frequent" }, { "hpo_id": "HP:0002777", "label": "Tracheal stenosis", "frequency": "very frequent" }, { "hpo_id": "HP:0006501", "label": "Aplasia/Hypoplasia of the radius", "frequency": "frequent" }, { "hpo_id": "HP:0000776", "label": "Congenital diaphragmatic hernia", "frequency": "frequent" }, { "hpo_id": "HP:0000086", "label": "Ectopic kidney", "frequency": "frequent" }, { "hpo_id": "HP:0001601", "label": "Laryngomalacia", "frequency": "frequent" }, { "hpo_id": "HP:0002575", "label": "Tracheoesophageal fistula", "frequency": "frequent" }, { "hpo_id": "HP:0005108", "label": "Abnormal intervertebral disk morphology", "frequency": "occasional" }, { "hpo_id": "HP:0000772", "label": "Abnormal rib morphology", "frequency": "occasional" } ], "shared": [ "HP:0000008", "HP:0000028", "HP:0000126", "HP:0000175", "HP:0000358", "HP:0001195", "HP:0001732", "HP:0003422", "HP:0005107", "HP:0030680" ], "overlap_summary": "Both profiles show most of the VACTERL axis: vertebral and sacral defects, cardiovascular malformation, hydronephrosis, and genital anomalies.", "comparable": true }, { "id": "ORPHA:2162", "name": "holoprosencephaly", "profile_size": 93, "only_in_exposure": [ { "hpo_id": "HP:0000008", "label": "Abnormal morphology of female internal genitalia", "frequency": "very frequent" }, { "hpo_id": "HP:0005107", "label": "Abnormal sacrum morphology", "frequency": "very frequent" }, { "hpo_id": "HP:0004414", "label": "Abnormality of the pulmonary artery", "frequency": "very frequent" }, { "hpo_id": "HP:0010318", "label": "Aplasia/Hypoplasia of the abdominal wall musculature", "frequency": "very frequent" }, { "hpo_id": "HP:0000126", "label": "Hydronephrosis", "frequency": "very frequent" }, { "hpo_id": "HP:0008551", "label": "Microtia", "frequency": "very frequent" }, { "hpo_id": "HP:0000358", "label": "Posteriorly rotated ears", "frequency": "very frequent" }, { "hpo_id": "HP:0008678", "label": "Renal hypoplasia/aplasia", "frequency": "very frequent" }, { "hpo_id": "HP:0000073", "label": "Ureteral duplication", "frequency": "very frequent" }, { "hpo_id": "HP:0003422", "label": "Vertebral segmentation defect", "frequency": "very frequent" }, { "hpo_id": "HP:0000365", "label": "Hearing impairment", "frequency": "frequent" }, { "hpo_id": "HP:0000347", "label": "Micrognathia", "frequency": "frequent" } ], "only_in_mimic": [ { "hpo_id": "HP:0001999", "label": "Abnormal facial shape", "frequency": "very frequent" }, { "hpo_id": "HP:0001360", "label": "Holoprosencephaly", "frequency": "very frequent" }, { "hpo_id": "HP:0000161", "label": "Median cleft upper lip", "frequency": "very frequent" }, { "hpo_id": "HP:0006315", "label": "Solitary median maxillary central incisor", "frequency": "very frequent" }, { "hpo_id": "HP:0000458", "label": "Anosmia", "frequency": "frequent" }, { "hpo_id": "HP:0000453", "label": "Choanal atresia", "frequency": "frequent" }, { "hpo_id": "HP:0100543", "label": "Cognitive impairment", "frequency": "frequent" }, { "hpo_id": "HP:0009914", "label": "Cyclopia", "frequency": "frequent" }, { "hpo_id": "HP:0000457", "label": "Depressed nasal ridge", "frequency": "frequent" }, { "hpo_id": "HP:0000819", "label": "Diabetes mellitus", "frequency": "frequent" }, { "hpo_id": "HP:0001332", "label": "Dystonia", "frequency": "frequent" }, { "hpo_id": "HP:0002020", "label": "Gastroesophageal reflux", "frequency": "frequent" } ], "shared": [ "HP:0000028", "HP:0000238", "HP:0000252", "HP:0001629", "HP:0001636", "HP:0001679", "HP:0002007", "HP:0007360", "HP:0007370", "HP:0010301" ], "overlap_summary": "Both profiles show midline brain findings and conotruncal heart defects, including microcephaly, hydrocephalus, callosal hypoplasia, and tetralogy of Fallot.", "comparable": true }, { "id": "ORPHA:3027", "name": "caudal regression", "profile_size": 28, "only_in_exposure": [ { "hpo_id": "HP:0001679", "label": "Abnormal aortic morphology", "frequency": "very frequent" }, { "hpo_id": "HP:0000008", "label": "Abnormal morphology of female internal genitalia", "frequency": "very frequent" }, { "hpo_id": "HP:0000464", "label": "Abnormality of the neck", "frequency": "very frequent" }, { "hpo_id": "HP:0004414", "label": "Abnormality of the pulmonary artery", "frequency": "very frequent" }, { "hpo_id": "HP:0008056", "label": "Aplasia/Hypoplasia affecting the eye", "frequency": "very frequent" }, { "hpo_id": "HP:0010318", "label": "Aplasia/Hypoplasia of the abdominal wall musculature", "frequency": "very frequent" }, { "hpo_id": "HP:0000126", "label": "Hydronephrosis", "frequency": "very frequent" }, { "hpo_id": "HP:0000252", "label": "Microcephaly", "frequency": "very frequent" }, { "hpo_id": "HP:0000054", "label": "Micropenis", "frequency": "very frequent" }, { "hpo_id": "HP:0008551", "label": "Microtia", "frequency": "very frequent" }, { "hpo_id": "HP:0000358", "label": "Posteriorly rotated ears", "frequency": "very frequent" }, { "hpo_id": "HP:0001636", "label": "Tetralogy of Fallot", "frequency": "very frequent" } ], "only_in_mimic": [ { "hpo_id": "HP:0011867", "label": "Abnormal iliac wing morphology", "frequency": "very frequent" }, { "hpo_id": "HP:0002644", "label": "Abnormal pelvic girdle bone morphology", "frequency": "very frequent" }, { "hpo_id": "HP:0002607", "label": "Bowel incontinence", "frequency": "very frequent" }, { "hpo_id": "HP:0003199", "label": "Decreased muscle mass", "frequency": "very frequent" }, { "hpo_id": "HP:0008479", "label": "Hypoplastic vertebral bodies", "frequency": "very frequent" }, { "hpo_id": "HP:0100710", "label": "Impulsivity", "frequency": "very frequent" }, { "hpo_id": "HP:0002023", "label": "Anal atresia", "frequency": "frequent" }, { "hpo_id": "HP:0001315", "label": "Diminished deep tendon reflex", "frequency": "frequent" }, { "hpo_id": "HP:0000086", "label": "Ectopic kidney", "frequency": "frequent" }, { "hpo_id": "HP:0001387", "label": "Joint stiffness", "frequency": "frequent" }, { "hpo_id": "HP:0002650", "label": "Scoliosis", "frequency": "frequent" }, { "hpo_id": "HP:0001762", "label": "Talipes equinovarus", "frequency": "frequent" } ], "shared": [ "HP:0000028", "HP:0000073", "HP:0030680" ], "overlap_summary": "Both profiles show cryptorchidism, ureteral duplication, and cardiovascular malformation.", "comparable": true } ] }, "publish": true, "withheld_because": [] }, { "pair_id": "TC018", "exposure": "misoprostol", "exposure_id": "CHEBI:63611", "direction": "exposure_mimics_genetic", "embryopathy": "Moebius sequence", "embryopathy_id": "ORPHA:570", "mimics": [], "genes": [], "mechanism_class": "vascular_disruption", "teratogenicity": "established", "mechanism_confidence": "not_applicable", "citations": [ { "pmid": "9637807", "first_author": "Pastuszak AL", "year": "1998", "journal": "N Engl J Med", "volume": "338", "pages": "1881-5", "title": "Use of misoprostol during pregnancy and M\u00f6bius' syndrome in infants", "level": "title_supports", "checked": "2026-09-17" } ], "notes": "Deliberately included as a negative control: an established teratogen with no Mendelian gene mirror.", "targets": [ { "edge_id": "TCE012", "target": null, "target_type": "none", "perturbation": null, "mechanism_confidence": "not_applicable", "window": "first trimester", "citations": [ { "pmid": "14745923", "first_author": "Marques-Dias MJ", "year": "2003", "journal": "Birth Defects Res A Clin Mol Teratol", "volume": "67", "pages": "1002-7", "title": "M\u00f6bius sequence in children exposed in utero to misoprostol: neuropathological study of three cases", "level": "title_supports", "checked": "2026-09-17" } ], "note": "Negative control. Vascular disruption, no molecular node. Derives nothing, by design.", "verdicts": [] } ], "provenance": { "has_citation": true, "has_pmid": true, "citation_verified": true, "mimic_resolved": false, "has_mimic": false, "has_mechanism_edge": true, "verified_against_primary_source": false }, "clinical": null, "phenotype": { "embryopathy_id": "ORPHA:570", "profile": [ { "hpo_id": "HP:0001608", "label": "Abnormality of the voice", "system": null, "system_label": "Other", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0006824", "label": "Cranial nerve paralysis", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0010628", "label": "Facial palsy", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0008872", "label": "Feeding difficulties in infancy", "system": "HP:0025031", "system_label": "Abnormality of the digestive system", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0000298", "label": "Mask-like facies", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0000194", "label": "Open mouth", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0000602", "label": "Ophthalmoplegia", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0000508", "label": "Ptosis", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0000486", "label": "Strabismus", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0009751", "label": "Aplasia of the pectoralis major muscle", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0001156", "label": "Brachydactyly", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0007957", "label": "Corneal opacity", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0002015", "label": "Dysphagia", "system": "HP:0025031", "system_label": "Abnormality of the digestive system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0000232", "label": "Everted lower lip vermilion", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0001252", "label": "Hypotonia", "system": "HP:0033127", "system_label": "Abnormality of the musculoskeletal system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0001270", "label": "Motor delay", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0001762", "label": "Talipes equinovarus", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0040071", "label": "Abnormal morphology of ulna", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0004408", "label": "Abnormality of the sense of smell", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0004050", "label": "Absent hand", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0005914", "label": "Aplasia/Hypoplasia involving the metacarpal bones", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0006501", "label": "Aplasia/Hypoplasia of the radius", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0009601", "label": "Aplasia/Hypoplasia of the thumb", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0010295", "label": "Aplasia/Hypoplasia of the tongue", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0002804", "label": "Arthrogryposis multiplex congenita", "system": "HP:0033127", "system_label": "Abnormality of the musculoskeletal system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0000717", "label": "Autism", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0000498", "label": "Blepharitis", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0100783", "label": "Breast aplasia", "system": "HP:0000769", "system_label": "Abnormality of the breast", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0000175", "label": "Cleft palate", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0004209", "label": "Clinodactyly of the 5th finger", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0000286", "label": "Epicanthus", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0006101", "label": "Finger syndactyly", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0000365", "label": "Hearing impairment", "system": "HP:0000598", "system_label": "Abnormality of the ear", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0000218", "label": "High palate", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0000044", "label": "Hypogonadotropic hypogonadism", "system": "HP:0000818", "system_label": "Abnormality of the endocrine system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0000691", "label": "Microdontia", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0000347", "label": "Micrognathia", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0007565", "label": "Multiple cafe-au-lait spots", "system": "HP:0001574", "system_label": "Abnormality of the integument", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0003202", "label": "Skeletal muscle atrophy", "system": "HP:0033127", "system_label": "Abnormality of the musculoskeletal system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0009804", "label": "Tooth agenesis", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" }, { "hpo_id": "HP:0000505", "label": "Visual impairment", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:570", "origin": "release" } ], "profile_source": "phenotype.hpoa 2026-09-02", "profile_references": [ "ORPHA:570" ], "profile_evidence_codes": [ "TAS" ], "excluded_features": [], "mimics": [] }, "publish": false, "withheld_because": [ "no Mendelian lookalike with an identifier", "no clinical synopsis written" ] }, { "pair_id": "TC019", "exposure": "phenytoin", "exposure_id": "CHEBI:8107", "direction": "exposure_mimics_genetic", "embryopathy": "fetal hydantoin syndrome", "embryopathy_id": "ORPHA:1912", "mimics": [], "genes": [], "mechanism_class": "unknown", "teratogenicity": "established", "mechanism_confidence": "limited", "citations": [ { "pmid": "50428", "first_author": "Hanson JW", "year": "1975", "journal": "J Pediatr", "volume": "87", "pages": "285-90", "title": "The fetal hydantoin syndrome", "level": "title_supports", "checked": "2026-09-17" } ], "notes": "Candidate. Mechanism and mirror both unresolved.", "targets": [], "provenance": { "has_citation": true, "has_pmid": true, "citation_verified": true, "mimic_resolved": false, "has_mimic": false, "has_mechanism_edge": false, "verified_against_primary_source": false }, "clinical": null, "phenotype": { "embryopathy_id": "ORPHA:1912", "profile": [ { "hpo_id": "HP:0007477", "label": "Abnormal dermatoglyphics", "system": "HP:0001574", "system_label": "Abnormality of the integument", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0000377", "label": "Abnormal pinna morphology", "system": "HP:0000598", "system_label": "Abnormality of the ear", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0000457", "label": "Depressed nasal ridge", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0000364", "label": "Hearing abnormality", "system": "HP:0000598", "system_label": "Abnormality of the ear", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0000358", "label": "Posteriorly rotated ears", "system": "HP:0000598", "system_label": "Abnormality of the ear", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0003196", "label": "Short nose", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "very frequent", "frequency_range": "80-99%", "rank": 90, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0000235", "label": "Abnormal cranial suture/fontanelle morphology", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0000048", "label": "Bifid scrotum", "system": "HP:0000119", "system_label": "Abnormality of the genitourinary system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0002208", "label": "Coarse hair", "system": "HP:0001574", "system_label": "Abnormality of the integument", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0000286", "label": "Epicanthus", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0000232", "label": "Everted lower lip vermilion", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0001263", "label": "Global developmental delay", "system": "HP:0000707", "system_label": "Abnormality of the nervous system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0100790", "label": "Hernia", "system": "HP:0033127", "system_label": "Abnormality of the musculoskeletal system", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0000316", "label": "Hypertelorism", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0001804", "label": "Hypoplastic fingernail", "system": "HP:0001574", "system_label": "Abnormality of the integument", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0001511", "label": "Intrauterine growth retardation", "system": "HP:0001507", "system_label": "Growth abnormality", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0002162", "label": "Low posterior hairline", "system": "HP:0001574", "system_label": "Abnormality of the integument", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0000252", "label": "Microcephaly", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0000508", "label": "Ptosis", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0009882", "label": "Short distal phalanx of finger", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0004322", "label": "Short stature", "system": "HP:0001507", "system_label": "Growth abnormality", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0000486", "label": "Strabismus", "system": "HP:0000478", "system_label": "Abnormality of the eye", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0000474", "label": "Thickened nuchal skin fold", "system": "HP:0001197", "system_label": "Abnormality of prenatal development or birth", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0001199", "label": "Triphalangeal thumb", "system": "HP:0040064", "system_label": "Abnormality of limbs", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0006610", "label": "Wide intermamillary distance", "system": "HP:0000769", "system_label": "Abnormality of the breast", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0000154", "label": "Wide mouth", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "frequent", "frequency_range": "30-79%", "rank": 55, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0001626", "label": "Abnormality of the cardiovascular system", "system": null, "system_label": "Other", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0000175", "label": "Cleft palate", "system": "HP:0000152", "system_label": "Abnormality of head or neck", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0000028", "label": "Cryptorchidism", "system": "HP:0000119", "system_label": "Abnormality of the genitourinary system", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" }, { "hpo_id": "HP:0002664", "label": "Neoplasm", "system": null, "system_label": "Other", "frequency": "occasional", "frequency_range": "5-29%", "rank": 17, "excluded": false, "evidence": "TAS", "reference": "ORPHA:1912", "origin": "release" } ], "profile_source": "phenotype.hpoa 2026-09-02", "profile_references": [ "ORPHA:1912" ], "profile_evidence_codes": [ "TAS" ], "excluded_features": [], "mimics": [] }, "publish": false, "withheld_because": [ "no Mendelian lookalike with an identifier", "no clinical synopsis written" ] }, { "pair_id": "TC020", "exposure": "statins; AY-9944", "exposure_id": null, "direction": "exposure_mimics_genetic", "embryopathy": null, "embryopathy_id": null, "mimics": [ { "name": "Smith-Lemli-Opitz syndrome and other cholesterol biosynthesis disorders", "id": "OMIM:270400", "genes": [], "resolved": true, "summary": null, "shared_count": 0, "overlap_summary": null } ], "genes": [ "DHCR7", "HMGCR" ], "mechanism_class": "direct_target_inhibition", "teratogenicity": "disputed", "mechanism_confidence": "limited", "citations": [ { "pmid": "15546153", "first_author": "Edison RJ", "year": "2004", "journal": "Am J Med Genet A", "volume": "131", "pages": "287-98", "title": "Mechanistic and epidemiologic considerations in the evaluation of adverse birth outcomes following gestational exposure to statins", "level": "title_supports", "checked": "2026-09-17" } ], "notes": "Candidate. Human teratogenicity of statins is contested; AY-9944 is the animal-model tool compound.", "targets": [], "provenance": { "has_citation": true, "has_pmid": true, "citation_verified": true, "mimic_resolved": true, "has_mimic": true, "has_mechanism_edge": false, "verified_against_primary_source": false }, "clinical": null, "phenotype": { "embryopathy_id": null, "profile": [], "profile_source": null, "profile_references": [], "profile_evidence_codes": [], "excluded_features": [], "mimics": [ { "id": "OMIM:270400", "name": "Smith-Lemli-Opitz syndrome and other cholesterol biosynthesis disorders", "profile_size": 117, "only_in_exposure": [], "only_in_mimic": [], "shared": [], "overlap_summary": null, "comparable": false } ] }, "publish": false, "withheld_because": [ "no phenotype profile", "no clinical synopsis written" ] }, { "pair_id": "TC021", "exposure": "leflunomide", "exposure_id": "CHEBI:6402", "direction": "exposure_mimics_genetic", "embryopathy": null, "embryopathy_id": null, "mimics": [], "genes": [ "DHODH" ], "mechanism_class": "nutrient_antagonism", "teratogenicity": "disputed", "mechanism_confidence": "limited", "citations": [ { "pmid": "27639441", "first_author": "Cassina M", "year": "2017", "journal": "Eur J Med Genet", "volume": "60", "pages": "22-31", "title": "Human teratogens and genetic phenocopies. Understanding pathogenesis through human genes mutation", "level": "title_supports", "checked": "2026-09-17" } ], "notes": "Included in the canonical review, but 2017 Embryotox and 2018 Quebec cohorts were largely negative for human teratogenicity. Retain as a worked example of downgrading.", "targets": [], "provenance": { "has_citation": true, "has_pmid": true, "citation_verified": true, "mimic_resolved": false, "has_mimic": false, "has_mechanism_edge": false, "verified_against_primary_source": false }, "clinical": null, "phenotype": { "embryopathy_id": null, "profile": [], "profile_source": null, "profile_references": [], "profile_evidence_codes": [], "excluded_features": [], "mimics": [] }, "publish": false, "withheld_because": [ "no phenotype profile", "no Mendelian lookalike with an identifier", "no clinical synopsis written" ] } ], "hpo_release": "2026-09-02" }