{"include_drafts":true,"sets":[{"ambiguity":["The rule reads: major criterion 1, plus either major criterion 3, or major criterion 2 together with at least two other minor criteria. The requirement for two minor criteria sits on the same clause as major criterion 2, so it is encoded as applying only to that branch. The stricter alternative would require two minor criteria on both branches. The layout of the source supports the reading encoded here, but a curator should confirm it: it is the one structural decision in this file that could go either way.","Major criterion 1 is congenital BILATERAL hip dislocation. HPO carries congenital hip dislocation but not its laterality, so bilaterality is a verify string. The source notes in a footnote that one molecularly proven patient had unilateral dislocation, so this criterion is not absolute in practice; that is recorded here and not encoded as logic.","Major criterion 2 conjoins severe generalized joint hypermobility with multiple dislocations or subluxations. It is encoded as a composite of both, with \"severe\" and \"multiple\" carried as verify strings. The source's own footnotes define a dislocation as displacement requiring manual reduction, and count sites regardless of laterality.","The mandatory major criterion 1 entails half of the alternative major criterion 2: HP:0001374 (congenital hip dislocation) is a descendant of HP:0001373 (joint dislocation), so any profile satisfying criterion 1 also satisfies the \"dislocations or subluxations\" half of criterion 2 by presence propagation. What separates them in the source is the word \"multiple\", which no HPO term carries, so it sits in a verify string and the item reports as provisionally met until a clinician confirms more than one site. A consequence worth knowing: a test vector cannot exclude joint dislocation while recording a congenital hip dislocation, because the two contradict.","Minor criterion 3 is radiologically mild osteopenia. HPO has one osteopenia term with no severity or modality, so both are carried as a verify string."],"curation":{"encoded_by":"claude-opus-5","notes":"Encoded from the primary. Inheritance is autosomal dominant, so unlike most of this family there is no family-history requirement in the rule.","reviews":[],"source_access":"primary","sources":[{"citation":{"authors":"Malfait F, Francomano C, Byers P, et al.","doi":"10.1002/ajmg.c.31552","journal":"Am J Med Genet C Semin Med Genet","pmid":"28306229","title":"","url":null,"year":2017},"note":"Publisher PDF, read 2026-09-18. The aEDS major and minor criteria, the minimal-criteria rule, and the footnotes defining dislocation and laterality were read directly.","read":true,"role":"primary","title":"Malfait F, et al. The 2017 international classification of the Ehlers-Danlos syndromes"}]},"disease":{"label":"Arthrochalasia Ehlers-Danlos syndrome","mondo":"MONDO:0009159","omim":["130060","617821"],"ordo":"ORPHA:1899"},"id":"aeds_malfait_2017","items":[{"hpo":["HP:0001374"],"id":"congenital_hip_dislocation","label":"Congenital bilateral hip dislocation","paraphrase":null,"rule":null,"source_ref":"aEDS major criterion 1","type":"phenotypic","verify":"Confirm the dislocation is bilateral and congenital. HPO does not carry laterality here. The source records one molecularly proven patient with unilateral dislocation."},{"hpo":["HP:0002761"],"id":"severe_gjh","label":"Severe generalized joint hypermobility","paraphrase":null,"rule":null,"source_ref":"aEDS major criterion 2 (first half)","type":"phenotypic","verify":"Confirm the hypermobility is severe. Assess with the Beighton scale; the source cross-references the classical EDS definition."},{"hpo":["HP:0001373","HP:0032153"],"id":"multiple_dislocations","label":"Multiple dislocations or subluxations","paraphrase":null,"rule":null,"source_ref":"aEDS major criterion 2 (second half)","type":"phenotypic","verify":"Confirm there is more than one. The source defines a dislocation as displacement out of the joint socket severe enough to limit motion and requiring manual reduction, and counts sites regardless of laterality."},{"hpo":[],"id":"gjh_with_dislocations","label":"Severe generalized joint hypermobility with multiple dislocations","paraphrase":null,"rule":{"items":[{"item":"severe_gjh","kind":"item"},{"item":"multiple_dislocations","kind":"item"}],"kind":"all_of"},"source_ref":"aEDS major criterion 2","type":"composite","verify":null},{"hpo":["HP:0000974"],"id":"skin_hyperextensibility","label":"Skin hyperextensibility","paraphrase":null,"rule":null,"source_ref":"aEDS major criterion 3","type":"phenotypic","verify":"Confirm against the standardised cutoffs the source gives for classical EDS, which it cross-references here."},{"hpo":["HP:0001252"],"id":"muscle_hypotonia","label":"Muscle hypotonia","paraphrase":null,"rule":null,"source_ref":"aEDS minor criterion 1","type":"phenotypic","verify":null},{"hpo":["HP:0002751"],"id":"kyphoscoliosis","label":"Kyphoscoliosis","paraphrase":null,"rule":null,"source_ref":"aEDS minor criterion 2","type":"phenotypic","verify":null},{"hpo":["HP:0000938"],"id":"mild_osteopenia","label":"Radiologically mild osteopenia","paraphrase":null,"rule":null,"source_ref":"aEDS minor criterion 3","type":"phenotypic","verify":"Confirm the osteopenia is mild and established radiologically. HPO carries neither the severity nor the modality."},{"hpo":["HP:0001030","HP:0001075","HP:0031158"],"id":"tissue_fragility","label":"Tissue fragility, including atrophic scars","paraphrase":null,"rule":null,"source_ref":"aEDS minor criterion 4","type":"phenotypic","verify":null},{"hpo":["HP:0000978","HP:0031364"],"id":"easy_bruising","label":"Easily bruisable skin","paraphrase":null,"rule":null,"source_ref":"aEDS minor criterion 5","type":"phenotypic","verify":null},{"hpo":[],"id":"two_minor_criteria","label":"At least two minor criteria","paraphrase":null,"rule":{"items":[{"item":"muscle_hypotonia","kind":"item"},{"item":"kyphoscoliosis","kind":"item"},{"item":"mild_osteopenia","kind":"item"},{"item":"tissue_fragility","kind":"item"},{"item":"easy_bruising","kind":"item"}],"k":2,"kind":"n_of"},"source_ref":"aEDS minimal criteria, second branch","type":"composite","verify":null},{"hpo":[],"id":"molecular_confirmation","label":"Pathogenic COL1A1 or COL1A2 variant affecting exon 6 splicing","paraphrase":"The source states confirmatory molecular testing is obligatory to reach a final diagnosis.","rule":null,"source_ref":"aEDS molecular basis","type":"assertable","verify":null},{"hpo":[],"id":"clinical_criteria","label":"Minimal criteria suggestive for aEDS","paraphrase":null,"rule":{"items":[{"item":"congenital_hip_dislocation","kind":"item"},{"items":[{"item":"skin_hyperextensibility","kind":"item"},{"items":[{"item":"gjh_with_dislocations","kind":"item"},{"item":"two_minor_criteria","kind":"item"}],"kind":"all_of"}],"kind":"any_of"}],"kind":"all_of"},"source_ref":"aEDS minimal criteria","type":"composite","verify":null}],"meta":{"citation":{"authors":"Malfait F, Francomano C, Byers P, et al.","doi":"10.1002/ajmg.c.31552","journal":"Am J Med Genet C Semin Med Genet","pmid":"28306229","title":"The 2017 international classification of the Ehlers-Danlos syndromes","url":null,"year":2017},"name":"2017 international classification of the Ehlers-Danlos syndromes, aEDS criteria","standing":"consensus","standing_note":"Part of the 2017 international classification, the consensus nosology for the Ehlers-Danlos syndromes, which defines aEDS with its own criteria.","supersedes":"eds_villefranche_1998","version":"2017"},"source_path":"criteria/aeds_malfait_2017.yaml","tests":[{"asserted":{"molecular_confirmation":true},"confirmed":["congenital_hip_dislocation","skin_hyperextensibility"],"excluded":[],"expect":"met","expect_tier":"Arthrochalasia EDS, molecularly confirmed","name":"hip dislocation plus skin hyperextensibility, with a variant","present":["HP:0001374","HP:0000974"]},{"asserted":{"molecular_confirmation":true},"confirmed":["congenital_hip_dislocation","severe_gjh","multiple_dislocations"],"excluded":["HP:0000974"],"expect":"met","expect_tier":"Arthrochalasia EDS, molecularly confirmed","name":"the other branch: exactly two minor criteria is enough (at the boundary)","present":["HP:0001374","HP:0002761","HP:0001373","HP:0001252","HP:0002751"]},{"asserted":{"molecular_confirmation":true},"confirmed":["congenital_hip_dislocation","severe_gjh","multiple_dislocations"],"excluded":["HP:0000974","HP:0002751","HP:0000938","HP:0001030","HP:0001075","HP:0031158","HP:0000978","HP:0031364"],"expect":"refuted","expect_tier":null,"name":"one minor criterion on the hypermobility branch is one below the boundary","present":["HP:0001374","HP:0002761","HP:0001373","HP:0001252"]},{"asserted":{"molecular_confirmation":true},"confirmed":["skin_hyperextensibility"],"excluded":["HP:0001374"],"expect":"refuted","expect_tier":null,"name":"no congenital hip dislocation refutes both branches","present":["HP:0000974","HP:0002761","HP:0001373"]},{"asserted":{"molecular_confirmation":false},"confirmed":["congenital_hip_dislocation","skin_hyperextensibility"],"excluded":[],"expect":"met","expect_tier":"Clinically suggestive of arthrochalasia EDS","name":"clinical criteria met, molecular testing not done","present":["HP:0001374","HP:0000974"]},{"asserted":{},"confirmed":["congenital_hip_dislocation"],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"hip dislocation alone, everything else unassessed","present":["HP:0001374"]},{"asserted":{},"confirmed":[],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"empty profile","present":[]},{"asserted":{"molecular_confirmation":true},"confirmed":["congenital_hip_dislocation","severe_gjh"],"excluded":["HP:0000974","HP:0001252","HP:0002751","HP:0000938","HP:0001030","HP:0001075","HP:0031158","HP:0000978","HP:0031364"],"expect":"refuted","expect_tier":null,"name":"no minor criteria at all on the hypermobility branch","present":["HP:0001374","HP:0002761"]}],"verdicts":[{"label":"Arthrochalasia EDS, molecularly confirmed","rule":{"items":[{"item":"clinical_criteria","kind":"item"},{"item":"molecular_confirmation","kind":"item"}],"kind":"all_of"},"tier":0},{"label":"Clinically suggestive of arthrochalasia EDS","rule":{"items":[{"item":"clinical_criteria","kind":"item"}],"kind":"all_of"},"tier":1}]},{"ambiguity":["The source contradicts itself on hyperinsulinism. Table 1 defines the cardinal feature as lasting beyond one week AND requiring escalated treatment; Recommendation 5 says beyond one week AND/OR requiring escalated treatment. The conjunction is the harder reading and is what the verify string states, per section 5.1.","Wilms tumour appears twice in Table 1 with different laterality: multifocal or bilateral is cardinal (2 points), unilateral is suggestive (1 point). HPO cannot carry laterality, so both items map to the same term and both will resolve as provisionally met from a profile that simply records nephroblastoma. A human must confirm one and reject the other. Until then the score shown is an upper bound by one point.","\"Genetic testing indicated (>= 2 points)\" is a testing recommendation, not a diagnostic category. It is encoded as the weakest tier so that the tool says something useful below the diagnostic threshold, and labelled as not a diagnosis."],"curation":{"encoded_by":"claude-opus-5","notes":"Encoded from Table 1 and its footnote in the PMC author manuscript. Pass A only.","reviews":[],"source_access":"primary","sources":[]},"disease":{"label":"Beckwith-Wiedemann syndrome","mondo":"MONDO:0007534","omim":["130650"],"ordo":"ORPHA:116"},"id":"bws_brioude_2018","items":[{"hpo":["HP:0000158"],"id":"macroglossia","label":"Macroglossia","paraphrase":null,"rule":null,"source_ref":"Table 1, cardinal feature 1","type":"phenotypic","verify":null},{"hpo":["HP:0001539"],"id":"exomphalos","label":"Exomphalos","paraphrase":null,"rule":null,"source_ref":"Table 1, cardinal feature 2","type":"phenotypic","verify":null},{"hpo":["HP:0001528"],"id":"lateralised_overgrowth","label":"Lateralised overgrowth","paraphrase":null,"rule":null,"source_ref":"Table 1, cardinal feature 3","type":"phenotypic","verify":null},{"hpo":["HP:0002667","HP:0008643"],"id":"multifocal_wilms_or_nephroblastomatosis","label":"Multifocal or bilateral Wilms tumour, or nephroblastomatosis","paraphrase":null,"rule":null,"source_ref":"Table 1, cardinal feature 4","type":"phenotypic","verify":"Confirm the Wilms tumour is multifocal and/or bilateral"},{"hpo":["HP:0000825"],"id":"hyperinsulinism","label":"Hyperinsulinism","paraphrase":null,"rule":null,"source_ref":"Table 1, cardinal feature 5","type":"phenotypic","verify":"Confirm it lasted beyond one week AND required escalated treatment (Table 1 wording; Recommendation 5 says and/or)"},{"hpo":["HP:0008186"],"id":"adrenal_cortex_cytomegaly","label":"Adrenal cortex cytomegaly","paraphrase":null,"rule":null,"source_ref":"Table 1, cardinal feature 6","type":"phenotypic","verify":null},{"hpo":["HP:0032165"],"id":"placental_mesenchymal_dysplasia","label":"Placental mesenchymal dysplasia","paraphrase":null,"rule":null,"source_ref":"Table 1, cardinal feature 6","type":"phenotypic","verify":null},{"hpo":[],"id":"pancreatic_adenomatosis","label":"Pancreatic adenomatosis","paraphrase":"No HPO term for pancreatic adenomatosis.","rule":null,"source_ref":"Table 1, cardinal feature 6","type":"assertable","verify":null},{"hpo":[],"id":"pathology_findings","label":"Pathology findings","paraphrase":null,"rule":{"items":[{"item":"adrenal_cortex_cytomegaly","kind":"item"},{"item":"placental_mesenchymal_dysplasia","kind":"item"},{"item":"pancreatic_adenomatosis","kind":"item"}],"kind":"any_of"},"source_ref":"Table 1, cardinal feature 6","type":"composite","verify":null},{"hpo":["HP:0001520"],"id":"high_birth_weight","label":"Birth weight more than 2 SDS above the mean","paraphrase":null,"rule":null,"source_ref":"Table 1, suggestive feature 1","type":"phenotypic","verify":"Confirm birth weight > 2 SDS above the mean for gestational age"},{"hpo":["HP:0001052"],"id":"facial_naevus_simplex","label":"Facial naevus simplex","paraphrase":null,"rule":null,"source_ref":"Table 1, suggestive feature 2","type":"phenotypic","verify":"Confirm the naevus simplex is facial"},{"hpo":["HP:0001561"],"id":"polyhydramnios","label":"Polyhydramnios","paraphrase":null,"rule":null,"source_ref":"Table 1, suggestive feature 3","type":"phenotypic","verify":null},{"hpo":[],"id":"placentomegaly","label":"Placentomegaly","paraphrase":"HPO's placental terms cover morphology and small placenta but not placentomegaly specifically.","rule":null,"source_ref":"Table 1, suggestive feature 3","type":"assertable","verify":null},{"hpo":[],"id":"polyhydramnios_or_placentomegaly","label":"Polyhydramnios and/or placentomegaly","paraphrase":null,"rule":{"items":[{"item":"polyhydramnios","kind":"item"},{"item":"placentomegaly","kind":"item"}],"kind":"any_of"},"source_ref":"Table 1, suggestive feature 3","type":"composite","verify":null},{"hpo":["HP:0004467"],"id":"ear_pits","label":"Ear pits","paraphrase":null,"rule":null,"source_ref":"Table 1, suggestive feature 4","type":"phenotypic","verify":null},{"hpo":[],"id":"ear_creases","label":"Ear creases","paraphrase":"HPO has no term for the anterior ear-lobe creases of BWS.","rule":null,"source_ref":"Table 1, suggestive feature 4","type":"assertable","verify":null},{"hpo":[],"id":"ear_creases_or_pits","label":"Ear creases and/or pits","paraphrase":null,"rule":{"items":[{"item":"ear_creases","kind":"item"},{"item":"ear_pits","kind":"item"}],"kind":"any_of"},"source_ref":"Table 1, suggestive feature 4","type":"composite","verify":null},{"hpo":["HP:0001943"],"id":"transient_hypoglycaemia","label":"Transient hypoglycaemia","paraphrase":null,"rule":null,"source_ref":"Table 1, suggestive feature 5","type":"phenotypic","verify":"Confirm the hypoglycaemia lasted less than a week"},{"hpo":["HP:0003006"],"id":"neuroblastoma","label":"Neuroblastoma","paraphrase":null,"rule":null,"source_ref":"Table 1, suggestive feature 6","type":"phenotypic","verify":null},{"hpo":["HP:0002859"],"id":"rhabdomyosarcoma","label":"Rhabdomyosarcoma","paraphrase":null,"rule":null,"source_ref":"Table 1, suggestive feature 6","type":"phenotypic","verify":null},{"hpo":["HP:0002667"],"id":"unilateral_wilms","label":"Unilateral Wilms tumour","paraphrase":null,"rule":null,"source_ref":"Table 1, suggestive feature 6","type":"phenotypic","verify":"Confirm the Wilms tumour is unilateral (not the cardinal feature)"},{"hpo":["HP:0002884"],"id":"hepatoblastoma","label":"Hepatoblastoma","paraphrase":null,"rule":null,"source_ref":"Table 1, suggestive feature 6","type":"phenotypic","verify":null},{"hpo":["HP:0006744"],"id":"adrenocortical_carcinoma","label":"Adrenocortical carcinoma","paraphrase":null,"rule":null,"source_ref":"Table 1, suggestive feature 6","type":"phenotypic","verify":null},{"hpo":["HP:0002666"],"id":"phaeochromocytoma","label":"Phaeochromocytoma","paraphrase":null,"rule":null,"source_ref":"Table 1, suggestive feature 6","type":"phenotypic","verify":null},{"hpo":[],"id":"typical_bwsp_tumour","label":"Typical BWSp tumour","paraphrase":null,"rule":{"items":[{"item":"neuroblastoma","kind":"item"},{"item":"rhabdomyosarcoma","kind":"item"},{"item":"unilateral_wilms","kind":"item"},{"item":"hepatoblastoma","kind":"item"},{"item":"adrenocortical_carcinoma","kind":"item"},{"item":"phaeochromocytoma","kind":"item"}],"kind":"any_of"},"source_ref":"Table 1, suggestive feature 6","type":"composite","verify":null},{"hpo":["HP:0000105","HP:0002240"],"id":"nephromegaly_or_hepatomegaly","label":"Nephromegaly and/or hepatomegaly","paraphrase":null,"rule":null,"source_ref":"Table 1, suggestive feature 7","type":"phenotypic","verify":null},{"hpo":["HP:0001537","HP:0001540"],"id":"umbilical_hernia_or_diastasis_recti","label":"Umbilical hernia and/or diastasis recti","paraphrase":null,"rule":null,"source_ref":"Table 1, suggestive feature 8","type":"phenotypic","verify":null}],"meta":{"citation":{"authors":"Brioude F, Kalish JM, Mussa A, et al.","doi":"10.1038/nrendo.2017.166","journal":"Nat Rev Endocrinol","pmid":"29377879","title":"Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC6022848/","year":2018},"name":"Beckwith-Wiedemann spectrum international consensus scoring system","standing":"consensus","standing_note":"The publication is titled an \"Expert consensus document\" and the scoring system is its Table 1. Evidence basis: the source's own title and framing.","supersedes":null,"version":"2018"},"source_path":"criteria/bws_brioude_2018.yaml","tests":[{"asserted":{},"confirmed":[],"excluded":[],"expect":"met","expect_tier":"Classical BWS (clinical diagnosis, score >= 4)","name":"two cardinal features reach exactly the diagnostic threshold","present":["HP:0000158","HP:0001539"]},{"asserted":{},"confirmed":["facial_naevus_simplex"],"excluded":[],"expect":"met","expect_tier":"Classical BWS (clinical diagnosis, score >= 4)","name":"one cardinal plus two suggestive features scores exactly 4","present":["HP:0000158","HP:0001052","HP:0001561"]},{"asserted":{"ear_creases":false,"pancreatic_adenomatosis":false,"placentomegaly":false},"confirmed":[],"excluded":["HP:0001539","HP:0001528","HP:0002667","HP:0008643","HP:0000825","HP:0008186","HP:0032165","HP:0001520","HP:0001052","HP:0004467","HP:0001943","HP:0003006","HP:0002859","HP:0002884","HP:0006744","HP:0002666","HP:0000105","HP:0002240","HP:0001537","HP:0001540"],"expect":"met","expect_tier":"Score >= 2 (below the 4 required for a clinical diagnosis)","name":"one cardinal plus one suggestive scores 3, one short of diagnosis","present":["HP:0000158","HP:0001561"]},{"asserted":{"ear_creases":false,"pancreatic_adenomatosis":false,"placentomegaly":false},"confirmed":[],"excluded":["HP:0000158","HP:0001539","HP:0001528","HP:0002667","HP:0008643","HP:0000825","HP:0008186","HP:0032165","HP:0001520","HP:0001052","HP:0004467","HP:0001943","HP:0003006","HP:0002859","HP:0002884","HP:0006744","HP:0002666","HP:0000105","HP:0002240","HP:0001537","HP:0001540"],"expect":"refuted","expect_tier":null,"name":"one suggestive feature only scores 1, below the testing threshold","present":["HP:0001561"]},{"asserted":{"ear_creases":false,"pancreatic_adenomatosis":false,"placentomegaly":false},"confirmed":[],"excluded":["HP:0000158","HP:0001539","HP:0001528","HP:0002667","HP:0008643","HP:0000825","HP:0008186","HP:0032165","HP:0001561","HP:0001520","HP:0001052","HP:0004467","HP:0001943","HP:0003006","HP:0002859","HP:0002884","HP:0006744","HP:0002666","HP:0000105","HP:0002240","HP:0001537","HP:0001540"],"expect":"refuted","expect_tier":null,"name":"nothing present","present":[]},{"asserted":{},"confirmed":[],"excluded":[],"expect":"met","expect_tier":"Score >= 2 (below the 4 required for a clinical diagnosis)","name":"one cardinal feature with everything else unassessed","present":["HP:0000158"]},{"asserted":{},"confirmed":[],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"one suggestive feature with everything else unassessed","present":["HP:0001561"]},{"asserted":{},"confirmed":[],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"empty profile","present":[]},{"asserted":{"ear_creases":false,"pancreatic_adenomatosis":false,"placentomegaly":false},"confirmed":[],"excluded":["HP:0000158","HP:0001539","HP:0001528","HP:0002667","HP:0008643","HP:0000825","HP:0008186","HP:0032165","HP:0001561","HP:0001520","HP:0001052","HP:0004467","HP:0001943","HP:0006744","HP:0002666","HP:0000105","HP:0002240","HP:0001537","HP:0001540"],"expect":"refuted","expect_tier":null,"name":"a composite suggestive feature scores once however many limbs are present","present":["HP:0003006","HP:0002859","HP:0002884"]}],"verdicts":[{"label":"Classical BWS (clinical diagnosis, score >= 4)","rule":{"kind":"score","threshold":4,"weights":[{"node":{"item":"macroglossia","kind":"item"},"w":2},{"node":{"item":"exomphalos","kind":"item"},"w":2},{"node":{"item":"lateralised_overgrowth","kind":"item"},"w":2},{"node":{"item":"multifocal_wilms_or_nephroblastomatosis","kind":"item"},"w":2},{"node":{"item":"hyperinsulinism","kind":"item"},"w":2},{"node":{"item":"pathology_findings","kind":"item"},"w":2},{"node":{"item":"high_birth_weight","kind":"item"},"w":1},{"node":{"item":"facial_naevus_simplex","kind":"item"},"w":1},{"node":{"item":"polyhydramnios_or_placentomegaly","kind":"item"},"w":1},{"node":{"item":"ear_creases_or_pits","kind":"item"},"w":1},{"node":{"item":"transient_hypoglycaemia","kind":"item"},"w":1},{"node":{"item":"typical_bwsp_tumour","kind":"item"},"w":1},{"node":{"item":"nephromegaly_or_hepatomegaly","kind":"item"},"w":1},{"node":{"item":"umbilical_hernia_or_diastasis_recti","kind":"item"},"w":1}]},"tier":0},{"label":"Score >= 2 (below the 4 required for a clinical diagnosis)","rule":{"kind":"score","threshold":2,"weights":[{"node":{"item":"macroglossia","kind":"item"},"w":2},{"node":{"item":"exomphalos","kind":"item"},"w":2},{"node":{"item":"lateralised_overgrowth","kind":"item"},"w":2},{"node":{"item":"multifocal_wilms_or_nephroblastomatosis","kind":"item"},"w":2},{"node":{"item":"hyperinsulinism","kind":"item"},"w":2},{"node":{"item":"pathology_findings","kind":"item"},"w":2},{"node":{"item":"high_birth_weight","kind":"item"},"w":1},{"node":{"item":"facial_naevus_simplex","kind":"item"},"w":1},{"node":{"item":"polyhydramnios_or_placentomegaly","kind":"item"},"w":1},{"node":{"item":"ear_creases_or_pits","kind":"item"},"w":1},{"node":{"item":"transient_hypoglycaemia","kind":"item"},"w":1},{"node":{"item":"typical_bwsp_tumour","kind":"item"},"w":1},{"node":{"item":"nephromegaly_or_hepatomegaly","kind":"item"},"w":1},{"node":{"item":"umbilical_hernia_or_diastasis_recti","kind":"item"},"w":1}]},"tier":1}]},{"ambiguity":["GeneReviews lists the suggestive findings as two bullets joined by the word \"OR\": \"Major criteria skin hyperextensibility and atrophic scarring\" OR \"Major criterion generalized joint hypermobility (GJH) and/or >=3 minor criteria\". Read literally as a disjunction, generalized joint hypermobility alone would make cEDS suspected, which would make cEDS indistinguishable from ordinary hypermobility on clinical grounds. The alternative reading is that the first major criterion is mandatory and the second bullet is what must accompany it. Per the curation protocol the conservative reading is encoded: skin hyperextensibility AND atrophic scarring are both required, PLUS either GJH or three minor criteria. A curator who obtains Malfait 2017 must check this; it is the single most consequential decision in this file and it was made without the primary.","\"Complications of joint hypermobility\" is exemplified in the source as sprains, dislocations/subluxations, pain and flexible flat foot. HPO has terms for dislocation, subluxation and pes planus but not for sprains or for joint pain arising specifically from hypermobility, so the item lists the three mappable alternatives and carries a verify string naming the two that are not. This makes the item slightly harder to satisfy from a profile alone than the source intends, which is the safe direction.","Skin hyperextensibility and generalized joint hypermobility both carry measurement definitions in the source (standardised stretch cutoffs at named sites; Beighton score >=5). HPO terms cannot carry either, so both are verify strings and the items report as provisionally met until a clinician confirms the measurement."],"curation":{"encoded_by":"claude-opus-5","notes":"Encoded from the GeneReviews chapter, not from Malfait 2017, which could not be obtained. The chapter is an expert reproduction by the primary's own first author, which is the strongest form of expert_secondary available, but it is still a reproduction and it renders the combination rule in a way that is open to two readings. See the first ambiguity note.\nRECONCILED against the primary, 2026-09-18. The primary states the rule as \"Major criterion (1): skin hyperextensibility and atrophic scarring / Plus / Either major criterion (2): GJH / And/or: at least three minor criteria\". The conservative reading encoded from GeneReviews was therefore correct: major criterion 1 is mandatory. GeneReviews renders the same rule as two bullets joined by \"OR\", which is a genuine distortion of the source, and had the conservative reading not been taken this file would have reported cEDS as suspected on generalized joint hypermobility alone.","reviews":[],"source_access":"primary","sources":[{"citation":{"authors":"Malfait F, Francomano C, Byers P, et al.","doi":"10.1002/ajmg.c.31552","journal":"Am J Med Genet C Semin Med Genet","pmid":"28306229","title":"","url":null,"year":2017},"note":"Obtained 2026-09-18 as the publisher PDF and read. This is now the source of record for the rule; the GeneReviews chapter below is retained because it was the basis of the original encoding and because the reconciliation against it is informative.","read":true,"role":"primary","title":"Malfait F, et al. The 2017 international classification of the Ehlers-Danlos syndromes"},{"citation":{"authors":"Malfait F, Symoens S, Syx D","doi":null,"journal":"GeneReviews, University of Washington, Seattle","pmid":null,"title":"","url":"https://www.ncbi.nlm.nih.gov/books/NBK1244/","year":2024},"note":"Reproduces both major criteria, all nine minor criteria and the molecular requirement, and is written by the first author of the 2017 classification. Source of every item and rule in this file. Read 2026-09-17 against the 2024-02-01 update.","read":true,"role":"reproduces","title":"GeneReviews: Classic Ehlers-Danlos Syndrome"}]},"disease":{"label":"Classical Ehlers-Danlos syndrome","mondo":"MONDO:0007522","omim":["130000","130010"],"ordo":"ORPHA:287"},"id":"ceds_malfait_2017","items":[{"hpo":["HP:0000974"],"id":"skin_hyperextensibility","label":"Skin hyperextensibility","paraphrase":"Skin that stretches beyond a standardised cutoff at named sites","rule":null,"source_ref":"Major criteria, item 1","type":"phenotypic","verify":"Confirm by pinching and lifting skin on the volar surface at the middle of the non-dominant forearm: hyperextensible if it stretches past the cutoff in three of 1.5 cm (distal forearms, dorsum of hands) or 3 cm (neck, elbows, knees)."},{"hpo":["HP:0001075"],"id":"atrophic_scarring","label":"Atrophic scarring","paraphrase":null,"rule":null,"source_ref":"Major criteria, item 2","type":"phenotypic","verify":null},{"hpo":["HP:0002761"],"id":"generalized_joint_hypermobility","label":"Generalized joint hypermobility","paraphrase":null,"rule":null,"source_ref":"Major criteria, item 3","type":"phenotypic","verify":"Confirm with the Beighton scale; a score of 5 or more is positive. In adults with a score below 5, the five-point questionnaire may be used, where 2 or more \"yes\" answers suggests hypermobility."},{"hpo":["HP:0000978"],"id":"easy_bruising","label":"Easy bruising","paraphrase":null,"rule":null,"source_ref":"Minor criteria, item 1","type":"phenotypic","verify":null},{"hpo":["HP:0001027"],"id":"soft_doughy_skin","label":"Soft, doughy skin","paraphrase":null,"rule":null,"source_ref":"Minor criteria, item 2","type":"phenotypic","verify":null},{"hpo":["HP:0001030"],"id":"skin_fragility","label":"Skin fragility","paraphrase":"Skin fragility, or traumatic splitting","rule":null,"source_ref":"Minor criteria, item 3","type":"phenotypic","verify":null},{"hpo":["HP:0000993"],"id":"molluscoid_pseudotumors","label":"Molluscoid pseudotumors","paraphrase":null,"rule":null,"source_ref":"Minor criteria, item 4","type":"phenotypic","verify":null},{"hpo":["HP:0025014"],"id":"subcutaneous_spheroids","label":"Subcutaneous spheroids","paraphrase":null,"rule":null,"source_ref":"Minor criteria, item 5","type":"phenotypic","verify":null},{"hpo":["HP:0100790"],"id":"hernia","label":"Hernia","paraphrase":"Hernia, or a history of one","rule":null,"source_ref":"Minor criteria, item 6","type":"phenotypic","verify":null},{"hpo":["HP:0000286"],"id":"epicanthal_folds","label":"Epicanthal folds","paraphrase":null,"rule":null,"source_ref":"Minor criteria, item 7","type":"phenotypic","verify":null},{"hpo":["HP:0001373","HP:0032153","HP:0001763"],"id":"hypermobility_complications","label":"Complications of joint hypermobility","paraphrase":"Sprains, dislocations or subluxations, pain, flexible flat foot","rule":null,"source_ref":"Minor criteria, item 8","type":"phenotypic","verify":"Sprains and hypermobility-related joint pain are named in the source but have no HPO term, so they cannot be picked up from a profile. Confirm directly if either is the complication present."},{"hpo":[],"id":"family_history_ceds","label":"Family history of classical EDS in a first-degree relative","paraphrase":"A first-degree relative who meets these diagnostic criteria","rule":null,"source_ref":"Minor criteria, item 9","type":"assertable","verify":null},{"hpo":[],"id":"molecular_confirmation","label":"Pathogenic COL1A1, COL5A1 or COL5A2 variant","paraphrase":"A heterozygous pathogenic or likely pathogenic variant in COL1A1, COL5A1 or COL5A2 identified by molecular genetic testing","rule":null,"source_ref":"Establishing the Diagnosis","type":"assertable","verify":null},{"hpo":[],"id":"major_criterion_1","label":"Skin hyperextensibility with atrophic scarring","paraphrase":null,"rule":{"items":[{"item":"skin_hyperextensibility","kind":"item"},{"item":"atrophic_scarring","kind":"item"}],"kind":"all_of"},"source_ref":"Major criteria, items 1 and 2 taken together","type":"composite","verify":null},{"hpo":[],"id":"three_minor_criteria","label":"At least three minor criteria","paraphrase":null,"rule":{"items":[{"item":"easy_bruising","kind":"item"},{"item":"soft_doughy_skin","kind":"item"},{"item":"skin_fragility","kind":"item"},{"item":"molluscoid_pseudotumors","kind":"item"},{"item":"subcutaneous_spheroids","kind":"item"},{"item":"hernia","kind":"item"},{"item":"epicanthal_folds","kind":"item"},{"item":"hypermobility_complications","kind":"item"},{"item":"family_history_ceds","kind":"item"}],"k":3,"kind":"n_of"},"source_ref":"Minor criteria","type":"composite","verify":null},{"hpo":[],"id":"clinically_suggestive","label":"Clinical criteria for cEDS","paraphrase":null,"rule":{"items":[{"item":"major_criterion_1","kind":"item"},{"items":[{"item":"generalized_joint_hypermobility","kind":"item"},{"item":"three_minor_criteria","kind":"item"}],"kind":"any_of"}],"kind":"all_of"},"source_ref":"Suggestive Findings","type":"composite","verify":null}],"meta":{"citation":{"authors":"Malfait F, Francomano C, Byers P, et al.","doi":"10.1002/ajmg.c.31552","journal":"Am J Med Genet C Semin Med Genet","pmid":"28306229","title":"The 2017 international classification of the Ehlers-Danlos syndromes","url":null,"year":2017},"name":"2017 international classification of the Ehlers-Danlos syndromes, cEDS criteria","standing":"consensus","standing_note":"GeneReviews (Classic Ehlers-Danlos Syndrome, NBK1244, last updated 2024-02-01, authored by Malfait, Symoens and Syx) states there are \"consensus clinical diagnostic criteria for classic Ehlers-Danlos syndrome (cEDS); diagnosis requires molecular testing\". Fransiska Malfait is first author of the 2017 classification these criteria come from.","supersedes":"eds_villefranche_1998","version":"2017"},"source_path":"criteria/ceds_malfait_2017.yaml","tests":[{"asserted":{"molecular_confirmation":true},"confirmed":["skin_hyperextensibility","generalized_joint_hypermobility"],"excluded":[],"expect":"met","expect_tier":"Classical EDS, molecularly confirmed","name":"both major criteria plus GJH, with a variant","present":["HP:0000974","HP:0001075","HP:0002761"]},{"asserted":{"molecular_confirmation":true},"confirmed":["skin_hyperextensibility"],"excluded":["HP:0002761"],"expect":"met","expect_tier":"Classical EDS, molecularly confirmed","name":"exactly three minor criteria is enough (at the boundary)","present":["HP:0000974","HP:0001075","HP:0000978","HP:0001027","HP:0100790"]},{"asserted":{"family_history_ceds":false,"molecular_confirmation":true},"confirmed":["skin_hyperextensibility"],"excluded":["HP:0002761","HP:0001030","HP:0000993","HP:0025014","HP:0100790","HP:0000286","HP:0001373","HP:0032153","HP:0001763"],"expect":"refuted","expect_tier":null,"name":"two minor criteria and no GJH is one below the boundary","present":["HP:0000974","HP:0001075","HP:0000978","HP:0001027"]},{"asserted":{},"confirmed":["generalized_joint_hypermobility"],"excluded":["HP:0000974","HP:0001075"],"expect":"refuted","expect_tier":null,"name":"GJH alone does not suggest cEDS under the conservative reading","present":["HP:0002761"]},{"asserted":{"molecular_confirmation":false},"confirmed":["skin_hyperextensibility","generalized_joint_hypermobility"],"excluded":[],"expect":"met","expect_tier":"Clinically suggestive of classical EDS","name":"clinical criteria met but no variant found","present":["HP:0000974","HP:0001075","HP:0002761"]},{"asserted":{},"confirmed":["skin_hyperextensibility"],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"both major criteria, everything else unassessed","present":["HP:0000974","HP:0001075"]},{"asserted":{},"confirmed":[],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"empty profile","present":[]},{"asserted":{"molecular_confirmation":true},"confirmed":["skin_hyperextensibility","generalized_joint_hypermobility"],"excluded":["HP:0001075"],"expect":"refuted","expect_tier":null,"name":"atrophic scarring excluded refutes the mandatory major criterion","present":["HP:0000974","HP:0002761","HP:0000978","HP:0001027","HP:0001030"]},{"asserted":{},"confirmed":["skin_hyperextensibility"],"excluded":["HP:0002761"],"expect":"indeterminate","expect_tier":null,"name":"minor criteria open, major criteria met: still reachable","present":["HP:0000974","HP:0001075","HP:0000978"]}],"verdicts":[{"label":"Classical EDS, molecularly confirmed","rule":{"items":[{"item":"clinically_suggestive","kind":"item"},{"item":"molecular_confirmation","kind":"item"}],"kind":"all_of"},"tier":0},{"label":"Clinically suggestive of classical EDS","rule":{"items":[{"item":"clinically_suggestive","kind":"item"}],"kind":"all_of"},"tier":1}]},{"ambiguity":["The source contradicts itself on the two-major route to a typical diagnosis. Table II says two of three major signs plus two of five minor signs; the body text says \"If 2/3 major elements are present, CHARGE can be diagnosed if at least 3/5 minor traits are present\". The three-minor reading is the harder one and is encoded here per section 5.1, which means a patient with two majors and exactly two minors falls to the partial tier rather than the typical tier. The Table II reading is the one usually reproduced downstream, so this choice must be confirmed by a Pass B curator and may need to change.","Verloes narrows several minor criteria in the body text: delayed growth counts only if it results from growth hormone deficiency; genital anomalies only with demonstrable central endocrine disturbance; inner ear malformations are excluded from the ear criterion because the semicircular canals are already a major sign. The narrowed readings are encoded.","\"Rhombencephalic dysfunction\" is a functional category covering brainstem dysfunction and cranial nerve VII to XII palsies. It is encoded as an alternation over the specific HPO terms the source names rather than mapped to a single broad brainstem term."],"curation":{"encoded_by":"claude-opus-5","notes":"Encoded from Tables I and II of the primary publication, with the body text consulted for the minor-criterion definitions. Blake et al. 1998 is the other candidate criteria set for CHARGE; it is paywalled, was not read, and would be a separate file (charge_blake_1998) rather than a revision of this one.","reviews":[],"source_access":"primary","sources":[]},"disease":{"label":"CHARGE syndrome","mondo":"MONDO:0008965","omim":["214800"],"ordo":"ORPHA:138"},"id":"charge_verloes_2005","items":[{"hpo":["HP:0000612","HP:0000567","HP:0000588"],"id":"coloboma","label":"Coloboma","paraphrase":"Coloboma of iris or choroid, with or without microphthalmia","rule":null,"source_ref":"Table I, major sign 1","type":"phenotypic","verify":null},{"hpo":["HP:0000453","HP:0000452"],"id":"choanal_atresia","label":"Atresia of choanae","paraphrase":null,"rule":null,"source_ref":"Table I, major sign 2","type":"phenotypic","verify":null},{"hpo":["HP:0011382","HP:0011381"],"id":"hypoplastic_semicircular_canals","label":"Hypoplastic semicircular canals","paraphrase":null,"rule":null,"source_ref":"Table I, major sign 3","type":"phenotypic","verify":null},{"hpo":["HP:0006824","HP:0010628"],"id":"cranial_nerve_palsy","label":"Cranial nerve palsy","paraphrase":null,"rule":null,"source_ref":"Table I, minor sign 1","type":"phenotypic","verify":null},{"hpo":["HP:0000407"],"id":"sensorineural_hearing_loss","label":"Neurosensory deafness","paraphrase":null,"rule":null,"source_ref":"Table I, minor sign 1","type":"phenotypic","verify":null},{"hpo":["HP:0000220"],"id":"velopharyngeal_incoordination","label":"Velopharyngeal incoordination","paraphrase":"One manifestation of the brainstem dysfunction the criterion names. The criterion is broader than this term; the other named manifestations are the cranial nerve and hearing items beside it. There is no single HPO term for \"rhombencephalic dysfunction\", so the criterion is encoded as an alternation over the manifestations the source lists rather than mapped to one broad term.","rule":null,"source_ref":"Table I, minor sign 1","type":"phenotypic","verify":null},{"hpo":[],"id":"rhombencephalic_dysfunction","label":"Rhombencephalic dysfunction","paraphrase":null,"rule":{"items":[{"item":"cranial_nerve_palsy","kind":"item"},{"item":"sensorineural_hearing_loss","kind":"item"},{"item":"velopharyngeal_incoordination","kind":"item"}],"kind":"any_of"},"source_ref":"Table I, minor sign 1","type":"composite","verify":null},{"hpo":["HP:0000044"],"id":"gonadotrophin_deficiency","label":"Gonadotrophin deficiency","paraphrase":null,"rule":null,"source_ref":"Table I, minor sign 2","type":"phenotypic","verify":"Genital anomalies count only when sustained by a demonstrable central-onset endocrine disturbance"},{"hpo":["HP:0034323","HP:0008240"],"id":"growth_hormone_deficiency","label":"Growth hormone deficiency","paraphrase":null,"rule":null,"source_ref":"Table I, minor sign 2","type":"phenotypic","verify":"Delayed growth counts only if it results from growth hormone deficiency"},{"hpo":[],"id":"hypothalamo_hypophyseal_dysfunction","label":"Hypothalamo-hypophyseal dysfunction","paraphrase":null,"rule":{"items":[{"item":"gonadotrophin_deficiency","kind":"item"},{"item":"growth_hormone_deficiency","kind":"item"}],"kind":"any_of"},"source_ref":"Table I, minor sign 2","type":"composite","verify":null},{"hpo":["HP:0008609"],"id":"middle_ear_malformation","label":"Abnormal middle ear","paraphrase":null,"rule":null,"source_ref":"Table I, minor sign 3","type":"phenotypic","verify":"Inner ear malformations are excluded from this criterion"},{"hpo":["HP:0000377","HP:0008772"],"id":"external_ear_malformation","label":"Abnormal external ear","paraphrase":null,"rule":null,"source_ref":"Table I, minor sign 3","type":"phenotypic","verify":null},{"hpo":[],"id":"ear_malformation","label":"Abnormal middle or external ear","paraphrase":null,"rule":{"items":[{"item":"middle_ear_malformation","kind":"item"},{"item":"external_ear_malformation","kind":"item"}],"kind":"any_of"},"source_ref":"Table I, minor sign 3","type":"composite","verify":null},{"hpo":["HP:0001627"],"id":"cardiac_malformation","label":"Cardiac malformation","paraphrase":null,"rule":null,"source_ref":"Table I, minor sign 4","type":"phenotypic","verify":null},{"hpo":["HP:0002032"],"id":"oesophageal_malformation","label":"Oesophageal malformation","paraphrase":null,"rule":null,"source_ref":"Table I, minor sign 4","type":"phenotypic","verify":null},{"hpo":[],"id":"mediastinal_malformation","label":"Malformation of mediastinal organs","paraphrase":"Heart defect and oesophageal atresia are counted once between them","rule":{"items":[{"item":"cardiac_malformation","kind":"item"},{"item":"oesophageal_malformation","kind":"item"}],"kind":"any_of"},"source_ref":"Table I, minor sign 4","type":"composite","verify":null},{"hpo":["HP:0001249","HP:0001263"],"id":"intellectual_disability","label":"Mental retardation","paraphrase":null,"rule":null,"source_ref":"Table I, minor sign 5","type":"phenotypic","verify":null}],"meta":{"citation":{"authors":"Verloes A","doi":"10.1002/ajmg.a.30559","journal":"Am J Med Genet A","pmid":"15666308","title":"Updated diagnostic criteria for CHARGE syndrome: a proposal","url":"https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.30559","year":2005},"name":"Verloes updated diagnostic criteria for CHARGE syndrome","standing":"proposed","standing_note":"NOT consensus. The publication titles itself \"Updated diagnostic criteria for CHARGE syndrome: a proposal\", so the source presents these criteria as a proposal rather than an agreed standard. It also does not displace Blake et al. 1998, which remains widely cited and which this repository records as a separate candidate criteria set (see curation.notes). A user should read a verdict here as \"meets the Verloes 2005 proposal\", not as \"has CHARGE syndrome\". Evidence basis: the source's own title.","supersedes":"charge_blake_1998","version":"2005"},"source_path":"criteria/charge_verloes_2005.yaml","tests":[{"asserted":{},"confirmed":[],"excluded":[],"expect":"met","expect_tier":"Typical CHARGE","name":"all three major signs","present":["HP:0000612","HP:0000453","HP:0011382"]},{"asserted":{},"confirmed":["gonadotrophin_deficiency"],"excluded":[],"expect":"met","expect_tier":"Typical CHARGE","name":"two major signs plus exactly three minor signs","present":["HP:0000612","HP:0000453","HP:0006824","HP:0000044","HP:0008609"]},{"asserted":{},"confirmed":["middle_ear_malformation"],"excluded":["HP:0006824","HP:0010628","HP:0000407","HP:0000220","HP:0000044","HP:0034323","HP:0008240","HP:0001627","HP:0002032","HP:0001249","HP:0001263"],"expect":"met","expect_tier":"Partial (incomplete) CHARGE","name":"two major signs plus exactly one minor sign is partial","present":["HP:0000612","HP:0000453","HP:0008609"]},{"asserted":{},"confirmed":[],"excluded":["HP:0006824","HP:0010628","HP:0000407","HP:0000220","HP:0000044","HP:0034323","HP:0008240","HP:0008609","HP:0000377","HP:0008772","HP:0001627","HP:0002032","HP:0001249","HP:0001263"],"expect":"met","expect_tier":"Atypical CHARGE","name":"two major signs and no minor signs is atypical","present":["HP:0000612","HP:0000453"]},{"asserted":{},"confirmed":["middle_ear_malformation"],"excluded":["HP:0000453","HP:0000452","HP:0011382","HP:0011381","HP:0006824","HP:0010628","HP:0000407","HP:0000220","HP:0000044","HP:0034323","HP:0008240","HP:0001249","HP:0001263"],"expect":"refuted","expect_tier":null,"name":"one major sign plus two minor signs falls short of every tier","present":["HP:0000612","HP:0008609","HP:0001627"]},{"asserted":{},"confirmed":[],"excluded":["HP:0000612","HP:0000567","HP:0000588","HP:0000453","HP:0000452","HP:0011382","HP:0011381"],"expect":"refuted","expect_tier":null,"name":"no major signs","present":["HP:0008609","HP:0001627","HP:0001249"]},{"asserted":{},"confirmed":[],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"one major sign with everything else unassessed","present":["HP:0000612"]},{"asserted":{},"confirmed":[],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"empty profile","present":[]},{"asserted":{},"confirmed":[],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"two major signs with the minor signs unassessed","present":["HP:0000612","HP:0000453"]}],"verdicts":[{"label":"Typical CHARGE","rule":{"items":[{"items":[{"item":"coloboma","kind":"item"},{"item":"choanal_atresia","kind":"item"},{"item":"hypoplastic_semicircular_canals","kind":"item"}],"kind":"all_of"},{"items":[{"items":[{"item":"coloboma","kind":"item"},{"item":"choanal_atresia","kind":"item"},{"item":"hypoplastic_semicircular_canals","kind":"item"}],"k":2,"kind":"n_of"},{"items":[{"item":"rhombencephalic_dysfunction","kind":"item"},{"item":"hypothalamo_hypophyseal_dysfunction","kind":"item"},{"item":"ear_malformation","kind":"item"},{"item":"mediastinal_malformation","kind":"item"},{"item":"intellectual_disability","kind":"item"}],"k":3,"kind":"n_of"}],"kind":"all_of"}],"kind":"any_of"},"tier":0},{"label":"Partial (incomplete) CHARGE","rule":{"items":[{"items":[{"item":"coloboma","kind":"item"},{"item":"choanal_atresia","kind":"item"},{"item":"hypoplastic_semicircular_canals","kind":"item"}],"k":2,"kind":"n_of"},{"items":[{"item":"rhombencephalic_dysfunction","kind":"item"},{"item":"hypothalamo_hypophyseal_dysfunction","kind":"item"},{"item":"ear_malformation","kind":"item"},{"item":"mediastinal_malformation","kind":"item"},{"item":"intellectual_disability","kind":"item"}],"k":1,"kind":"n_of"}],"kind":"all_of"},"tier":1},{"label":"Atypical CHARGE","rule":{"items":[{"items":[{"items":[{"item":"coloboma","kind":"item"},{"item":"choanal_atresia","kind":"item"},{"item":"hypoplastic_semicircular_canals","kind":"item"}],"k":2,"kind":"n_of"},{"items":[{"item":"rhombencephalic_dysfunction","kind":"item"},{"item":"hypothalamo_hypophyseal_dysfunction","kind":"item"},{"item":"ear_malformation","kind":"item"},{"item":"mediastinal_malformation","kind":"item"},{"item":"intellectual_disability","kind":"item"}],"kind":"none_of"}],"kind":"all_of"},{"items":[{"items":[{"item":"coloboma","kind":"item"},{"item":"choanal_atresia","kind":"item"},{"item":"hypoplastic_semicircular_canals","kind":"item"}],"k":1,"kind":"n_of"},{"items":[{"item":"rhombencephalic_dysfunction","kind":"item"},{"item":"hypothalamo_hypophyseal_dysfunction","kind":"item"},{"item":"ear_malformation","kind":"item"},{"item":"mediastinal_malformation","kind":"item"},{"item":"intellectual_disability","kind":"item"}],"k":3,"kind":"n_of"}],"kind":"all_of"}],"kind":"any_of"},"tier":2}]},{"ambiguity":["The first major criterion is a conjunction that includes a negative: skin hyperextensibility with a velvety texture AND the ABSENCE of atrophic scarring. The absence is what separates clEDS from classical EDS, so it is encoded as logic (a none_of over atrophic scarring) rather than as a note. A profile that records atrophic scarring therefore refutes this criterion outright, which is the source's intent.","HPO has no term for a velvety skin texture. The item maps to skin hyperextensibility and carries the texture as a verify string, so it reads as provisionally met until a clinician confirms it. This makes the item easier to satisfy from a profile alone than the source intends.","The seven minor criteria do not enter the rule: the minimal criteria are the three majors plus the family history, and the minors are supporting description only. They are not encoded as items, because an item no rule can reach is an item a reader would believe is doing work. For the record they are: foot deformities; leg oedema without cardiac failure; mild proximal and distal muscle weakness; axonal polyneuropathy; atrophy of the hand and foot muscles; acrogeric hands with mallet finger, clinodactyly or brachydactyly; and vaginal, uterine or rectal prolapse.","\"A family history compatible with autosomal recessive transmission\" is a judgement about a pedigree, not a phenotype, so it is assertable. Note the source requires compatibility, not a confirmed affected relative."],"curation":{"encoded_by":"claude-opus-5","notes":"Encoded from the primary. The rule is unusually simple for this family: all three major criteria plus a family history compatible with autosomal recessive transmission, with no counting.","reviews":[],"source_access":"primary","sources":[{"citation":{"authors":"Malfait F, Francomano C, Byers P, et al.","doi":"10.1002/ajmg.c.31552","journal":"Am J Med Genet C Semin Med Genet","pmid":"28306229","title":"","url":null,"year":2017},"note":"Publisher PDF, read 2026-09-18. The clEDS major criteria, minor criteria and the \"minimal criteria suggestive for clEDS\" rule were read directly.","read":true,"role":"primary","title":"Malfait F, et al. The 2017 international classification of the Ehlers-Danlos syndromes"}]},"disease":{"label":"Classical-like Ehlers-Danlos syndrome","mondo":"MONDO:0100138","omim":["606408"],"ordo":"ORPHA:230839"},"id":"cleds_malfait_2017","items":[{"hpo":["HP:0000974"],"id":"skin_hyperextensibility","label":"Skin hyperextensibility with velvety texture","paraphrase":null,"rule":null,"source_ref":"clEDS major criterion 1 (first half)","type":"phenotypic","verify":"Confirm the skin texture is velvety. HPO has no term for it, so the profile alone cannot establish this half of the criterion."},{"hpo":["HP:0001075","HP:0031158"],"id":"atrophic_scarring","label":"Atrophic scarring","paraphrase":"The criterion requires atrophic scarring to be ABSENT. Recorded here as the finding itself; the rule negates it.","rule":null,"source_ref":"clEDS major criterion 1 (second half, as an absence)","type":"phenotypic","verify":null},{"hpo":[],"id":"skin_criterion","label":"Skin hyperextensibility with velvety texture and no atrophic scarring","paraphrase":null,"rule":{"items":[{"item":"skin_hyperextensibility","kind":"item"},{"items":[{"item":"atrophic_scarring","kind":"item"}],"kind":"none_of"}],"kind":"all_of"},"source_ref":"clEDS major criterion 1","type":"composite","verify":null},{"hpo":["HP:0002761"],"id":"generalized_joint_hypermobility","label":"Generalized joint hypermobility","paraphrase":"With or without recurrent dislocations, most commonly of the shoulder and ankle","rule":null,"source_ref":"clEDS major criterion 2","type":"phenotypic","verify":"Confirm with the Beighton scale; a score of 5 or more is positive. The source cross-references the classical EDS definition of GJH."},{"hpo":["HP:0000978","HP:0031364"],"id":"easy_bruising","label":"Easily bruisable skin or spontaneous ecchymoses","paraphrase":null,"rule":null,"source_ref":"clEDS major criterion 3","type":"phenotypic","verify":null},{"hpo":[],"id":"family_history_ar","label":"Family history compatible with autosomal recessive transmission","paraphrase":"A pedigree consistent with autosomal recessive inheritance. The source asks for compatibility, not a confirmed affected relative.","rule":null,"source_ref":"clEDS minimal criteria","type":"assertable","verify":null},{"hpo":[],"id":"molecular_confirmation","label":"Biallelic pathogenic TNXB variants","paraphrase":"Biallelic pathogenic variants in TNXB, encoding tenascin XB. The source states that confirmatory molecular testing is obligatory for a final diagnosis.","rule":null,"source_ref":"clEDS molecular basis","type":"assertable","verify":null},{"hpo":[],"id":"clinical_criteria","label":"Minimal criteria suggestive for clEDS","paraphrase":null,"rule":{"items":[{"item":"skin_criterion","kind":"item"},{"item":"generalized_joint_hypermobility","kind":"item"},{"item":"easy_bruising","kind":"item"},{"item":"family_history_ar","kind":"item"}],"kind":"all_of"},"source_ref":"clEDS minimal criteria","type":"composite","verify":null}],"meta":{"citation":{"authors":"Malfait F, Francomano C, Byers P, et al.","doi":"10.1002/ajmg.c.31552","journal":"Am J Med Genet C Semin Med Genet","pmid":"28306229","title":"The 2017 international classification of the Ehlers-Danlos syndromes","url":null,"year":2017},"name":"2017 international classification of the Ehlers-Danlos syndromes, clEDS criteria","standing":"consensus","standing_note":"Part of the 2017 international classification, which is the consensus nosology for the Ehlers-Danlos syndromes and defines clEDS as a distinct subtype with its own criteria.","supersedes":"eds_villefranche_1998","version":"2017"},"source_path":"criteria/cleds_malfait_2017.yaml","tests":[{"asserted":{"family_history_ar":true,"molecular_confirmation":true},"confirmed":["skin_hyperextensibility","generalized_joint_hypermobility"],"excluded":["HP:0001075","HP:0031158"],"expect":"met","expect_tier":"Classical-like EDS, molecularly confirmed","name":"all three major criteria and a compatible family history, with variants","present":["HP:0000974","HP:0002761","HP:0000978"]},{"asserted":{"family_history_ar":true,"molecular_confirmation":false},"confirmed":["skin_hyperextensibility","generalized_joint_hypermobility"],"excluded":["HP:0001075","HP:0031158"],"expect":"met","expect_tier":"Clinically suggestive of classical-like EDS","name":"clinical criteria met, molecular testing not done","present":["HP:0000974","HP:0002761","HP:0000978"]},{"asserted":{"family_history_ar":true,"molecular_confirmation":true},"confirmed":["skin_hyperextensibility","generalized_joint_hypermobility"],"excluded":[],"expect":"refuted","expect_tier":null,"name":"atrophic scarring present refutes the skin criterion","present":["HP:0000974","HP:0001075","HP:0002761","HP:0000978"]},{"asserted":{"family_history_ar":true,"molecular_confirmation":true},"confirmed":["skin_hyperextensibility","generalized_joint_hypermobility"],"excluded":["HP:0001075","HP:0031158","HP:0000978","HP:0031364"],"expect":"refuted","expect_tier":null,"name":"two of three majors, the third excluded, is one short","present":["HP:0000974","HP:0002761"]},{"asserted":{"family_history_ar":false,"molecular_confirmation":true},"confirmed":["skin_hyperextensibility","generalized_joint_hypermobility"],"excluded":["HP:0001075","HP:0031158"],"expect":"refuted","expect_tier":null,"name":"all three majors but the family history is not compatible","present":["HP:0000974","HP:0002761","HP:0000978"]},{"asserted":{},"confirmed":["skin_hyperextensibility","generalized_joint_hypermobility"],"excluded":["HP:0001075","HP:0031158"],"expect":"indeterminate","expect_tier":null,"name":"all three majors, family history not assessed","present":["HP:0000974","HP:0002761","HP:0000978"]},{"asserted":{},"confirmed":[],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"empty profile","present":[]},{"asserted":{"family_history_ar":true,"molecular_confirmation":true},"confirmed":["skin_hyperextensibility","generalized_joint_hypermobility"],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"scarring status unrecorded leaves the skin criterion open","present":["HP:0000974","HP:0002761","HP:0000978"]}],"verdicts":[{"label":"Classical-like EDS, molecularly confirmed","rule":{"items":[{"item":"clinical_criteria","kind":"item"},{"item":"molecular_confirmation","kind":"item"}],"kind":"all_of"},"tier":0},{"label":"Clinically suggestive of classical-like EDS","rule":{"items":[{"item":"clinical_criteria","kind":"item"}],"kind":"all_of"},"tier":1}]},{"ambiguity":["\"One other major criterion\" is read as one of the two majors other than criterion 1, which the rule already requires. The alternative reading, that any major counts including the one already used, would make the clause vacuous, so it is not credible.","Major criterion 1 is severe, progressive cardiac-valvular disease of the aortic or mitral valve. HPO has terms for abnormal aortic and mitral valve morphology but carries neither severity nor progression, so both are in a verify string. Without that confirmation the item reports as provisionally met, which is the honest reading: an incidental valve finding is not this criterion.","Major criterion 2 is a single criterion satisfied by skin involvement of several kinds, so it is one item over an any_of of those findings rather than several items. The source lists hyperextensibility, atrophic scars, thin skin and easy bruising together under one numbered criterion.","Joint hypermobility here may be generalized or restricted to small joints, so both terms are alternatives. Note this is looser than the generalized-only requirement used elsewhere in this family.","The source names pes planovalgus among the foot deformities and HPO has no term for it. Pes planus and hallux valgus are mapped; planovalgus is named in a verify string, so a profile recording only planovalgus will not satisfy the item automatically."],"curation":{"encoded_by":"claude-opus-5","notes":"Encoded from the primary. Inheritance is autosomal recessive and the family history is part of the mandatory clause, not an alternative to it.","reviews":[],"source_access":"primary","sources":[{"citation":{"authors":"Malfait F, Francomano C, Byers P, et al.","doi":"10.1002/ajmg.c.31552","journal":"Am J Med Genet C Semin Med Genet","pmid":"28306229","title":"","url":null,"year":2017},"note":"Publisher PDF, read 2026-09-18. The cvEDS major criteria, minor criteria and minimal-criteria rule were read directly.","read":true,"role":"primary","title":"Malfait F, et al. The 2017 international classification of the Ehlers-Danlos syndromes"}]},"disease":{"label":"Cardiac-valvular Ehlers-Danlos syndrome","mondo":"MONDO:0013127","omim":["225320"],"ordo":"ORPHA:230851"},"id":"cveds_malfait_2017","items":[{"hpo":["HP:0001646","HP:0001633"],"id":"cardiac_valvular_disease","label":"Severe progressive cardiac-valvular disease","paraphrase":"Of the aortic or the mitral valve","rule":null,"source_ref":"cvEDS major criterion 1","type":"phenotypic","verify":"Confirm the valve disease is severe and progressive. HPO carries neither, and an incidental valve abnormality does not meet this criterion."},{"hpo":["HP:0000974","HP:0001075","HP:0031158","HP:0000963","HP:0000978"],"id":"skin_involvement","label":"Skin involvement","paraphrase":"Skin hyperextensibility, atrophic scars, thin skin, or easy bruising; the source groups these as one criterion","rule":null,"source_ref":"cvEDS major criterion 2","type":"phenotypic","verify":"If the finding is hyperextensibility, confirm it against the standardised cutoffs the source gives for classical EDS and cross-references here."},{"hpo":["HP:0002761","HP:0430046"],"id":"joint_hypermobility","label":"Joint hypermobility, generalized or of the small joints","paraphrase":null,"rule":null,"source_ref":"cvEDS major criterion 3","type":"phenotypic","verify":"Confirm with the Beighton scale, per the classical EDS definition the source cross-references. Unlike elsewhere in this family, hypermobility restricted to the small joints also satisfies this criterion."},{"hpo":["HP:0000023"],"id":"inguinal_hernia","label":"Inguinal hernia","paraphrase":null,"rule":null,"source_ref":"cvEDS minor criterion 1","type":"phenotypic","verify":null},{"hpo":["HP:0000767","HP:0000768"],"id":"pectus_deformity","label":"Pectus deformity","paraphrase":"The source notes pectus excavatum especially","rule":null,"source_ref":"cvEDS minor criterion 2","type":"phenotypic","verify":null},{"hpo":["HP:0001373","HP:0032153"],"id":"joint_dislocations","label":"Joint dislocations","paraphrase":null,"rule":null,"source_ref":"cvEDS minor criterion 3","type":"phenotypic","verify":"The source defines a dislocation as displacement out of the joint socket severe enough to limit motion and requiring manual reduction."},{"hpo":["HP:0001763","HP:0001822"],"id":"foot_deformities","label":"Foot deformities","paraphrase":null,"rule":null,"source_ref":"cvEDS minor criterion 4","type":"phenotypic","verify":"The source also names pes planovalgus, for which HPO has no term. Confirm directly if that is the deformity present."},{"hpo":[],"id":"family_history_ar","label":"Family history compatible with autosomal recessive inheritance","paraphrase":null,"rule":null,"source_ref":"cvEDS minimal criteria","type":"assertable","verify":null},{"hpo":[],"id":"molecular_confirmation","label":"Biallelic COL1A2 variants causing absence of pro-alpha-2(I) chains","paraphrase":"The source states confirmatory molecular testing is obligatory to reach a final diagnosis.","rule":null,"source_ref":"cvEDS molecular basis","type":"assertable","verify":null},{"hpo":[],"id":"one_other_major","label":"One other major criterion","paraphrase":null,"rule":{"items":[{"item":"skin_involvement","kind":"item"},{"item":"joint_hypermobility","kind":"item"}],"kind":"any_of"},"source_ref":"cvEDS minimal criteria, first branch","type":"composite","verify":null},{"hpo":[],"id":"two_minor_criteria","label":"At least two minor criteria","paraphrase":null,"rule":{"items":[{"item":"inguinal_hernia","kind":"item"},{"item":"pectus_deformity","kind":"item"},{"item":"joint_dislocations","kind":"item"},{"item":"foot_deformities","kind":"item"}],"k":2,"kind":"n_of"},"source_ref":"cvEDS minimal criteria, second branch","type":"composite","verify":null},{"hpo":[],"id":"clinical_criteria","label":"Minimal criteria suggestive for cvEDS","paraphrase":null,"rule":{"items":[{"item":"cardiac_valvular_disease","kind":"item"},{"item":"family_history_ar","kind":"item"},{"items":[{"item":"one_other_major","kind":"item"},{"item":"two_minor_criteria","kind":"item"}],"kind":"any_of"}],"kind":"all_of"},"source_ref":"cvEDS minimal criteria","type":"composite","verify":null}],"meta":{"citation":{"authors":"Malfait F, Francomano C, Byers P, et al.","doi":"10.1002/ajmg.c.31552","journal":"Am J Med Genet C Semin Med Genet","pmid":"28306229","title":"The 2017 international classification of the Ehlers-Danlos syndromes","url":null,"year":2017},"name":"2017 international classification of the Ehlers-Danlos syndromes, cvEDS criteria","standing":"consensus","standing_note":"Part of the 2017 international classification, the consensus nosology for the Ehlers-Danlos syndromes, which defines cvEDS with its own criteria.","supersedes":"eds_villefranche_1998","version":"2017"},"source_path":"criteria/cveds_malfait_2017.yaml","tests":[{"asserted":{"family_history_ar":true,"molecular_confirmation":true},"confirmed":["cardiac_valvular_disease"],"excluded":[],"expect":"met","expect_tier":"Cardiac-valvular EDS, molecularly confirmed","name":"valve disease, compatible family history and one other major","present":["HP:0001646","HP:0000974"]},{"asserted":{"family_history_ar":true,"molecular_confirmation":true},"confirmed":["cardiac_valvular_disease"],"excluded":["HP:0000974","HP:0001075","HP:0031158","HP:0000963","HP:0000978","HP:0002761","HP:0430046"],"expect":"met","expect_tier":"Cardiac-valvular EDS, molecularly confirmed","name":"the minor branch: exactly two minor criteria (at the boundary)","present":["HP:0001633","HP:0000023","HP:0000767"]},{"asserted":{"family_history_ar":true,"molecular_confirmation":true},"confirmed":["cardiac_valvular_disease"],"excluded":["HP:0000974","HP:0001075","HP:0031158","HP:0000963","HP:0000978","HP:0002761","HP:0430046","HP:0000767","HP:0000768","HP:0001373","HP:0032153","HP:0001763","HP:0001822"],"expect":"refuted","expect_tier":null,"name":"one minor criterion and no other major is one below the boundary","present":["HP:0001646","HP:0000023"]},{"asserted":{"family_history_ar":true,"molecular_confirmation":true},"confirmed":[],"excluded":["HP:0001646","HP:0001633"],"expect":"refuted","expect_tier":null,"name":"no valve disease refutes the mandatory criterion","present":["HP:0000974","HP:0002761","HP:0000023","HP:0000767"]},{"asserted":{"family_history_ar":false,"molecular_confirmation":true},"confirmed":["cardiac_valvular_disease"],"excluded":[],"expect":"refuted","expect_tier":null,"name":"family history not compatible with autosomal recessive inheritance","present":["HP:0001646","HP:0000974"]},{"asserted":{"family_history_ar":true,"molecular_confirmation":false},"confirmed":["cardiac_valvular_disease"],"excluded":[],"expect":"met","expect_tier":"Clinically suggestive of cardiac-valvular EDS","name":"clinical criteria met, molecular testing not done","present":["HP:0001646","HP:0000974"]},{"asserted":{},"confirmed":["cardiac_valvular_disease"],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"valve disease alone, everything else unassessed","present":["HP:0001646"]},{"asserted":{},"confirmed":[],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"empty profile","present":[]}],"verdicts":[{"label":"Cardiac-valvular EDS, molecularly confirmed","rule":{"items":[{"item":"clinical_criteria","kind":"item"},{"item":"molecular_confirmation","kind":"item"}],"kind":"all_of"},"tier":0},{"label":"Clinically suggestive of cardiac-valvular EDS","rule":{"items":[{"item":"clinical_criteria","kind":"item"}],"kind":"all_of"},"tier":1}]},{"ambiguity":["\"One other major criterion\" is read as one of majors 3 to 9, excluding the two the rule already requires. Reading it to include majors 1 or 2 would make the clause vacuous.","Major criterion 2 is a craniofacial gestalt. The source's footnote lists eleven component findings with no threshold, so it is assertable rather than mapped to an any_of over them, which would make it far easier to satisfy than intended. Same treatment as musculocontractural EDS.","Major criterion 4, increased palmar wrinkling, has no HPO term. The palmar crease terms describe crease number and morphology, not wrinkling, so mapping to one would be wrong rather than merely broad. Left assertable.","Major criterion 8 conjoins short limbs with short hands and feet. HPO's limb-shortening terms are all qualified by segment (mesomelic, rhizomelic) and none carries the conjunction, so this is assertable.","Major criterion 9, perinatal complications due to connective tissue fragility, is a category whose footnote list (congenital skull fractures, intracerebral haemorrhage, friable umbilical cord, congenital skin tears, neonatal pneumothorax) is explicitly illustrative. Assertable.","Major criterion 1 is EXTREME skin fragility with skin tears, which is a stricter requirement than the plain skin fragility that appears as a criterion in classical and arthrochalasia EDS. The same HPO term therefore carries a qualifier here and not there; that is a real difference between the sources, not an inconsistency in the encoding.","Minor criterion 5, complications of visceral fragility, is illustrated by bladder rupture, diaphragmatic rupture and rectal prolapse. All three have HPO terms and are mapped, but the source's list is illustrative, so a verify string records that other visceral complications also satisfy it."],"curation":{"encoded_by":"claude-opus-5","notes":"Encoded from the primary. Inheritance is autosomal recessive, but unlike clEDS and cvEDS the rule carries no family-history requirement.","reviews":[],"source_access":"primary","sources":[{"citation":{"authors":"Malfait F, Francomano C, Byers P, et al.","doi":"10.1002/ajmg.c.31552","journal":"Am J Med Genet C Semin Med Genet","pmid":"28306229","title":"","url":null,"year":2017},"note":"Publisher PDF, read 2026-09-18. The nine dEDS major criteria, eleven minor criteria, the minimal-criteria rule and the two footnotes defining the craniofacial features and the perinatal complications were read directly.","read":true,"role":"primary","title":"Malfait F, et al. The 2017 international classification of the Ehlers-Danlos syndromes"}]},"disease":{"label":"Dermatosparaxis Ehlers-Danlos syndrome","mondo":"MONDO:0009160","omim":["225410"],"ordo":"ORPHA:1901"},"id":"deds_malfait_2017","items":[{"hpo":["HP:0001030"],"id":"extreme_skin_fragility","label":"Extreme skin fragility with skin tears","paraphrase":null,"rule":null,"source_ref":"dEDS major criterion 1","type":"phenotypic","verify":"Confirm the fragility is extreme and that there are congenital or postnatal skin tears. Plain skin fragility does not meet this criterion."},{"hpo":[],"id":"craniofacial_features","label":"Characteristic craniofacial features","paraphrase":"Evident at birth or in early infancy, or evolving later in childhood. The source's footnote lists eleven component findings with no threshold, so this is a gestalt and is not derived from a profile.","rule":null,"source_ref":"dEDS major criterion 2","type":"assertable","verify":null},{"hpo":["HP:0001582","HP:0000973"],"id":"redundant_skin","label":"Redundant, almost lax skin","paraphrase":null,"rule":null,"source_ref":"dEDS major criterion 3","type":"phenotypic","verify":"Confirm there are excessive skin folds at the wrists and ankles."},{"hpo":[],"id":"palmar_wrinkling","label":"Increased palmar wrinkling","paraphrase":"No HPO term captures palmar wrinkling; the available palmar crease terms describe crease number and morphology instead.","rule":null,"source_ref":"dEDS major criterion 4","type":"assertable","verify":null},{"hpo":["HP:0000978","HP:0001933","HP:0007420"],"id":"severe_bruisability","label":"Severe bruisability","paraphrase":null,"rule":null,"source_ref":"dEDS major criterion 5","type":"phenotypic","verify":"Confirm the bruisability is severe, with a risk of subcutaneous haematomas and haemorrhage."},{"hpo":["HP:0001537"],"id":"umbilical_hernia","label":"Umbilical hernia","paraphrase":null,"rule":null,"source_ref":"dEDS major criterion 6","type":"phenotypic","verify":null},{"hpo":["HP:0008897"],"id":"postnatal_growth_retardation","label":"Postnatal growth retardation","paraphrase":null,"rule":null,"source_ref":"dEDS major criterion 7","type":"phenotypic","verify":null},{"hpo":[],"id":"short_limbs_hands_feet","label":"Short limbs, hands and feet","paraphrase":"HPO's limb-shortening terms are all qualified by segment and none carries the conjunction of limbs with hands and feet.","rule":null,"source_ref":"dEDS major criterion 8","type":"assertable","verify":null},{"hpo":[],"id":"perinatal_complications","label":"Perinatal complications due to connective tissue fragility","paraphrase":"The source's footnote gives congenital skull fractures, intracerebral haemorrhage, a friable umbilical cord, congenital skin tears and neonatal pneumothorax as examples. The list is illustrative, so this is assertable.","rule":null,"source_ref":"dEDS major criterion 9","type":"assertable","verify":null},{"hpo":["HP:0001027","HP:0000977"],"id":"soft_doughy_skin","label":"Soft and doughy skin texture","paraphrase":null,"rule":null,"source_ref":"dEDS minor criterion 1","type":"phenotypic","verify":null},{"hpo":["HP:0000974"],"id":"skin_hyperextensibility","label":"Skin hyperextensibility","paraphrase":null,"rule":null,"source_ref":"dEDS minor criterion 2","type":"phenotypic","verify":"Confirm against the standardised cutoffs the source gives for classical EDS."},{"hpo":["HP:0001075","HP:0031158"],"id":"atrophic_scars","label":"Atrophic scars","paraphrase":null,"rule":null,"source_ref":"dEDS minor criterion 3","type":"phenotypic","verify":null},{"hpo":["HP:0002761"],"id":"generalized_joint_hypermobility","label":"Generalized joint hypermobility","paraphrase":null,"rule":null,"source_ref":"dEDS minor criterion 4","type":"phenotypic","verify":"Confirm with the Beighton scale; the source cross-references the classical EDS definition."},{"hpo":["HP:6000662","HP:6001468","HP:0002035"],"id":"visceral_fragility","label":"Complications of visceral fragility","paraphrase":null,"rule":null,"source_ref":"dEDS minor criterion 5","type":"phenotypic","verify":"The source gives bladder rupture, diaphragmatic rupture and rectal prolapse as examples. Other complications of visceral fragility also satisfy the criterion; confirm directly if one of those is present."},{"hpo":["HP:0001270","HP:0002194"],"id":"delayed_motor_development","label":"Delayed motor development","paraphrase":null,"rule":null,"source_ref":"dEDS minor criterion 6","type":"phenotypic","verify":null},{"hpo":["HP:0000938"],"id":"osteopenia","label":"Osteopenia","paraphrase":null,"rule":null,"source_ref":"dEDS minor criterion 7","type":"phenotypic","verify":null},{"hpo":["HP:0001007"],"id":"hirsutism","label":"Hirsutism","paraphrase":null,"rule":null,"source_ref":"dEDS minor criterion 8","type":"phenotypic","verify":null},{"hpo":["HP:0000164"],"id":"tooth_abnormalities","label":"Tooth abnormalities","paraphrase":null,"rule":null,"source_ref":"dEDS minor criterion 9","type":"phenotypic","verify":null},{"hpo":["HP:0000545","HP:0000483"],"id":"refractive_errors","label":"Refractive errors","paraphrase":"The source names myopia and astigmatism","rule":null,"source_ref":"dEDS minor criterion 10","type":"phenotypic","verify":null},{"hpo":["HP:0000486"],"id":"strabismus","label":"Strabismus","paraphrase":null,"rule":null,"source_ref":"dEDS minor criterion 11","type":"phenotypic","verify":null},{"hpo":[],"id":"one_other_major","label":"One other major criterion","paraphrase":null,"rule":{"items":[{"item":"redundant_skin","kind":"item"},{"item":"palmar_wrinkling","kind":"item"},{"item":"severe_bruisability","kind":"item"},{"item":"umbilical_hernia","kind":"item"},{"item":"postnatal_growth_retardation","kind":"item"},{"item":"short_limbs_hands_feet","kind":"item"},{"item":"perinatal_complications","kind":"item"}],"kind":"any_of"},"source_ref":"dEDS minimal criteria, first branch","type":"composite","verify":null},{"hpo":[],"id":"three_minor_criteria","label":"At least three minor criteria","paraphrase":null,"rule":{"items":[{"item":"soft_doughy_skin","kind":"item"},{"item":"skin_hyperextensibility","kind":"item"},{"item":"atrophic_scars","kind":"item"},{"item":"generalized_joint_hypermobility","kind":"item"},{"item":"visceral_fragility","kind":"item"},{"item":"delayed_motor_development","kind":"item"},{"item":"osteopenia","kind":"item"},{"item":"hirsutism","kind":"item"},{"item":"tooth_abnormalities","kind":"item"},{"item":"refractive_errors","kind":"item"},{"item":"strabismus","kind":"item"}],"k":3,"kind":"n_of"},"source_ref":"dEDS minimal criteria, second branch","type":"composite","verify":null},{"hpo":[],"id":"molecular_confirmation","label":"Biallelic pathogenic ADAMTS2 variants","paraphrase":"The source states confirmatory molecular testing is obligatory to reach a final diagnosis.","rule":null,"source_ref":"dEDS molecular basis","type":"assertable","verify":null},{"hpo":[],"id":"clinical_criteria","label":"Minimal criteria suggestive for dEDS","paraphrase":null,"rule":{"items":[{"item":"extreme_skin_fragility","kind":"item"},{"item":"craniofacial_features","kind":"item"},{"items":[{"item":"one_other_major","kind":"item"},{"item":"three_minor_criteria","kind":"item"}],"kind":"any_of"}],"kind":"all_of"},"source_ref":"dEDS minimal criteria","type":"composite","verify":null}],"meta":{"citation":{"authors":"Malfait F, Francomano C, Byers P, et al.","doi":"10.1002/ajmg.c.31552","journal":"Am J Med Genet C Semin Med Genet","pmid":"28306229","title":"The 2017 international classification of the Ehlers-Danlos syndromes","url":null,"year":2017},"name":"2017 international classification of the Ehlers-Danlos syndromes, dEDS criteria","standing":"consensus","standing_note":"Part of the 2017 international classification, the consensus nosology for the Ehlers-Danlos syndromes, which defines dEDS with its own criteria.","supersedes":"eds_villefranche_1998","version":"2017"},"source_path":"criteria/deds_malfait_2017.yaml","tests":[{"asserted":{"craniofacial_features":true,"molecular_confirmation":true},"confirmed":["extreme_skin_fragility"],"excluded":[],"expect":"met","expect_tier":"Dermatosparaxis EDS, molecularly confirmed","name":"both mandatory majors plus one other major, with variants","present":["HP:0001030","HP:0001537"]},{"asserted":{"craniofacial_features":true,"molecular_confirmation":true,"palmar_wrinkling":false,"perinatal_complications":false,"short_limbs_hands_feet":false},"confirmed":["extreme_skin_fragility"],"excluded":["HP:0001582","HP:0000973","HP:0001537","HP:0008897","HP:0000978","HP:0001933","HP:0007420"],"expect":"met","expect_tier":"Dermatosparaxis EDS, molecularly confirmed","name":"the minor branch: exactly three minor criteria (at the boundary)","present":["HP:0001030","HP:0001027","HP:0000938","HP:0001007"]},{"asserted":{"craniofacial_features":true,"molecular_confirmation":true,"palmar_wrinkling":false,"perinatal_complications":false,"short_limbs_hands_feet":false},"confirmed":["extreme_skin_fragility"],"excluded":["HP:0001582","HP:0000973","HP:0001537","HP:0008897","HP:0000978","HP:0001933","HP:0007420","HP:0000974","HP:0001075","HP:0031158","HP:0002761","HP:6000662","HP:6001468","HP:0002035","HP:0001270","HP:0002194","HP:0001007","HP:0000164","HP:0000545","HP:0000483","HP:0000486","HP:0000977"],"expect":"refuted","expect_tier":null,"name":"two minor criteria and no other major is one below the boundary","present":["HP:0001030","HP:0001027","HP:0000938"]},{"asserted":{"craniofacial_features":false,"molecular_confirmation":true},"confirmed":["extreme_skin_fragility"],"excluded":[],"expect":"refuted","expect_tier":null,"name":"no craniofacial features refutes a mandatory criterion","present":["HP:0001030","HP:0001537"]},{"asserted":{"craniofacial_features":true,"molecular_confirmation":true},"confirmed":[],"excluded":["HP:0001030"],"expect":"refuted","expect_tier":null,"name":"skin fragility excluded refutes the other mandatory criterion","present":["HP:0001537"]},{"asserted":{"craniofacial_features":true,"molecular_confirmation":false},"confirmed":["extreme_skin_fragility"],"excluded":[],"expect":"met","expect_tier":"Clinically suggestive of dermatosparaxis EDS","name":"clinical criteria met, molecular testing not done","present":["HP:0001030","HP:0001537"]},{"asserted":{},"confirmed":["extreme_skin_fragility"],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"skin fragility present, everything else unassessed","present":["HP:0001030"]},{"asserted":{},"confirmed":[],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"empty profile","present":[]}],"verdicts":[{"label":"Dermatosparaxis EDS, molecularly confirmed","rule":{"items":[{"item":"clinical_criteria","kind":"item"},{"item":"molecular_confirmation","kind":"item"}],"kind":"all_of"},"tier":0},{"label":"Clinically suggestive of dermatosparaxis EDS","rule":{"items":[{"item":"clinical_criteria","kind":"item"}],"kind":"all_of"},"tier":1}]},{"ambiguity":["Criterion 3 requires exclusion of other heritable AND acquired connective tissue disorders, yet its own second clause describes how to diagnose hEDS in a patient who has an acquired connective tissue disorder. The two cannot both be read literally. Encoded as: heritable connective tissue disorders must be excluded outright; an acquired connective tissue disorder does not bar the diagnosis but replaces the \"two of A, B, C\" rule with a mandatory \"A and B\", with feature C unable to contribute. That is what the override clause says and it is the stricter of the two readings.","The paper and the Society checklist disagree on the eponyms in Feature A item 9: the paper calls the wrist sign the Steinberg sign and the thumb sign the Walker sign, the checklist reverses them. The manoeuvres are unambiguous either way, so the HPO terms are mapped to the manoeuvres and the eponyms are omitted.","Criterion 1 is the Beighton score against an age- and sex-specific cut-off, with a fallback through the five-point questionnaire when the score is exactly one point below the cut-off. None of that is expressible in HPO, so the Beighton result is assertable. A profile carrying HP:0002761 (generalized joint hypermobility) does NOT satisfy criterion 1 on its own and the engine will not treat it as doing so."],"curation":{"encoded_by":"claude-opus-5","notes":"Encoded from the published article text (criteria 1, 2 and 3 with all footnotes). The Ehlers-Danlos Society checklist was consulted only to recover two comparison glyphs the PDF text layer dropped. This is the schema stress test named in build plan section 7: nested counting inside one of three mandatory criteria, a conditional override on the counting rule, and three prerequisites that are true exclusions.\nRE-CHECKED against the primary PDF, 2026-09-18. Criterion 3 prerequisite 2 reads: \"In patients with an acquired connective tissue disorder (e.g., lupus, rheumatoid arthritis, etc.), additional diagnosis of hEDS requires meeting both Features A and B of Criterion 2. Feature C of Criterion 2 (chronic pain and/or instability) cannot be counted towards a diagnosis of hEDS in this situation.\" That is exactly the override encoded here, so the reading recorded in the first ambiguity entry is confirmed by the source.","reviews":[],"source_access":"primary","sources":[]},"disease":{"label":"Hypermobile Ehlers-Danlos syndrome","mondo":"MONDO:0007523","omim":["130020"],"ordo":"ORPHA:285"},"id":"heds_malfait_2017","items":[{"hpo":[],"id":"beighton_at_or_above_cutoff","label":"Beighton score at or above the age- and sex-specific cut-off","paraphrase":"At least 6 for prepubertal children and adolescents, at least 5 for pubertal men and women up to age 50, at least 4 over the age of 50","rule":null,"source_ref":"Criterion 1","type":"assertable","verify":null},{"hpo":[],"id":"beighton_one_below_cutoff","label":"Beighton score exactly one point below the cut-off","paraphrase":null,"rule":null,"source_ref":"Criterion 1","type":"assertable","verify":null},{"hpo":[],"id":"five_point_questionnaire_positive","label":"Five-point questionnaire positive","paraphrase":"At least two positive items of five. Not validated in children.","rule":null,"source_ref":"Criterion 1; Table III","type":"assertable","verify":null},{"hpo":[],"id":"criterion_1_gjh","label":"Criterion 1: generalized joint hypermobility","paraphrase":null,"rule":{"items":[{"item":"beighton_at_or_above_cutoff","kind":"item"},{"items":[{"item":"beighton_one_below_cutoff","kind":"item"},{"item":"five_point_questionnaire_positive","kind":"item"}],"kind":"all_of"}],"kind":"any_of"},"source_ref":"Criterion 1","type":"composite","verify":null},{"hpo":["HP:0000977"],"id":"soft_skin","label":"Unusually soft or velvety skin","paraphrase":null,"rule":null,"source_ref":"Criterion 2, Feature A, item 1","type":"phenotypic","verify":"Subjective; the source recommends a high threshold for positivity"},{"hpo":["HP:0000974"],"id":"mild_skin_hyperextensibility","label":"Mild skin hyperextensibility","paraphrase":null,"rule":null,"source_ref":"Criterion 2, Feature A, item 2","type":"phenotypic","verify":"Confirm extensibility greater than 1.5 cm, pinched at the middle of the volar surface of the non-dominant forearm. Above 2.0 cm, consider other EDS types."},{"hpo":["HP:0001065"],"id":"unexplained_striae","label":"Unexplained striae","paraphrase":null,"rule":null,"source_ref":"Criterion 2, Feature A, item 3","type":"phenotypic","verify":"Confirm striae distensae or rubrae at back, groins, thighs, breasts or abdomen in an adolescent, man or prepubertal woman, without significant gain or loss of body fat or weight"},{"hpo":["HP:0025509"],"id":"piezogenic_papules","label":"Bilateral piezogenic papules of the heel","paraphrase":null,"rule":null,"source_ref":"Criterion 2, Feature A, item 4","type":"phenotypic","verify":"Confirm bilateral"},{"hpo":["HP:0001537","HP:0000023"],"id":"recurrent_abdominal_hernias","label":"Recurrent or multiple abdominal hernias","paraphrase":null,"rule":null,"source_ref":"Criterion 2, Feature A, item 5","type":"phenotypic","verify":"Confirm recurrent or multiple (umbilical, inguinal, crural)"},{"hpo":["HP:0001075"],"id":"atrophic_scarring","label":"Atrophic scarring","paraphrase":null,"rule":null,"source_ref":"Criterion 2, Feature A, item 6","type":"phenotypic","verify":"Confirm at least two sites, without truly papyraceous or hemosideric scars, and not the result of multiple incisions, wound infection or inflammatory conditions"},{"hpo":["HP:0031607"],"id":"prolapse","label":"Pelvic floor, rectal or uterine prolapse","paraphrase":null,"rule":null,"source_ref":"Criterion 2, Feature A, item 7","type":"phenotypic","verify":"Confirm in a child, man or nulliparous woman without morbid obesity or another known predisposing condition"},{"hpo":["HP:0000678"],"id":"dental_crowding","label":"Dental crowding","paraphrase":"Includes a history of orthodontic intervention to correct it","rule":null,"source_ref":"Criterion 2, Feature A, item 8","type":"phenotypic","verify":null},{"hpo":["HP:0000218","HP:0000189","HP:0002705"],"id":"high_or_narrow_palate","label":"High or narrow palate","paraphrase":null,"rule":null,"source_ref":"Criterion 2, Feature A, item 8","type":"phenotypic","verify":null},{"hpo":[],"id":"dental_crowding_and_palate","label":"Dental crowding and high or narrow palate","paraphrase":null,"rule":{"items":[{"item":"dental_crowding","kind":"item"},{"item":"high_or_narrow_palate","kind":"item"}],"kind":"all_of"},"source_ref":"Criterion 2, Feature A, item 8 (footnote: both must be positive)","type":"composite","verify":null},{"hpo":["HP:0025091"],"id":"wrist_sign","label":"Wrist sign, bilateral","paraphrase":null,"rule":null,"source_ref":"Criterion 2, Feature A, item 9(i)","type":"phenotypic","verify":"Confirm positive on both sides"},{"hpo":["HP:6001274"],"id":"thumb_sign","label":"Thumb sign, bilateral","paraphrase":null,"rule":null,"source_ref":"Criterion 2, Feature A, item 9(ii)","type":"phenotypic","verify":"Confirm positive on both sides"},{"hpo":[],"id":"arachnodactyly","label":"Arachnodactyly","paraphrase":null,"rule":{"items":[{"item":"wrist_sign","kind":"item"},{"item":"thumb_sign","kind":"item"}],"kind":"any_of"},"source_ref":"Criterion 2, Feature A, item 9","type":"composite","verify":null},{"hpo":["HP:0012771"],"id":"arm_span_ratio","label":"Arm span to height ratio of at least 1.05","paraphrase":null,"rule":null,"source_ref":"Criterion 2, Feature A, item 10","type":"phenotypic","verify":"Confirm arm span to height ratio >= 1.05"},{"hpo":["HP:0001634"],"id":"mitral_valve_prolapse","label":"Mitral valve prolapse","paraphrase":null,"rule":null,"source_ref":"Criterion 2, Feature A, item 11","type":"phenotypic","verify":"Confirm mild or greater by strict echocardiographic criteria"},{"hpo":["HP:0002616"],"id":"aortic_root_dilatation","label":"Aortic root dilatation","paraphrase":null,"rule":null,"source_ref":"Criterion 2, Feature A, item 12","type":"phenotypic","verify":"Confirm Z-score strictly greater than +2"},{"hpo":[],"id":"feature_a","label":"Feature A: five of twelve systemic manifestations","paraphrase":null,"rule":{"items":[{"item":"soft_skin","kind":"item"},{"item":"mild_skin_hyperextensibility","kind":"item"},{"item":"unexplained_striae","kind":"item"},{"item":"piezogenic_papules","kind":"item"},{"item":"recurrent_abdominal_hernias","kind":"item"},{"item":"atrophic_scarring","kind":"item"},{"item":"prolapse","kind":"item"},{"item":"dental_crowding_and_palate","kind":"item"},{"item":"arachnodactyly","kind":"item"},{"item":"arm_span_ratio","kind":"item"},{"item":"mitral_valve_prolapse","kind":"item"},{"item":"aortic_root_dilatation","kind":"item"}],"k":5,"kind":"n_of"},"source_ref":"Criterion 2, Feature A","type":"composite","verify":null},{"hpo":[],"id":"feature_b","label":"Feature B: positive family history","paraphrase":"One or more first-degree relatives independently meeting the current diagnostic criteria for hEDS. Being merely hypermobile does not count.","rule":null,"source_ref":"Criterion 2, Feature B","type":"assertable","verify":null},{"hpo":["HP:0009763"],"id":"limb_pain","label":"Musculoskeletal pain in two or more limbs, daily for at least 3 months","paraphrase":null,"rule":null,"source_ref":"Criterion 2, Feature C, item 1","type":"phenotypic","verify":"Confirm two or more limbs, recurring daily for at least 3 months"},{"hpo":["HP:0012532"],"id":"chronic_widespread_pain","label":"Chronic widespread pain for at least 3 months","paraphrase":null,"rule":null,"source_ref":"Criterion 2, Feature C, item 2","type":"phenotypic","verify":"Confirm widespread and lasting at least 3 months"},{"hpo":["HP:0031869"],"id":"atraumatic_dislocations","label":"Recurrent atraumatic joint dislocations","paraphrase":null,"rule":null,"source_ref":"Criterion 2, Feature C, item 3a","type":"phenotypic","verify":"Confirm three or more atraumatic dislocations in one joint, or two or more in two different joints at different times, with no trauma"},{"hpo":[],"id":"confirmed_joint_instability","label":"Medically confirmed joint instability at two or more sites","paraphrase":"Sites counted regardless of laterality; right and left patellar instability count as two. HPO carries no site count, so this is assertable.","rule":null,"source_ref":"Criterion 2, Feature C, item 3b","type":"assertable","verify":null},{"hpo":[],"id":"instability_criterion","label":"Recurrent dislocations or frank joint instability","paraphrase":null,"rule":{"items":[{"item":"atraumatic_dislocations","kind":"item"},{"item":"confirmed_joint_instability","kind":"item"}],"kind":"any_of"},"source_ref":"Criterion 2, Feature C, item 3","type":"composite","verify":null},{"hpo":[],"id":"feature_c","label":"Feature C: at least one musculoskeletal complication","paraphrase":null,"rule":{"items":[{"item":"limb_pain","kind":"item"},{"item":"chronic_widespread_pain","kind":"item"},{"item":"instability_criterion","kind":"item"}],"k":1,"kind":"n_of"},"source_ref":"Criterion 2, Feature C","type":"composite","verify":null},{"hpo":[],"id":"unusual_skin_fragility","label":"Unusual skin fragility","paraphrase":"Its presence should prompt consideration of other types of EDS. A propensity to open wounds from trivial trauma is not typical of hEDS.","rule":null,"source_ref":"Criterion 3, prerequisite 1","type":"assertable","verify":null},{"hpo":[],"id":"heritable_ctd_excluded","label":"Other heritable connective tissue disorders excluded","paraphrase":null,"rule":null,"source_ref":"Criterion 3, prerequisite 2","type":"assertable","verify":null},{"hpo":[],"id":"acquired_ctd_present","label":"An acquired connective tissue disorder is present","paraphrase":"For example lupus or rheumatoid arthritis. Its presence does not bar hEDS, but it forces Features A and B and disallows Feature C.","rule":null,"source_ref":"Criterion 3, prerequisite 2 (override clause)","type":"assertable","verify":null},{"hpo":[],"id":"alternative_diagnoses_excluded","label":"Alternative diagnoses excluded","paraphrase":"Neuromuscular disorders, other heritable connective tissue disorders and skeletal dysplasias that also produce joint hypermobility through hypotonia or connective tissue laxity","rule":null,"source_ref":"Criterion 3, prerequisite 3","type":"assertable","verify":null},{"hpo":[],"id":"criterion_3_prerequisites","label":"Criterion 3: all prerequisites met","paraphrase":null,"rule":{"items":[{"items":[{"item":"unusual_skin_fragility","kind":"item"}],"kind":"none_of"},{"item":"heritable_ctd_excluded","kind":"item"},{"item":"alternative_diagnoses_excluded","kind":"item"}],"kind":"all_of"},"source_ref":"Criterion 3","type":"composite","verify":null},{"hpo":[],"id":"criterion_2_features","label":"Criterion 2: two or more of features A, B and C","paraphrase":null,"rule":{"items":[{"items":[{"items":[{"item":"acquired_ctd_present","kind":"item"}],"kind":"none_of"},{"items":[{"item":"feature_a","kind":"item"},{"item":"feature_b","kind":"item"},{"item":"feature_c","kind":"item"}],"k":2,"kind":"n_of"}],"kind":"all_of"},{"items":[{"item":"acquired_ctd_present","kind":"item"},{"item":"feature_a","kind":"item"},{"item":"feature_b","kind":"item"}],"kind":"all_of"}],"kind":"any_of"},"source_ref":"Criterion 2, with the Criterion 3 override","type":"composite","verify":null}],"meta":{"citation":{"authors":"Malfait F, Francomano C, Byers P, et al.","doi":"10.1002/ajmg.c.31552","journal":"Am J Med Genet C Semin Med Genet","pmid":"28306229","title":"The 2017 international classification of the Ehlers-Danlos syndromes","url":null,"year":2017},"name":"2017 international classification of the Ehlers-Danlos syndromes, hEDS criteria","standing":"consensus","standing_note":"Part of the 2017 international classification, the consensus nosology for the Ehlers-Danlos syndromes, which defines hEDS with its own criteria. Same basis as the seven sibling EDS files in this directory.","supersedes":"eds_villefranche_1998","version":"2017"},"source_path":"criteria/heds_malfait_2017.yaml","tests":[{"asserted":{"acquired_ctd_present":false,"alternative_diagnoses_excluded":true,"beighton_at_or_above_cutoff":true,"heritable_ctd_excluded":true,"unusual_skin_fragility":false},"confirmed":["soft_skin","mild_skin_hyperextensibility","unexplained_striae","piezogenic_papules","recurrent_abdominal_hernias","limb_pain"],"excluded":[],"expect":"met","expect_tier":"hEDS criteria met","name":"Beighton at cut-off, features A and C, prerequisites 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That quantifier is a later refinement and is NOT part of the 2000 criteria, so it is not encoded. It is mentioned in the verify string as context only.","The telangiectasia criterion specifies characteristic sites (lips, oral cavity, fingers, nose). HPO has terms for lip and oral mucosal telangiectasia but not for the finger or nasal sites, so the general skin term is included as an alternative and the site restriction is carried as a verify string rather than as logic. This makes the item slightly easier to satisfy than the source until a human confirms the sites."],"curation":{"encoded_by":"claude-opus-5","notes":"Encoded from two independent expert reproductions of the Curacao criteria rather than from Shovlin 2000, which is paywalled; its abstract, which states the tier thresholds, was read. Faughnan 2011 Table 2 and GeneReviews NBK1351 agree with each other and with the abstract on the four criteria and both thresholds, which is the agreement the source policy asks for. A Pass B curator should still obtain Shovlin 2000 to reconcile the exact wording.","reviews":[],"source_access":"expert_secondary","sources":[{"citation":{"authors":"Shovlin CL, Guttmacher AE, Buscarini E, et al.","doi":"10.1002/(SICI)1096-8628(20000306)91:1<66::AID-AJMG12>3.0.CO;2-P","journal":"Am J Med Genet","pmid":"10751092","title":"","url":null,"year":2000},"note":"Paywalled. The abstract was read and states the tier thresholds; the full text and its wording of the four criteria were not obtained.","read":false,"role":"primary","title":"Shovlin CL, et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia"},{"citation":{"authors":"Faughnan ME, Palda VA, Garcia-Tsao G, et al.","doi":"10.1136/jmg.2009.069013","journal":"J Med Genet","pmid":"19553198","title":"","url":null,"year":2011},"note":"Source of the wording of the four criteria.","read":true,"role":"reproduces","title":"First International Guidelines for HHT, Table 2"},{"citation":{"authors":"McDonald J, Gossage JR, Stevenson DA","doi":null,"journal":"GeneReviews, University of Washington, Seattle","pmid":"20301525","title":"","url":"https://www.ncbi.nlm.nih.gov/books/NBK1351/","year":2026},"note":"Independently reproduces all four criteria and both tier thresholds, matching Faughnan 2011. Read 2026-09-17 against the 2026-02-19 update.","read":true,"role":"reproduces","title":"GeneReviews: Hereditary Hemorrhagic Telangiectasia"}]},"disease":{"label":"Hereditary haemorrhagic telangiectasia","mondo":"MONDO:0019180","omim":["187300","600376"],"ordo":"ORPHA:774"},"id":"hht_curacao_2000","items":[{"hpo":["HP:0004406"],"id":"epistaxis","label":"Epistaxis","paraphrase":"Spontaneous and recurrent nosebleeds","rule":null,"source_ref":"Curacao criterion 1","type":"phenotypic","verify":"Confirm the epistaxis is spontaneous and recurrent. Note that later restatements add a quantifier of at least four episodes per year; that is not part of the 2000 criteria."},{"hpo":["HP:0000214","HP:0007428","HP:0100585"],"id":"telangiectases","label":"Telangiectases at characteristic sites","paraphrase":"Multiple, at characteristic sites: lips, oral cavity, fingers, nose","rule":null,"source_ref":"Curacao criterion 2","type":"phenotypic","verify":"Confirm the telangiectases are multiple and at characteristic sites (lips, oral cavity, fingers, nose)"},{"hpo":["HP:0002604"],"id":"gi_telangiectasia","label":"Gastrointestinal telangiectasia","paraphrase":null,"rule":null,"source_ref":"Curacao criterion 3 (visceral lesion type 1)","type":"phenotypic","verify":null},{"hpo":["HP:0006548"],"id":"pulmonary_avm","label":"Pulmonary arteriovenous malformation","paraphrase":null,"rule":null,"source_ref":"Curacao criterion 3 (visceral lesion type 2)","type":"phenotypic","verify":null},{"hpo":["HP:0006574"],"id":"hepatic_avm","label":"Hepatic arteriovenous malformation","paraphrase":null,"rule":null,"source_ref":"Curacao criterion 3 (visceral lesion type 3)","type":"phenotypic","verify":null},{"hpo":["HP:0002408"],"id":"cerebral_avm","label":"Cerebral arteriovenous malformation","paraphrase":null,"rule":null,"source_ref":"Curacao criterion 3 (visceral lesion type 4)","type":"phenotypic","verify":null},{"hpo":["HP:0002390"],"id":"spinal_avm","label":"Spinal arteriovenous malformation","paraphrase":null,"rule":null,"source_ref":"Curacao criterion 3 (visceral lesion type 5)","type":"phenotypic","verify":null},{"hpo":[],"id":"visceral_lesions","label":"Visceral lesions","paraphrase":null,"rule":{"items":[{"item":"gi_telangiectasia","kind":"item"},{"item":"pulmonary_avm","kind":"item"},{"item":"hepatic_avm","kind":"item"},{"item":"cerebral_avm","kind":"item"},{"item":"spinal_avm","kind":"item"}],"kind":"any_of"},"source_ref":"Curacao criterion 3","type":"composite","verify":null},{"hpo":[],"id":"family_history","label":"Family history","paraphrase":"A first-degree relative with HHT according to these criteria. Any family history of the clinical features is suggestive, but only a first-degree relative diagnosed by these criteria satisfies the criterion.","rule":null,"source_ref":"Curacao criterion 4","type":"assertable","verify":null}],"meta":{"citation":{"authors":"Shovlin CL, Guttmacher AE, Buscarini E, et al.","doi":"10.1002/(SICI)1096-8628(20000306)91:1<66::AID-AJMG12>3.0.CO;2-P","journal":"Am J Med Genet","pmid":"10751092","title":"Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome)","url":null,"year":2000},"name":"Curacao criteria","standing":"consensus","standing_note":"In current use. GeneReviews (Hereditary Hemorrhagic Telangiectasia, NBK1351, last updated 2026-02-19) states the clinical diagnosis by these four criteria, at the same two thresholds, citing Shovlin 2000, Anderson 2022 and McDonald 2023. It calls the current form the \"revised\" Curacao criteria; the revision refines the epistaxis criterion with a frequency quantifier and does not change the criteria, their number or the tier thresholds. See the first ambiguity note.","supersedes":null,"version":"2000"},"source_path":"criteria/hht_curacao_2000.yaml","tests":[{"asserted":{"family_history":false},"confirmed":["epistaxis","telangiectases"],"excluded":[],"expect":"met","expect_tier":"Definite HHT","name":"exactly three criteria is definite (at the boundary)","present":["HP:0004406","HP:0000214","HP:0006548"]},{"asserted":{"family_history":true},"confirmed":["epistaxis","telangiectases"],"excluded":[],"expect":"met","expect_tier":"Definite HHT","name":"four of four criteria","present":["HP:0004406","HP:0007428","HP:0002408"]},{"asserted":{"family_history":false},"confirmed":["epistaxis","telangiectases"],"excluded":["HP:0002604","HP:0006548","HP:0006574","HP:0002408","HP:0002390"],"expect":"met","expect_tier":"Possible or suspected HHT","name":"exactly two criteria is possible, one below definite","present":["HP:0004406","HP:0000214"]},{"asserted":{"family_history":false},"confirmed":["epistaxis"],"excluded":["HP:0000214","HP:0007428","HP:0100585","HP:0002604","HP:0006548","HP:0006574","HP:0002408","HP:0002390"],"expect":"refuted","expect_tier":null,"name":"exactly one criterion is one below possible","present":["HP:0004406"]},{"asserted":{"family_history":false},"confirmed":[],"excluded":["HP:0004406","HP:0000214","HP:0007428","HP:0100585","HP:0002604","HP:0006548","HP:0006574","HP:0002408","HP:0002390"],"expect":"refuted","expect_tier":null,"name":"no criteria met","present":[]},{"asserted":{},"confirmed":["epistaxis","telangiectases"],"excluded":[],"expect":"met","expect_tier":"Possible or suspected HHT","name":"two met and two open: definite still reachable","present":["HP:0004406","HP:0000214"]},{"asserted":{},"confirmed":["epistaxis"],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"one met, three open","present":["HP:0004406"]},{"asserted":{},"confirmed":[],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"empty profile","present":[]},{"asserted":{"family_history":false},"confirmed":[],"excluded":["HP:0004406","HP:0000214","HP:0007428","HP:0100585"],"expect":"refuted","expect_tier":null,"name":"a single visceral lesion satisfies the visceral criterion once only","present":["HP:0006548","HP:0002408","HP:0006574"]}],"verdicts":[{"label":"Definite HHT","rule":{"items":[{"item":"epistaxis","kind":"item"},{"item":"telangiectases","kind":"item"},{"item":"visceral_lesions","kind":"item"},{"item":"family_history","kind":"item"}],"k":3,"kind":"n_of"},"tier":0},{"label":"Possible or suspected HHT","rule":{"items":[{"item":"epistaxis","kind":"item"},{"item":"telangiectases","kind":"item"},{"item":"visceral_lesions","kind":"item"},{"item":"family_history","kind":"item"}],"k":2,"kind":"n_of"},"tier":1}]},{"ambiguity":["Table 2A is worded \"if the following CRITERIA are present\" and then lists two bullets, without the count that Table 1A carries (\"two or more of the following\"). It is read here as a conjunction: a sporadic diagnosis needs BOTH the pigmentary criterion AND a pathogenic SPRED1 variant. Four things point that way. The capitalised plural \"CRITERIA\" with no count word, where the same table's part B says \"one or more\"; the fact that part B would be redundant if part A already meant \"one or more\"; the paper's own statement that LGSS could be clinically diagnosed as NF1 under the NIH criteria, with 50% satisfying them, which is to say the pigmentary finding alone does not separate the two conditions; and section 5.1, the conservative reading, since a conjunction is the harder rule to meet. A reading in which either bullet alone suffices would let a sporadic patient with six macules and no molecular testing meet consensus criteria for Legius syndrome, which the paper's own discussion argues against.","\"No other NF1-related diagnostic criteria except for axillary or inguinal freckling\" is encoded as the absence of the Table 1A criteria, so the exclusion is on an NF1 criterion being MET, not on a raw feature being seen. This matters where a Table 1A criterion carries a count: a single non-plexiform neurofibroma does not meet Table 1A criterion 3 and so does not block a Legius diagnosis, while two do. The verify strings are what carry those counts, and an unconfirmed finding therefore leaves the exclusion unknown rather than firing it. This is the intended behaviour and it is why the neurofibroma and Lisch items keep their counts here even though they appear only inside a none_of.","Whether \"other NF1-related diagnostic criteria\" includes Table 1A's seventh bullet, a heterozygous pathogenic NF1 variant, is not stated. It is included in the exclusion here, on the conservative reading and because a pathogenic NF1 variant alongside a pathogenic SPRED1 variant would not leave Legius syndrome the right label. Whether it also reaches Table 1B, a parent who meets the NF1 criteria, is likewise unstated; that one is NOT encoded, because Table 1B is not part of the Table 1A list the phrase most naturally names. A curator should settle both.","Footnote a says \"The presence of fewer than six café-au-lait macules does not exclude Legius syndrome.\" This is a statement about the sensitivity of the criteria, not a rule: it tells a clinician that failing the count does not rule the condition out, but it supplies no alternative threshold that could be encoded. It is not encoded. A refuted verdict from this file must therefore be read as \"does not meet the 2021 criteria\", never as \"does not have Legius syndrome\", which is true of every file here but is unusually load-bearing for this one.","Axillary and inguinal freckling is explicitly permitted by Table 2A but is not itself a Legius criterion, so it appears nowhere in this file: adding an item for it would be unreachable by any rule, and the engine rejects unreachable items. Its permission is encoded as absence from the exclusion list. A reader comparing this file against Table 2 will not find freckling, and that is correct rather than an omission.","The pigmentary criterion says \"six or more café-au-lait macules bilaterally distributed\" and, unlike Table 1A criterion 1 for NF1, sets no size threshold. The verify string carries the count and the bilaterality and deliberately does not carry a size, because the source does not.","UNRESOLVED, raised by the Pass B re-derivation of 2026-09-19. Does \"a parent diagnosed with NF1\" count as one of the \"other NF1-related diagnostic criteria\" that Table 2A criterion 1 forbids? This file says no; Pass B said yes and put `parent_with_nf1` into the exclusion. Pass B's argument is textual and good: Table 3, for mosaic NF1, writes \"another NF1 diagnostic criterion (except a parent fulfilling diagnostic criteria for NF1)\", so the authors evidently think the phrase can reach parental diagnosis and had to except it by name, and Table 2 excepts nothing. The argument against is clinical and was tested rather than asserted: under Pass B's reading, a child with six or more bilateral macules, every other NF1 feature excluded, and a CONFIRMED pathogenic SPRED1 variant is REFUTED for Legius syndrome the moment a parent carries an NF1 label - and this paper states that Legius syndrome could be clinically diagnosed as NF1 under the NIH criteria, with 50% satisfying them. That is to say Pass B's reading refuses the diagnosis in precisely the families where it is most likely, against a definitional molecular finding. This file therefore keeps the narrower reading, in which the forbidden criteria are the bullets of Table 1A describing the individual's own findings. A curator or clinician should settle it; it is the single largest open question in this file.","Pass B omitted HP:0009732 (plexiform neurofibroma) from the exclusion, carrying the neurofibroma limb on HP:0001067 alone. Both encodings behave identically today, because HP:0009732 is a descendant of HP:0001067 and presence propagates up the DAG. This file keeps both terms. Table 1A criterion 3 states two limbs with different thresholds - \"two or more neurofibromas of any type OR one plexiform neurofibroma\" - so the structure mirrors the source; and relying on the descendant relation would make the exclusion silently stop catching a plexiform neurofibroma if a future HPO release moved the term, which the review staleness check now exists to surface. Section 5.1's rule against leaning on a broader ancestor applies."],"curation":{"encoded_by":"claude-opus-5","notes":"Encoded from Table 2 (parts A and B) and its footnote. Table 4 (mosaic Legius syndrome) is a separate criteria set and is not encoded here, nor are Tables 1 and 3, which belong to NF1.\nThis file is the sibling of nf1_legius_2021.yaml: one publication, two criteria sets, two files. They share the source and the NF1 feature vocabulary, and they are deliberately not merged, because a patient meets one or the other and the verdict has to say which.\nThe nine NF1 features appear here only inside an exclusion. They are not Legius criteria and cannot contribute to a Legius diagnosis; they are the \"no other NF1-related diagnostic criteria\" clause of Table 2A, criterion 1.\nPass B: an independent LLM re-derivation from the same publication was run in an isolated context on 2026-09-19. The two passes agree on the most contested structural call, that Table 2A is a conjunction rather than \"one or more\" - reached independently, which is the strongest evidence in this file. The programmatic diff raised three differences. Two are not differences: the rule-tree shapes were shown equivalent across all 2187 three-valued completions (Pass B groups the osseous and ocular limbs into any_of nodes; this file lists them flat), and the item counts differ only because Pass B names more groups as composites. The third and the plexiform-term question are recorded in the ambiguity list and one of them, whether a parent's NF1 diagnosis blocks a Legius diagnosis, is NOT resolved.\nThis file is therefore still `draft`, deliberately. The Pass B protocol forbids adding a `reviews` entry while a discrepancy remains unreconciled, and that one does. It needs a curator or clinician to settle, after which the review entry can be added.","reviews":[],"source_access":"primary","sources":[{"citation":{"authors":"Legius E, Messiaen L, Wolkenstein P, et al.","doi":"10.1038/s41436-021-01170-5","journal":"Genet Med","pmid":"34012067","title":"","url":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354850/","year":2021},"note":"Open access. Read 2026-09-18 as the PMC rendering of PMC8354850. Table 2 parts A and B, footnote a, and the introduction's statement that no individual with LGSS has developed Lisch nodules, neurofibromas or other complications of NF1, are all taken from here. Table 1 (NF1) is read only to fix what \"other NF1-related diagnostic criteria\" denotes; it is encoded separately in nf1_legius_2021.yaml.","read":true,"role":"primary","title":"Legius E, et al. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome, Table 2 and its footnote"}]},"disease":{"label":"Legius syndrome","mondo":"MONDO:0012669","omim":["611431"],"ordo":"ORPHA:137605"},"id":"legius_legius_2021","items":[{"hpo":["HP:0000957"],"id":"cafe_au_lait_macules","label":"Six or more cafe-au-lait macules, bilaterally distributed","paraphrase":null,"rule":null,"source_ref":"Table 2A, criterion 1 (first limb)","type":"phenotypic","verify":"Confirm at least 6 macules and that they are bilaterally distributed. The source sets no size threshold for Legius syndrome, unlike the NF1 criteria"},{"hpo":["HP:0001067"],"id":"multiple_neurofibromas","label":"Two or more neurofibromas of any type","paraphrase":null,"rule":null,"source_ref":"Table 1A, criterion 3 (first limb), via Table 2A criterion 1","type":"phenotypic","verify":"Confirm at least 2 neurofibromas of any type"},{"hpo":["HP:0009732"],"id":"plexiform_neurofibroma","label":"Plexiform neurofibroma","paraphrase":null,"rule":null,"source_ref":"Table 1A, criterion 3 (second limb), via Table 2A criterion 1","type":"phenotypic","verify":null},{"hpo":["HP:0009734"],"id":"optic_pathway_glioma","label":"Optic pathway glioma","paraphrase":null,"rule":null,"source_ref":"Table 1A, criterion 4, via Table 2A criterion 1","type":"phenotypic","verify":null},{"hpo":["HP:0009737"],"id":"lisch_nodules","label":"Iris Lisch nodules","paraphrase":null,"rule":null,"source_ref":"Table 1A, criterion 5 (first limb), via Table 2A criterion 1","type":"phenotypic","verify":"Confirm at least 2 nodules, identified by slit lamp examination"},{"hpo":[],"id":"choroidal_abnormalities","label":"Choroidal abnormalities","paraphrase":"Two or more bright patchy choroidal nodules on optical coherence tomography or near-infrared reflectance imaging. HPO has no term for this finding; the available choroid terms describe unrelated pathology, so mapping to one would be wrong rather than merely broad.","rule":null,"source_ref":"Table 1A, criterion 5 (second limb), via Table 2A criterion 1","type":"assertable","verify":null},{"hpo":["HP:6001124"],"id":"sphenoid_dysplasia","label":"Sphenoid wing dysplasia","paraphrase":null,"rule":null,"source_ref":"Table 1A, criterion 6 (first limb), via Table 2A criterion 1","type":"phenotypic","verify":null},{"hpo":["HP:0002982"],"id":"anterolateral_tibial_bowing","label":"Anterolateral bowing of the tibia","paraphrase":null,"rule":null,"source_ref":"Table 1A, criterion 6 (second limb), via Table 2A criterion 1","type":"phenotypic","verify":"Confirm the bowing is anterolateral. HPO has no anterolateral term, and the anterior term is a descendant that would miss a profile recorded at the general term"},{"hpo":["HP:0005864"],"id":"long_bone_pseudarthrosis","label":"Pseudarthrosis of a long bone","paraphrase":null,"rule":null,"source_ref":"Table 1A, criterion 6 (third limb), via Table 2A criterion 1","type":"phenotypic","verify":"Confirm the affected bone is a long bone"},{"hpo":[],"id":"nf1_pathogenic_variant","label":"Heterozygous pathogenic NF1 variant","paraphrase":"Heterozygous pathogenic NF1 variant with a variant allele fraction of 50% in apparently normal tissue such as white blood cells","rule":null,"source_ref":"Table 1A, criterion 7, via Table 2A criterion 1","type":"assertable","verify":null},{"hpo":[],"id":"other_nf1_criteria","label":"Any NF1 diagnostic criterion other than the pigmentary findings","paraphrase":null,"rule":{"items":[{"item":"multiple_neurofibromas","kind":"item"},{"item":"plexiform_neurofibroma","kind":"item"},{"item":"optic_pathway_glioma","kind":"item"},{"item":"lisch_nodules","kind":"item"},{"item":"choroidal_abnormalities","kind":"item"},{"item":"sphenoid_dysplasia","kind":"item"},{"item":"anterolateral_tibial_bowing","kind":"item"},{"item":"long_bone_pseudarthrosis","kind":"item"},{"item":"nf1_pathogenic_variant","kind":"item"}],"kind":"any_of"},"source_ref":"Table 2A, criterion 1 (second limb), against Table 1A","type":"composite","verify":null},{"hpo":[],"id":"pigmentary_criterion","label":"Six or more bilateral cafe-au-lait macules with no other NF1 criteria","paraphrase":null,"rule":{"items":[{"item":"cafe_au_lait_macules","kind":"item"},{"items":[{"item":"other_nf1_criteria","kind":"item"}],"kind":"none_of"}],"kind":"all_of"},"source_ref":"Table 2A, criterion 1","type":"composite","verify":null},{"hpo":[],"id":"spred1_pathogenic_variant","label":"Heterozygous pathogenic SPRED1 variant","paraphrase":"Heterozygous pathogenic SPRED1 variant with a variant allele fraction of 50% in apparently normal tissue such as white blood cells","rule":null,"source_ref":"Table 2A, criterion 2","type":"assertable","verify":null},{"hpo":[],"id":"parent_with_legius","label":"A parent who meets the diagnostic criteria for Legius syndrome","paraphrase":null,"rule":null,"source_ref":"Table 2B","type":"assertable","verify":null}],"meta":{"citation":{"authors":"Legius E, Messiaen L, Wolkenstein P, et al.","doi":"10.1038/s41436-021-01170-5","journal":"Genet Med","pmid":"34012067","title":"Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation","url":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354850/","year":2021},"name":"Diagnostic criteria for Legius syndrome","standing":"consensus","standing_note":"The publication is titled \"Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation\", and its stated aim is \"to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS)\". These are the first consensus criteria for the condition, so there is nothing to supersede. Evidence basis: the source's own title and aim.","supersedes":null,"version":"2021"},"source_path":"criteria/legius_legius_2021.yaml","tests":[{"asserted":{"choroidal_abnormalities":false,"nf1_pathogenic_variant":false,"parent_with_legius":false,"spred1_pathogenic_variant":true},"confirmed":["cafe_au_lait_macules"],"excluded":["HP:0001067","HP:0009732","HP:0009734","HP:0009737","HP:6001124","HP:0002982","HP:0005864"],"expect":"met","expect_tier":"Legius syndrome criteria met","name":"sporadic: pigmentary criterion plus a SPRED1 variant","present":["HP:0000957","HP:0000997"]},{"asserted":{"choroidal_abnormalities":false,"nf1_pathogenic_variant":false,"parent_with_legius":true,"spred1_pathogenic_variant":false},"confirmed":["cafe_au_lait_macules"],"excluded":["HP:0001067","HP:0009732","HP:0009734","HP:0009737","HP:6001124","HP:0002982","HP:0005864"],"expect":"met","expect_tier":"Legius syndrome criteria met","name":"affected parent plus exactly one criterion (at the boundary)","present":["HP:0000957"]},{"asserted":{"choroidal_abnormalities":false,"nf1_pathogenic_variant":false,"parent_with_legius":false,"spred1_pathogenic_variant":false},"confirmed":["cafe_au_lait_macules"],"excluded":["HP:0001067","HP:0009732","HP:0009734","HP:0009737","HP:6001124","HP:0002982","HP:0005864"],"expect":"refuted","expect_tier":null,"name":"sporadic with the pigmentary criterion but no SPRED1 variant is one short","present":["HP:0000957"]},{"asserted":{"choroidal_abnormalities":false,"nf1_pathogenic_variant":false,"parent_with_legius":false,"spred1_pathogenic_variant":true},"confirmed":["cafe_au_lait_macules","lisch_nodules"],"excluded":["HP:0001067","HP:0009732","HP:0009734","HP:6001124","HP:0002982","HP:0005864"],"expect":"refuted","expect_tier":null,"name":"a SPRED1 variant does not rescue a patient who meets another NF1 criterion","present":["HP:0000957","HP:0009737"]},{"asserted":{"choroidal_abnormalities":false,"nf1_pathogenic_variant":false,"parent_with_legius":true,"spred1_pathogenic_variant":false},"confirmed":[],"excluded":["HP:0000957","HP:0001067","HP:0009732","HP:0009734","HP:0009737","HP:6001124","HP:0002982","HP:0005864"],"expect":"refuted","expect_tier":null,"name":"affected parent but every criterion excluded","present":[]},{"asserted":{"spred1_pathogenic_variant":true},"confirmed":["cafe_au_lait_macules"],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"macules present but nobody looked for the NF1 features","present":["HP:0000957"]},{"asserted":{"choroidal_abnormalities":false,"nf1_pathogenic_variant":false,"parent_with_legius":false},"confirmed":["cafe_au_lait_macules"],"excluded":["HP:0001067","HP:0009732","HP:0009734","HP:0009737","HP:6001124","HP:0002982","HP:0005864"],"expect":"indeterminate","expect_tier":null,"name":"pigmentary criterion met, molecular testing not yet done","present":["HP:0000957"]},{"asserted":{},"confirmed":[],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"empty profile","present":[]}],"verdicts":[{"label":"Legius syndrome criteria met","rule":{"items":[{"items":[{"items":[{"item":"parent_with_legius","kind":"item"}],"kind":"none_of"},{"item":"pigmentary_criterion","kind":"item"},{"item":"spred1_pathogenic_variant","kind":"item"}],"kind":"all_of"},{"items":[{"item":"parent_with_legius","kind":"item"},{"items":[{"item":"pigmentary_criterion","kind":"item"},{"item":"spred1_pathogenic_variant","kind":"item"}],"kind":"any_of"}],"kind":"all_of"}],"kind":"any_of"},"tier":0}]},{"ambiguity":["Box 1 marks four of the seven branches with a caveat requiring absence of discriminating features of SGS, LDS or vEDS AND completion of TGFBR1/2, collagen biochemistry and COL3A1 testing \"if indicated\". \"If indicated\" is a clinical judgement the engine cannot make, so both halves are folded into a single assertable item that the user must affirm. Leaving it unasserted makes those branches indeterminate rather than met, which is the conservative reading.","Box 2 rows are exclusive: the wrist-and-thumb row scores 3 OR the wrist-or-thumb row scores 1, never both. A plain sum over the two would give 4. Each such row is encoded as a high-value item plus a lesser item that is explicitly gated on the high-value one being absent. Read the systemic_score item alongside Box 2.","An FBN1 variant \"known with Ao\" is by definition also a bona fide FBN1 variant, so asserting the former should imply the latter. The schema has no implication operator, so the two are separate assertables and the UI will ask about both. A curator should not read them as independent."],"curation":{"encoded_by":"claude-opus-5","notes":"Encoded from Boxes 1, 2 and 3 of the primary publication. Only the Marfan syndrome branches are encoded. Ectopia lentis syndrome, MASS phenotype and MVP syndrome are separate clinical entities in the same nosology and belong in their own criteria files, not as verdict tiers here. Pass A only.\nVERIFIED against the primary PDF, 2026-09-18, obtained from Ghent University's institutional repository (green open access deposit). Every row and weight of the systemic score matches Box 2 exactly, as does the threshold of 7.\nOne subtlety worth recording. Box 2 states a maximum total of 20 points. The validator reports the maximum attainable here as 23, because the three graded rows (wrist/thumb, pectus, hindfoot) are each encoded as two separately weighted items and it sums all sixteen. No patient can score both halves of a graded row - the lesser item carries a none_of guard against the greater - so the realisable maximum is 20, matching the source. The overcount is therefore harmless here, but it means the score.threshold_unreachable gate is unsound in general: it would pass a threshold between the realisable and the naive maximum. Recorded rather than fixed, because computing the realisable maximum needs the polarity-aware evaluator rather than a sum.\nPass B: an independent LLM re-derivation from the same publication was run in an isolated context on 2026-09-19. The Marfan rule itself converged almost exactly, which is the strongest evidence this file has. Both passes independently derived the same seven Box 1 paths, the same \"no family history\" conjunct on paths 1-4, the same systemic threshold of 7, the same n_of k=3 of 5 facial features, the same mutual-exclusion gating on the graded rows, and - the detail most likely to have been botched - the caveat attached to exactly paths 1, 3, 6 and 7, which is where the source prints its asterisks and nowhere else.\nOne defect found and fixed: `chest_asymmetry` was assertable, carrying the claim that HPO had no term for it. HP:0001555, Asymmetry of the thorax, is in the pinned release. It is now phenotypic, so the row resolves from a profile rather than needing a toggle.\nOne apparent difference is not one: this file carries scoliosis and thoracolumbar kyphosis as a single item with two terms, Pass B as an any_of over two items. A multi-term item means any one term satisfies it, so the two are the same rule.\nThe real disagreement is scope, not content. Pass B encoded ectopia lentis syndrome, MASS phenotype and MVP syndrome as verdict tiers of this file, with the second systemic threshold of 5 that MASS needs. This file holds that they are separate entities belonging in their own files, per the paragraph above and following the precedent set by nf1_legius_2021 and legius_legius_2021 - one publication, two criteria sets, two files. That decision stands, but the three files do not exist yet, so the nosology is only partly encoded in this repository.\nNot reconciled, and a genuine gap in THIS file: \"potential MFS\". The source proposes it for individuals under 20 with insufficient systemic features and borderline aortic measurements. Unlike ELS, MASS and MVPS it is not a separate entity - it is a provisional Marfan band - so it belongs here as a weaker verdict tier, and there is none. Pass B encoded one. This file remains draft until that is settled.","reviews":[],"source_access":"primary","sources":[{"citation":{"authors":"Loeys BL, Dietz HC, Braverman AC, et al.","doi":"10.1136/jmg.2009.072785","journal":"J Med Genet","pmid":"20591885","title":"","url":"https://biblio.ugent.be/publication/1013955","year":2010},"note":"Obtained 2026-09-18 from Ghent University's institutional repository, a green open access deposit of the published article. Box 1 (diagnostic criteria) and Box 2 (systemic score) read directly.","read":true,"role":"primary","title":"Loeys BL, et al. The revised Ghent nosology for the Marfan syndrome"}]},"disease":{"label":"Marfan syndrome","mondo":"MONDO:0007947","omim":["154700"],"ordo":"ORPHA:558"},"id":"marfan_ghent_2010","items":[{"hpo":["HP:0002616"],"id":"aortic_root_z2","label":"Aortic root dilatation (Z >= 2) or dissection","paraphrase":"Aortic diameter at the sinuses of Valsalva at or above Z-score 2 when standardised to age and body size, or aortic root dissection","rule":null,"source_ref":"Box 1, Ao","type":"phenotypic","verify":"Confirm Z >= 2 at the sinuses of Valsalva, measured by the same method used to generate the normative data, or aortic root dissection"},{"hpo":["HP:0002616"],"id":"aortic_root_family_threshold","label":"Aortic root dilatation at the family-history threshold","paraphrase":"Z >= 2 at or above 20 years of age, Z >= 3 below 20 years of age","rule":null,"source_ref":"Box 1, criterion 7","type":"phenotypic","verify":"Confirm Z >= 2 if aged 20 or over, or Z >= 3 if under 20"},{"hpo":["HP:0001083"],"id":"ectopia_lentis","label":"Ectopia lentis","paraphrase":null,"rule":null,"source_ref":"Box 1, EL","type":"phenotypic","verify":null},{"hpo":[],"id":"fbn1_variant","label":"Bona fide FBN1 variant","paraphrase":"An FBN1 variant meeting the Box 3 criteria: previously shown to segregate in a Marfan family; or de novo with proven paternity in one of five listed classes; or another missense with segregation and/or absence in 400 ethnically matched control chromosomes; or linkage over at least six meioses","rule":null,"source_ref":"Box 1, FBN1; definition in Box 3","type":"assertable","verify":null},{"hpo":[],"id":"fbn1_known_with_aortic_disease","label":"FBN1 variant previously associated with aortic root aneurysm or dissection","paraphrase":"An FBN1 variant that has been identified in an individual with aortic aneurysm. Required for criterion 4; without it, ectopia lentis plus an FBN1 variant is ectopia lentis syndrome, not Marfan syndrome.","rule":null,"source_ref":"Box 1, 'FBN1 with known Ao'","type":"assertable","verify":null},{"hpo":[],"id":"family_history_mfs","label":"Family history of Marfan syndrome","paraphrase":"A family member independently diagnosed as having Marfan syndrome using these criteria","rule":null,"source_ref":"Box 1, FH of MFS","type":"assertable","verify":null},{"hpo":[],"id":"sgs_lds_veds_excluded","label":"SGS, LDS and vEDS excluded","paraphrase":"No discriminating features of Shprintzen-Goldberg syndrome, Loeys-Dietz syndrome or vascular Ehlers-Danlos syndrome, and TGFBR1/2 testing, collagen biochemistry and COL3A1 testing performed if indicated","rule":null,"source_ref":"Box 1, asterisk caveat","type":"assertable","verify":null},{"hpo":["HP:0025091"],"id":"wrist_sign","label":"Wrist sign","paraphrase":null,"rule":null,"source_ref":"Box 2, row 1","type":"phenotypic","verify":null},{"hpo":["HP:6001274"],"id":"thumb_sign","label":"Thumb sign","paraphrase":null,"rule":null,"source_ref":"Box 2, row 1","type":"phenotypic","verify":null},{"hpo":[],"id":"wrist_and_thumb","label":"Wrist and thumb sign","paraphrase":null,"rule":{"items":[{"item":"wrist_sign","kind":"item"},{"item":"thumb_sign","kind":"item"}],"kind":"all_of"},"source_ref":"Box 2, row 1 (3 points)","type":"composite","verify":null},{"hpo":[],"id":"wrist_or_thumb_only","label":"Wrist or thumb sign, but not both","paraphrase":null,"rule":{"items":[{"items":[{"item":"wrist_and_thumb","kind":"item"}],"kind":"none_of"},{"items":[{"item":"wrist_sign","kind":"item"},{"item":"thumb_sign","kind":"item"}],"kind":"any_of"}],"kind":"all_of"},"source_ref":"Box 2, row 1 (1 point)","type":"composite","verify":null},{"hpo":["HP:0000768"],"id":"pectus_carinatum","label":"Pectus carinatum deformity","paraphrase":null,"rule":null,"source_ref":"Box 2, row 2 (2 points)","type":"phenotypic","verify":null},{"hpo":["HP:0000767"],"id":"pectus_excavatum","label":"Pectus excavatum","paraphrase":null,"rule":null,"source_ref":"Box 2, row 2 (1 point)","type":"phenotypic","verify":null},{"hpo":["HP:0001555"],"id":"chest_asymmetry","label":"Chest asymmetry","paraphrase":"Pass A recorded that HPO had no term for chest wall asymmetry and left this assertable. That was wrong: HP:0001555, Asymmetry of the thorax, is in the pinned release and is the criterion, not a broader ancestor of it. The Pass B re-derivation of 2026-09-19 found the term. The row now resolves from a phenotype profile instead of needing a manual toggle.","rule":null,"source_ref":"Box 2, row 2 (1 point)","type":"phenotypic","verify":null},{"hpo":[],"id":"lesser_chest_deformity","label":"Pectus excavatum or chest asymmetry, without pectus carinatum","paraphrase":null,"rule":{"items":[{"items":[{"item":"pectus_carinatum","kind":"item"}],"kind":"none_of"},{"items":[{"item":"pectus_excavatum","kind":"item"},{"item":"chest_asymmetry","kind":"item"}],"kind":"any_of"}],"kind":"all_of"},"source_ref":"Box 2, row 2 (1 point)","type":"composite","verify":null},{"hpo":["HP:5210430"],"id":"hindfoot_deformity","label":"Hindfoot deformity","paraphrase":null,"rule":null,"source_ref":"Box 2, row 3 (2 points)","type":"phenotypic","verify":null},{"hpo":["HP:0001763"],"id":"pes_planus","label":"Plain pes planus","paraphrase":null,"rule":null,"source_ref":"Box 2, row 3 (1 point)","type":"phenotypic","verify":null},{"hpo":[],"id":"pes_planus_only","label":"Plain pes planus without hindfoot deformity","paraphrase":null,"rule":{"items":[{"items":[{"item":"hindfoot_deformity","kind":"item"}],"kind":"none_of"},{"item":"pes_planus","kind":"item"}],"kind":"all_of"},"source_ref":"Box 2, row 3 (1 point)","type":"composite","verify":null},{"hpo":["HP:0002108"],"id":"pneumothorax","label":"Pneumothorax","paraphrase":null,"rule":null,"source_ref":"Box 2, row 4 (2 points)","type":"phenotypic","verify":null},{"hpo":["HP:0100775"],"id":"dural_ectasia","label":"Dural ectasia","paraphrase":null,"rule":null,"source_ref":"Box 2, row 5 (2 points)","type":"phenotypic","verify":null},{"hpo":["HP:0003179"],"id":"protrusio_acetabuli","label":"Protrusio acetabuli","paraphrase":null,"rule":null,"source_ref":"Box 2, row 6 (2 points)","type":"phenotypic","verify":null},{"hpo":["HP:0012773"],"id":"reduced_us_ls_ratio","label":"Reduced upper segment to lower segment ratio","paraphrase":null,"rule":null,"source_ref":"Box 2, row 7","type":"phenotypic","verify":null},{"hpo":["HP:0012771"],"id":"increased_arm_span","label":"Increased arm span to height ratio","paraphrase":null,"rule":null,"source_ref":"Box 2, row 7","type":"phenotypic","verify":null},{"hpo":[],"id":"severe_scoliosis","label":"Severe scoliosis","paraphrase":"HPO carries no severity-qualified scoliosis term, and the row turns on severity, so this is assertable rather than mapped to plain scoliosis.","rule":null,"source_ref":"Box 2, row 7","type":"assertable","verify":null},{"hpo":[],"id":"reduced_ratio_combination","label":"Reduced US/LS and increased arm span, without severe scoliosis","paraphrase":null,"rule":{"items":[{"item":"reduced_us_ls_ratio","kind":"item"},{"item":"increased_arm_span","kind":"item"},{"items":[{"item":"severe_scoliosis","kind":"item"}],"kind":"none_of"}],"kind":"all_of"},"source_ref":"Box 2, row 7 (1 point)","type":"composite","verify":null},{"hpo":["HP:0002650","HP:0005619"],"id":"scoliosis_or_kyphosis","label":"Scoliosis or thoracolumbar kyphosis","paraphrase":null,"rule":null,"source_ref":"Box 2, row 8 (1 point)","type":"phenotypic","verify":null},{"hpo":["HP:0001377"],"id":"reduced_elbow_extension","label":"Reduced elbow extension","paraphrase":null,"rule":null,"source_ref":"Box 2, row 9 (1 point)","type":"phenotypic","verify":null},{"hpo":["HP:0000268"],"id":"dolichocephaly","label":"Dolichocephaly","paraphrase":null,"rule":null,"source_ref":"Box 2, row 10","type":"phenotypic","verify":null},{"hpo":["HP:0000490"],"id":"enophthalmos","label":"Enophthalmos","paraphrase":null,"rule":null,"source_ref":"Box 2, row 10","type":"phenotypic","verify":null},{"hpo":["HP:0000494"],"id":"downslanting_palpebral_fissures","label":"Downslanting palpebral fissures","paraphrase":null,"rule":null,"source_ref":"Box 2, row 10","type":"phenotypic","verify":null},{"hpo":["HP:0000272"],"id":"malar_hypoplasia","label":"Malar hypoplasia","paraphrase":null,"rule":null,"source_ref":"Box 2, row 10","type":"phenotypic","verify":null},{"hpo":["HP:0000278"],"id":"retrognathia","label":"Retrognathia","paraphrase":null,"rule":null,"source_ref":"Box 2, row 10","type":"phenotypic","verify":null},{"hpo":[],"id":"facial_features","label":"Facial features (three of five)","paraphrase":null,"rule":{"items":[{"item":"dolichocephaly","kind":"item"},{"item":"enophthalmos","kind":"item"},{"item":"downslanting_palpebral_fissures","kind":"item"},{"item":"malar_hypoplasia","kind":"item"},{"item":"retrognathia","kind":"item"}],"k":3,"kind":"n_of"},"source_ref":"Box 2, row 10 (1 point)","type":"composite","verify":null},{"hpo":["HP:0001065"],"id":"skin_striae","label":"Skin striae","paraphrase":null,"rule":null,"source_ref":"Box 2, row 11 (1 point)","type":"phenotypic","verify":null},{"hpo":["HP:0000545"],"id":"myopia","label":"Myopia over 3 dioptres","paraphrase":null,"rule":null,"source_ref":"Box 2, row 12 (1 point)","type":"phenotypic","verify":"Confirm myopia greater than 3 dioptres"},{"hpo":["HP:0001634"],"id":"mitral_valve_prolapse","label":"Mitral valve prolapse (all types)","paraphrase":null,"rule":null,"source_ref":"Box 2, row 13 (1 point)","type":"phenotypic","verify":null},{"hpo":[],"id":"systemic_score","label":"Systemic score of 7 or more","paraphrase":null,"rule":{"kind":"score","threshold":7,"weights":[{"node":{"item":"wrist_and_thumb","kind":"item"},"w":3},{"node":{"item":"wrist_or_thumb_only","kind":"item"},"w":1},{"node":{"item":"pectus_carinatum","kind":"item"},"w":2},{"node":{"item":"lesser_chest_deformity","kind":"item"},"w":1},{"node":{"item":"hindfoot_deformity","kind":"item"},"w":2},{"node":{"item":"pes_planus_only","kind":"item"},"w":1},{"node":{"item":"pneumothorax","kind":"item"},"w":2},{"node":{"item":"dural_ectasia","kind":"item"},"w":2},{"node":{"item":"protrusio_acetabuli","kind":"item"},"w":2},{"node":{"item":"reduced_ratio_combination","kind":"item"},"w":1},{"node":{"item":"scoliosis_or_kyphosis","kind":"item"},"w":1},{"node":{"item":"reduced_elbow_extension","kind":"item"},"w":1},{"node":{"item":"facial_features","kind":"item"},"w":1},{"node":{"item":"skin_striae","kind":"item"},"w":1},{"node":{"item":"myopia","kind":"item"},"w":1},{"node":{"item":"mitral_valve_prolapse","kind":"item"},"w":1}]},"source_ref":"Box 2; threshold stated as 'score >= 7 indicates systemic involvement'","type":"composite","verify":null}],"meta":{"citation":{"authors":"Loeys BL, Dietz HC, Braverman AC, et al.","doi":"10.1136/jmg.2009.072785","journal":"J Med Genet","pmid":"20591885","title":"The revised Ghent nosology for the Marfan syndrome","url":"https://jmg.bmj.com/content/47/7/476.long","year":2010},"name":"Revised Ghent nosology","standing":"consensus","standing_note":"Produced by an international panel of experts in the diagnosis and management of Marfan syndrome, convened in Brussels by the National Marfan Foundation and charged with revising the Ghent criteria. Evidence basis: the paper's own account of how it was produced, in its introduction.","supersedes":"marfan_ghent_1996","version":"2010"},"source_path":"criteria/marfan_ghent_2010.yaml","tests":[{"asserted":{"family_history_mfs":false,"sgs_lds_veds_excluded":true},"confirmed":["aortic_root_z2","aortic_root_family_threshold"],"excluded":[],"expect":"met","expect_tier":"Marfan syndrome criteria met","name":"sporadic: aortic root plus ectopia lentis","present":["HP:0002616","HP:0001083"]},{"asserted":{"family_history_mfs":false,"sgs_lds_veds_excluded":true},"confirmed":["aortic_root_z2","aortic_root_family_threshold"],"excluded":["HP:0001083"],"expect":"met","expect_tier":"Marfan syndrome criteria met","name":"sporadic: aortic root plus a systemic score of exactly 7","present":["HP:0002616","HP:0025091","HP:6001274","HP:0000768","HP:0100775"]},{"asserted":{"chest_asymmetry":false,"family_history_mfs":false,"fbn1_known_with_aortic_disease":false,"fbn1_variant":false,"severe_scoliosis":false,"sgs_lds_veds_excluded":true},"confirmed":["aortic_root_z2","aortic_root_family_threshold","myopia"],"excluded":["HP:0001083","HP:0000768","HP:0000767","HP:5210430","HP:0001763","HP:0002108","HP:0003179","HP:0012773","HP:0012771","HP:0002650","HP:0005619","HP:0001377","HP:0000268","HP:0000490","HP:0000494","HP:0000272","HP:0000278","HP:0001065","HP:0001634"],"expect":"refuted","expect_tier":null,"name":"a systemic score of exactly 6 is one point short","present":["HP:0002616","HP:0025091","HP:6001274","HP:0100775","HP:0000545"]},{"asserted":{"chest_asymmetry":false,"family_history_mfs":false,"fbn1_known_with_aortic_disease":false,"fbn1_variant":false,"severe_scoliosis":false,"sgs_lds_veds_excluded":true},"confirmed":["aortic_root_z2","aortic_root_family_threshold"],"excluded":["HP:0001083","HP:0000768","HP:0000767","HP:5210430","HP:0001763","HP:0002108","HP:0100775","HP:0012773","HP:0012771","HP:0002650","HP:0005619","HP:0001377","HP:0000268","HP:0000490","HP:0000494","HP:0000272","HP:0000278","HP:0000545","HP:0001634"],"expect":"refuted","expect_tier":null,"name":"the wrist-and-thumb row scores 3, not 4","present":["HP:0002616","HP:0025091","HP:6001274","HP:0003179","HP:0001065"]},{"asserted":{"family_history_mfs":true},"confirmed":[],"excluded":[],"expect":"met","expect_tier":"Marfan syndrome criteria met","name":"familial: ectopia lentis alone suffices","present":["HP:0001083"]},{"asserted":{"family_history_mfs":false,"fbn1_known_with_aortic_disease":false,"fbn1_variant":true,"sgs_lds_veds_excluded":true},"confirmed":[],"excluded":["HP:0002616"],"expect":"refuted","expect_tier":null,"name":"ectopia lentis with an FBN1 variant not known with aortic disease is not Marfan","present":["HP:0001083"]},{"asserted":{},"confirmed":["aortic_root_z2","aortic_root_family_threshold"],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"aortic root alone, everything else unassessed","present":["HP:0002616"]},{"asserted":{},"confirmed":[],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"empty profile","present":[]},{"asserted":{"family_history_mfs":false},"confirmed":["aortic_root_z2","aortic_root_family_threshold"],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"aortic root plus ectopia lentis with SGS/LDS/vEDS not yet excluded","present":["HP:0002616","HP:0001083"]}],"verdicts":[{"label":"Marfan syndrome criteria met","rule":{"items":[{"items":[{"items":[{"item":"family_history_mfs","kind":"item"}],"kind":"none_of"},{"item":"aortic_root_z2","kind":"item"},{"item":"ectopia_lentis","kind":"item"},{"item":"sgs_lds_veds_excluded","kind":"item"}],"kind":"all_of"},{"items":[{"items":[{"item":"family_history_mfs","kind":"item"}],"kind":"none_of"},{"item":"aortic_root_z2","kind":"item"},{"item":"fbn1_variant","kind":"item"}],"kind":"all_of"},{"items":[{"items":[{"item":"family_history_mfs","kind":"item"}],"kind":"none_of"},{"item":"aortic_root_z2","kind":"item"},{"item":"systemic_score","kind":"item"},{"item":"sgs_lds_veds_excluded","kind":"item"}],"kind":"all_of"},{"items":[{"items":[{"item":"family_history_mfs","kind":"item"}],"kind":"none_of"},{"item":"ectopia_lentis","kind":"item"},{"item":"fbn1_known_with_aortic_disease","kind":"item"}],"kind":"all_of"},{"items":[{"item":"family_history_mfs","kind":"item"},{"item":"ectopia_lentis","kind":"item"}],"kind":"all_of"},{"items":[{"item":"family_history_mfs","kind":"item"},{"item":"systemic_score","kind":"item"},{"item":"sgs_lds_veds_excluded","kind":"item"}],"kind":"all_of"},{"items":[{"item":"family_history_mfs","kind":"item"},{"item":"aortic_root_family_threshold","kind":"item"},{"item":"sgs_lds_veds_excluded","kind":"item"}],"kind":"all_of"}],"kind":"any_of"},"tier":0}]},{"ambiguity":["CORRECTED against the primary, 2026-09-18. The primary does not say \"two of the three major criteria\". It gives two age-dependent combinations: \"At birth or in early childhood: Major criterion (1) congenital multiple contractures AND (2) characteristic craniofacial features. In adolescence and in adulthood: Major criterion (1) congenital multiple contractures AND (3) characteristic cutaneous features.\" Criterion 1 is mandatory in both. This file originally encoded n_of k=2 over the three majors, taken from the GeneReviews chapter's summary \"should be suspected in probands with two major criteria\", which loses both the mandatory status of criterion 1 and the age split. Under that encoding a patient with craniofacial and cutaneous features but no contractures met the criteria; under the source they meet neither branch. Now encoded as contractures AND (craniofacial OR cutaneous).","The schema has no age model, so the two branches cannot be gated on age. Encoded as a disjunction, which is more permissive than the source: an infant with contractures and cutaneous features satisfies it here, where the source would direct that combination at the adolescent/adult branch. The age context is carried on the verify strings of the two gestalt items.","The source states that mcEDS \"should be suspected in probands with two major criteria; the presence of any additional minor criteria supports the diagnosis\". The fifteen minor criteria are therefore supportive only: they do not enter the rule and cannot change the verdict. They are deliberately not encoded as items, because an item that no rule can reach is an item a reader would believe is doing work. For the record they are: recurrent or chronic joint dislocations; pectus excavatum or flat sternum; spinal deformities; tapered slender cylindrical fingers; progressive foot and ankle deformities; large subcutaneous haematomas; chronic constipation; colonic diverticula; pneumothorax or pneumohaemothorax; nephrolithiasis or cystolithiasis; hydronephrosis; cryptorchidism in males; strabismus; refractive errors; and glaucoma or elevated intraocular pressure.","\"Characteristic craniofacial features\" enumerates eleven findings with no stated threshold, and \"characteristic cutaneous features\" enumerates four introduced by the word \"including\", which makes the list non-exhaustive. Neither is a countable criterion, so both are assertable rather than mapped to an any_of over their components. Mapping either to \"any one of these features\" would make the criterion markedly easier to satisfy than the source intends.","The contracture criterion is \"multiple congenital contractures, characteristically adduction-flexion contractures and/or talipes equinovarus\". HPO has no term for adduction-flexion contracture. The item maps to multiple joint contractures and to talipes equinovarus, which the source names as independently characteristic, and carries a verify string for congenital onset, which HPO does not express here."],"curation":{"encoded_by":"claude-opus-5","notes":"Encoded from the GeneReviews chapter; Malfait 2017 could not be obtained. The combination rule is stated plainly in the source and needed no conservative reading. Two of the three major criteria are gestalt judgements over lists of features with no stated threshold, so they are assertable; this file therefore derives less from an HPO profile than most in this directory, which is a property of the criteria rather than of the encoding.\nRECONCILED against the primary, 2026-09-18, and CORRECTED: the rule is not \"two of three major criteria\". See the first ambiguity entry. The primary also gives the molecular basis as biallelic CHST14 mutations only; DSE was added to the molecular item from the GeneReviews chapter, which reflects later literature rather than the 2017 source.","reviews":[],"source_access":"primary","sources":[{"citation":{"authors":"Malfait F, Francomano C, Byers P, et al.","doi":"10.1002/ajmg.c.31552","journal":"Am J Med Genet C Semin Med Genet","pmid":"28306229","title":"","url":null,"year":2017},"note":"Obtained 2026-09-18 as the publisher PDF and read. This is now the source of record for the rule; the GeneReviews chapter below is retained because it was the basis of the original encoding and because the reconciliation against it is informative.","read":true,"role":"primary","title":"Malfait F, et al. The 2017 international classification of the Ehlers-Danlos syndromes"},{"citation":{"authors":"Kosho T, Yamaguchi T, Mizumoto S, et al.","doi":null,"journal":"GeneReviews, University of Washington, Seattle","pmid":null,"title":"","url":"https://www.ncbi.nlm.nih.gov/books/n/gene/eds-mc/","year":2024},"note":"Reproduces the three major criteria, the fifteen minor criteria and the combination rule, citing Malfait et al 2017 directly. Read 2026-09-17.","read":true,"role":"reproduces","title":"GeneReviews: Musculocontractural Ehlers-Danlos Syndrome"}]},"disease":{"label":"Musculocontractural Ehlers-Danlos syndrome","mondo":"MONDO:0013706","omim":["601776","615539"],"ordo":"ORPHA:2953"},"id":"mceds_malfait_2017","items":[{"hpo":["HP:0002828","HP:0001762"],"id":"congenital_contractures","label":"Multiple congenital contractures","paraphrase":"Multiple congenital contractures, characteristically adduction-flexion contractures and/or talipes equinovarus","rule":null,"source_ref":"Major criteria, item 1","type":"phenotypic","verify":"Confirm the contractures are multiple and congenital. HPO does not carry congenital onset for this term, and has no term for adduction-flexion contracture specifically."},{"hpo":[],"id":"craniofacial_features","label":"Characteristic craniofacial features","paraphrase":"Evident at birth or in early infancy: large anterior fontanel with delayed closure, short and downslanted palpebral fissures, hypertelorism, blue sclera, low-set posteriorly rotated ears, short nose with hypoplastic columella, long philtrum, thin vermilion of the upper lip, small mouth, high palate, micrognathia. A gestalt with no stated threshold, so not derived from a profile.","rule":null,"source_ref":"Major criteria, item 2","type":"assertable","verify":"The source pairs this criterion with congenital contractures for presentation at birth or in early childhood. Confirm the age context."},{"hpo":[],"id":"cutaneous_features","label":"Characteristic cutaneous features","paraphrase":"Including skin hyperextensibility, easy bruisability, skin fragility with atrophic scars, and increased palmar wrinkling. The source's list is introduced by \"including\" and is therefore not exhaustive, so this is not derived from a profile.","rule":null,"source_ref":"Major criteria, item 3","type":"assertable","verify":"The source pairs this criterion with congenital contractures for presentation in adolescence and adulthood. Confirm the age context."},{"hpo":[],"id":"molecular_confirmation","label":"Biallelic pathogenic CHST14 or DSE variants","paraphrase":"Biallelic pathogenic or likely pathogenic variants in CHST14 or DSE identified by molecular genetic testing. Inheritance is autosomal recessive.","rule":null,"source_ref":"Establishing the Diagnosis","type":"assertable","verify":null},{"hpo":[],"id":"two_major_criteria","label":"Congenital contractures plus the age-appropriate second major criterion","paraphrase":null,"rule":{"items":[{"item":"congenital_contractures","kind":"item"},{"items":[{"item":"craniofacial_features","kind":"item"},{"item":"cutaneous_features","kind":"item"}],"kind":"any_of"}],"kind":"all_of"},"source_ref":"Minimal criteria suggestive for mcEDS","type":"composite","verify":null}],"meta":{"citation":{"authors":"Malfait F, Francomano C, Byers P, et al.","doi":"10.1002/ajmg.c.31552","journal":"Am J Med Genet C Semin Med Genet","pmid":"28306229","title":"The 2017 international classification of the Ehlers-Danlos syndromes","url":null,"year":2017},"name":"2017 international classification of the Ehlers-Danlos syndromes, mcEDS criteria","standing":"consensus","standing_note":"GeneReviews (Musculocontractural Ehlers-Danlos Syndrome, last updated 2024, authored by Kosho and colleagues, who describe the mcEDS phenotype in the primary literature) states that \"consensus clinical diagnostic criteria for musculocontractural Ehlers-Danlos syndrome (mcEDS) have been published\", and attributes them to Malfait et al 2017.","supersedes":"eds_villefranche_1998","version":"2017"},"source_path":"criteria/mceds_malfait_2017.yaml","tests":[{"asserted":{"craniofacial_features":true,"cutaneous_features":false,"molecular_confirmation":true},"confirmed":["congenital_contractures"],"excluded":[],"expect":"met","expect_tier":"Musculocontractural EDS, molecularly confirmed","name":"contractures plus craniofacial features: the early-childhood branch","present":["HP:0002828"]},{"asserted":{"craniofacial_features":true,"cutaneous_features":true,"molecular_confirmation":true},"confirmed":["congenital_contractures"],"excluded":[],"expect":"met","expect_tier":"Musculocontractural EDS, molecularly confirmed","name":"contractures plus both gestalt criteria","present":["HP:0001762"]},{"asserted":{"craniofacial_features":false,"cutaneous_features":false,"molecular_confirmation":true},"confirmed":["congenital_contractures"],"excluded":[],"expect":"refuted","expect_tier":null,"name":"contractures alone, both gestalt criteria absent","present":["HP:0002828"]},{"asserted":{"craniofacial_features":false,"cutaneous_features":false},"confirmed":[],"excluded":["HP:0002828","HP:0001762"],"expect":"refuted","expect_tier":null,"name":"no major criteria at all","present":[]},{"asserted":{"craniofacial_features":true,"molecular_confirmation":false},"confirmed":["congenital_contractures"],"excluded":[],"expect":"met","expect_tier":"Clinically suggestive of musculocontractural EDS","name":"two major criteria met but biallelic variants not found","present":["HP:0002828"]},{"asserted":{},"confirmed":["congenital_contractures"],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"one major criterion met, the other two unassessed","present":["HP:0002828"]},{"asserted":{},"confirmed":[],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"empty profile","present":[]},{"asserted":{},"confirmed":[],"excluded":["HP:0002828","HP:0001762"],"expect":"refuted","expect_tier":null,"name":"contractures excluded refutes both branches, whatever else is present","present":[]},{"asserted":{"craniofacial_features":true,"cutaneous_features":true,"molecular_confirmation":true},"confirmed":[],"excluded":["HP:0002828","HP:0001762"],"expect":"refuted","expect_tier":null,"name":"both gestalt criteria without contractures meets neither branch","present":[]},{"asserted":{},"confirmed":["congenital_contractures"],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"contractures present, both gestalt criteria unassessed","present":["HP:0002828"]}],"verdicts":[{"label":"Musculocontractural EDS, molecularly confirmed","rule":{"items":[{"item":"two_major_criteria","kind":"item"},{"item":"molecular_confirmation","kind":"item"}],"kind":"all_of"},"tier":0},{"label":"Clinically suggestive of musculocontractural EDS","rule":{"items":[{"item":"two_major_criteria","kind":"item"}],"kind":"all_of"},"tier":1}]},{"ambiguity":["Footnote a to Table 1 says that if only cafe-au-lait macules and freckling are present the diagnosis is most likely NF1 but might be another condition such as Legius syndrome, and that at least one of the two pigmentary findings should be bilateral. The first half is guidance rather than a rule and is not encoded. The bilaterality requirement is carried on the verify strings of both pigmentary items.","Footnote b says sphenoid wing dysplasia is not a separate criterion when there is an ipsilateral orbital plexiform neurofibroma. Laterality cannot be expressed by the combinators or carried by an HPO term, so it is folded into what the user asserts: `ipsilateral_orbital_plexiform_nf` is asserted true only when the neurofibroma is on the same side as the dysplasia, and the footnote then applies as a none_of. Pass A originally carried this as a verify string, which left it unenforced; the Pass B re-derivation encoded it as logic and that reading was adopted.","Criterion A applies to \"an individual who does not have a parent diagnosed with NF1\", while criterion B speaks of \"a parent who meets the diagnostic criteria specified in A\". Those are not identical: a parent could be diagnosed with NF1 by some other route, such as mosaic NF1 under Table 3 or a historical clinical diagnosis. Both clauses are encoded against the single item `parent_with_nf1`, which reads them as the same thing. A curator should decide whether they warrant separate items; the distinction was raised by the Pass B re-derivation and is not resolved here."],"curation":{"encoded_by":"claude-opus-5","notes":"Encoded from Table 1 (parts A and B) and its two footnotes. Table 3 (mosaic NF1) and Table 2 (Legius syndrome) are separate criteria sets and are not encoded here.\nPass B: an independent LLM re-derivation was run from the same publication in an isolated context on 2026-09-17. It found two real defects, both now fixed: pseudarthrosis was mapped to the tibial term when the criterion says \"a long bone\", and footnote b was carried as an unenforced verify string rather than as logic. Pass B also proposed dropping the \"does not have a parent diagnosed with NF1\" clause from criterion A as scoping prose; that was rejected on the source text, which states it as a condition. That pass is recorded in `curation.reviews`, which carries the file at `reviewed`. It is not a clinician review.","reviews":[{"by":"claude-opus-5 (Pass B, isolated context)","date":"2026-09-17","hpo_release":"v2026-09-01","level":"reviewed","method":"pass_b","note":"Independent re-derivation from the same publication, run under the isolation rule in CONTRIBUTING.md. Two real defects found and fixed: pseudarthrosis was mapped to the tibial term where the criterion says \"a long bone\", and footnote b was carried as an unenforced verify string rather than as logic. One proposal was rejected on the source text: dropping the \"does not have a parent diagnosed with NF1\" clause from criterion A as scoping prose. Same model as Pass A in a separate context, which is weaker than a second curator and is not clinician review."}],"source_access":"primary","sources":[]},"disease":{"label":"Neurofibromatosis type 1","mondo":"MONDO:0018975","omim":["162200"],"ordo":"ORPHA:636"},"id":"nf1_legius_2021","items":[{"hpo":["HP:0000957"],"id":"cafe_au_lait_macules","label":"Cafe-au-lait macules","paraphrase":"Six or more cafe-au-lait macules, over 5 mm in greatest diameter before puberty and over 15 mm after puberty","rule":null,"source_ref":"Table 1A, criterion 1","type":"phenotypic","verify":"Confirm at least 6 macules; >5 mm prepubertal or >15 mm postpubertal; and that at least one pigmentary finding is bilateral"},{"hpo":["HP:0000997","HP:0030052"],"id":"freckling","label":"Skinfold freckling","paraphrase":"Freckling in the axillary or inguinal region","rule":null,"source_ref":"Table 1A, criterion 2","type":"phenotypic","verify":"Confirm at least one pigmentary finding is bilateral"},{"hpo":["HP:0001067"],"id":"multiple_neurofibromas","label":"Two or more neurofibromas of any type","paraphrase":null,"rule":null,"source_ref":"Table 1A, criterion 3 (first limb)","type":"phenotypic","verify":"Confirm at least 2 neurofibromas of any type"},{"hpo":["HP:0009732"],"id":"plexiform_neurofibroma","label":"Plexiform neurofibroma","paraphrase":null,"rule":null,"source_ref":"Table 1A, criterion 3 (second limb)","type":"phenotypic","verify":null},{"hpo":[],"id":"neurofibroma_criterion","label":"Two or more neurofibromas of any type, or one plexiform neurofibroma","paraphrase":null,"rule":{"items":[{"item":"multiple_neurofibromas","kind":"item"},{"item":"plexiform_neurofibroma","kind":"item"}],"kind":"any_of"},"source_ref":"Table 1A, criterion 3","type":"composite","verify":null},{"hpo":["HP:0009734"],"id":"optic_pathway_glioma","label":"Optic pathway glioma","paraphrase":null,"rule":null,"source_ref":"Table 1A, criterion 4","type":"phenotypic","verify":null},{"hpo":["HP:0009737"],"id":"lisch_nodules","label":"Iris Lisch nodules","paraphrase":null,"rule":null,"source_ref":"Table 1A, criterion 5 (first limb)","type":"phenotypic","verify":"Confirm at least 2 nodules, identified by slit lamp examination"},{"hpo":[],"id":"choroidal_abnormalities","label":"Choroidal abnormalities","paraphrase":"Two or more bright patchy choroidal nodules on optical coherence tomography or near-infrared reflectance imaging. Added in the 2021 revision. HPO has no term for this finding; the available choroid terms describe unrelated pathology, so mapping to one would be wrong rather than merely broad.","rule":null,"source_ref":"Table 1A, criterion 5 (second limb)","type":"assertable","verify":null},{"hpo":[],"id":"eye_criterion","label":"Two or more Lisch nodules, or two or more choroidal abnormalities","paraphrase":null,"rule":{"items":[{"item":"lisch_nodules","kind":"item"},{"item":"choroidal_abnormalities","kind":"item"}],"kind":"any_of"},"source_ref":"Table 1A, criterion 5","type":"composite","verify":null},{"hpo":["HP:6001124"],"id":"sphenoid_dysplasia","label":"Sphenoid wing dysplasia","paraphrase":null,"rule":null,"source_ref":"Table 1A, criterion 6 (first limb)","type":"phenotypic","verify":null},{"hpo":[],"id":"ipsilateral_orbital_plexiform_nf","label":"Orbital plexiform neurofibroma ipsilateral to the sphenoid dysplasia","paraphrase":"Laterality cannot be expressed by the combinators or carried by an HPO term, so the ipsilateral relation is folded into what the user asserts: assert this true only when an orbital plexiform neurofibroma is present on the same side as the sphenoid dysplasia.","rule":null,"source_ref":"Table 1A, footnote b","type":"assertable","verify":null},{"hpo":[],"id":"sphenoid_dysplasia_counts","label":"Sphenoid wing dysplasia counting as a separate criterion","paraphrase":null,"rule":{"items":[{"item":"sphenoid_dysplasia","kind":"item"},{"items":[{"item":"ipsilateral_orbital_plexiform_nf","kind":"item"}],"kind":"none_of"}],"kind":"all_of"},"source_ref":"Table 1A, criterion 6 (first limb) with footnote b","type":"composite","verify":null},{"hpo":["HP:0002982"],"id":"anterolateral_tibial_bowing","label":"Anterolateral bowing of the tibia","paraphrase":null,"rule":null,"source_ref":"Table 1A, criterion 6 (second limb)","type":"phenotypic","verify":"Confirm the bowing is anterolateral. HPO has no anterolateral term. HP:0006390 (anterior tibial bowing) is a descendant of this one and would miss a profile recorded at the general term, so the general term carries the item and the direction is confirmed here."},{"hpo":["HP:0005864"],"id":"long_bone_pseudarthrosis","label":"Pseudarthrosis of a long bone","paraphrase":"The criterion says pseudarthrosis of a long bone, naming no particular bone. HP:0005864 is that general term, and the bone-specific terms are its descendants, so a profile recording tibial pseudarthrosis still satisfies it.","rule":null,"source_ref":"Table 1A, criterion 6 (third limb)","type":"phenotypic","verify":"Confirm the affected bone is a long bone. HP:0005864 is not restricted to long bones."},{"hpo":[],"id":"osseous_lesion","label":"Distinctive osseous lesion","paraphrase":null,"rule":{"items":[{"item":"sphenoid_dysplasia_counts","kind":"item"},{"item":"anterolateral_tibial_bowing","kind":"item"},{"item":"long_bone_pseudarthrosis","kind":"item"}],"kind":"any_of"},"source_ref":"Table 1A, criterion 6","type":"composite","verify":null},{"hpo":[],"id":"nf1_pathogenic_variant","label":"Heterozygous pathogenic NF1 variant","paraphrase":"Heterozygous pathogenic NF1 variant with a variant allele fraction of 50% in apparently normal tissue such as white blood cells","rule":null,"source_ref":"Table 1A, criterion 7","type":"assertable","verify":null},{"hpo":[],"id":"parent_with_nf1","label":"A parent who meets the diagnostic criteria for NF1","paraphrase":null,"rule":null,"source_ref":"Table 1B","type":"assertable","verify":null}],"meta":{"citation":{"authors":"Legius E, Messiaen L, Wolkenstein P, et al.","doi":"10.1038/s41436-021-01170-5","journal":"Genet Med","pmid":"34012067","title":"Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation","url":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354850/","year":2021},"name":"Revised diagnostic criteria for neurofibromatosis type 1","standing":"consensus","standing_note":"The publication is titled \"Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation\". Evidence basis: the source's own title.","supersedes":"nf1_nih_1988","version":"2021"},"source_path":"criteria/nf1_legius_2021.yaml","tests":[{"asserted":{"parent_with_nf1":false},"confirmed":["cafe_au_lait_macules","freckling"],"excluded":[],"expect":"met","expect_tier":"NF1 criteria met","name":"sporadic, exactly two criteria (at the boundary)","present":["HP:0000957","HP:0000997"]},{"asserted":{"parent_with_nf1":true},"confirmed":[],"excluded":[],"expect":"met","expect_tier":"NF1 criteria met","name":"affected parent plus exactly one criterion","present":["HP:0009734"]},{"asserted":{},"confirmed":["cafe_au_lait_macules"],"excluded":[],"expect":"met","expect_tier":"NF1 criteria met","name":"two criteria met while parental status is unknown is still met","present":["HP:0000957","HP:0009732"]},{"asserted":{"choroidal_abnormalities":false,"nf1_pathogenic_variant":false,"parent_with_nf1":false},"confirmed":["cafe_au_lait_macules"],"excluded":["HP:0000997","HP:0030052","HP:0001067","HP:0009732","HP:0009734","HP:0009737","HP:6001124","HP:0002982","HP:0005864"],"expect":"refuted","expect_tier":null,"name":"sporadic with exactly one criterion is one below the boundary","present":["HP:0000957"]},{"asserted":{"choroidal_abnormalities":false,"nf1_pathogenic_variant":false,"parent_with_nf1":true},"confirmed":[],"excluded":["HP:0000957","HP:0000997","HP:0030052","HP:0001067","HP:0009732","HP:0009734","HP:0009737","HP:6001124","HP:0002982","HP:0005864"],"expect":"refuted","expect_tier":null,"name":"affected parent but every criterion excluded","present":[]},{"asserted":{},"confirmed":["cafe_au_lait_macules"],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"one criterion met, parent unknown, nothing else assessed","present":["HP:0000957"]},{"asserted":{},"confirmed":[],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"empty profile","present":[]},{"asserted":{"choroidal_abnormalities":false,"nf1_pathogenic_variant":true,"parent_with_nf1":false},"confirmed":[],"excluded":["HP:0000957","HP:0000997","HP:0030052","HP:0001067","HP:0009732","HP:0009734","HP:0009737","HP:6001124","HP:0002982","HP:0005864"],"expect":"refuted","expect_tier":null,"name":"molecular variant alone in a sporadic case is one criterion, not two","present":[]}],"verdicts":[{"label":"NF1 criteria met","rule":{"items":[{"items":[{"items":[{"item":"parent_with_nf1","kind":"item"}],"kind":"none_of"},{"items":[{"item":"cafe_au_lait_macules","kind":"item"},{"item":"freckling","kind":"item"},{"item":"neurofibroma_criterion","kind":"item"},{"item":"optic_pathway_glioma","kind":"item"},{"item":"eye_criterion","kind":"item"},{"item":"osseous_lesion","kind":"item"},{"item":"nf1_pathogenic_variant","kind":"item"}],"k":2,"kind":"n_of"}],"kind":"all_of"},{"items":[{"item":"parent_with_nf1","kind":"item"},{"items":[{"item":"cafe_au_lait_macules","kind":"item"},{"item":"freckling","kind":"item"},{"item":"neurofibroma_criterion","kind":"item"},{"item":"optic_pathway_glioma","kind":"item"},{"item":"eye_criterion","kind":"item"},{"item":"osseous_lesion","kind":"item"},{"item":"nf1_pathogenic_variant","kind":"item"}],"k":1,"kind":"n_of"}],"kind":"all_of"}],"kind":"any_of"},"tier":0}]},{"ambiguity":["The combination rule reads \"1 A plus one other major sign or two minor signs; 1 B plus two major signs or three minor signs\". \"1 A\" and \"1 B\" are read as row 1 (facial), column A and column B, which makes facial involvement obligatory in every combination and makes sense of the word \"other\". A reading in which \"1 A\" means any one major sign would make the criteria much easier to meet, so the obligatory-facial reading is encoded per section 5.1. RESOLVED 2026-09-18. Zenker 2022 Table 1 restates the same rule without the shorthand: definitive NS is criterion 1A (typical face) plus one major from rows 2-6 or two minors from rows 2-6, or criterion 1B (suggestive face) plus two majors from rows 2-6 or three minors from rows 2-6. That names 1A and 1B as the two facial columns, makes facial involvement obligatory, and confines the counted majors and minors to rows 2-6. It is exactly what this file encodes. The reading is no longer a judgement call, and the verdict rules are unchanged.","Rows 2, 3 and 6 have minor definitions that subsume their major definitions: any height below the 3rd percentile is also below the 10th, and all three of the row 6 features include any one of them. Each row is encoded so that it contributes as major or as minor but never both.","\"Typical face dysmorphology\" and \"suggestive face dysmorphology\" are gestalt judgements with no HPO representation and no operational definition in the source. Both are left assertable.","The height row's major and minor definitions differ only by centile, and HPO has one term for short stature, so a profile alone cannot tell them apart: recording HP:0004322 makes both provisionally met and the minor row, which is gated on the major row being absent, can never fire. Assert height_below_p3 false and height_below_p10 true to state that the patient is below the 10th but not the 3rd centile. The engine treats an explicit assertion as overriding what it derived from the profile. UNRESOLVED (raised by Pass B, but see the contamination note): the minor height row reduces to all_of[HP:0004322, none_of[HP:0004322]], which is false under every profile and only ever fires through the assertion override described above. The Pass B re-derivation instead made the minor height an assertable item outright, which is self-documenting and cannot self-cancel. That is probably the better encoding and it changes which patients score the row. It was not adopted here because doing so restructures the row and its test vectors, and a curator should make that call against the 1994 primary. CONTAMINATION: the Pass B agent read the engine's resolution module (then in Python, now src/resolve.js), whose comment names this exact decision. It reports having chosen the opposite before reading and kept its choice, and divergence is not what anchoring produces, but its view on THIS row is not independent evidence. Its findings on every other part of the file are unaffected.","UNRESOLVED (raised by Pass B): two further mappings in row 2 and row 6 are broader than the source wording. \"HOCM\" is mapped to HP:0001639 (hypertrophic cardiomyopathy), which drops the \"obstructive\" qualifier and carries no verify string. PARTLY ADDRESSED 2026-09-18: Zenker 2022 states this row as plain \"hypertrophic cardiomyopathy\", so HP:0001639 is the right term for the criterion as a later expert restatement puts it. The 2007 text this file encodes still says HOCM, so the gap is real but is now a difference between two reproductions rather than an unforced widening; the cardiac-row divergence entry below records the same source disagreement and covers the \"obstructive\" qualifier too. The lymphatic half is untouched. \"Lymphatic dysplasia\" is mapped to HP:0001004 (lymphedema), which is a consequence of lymphatic dysplasia rather than the thing itself. Pass B left both assertable. Either add verify strings or follow Pass B; both readings are currently looser than the source.","DIVERGENCE between the two reproductions, cardiac major (row 2A). van der Burgt 2007, the version this file encodes, admits three alternatives: pulmonary valve stenosis, HOCM, or an ECG typical of NS. Zenker 2022 states the row as pulmonary valve stenosis and/or hypertrophic cardiomyopathy, with no ECG limb and no \"obstructive\". Dropping the ECG limb makes the row harder to satisfy, so the 2022 restatement is the more conservative of the two on this row. The 2007 wording is retained because this file names 2007 as its version; a curator encoding the 2022 restatement instead would remove typical_ecg from cardiac_major. Recorded because the two readings disagree about which patients qualify, not merely about phrasing.","DIVERGENCE between the two reproductions, row 6. van der Burgt 2007 words the row as \"mental retardation\"; Zenker 2022 words it as \"mild developmental delay\". This file maps the item to HP:0001249 (intellectual disability), which follows the 2007 text. HP:0001249 and a developmental delay term are not interchangeable, and the 2022 wording additionally qualifies the delay as mild, which HPO cannot carry. A curator who follows the 2022 restatement would need a different term and a verify string; it is not a relabelling.","Pass B made the minor cardiac row assertable rather than mapping it to HP:0001627 (abnormal heart morphology). That mapping is retained here: the criterion is literally \"other defect\", so a broad term matches the breadth the source intends, and the none_of gate against the major row is what makes it \"other\". Recorded because it is the one place Pass A was judged the better reading of the two."],"curation":{"encoded_by":"claude-opus-5","notes":"Encoded from Table 1 of the 2007 Orphanet review, which is open access, peer reviewed and written by the originator of the scoring system, and which is footnoted \"adapted from\" the 1994 paper. The 1994 paper is paywalled and was NOT read; a Pass B curator should obtain it and reconcile the wording. Note that the 1994 paper is the primary for the *scoring system* only. There is no primary for \"the Noonan criteria\" because, per GeneReviews, none exist: see criteria_set.standing_note, which a reader must see before using anything in this file.\nPass B: an independent LLM re-derivation from the same Table 1 was run on 2026-09-17. Isolation was imperfect: it read engine source that names this condition's height-row decision, which is recorded in the ambiguity list below. Notably, both passes independently reached the same reading of the combination rule footnote - that row 1 column A and column B are the obligatory facial gate rather than \"any one major sign\" - which is the single most contested decision in this file and is untouched by the leak. One fix was adopted: the major cardiac sign was mapped to HP:0001642 (pulmonic stenosis) where the source says pulmonary VALVE stenosis, so it now uses HP:0034350. Three further disagreements are recorded in the ambiguity list below and are NOT resolved. That pass is recorded in `curation.reviews`, which carries the file at `reviewed`. It is not a clinician review, and its isolation was imperfect.\n2026-09-18: Zenker 2022 (Arch Dis Child) was read and added to the source list as a second reproduction, prompted by slide 16 of a RASopathies teaching deck that reprints its Table 1. No rule, item, HPO mapping, verdict or test vector changed. It settles the combination-rule ambiguity in favour of the reading already encoded, and it surfaces two rows on which the two reproductions disagree about substance rather than wording: the cardiac major loses its ECG limb, and row 6 becomes mild developmental delay rather than mental retardation. Both are recorded in the ambiguity list and neither was adopted, because this file encodes the 2007 version. If a curator wants the 2022 wording, that is a separate criteria set, not an edit to this one.","reviews":[{"by":"claude-opus-5 (Pass B, isolated context)","date":"2026-09-17","hpo_release":"v2026-09-01","level":"reviewed","method":"pass_b","note":"Independent re-derivation from the same Table 1. ISOLATION WAS IMPERFECT: the agent read engine source naming this condition's height-row decision and disclosed it unprompted. The leak concerned one row; the finding about that row is recorded as raised-but-not-independently-confirmed. Both passes independently reached the same reading of the combination-rule footnote, which is the most contested decision in this file and is untouched by the leak. One fix was adopted (major cardiac sign remapped to HP:0034350, pulmonary valve stenosis). Three disagreements remain unresolved in the ambiguity list. A curator may reasonably hold that a partially contaminated pass should not carry a file past draft."}],"source_access":"expert_secondary","sources":[{"citation":{"authors":"van der Burgt I, Berends E, Lommen E, et al.","doi":"10.1002/ajmg.1320530213","journal":"Am J Med Genet","pmid":null,"title":"","url":null,"year":1994},"note":"Paywalled, not read. The original source of the scoring system; van der Burgt 2007 Table 1 is footnoted \"adapted from\" it.","read":false,"role":"primary","title":"van der Burgt I, Berends E, Lommen E, et al. Clinical and molecular studies in a large Dutch family with Noonan syndrome"},{"citation":{"authors":"van der Burgt I","doi":"10.1186/1750-1172-2-4","journal":"Orphanet J Rare Dis","pmid":"17222357","title":"","url":null,"year":2007},"note":"Open access, peer reviewed, authored by the originator of the scoring system. The rows, the major/minor definitions and the combination rule are taken from here.","read":true,"role":"reproduces","title":"van der Burgt I. Noonan syndrome. Orphanet J Rare Dis, Table 1"},{"citation":{"authors":"Zenker M, Edouard T, Blair JC, Cappa M","doi":"10.1136/archdischild-2021-322858","journal":"Arch Dis Child","pmid":"35246453","title":"Noonan syndrome: improving recognition and diagnosis","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC9685729/","year":2022},"note":"A second, independent reproduction of the same scoring system: open access, peer reviewed, and footnoted \"adapted from\" van der Burgt 2007. Read 2026-09-18, as the PMC full text and as the table image on slide 16 of the Baynam RASopathies teaching deck that prompted this revision. It restates the combination rule in explicit form and so settles the first ambiguity below. It is NOT the source of any rule in this file: where its wording differs from the 2007 text, the 2007 text is what is encoded, and each difference is recorded in the ambiguity list. Two reproductions that agree on the rule structure is a stronger position than one; they do not agree on every row, and the file says which.","read":true,"role":"reproduces","title":"Zenker M, Edouard T, Blair JC, Cappa M. Noonan syndrome: improving recognition and diagnosis. Arch Dis Child, Table 1"},{"citation":{"authors":"Roberts AE","doi":null,"journal":"GeneReviews, University of Washington, Seattle","pmid":"20301303","title":"","url":"https://www.ncbi.nlm.nih.gov/books/NBK1124/","year":2025},"note":"Consulted for standing, not for rules. Nothing in this file is derived from it. It is the source of criteria_set.standing, and it is the reason this file carries a proposed rather than a consensus label. Read 2026-09-17 against the 2025-12-04 revision.","read":true,"role":"context","title":"GeneReviews: Noonan Syndrome"}]},"disease":{"label":"Noonan syndrome","mondo":"MONDO:0018997","omim":["163950"],"ordo":"ORPHA:648"},"id":"noonan_vanderburgt_2007","items":[{"hpo":[],"id":"typical_face","label":"Typical Noonan facial dysmorphology","paraphrase":null,"rule":null,"source_ref":"Table 1, row 1, column A","type":"assertable","verify":null},{"hpo":[],"id":"suggestive_face","label":"Suggestive Noonan facial dysmorphology","paraphrase":null,"rule":null,"source_ref":"Table 1, row 1, column B","type":"assertable","verify":null},{"hpo":["HP:0034350"],"id":"pulmonary_valve_stenosis","label":"Pulmonary valve stenosis","paraphrase":null,"rule":null,"source_ref":"Table 1, row 2, column A","type":"phenotypic","verify":null},{"hpo":["HP:0001639"],"id":"hocm","label":"Hypertrophic obstructive cardiomyopathy","paraphrase":null,"rule":null,"source_ref":"Table 1, row 2, column A","type":"phenotypic","verify":null},{"hpo":[],"id":"typical_ecg","label":"ECG typical of Noonan syndrome","paraphrase":"HPO has no term for the characteristic Noonan ECG pattern.","rule":null,"source_ref":"Table 1, row 2, column A","type":"assertable","verify":null},{"hpo":[],"id":"cardiac_major","label":"Cardiac: major","paraphrase":null,"rule":{"items":[{"item":"pulmonary_valve_stenosis","kind":"item"},{"item":"hocm","kind":"item"},{"item":"typical_ecg","kind":"item"}],"kind":"any_of"},"source_ref":"Table 1, row 2, column A","type":"composite","verify":null},{"hpo":["HP:0001627"],"id":"other_cardiac_defect","label":"Other cardiac defect","paraphrase":null,"rule":null,"source_ref":"Table 1, row 2, column B","type":"phenotypic","verify":null},{"hpo":[],"id":"cardiac_minor","label":"Cardiac: minor","paraphrase":null,"rule":{"items":[{"items":[{"item":"cardiac_major","kind":"item"}],"kind":"none_of"},{"item":"other_cardiac_defect","kind":"item"}],"kind":"all_of"},"source_ref":"Table 1, row 2, column B","type":"composite","verify":null},{"hpo":["HP:0004322"],"id":"height_below_p3","label":"Height below the 3rd percentile","paraphrase":null,"rule":null,"source_ref":"Table 1, row 3, column A","type":"phenotypic","verify":"Confirm height below the 3rd percentile for age"},{"hpo":["HP:0004322"],"id":"height_below_p10","label":"Height below the 10th percentile","paraphrase":null,"rule":null,"source_ref":"Table 1, row 3, column B","type":"phenotypic","verify":"Confirm height below the 10th percentile for age"},{"hpo":[],"id":"height_minor","label":"Height: minor","paraphrase":null,"rule":{"items":[{"items":[{"item":"height_below_p3","kind":"item"}],"kind":"none_of"},{"item":"height_below_p10","kind":"item"}],"kind":"all_of"},"source_ref":"Table 1, row 3, column B","type":"composite","verify":null},{"hpo":["HP:0000768","HP:0000767"],"id":"pectus_deformity","label":"Pectus carinatum or excavatum","paraphrase":null,"rule":null,"source_ref":"Table 1, row 4, column A","type":"phenotypic","verify":null},{"hpo":["HP:0000914"],"id":"broad_thorax","label":"Broad thorax","paraphrase":null,"rule":null,"source_ref":"Table 1, row 4, column B","type":"phenotypic","verify":null},{"hpo":[],"id":"chest_minor","label":"Chest wall: minor","paraphrase":null,"rule":{"items":[{"items":[{"item":"pectus_deformity","kind":"item"}],"kind":"none_of"},{"item":"broad_thorax","kind":"item"}],"kind":"all_of"},"source_ref":"Table 1, row 4, column B","type":"composite","verify":null},{"hpo":[],"id":"relative_definite_ns","label":"First-degree relative with definite Noonan syndrome","paraphrase":null,"rule":null,"source_ref":"Table 1, row 5, column A","type":"assertable","verify":null},{"hpo":[],"id":"relative_suggestive_ns","label":"First-degree relative with suggestive Noonan syndrome","paraphrase":null,"rule":null,"source_ref":"Table 1, row 5, column B","type":"assertable","verify":null},{"hpo":[],"id":"family_history_minor","label":"Family history: minor","paraphrase":null,"rule":{"items":[{"items":[{"item":"relative_definite_ns","kind":"item"}],"kind":"none_of"},{"item":"relative_suggestive_ns","kind":"item"}],"kind":"all_of"},"source_ref":"Table 1, row 5, column B","type":"composite","verify":null},{"hpo":["HP:0001249"],"id":"intellectual_disability","label":"Intellectual disability","paraphrase":null,"rule":null,"source_ref":"Table 1, row 6","type":"phenotypic","verify":null},{"hpo":["HP:0000028"],"id":"cryptorchidism","label":"Cryptorchidism","paraphrase":null,"rule":null,"source_ref":"Table 1, row 6","type":"phenotypic","verify":null},{"hpo":["HP:0001004"],"id":"lymphatic_dysplasia","label":"Lymphatic dysplasia","paraphrase":null,"rule":null,"source_ref":"Table 1, row 6","type":"phenotypic","verify":null},{"hpo":[],"id":"other_major","label":"Other: all three of intellectual disability, cryptorchidism and lymphatic dysplasia","paraphrase":null,"rule":{"items":[{"item":"intellectual_disability","kind":"item"},{"item":"cryptorchidism","kind":"item"},{"item":"lymphatic_dysplasia","kind":"item"}],"kind":"all_of"},"source_ref":"Table 1, row 6, column A","type":"composite","verify":null},{"hpo":[],"id":"other_minor","label":"Other: one of the three, but not all three","paraphrase":null,"rule":{"items":[{"items":[{"item":"other_major","kind":"item"}],"kind":"none_of"},{"items":[{"item":"intellectual_disability","kind":"item"},{"item":"cryptorchidism","kind":"item"},{"item":"lymphatic_dysplasia","kind":"item"}],"kind":"any_of"}],"kind":"all_of"},"source_ref":"Table 1, row 6, column B","type":"composite","verify":null}],"meta":{"citation":{"authors":"van der Burgt I","doi":"10.1186/1750-1172-2-4","journal":"Orphanet J Rare Dis","pmid":"17222357","title":"Noonan syndrome","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC1781428/","year":2007},"name":"van der Burgt scoring system for Noonan syndrome","standing":"proposed","standing_note":"NOT consensus criteria. GeneReviews (Noonan Syndrome, NBK1124, last revised 2025-12-04) states plainly: \"No consensus clinical diagnostic criteria for Noonan syndrome have been published. Diagnostic scoring systems, most recently published in van der Burgt [2007] and embedded in the management guidelines developed by DYSCERNE in the United Kingdom [Noonan Syndrome Guideline Development Group 2010], have been proposed but have not been used extensively in North America.\" GeneReviews establishes the diagnosis molecularly instead, on suggestive findings plus a pathogenic variant. This file therefore encodes a proposed scoring system faithfully; it does not encode \"the\" Noonan criteria, because there are none. A user should read a verdict here as \"meets the van der Burgt score\", never as \"has Noonan syndrome\".","supersedes":null,"version":"2007"},"source_path":"criteria/noonan_vanderburgt_2007.yaml","tests":[{"asserted":{"typical_face":true},"confirmed":[],"excluded":[],"expect":"met","expect_tier":"Definite Noonan syndrome","name":"typical face plus one major sign","present":["HP:0034350"]},{"asserted":{"suggestive_face":true,"typical_face":false},"confirmed":[],"excluded":[],"expect":"met","expect_tier":"Definite Noonan syndrome","name":"suggestive face plus exactly two major signs","present":["HP:0034350","HP:0000768"]},{"asserted":{"relative_definite_ns":false,"relative_suggestive_ns":false,"suggestive_face":true,"typical_ecg":false,"typical_face":false},"confirmed":[],"excluded":["HP:0004322","HP:0000768","HP:0000767","HP:0000914","HP:0001249","HP:0000028","HP:0001004","HP:0001627"],"expect":"refuted","expect_tier":null,"name":"suggestive face plus exactly one major sign is one short","present":["HP:0034350"]},{"asserted":{"typical_ecg":false,"typical_face":true},"confirmed":[],"excluded":["HP:0034350","HP:0001639","HP:0000768","HP:0000767"],"expect":"met","expect_tier":"Definite Noonan syndrome","name":"typical face plus exactly two minor signs","present":["HP:0001627","HP:0000914"]},{"asserted":{"suggestive_face":false,"typical_face":false},"confirmed":[],"excluded":[],"expect":"refuted","expect_tier":null,"name":"no facial involvement refutes every combination","present":["HP:0034350","HP:0004322","HP:0000768","HP:0001249","HP:0000028","HP:0001004"]},{"asserted":{"relative_definite_ns":false,"relative_suggestive_ns":false,"suggestive_face":true,"typical_ecg":false,"typical_face":false},"confirmed":["height_below_p3","height_below_p10"],"excluded":["HP:0034350","HP:0001639","HP:0001627","HP:0000768","HP:0000767","HP:0000914","HP:0001249","HP:0000028","HP:0001004"],"expect":"refuted","expect_tier":null,"name":"a height below the 3rd percentile counts as major, not also as minor","present":["HP:0004322"]},{"asserted":{},"confirmed":[],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"facial status unknown with several major signs present","present":["HP:0034350","HP:0000768"]},{"asserted":{},"confirmed":[],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"empty profile","present":[]},{"asserted":{"relative_definite_ns":false,"relative_suggestive_ns":false,"suggestive_face":false,"typical_ecg":false,"typical_face":true},"confirmed":[],"excluded":["HP:0034350","HP:0001639","HP:0001627","HP:0004322","HP:0000768","HP:0000767","HP:0000914","HP:0001249","HP:0000028","HP:0001004"],"expect":"refuted","expect_tier":null,"name":"typical face alone is not sufficient","present":[]}],"verdicts":[{"label":"Definite Noonan syndrome","rule":{"items":[{"items":[{"item":"typical_face","kind":"item"},{"items":[{"item":"cardiac_major","kind":"item"},{"item":"height_below_p3","kind":"item"},{"item":"pectus_deformity","kind":"item"},{"item":"relative_definite_ns","kind":"item"},{"item":"other_major","kind":"item"}],"k":1,"kind":"n_of"}],"kind":"all_of"},{"items":[{"item":"typical_face","kind":"item"},{"items":[{"item":"cardiac_minor","kind":"item"},{"item":"height_minor","kind":"item"},{"item":"chest_minor","kind":"item"},{"item":"family_history_minor","kind":"item"},{"item":"other_minor","kind":"item"}],"k":2,"kind":"n_of"}],"kind":"all_of"},{"items":[{"item":"suggestive_face","kind":"item"},{"items":[{"item":"cardiac_major","kind":"item"},{"item":"height_below_p3","kind":"item"},{"item":"pectus_deformity","kind":"item"},{"item":"relative_definite_ns","kind":"item"},{"item":"other_major","kind":"item"}],"k":2,"kind":"n_of"}],"kind":"all_of"},{"items":[{"item":"suggestive_face","kind":"item"},{"items":[{"item":"cardiac_minor","kind":"item"},{"item":"height_minor","kind":"item"},{"item":"chest_minor","kind":"item"},{"item":"family_history_minor","kind":"item"},{"item":"other_minor","kind":"item"}],"k":3,"kind":"n_of"}],"kind":"all_of"}],"kind":"any_of"},"tier":0}]},{"ambiguity":["The source states that the criteria \"will not be suitable to make a diagnosis in children\" younger than about ten, because generalized lack of attached gingiva is the only finding consistently present at that age. The schema has no way to gate a whole criteria set on age, so this is not encoded as logic. It is stated here and in the age verify string on the periodontitis item. A verdict from this file on a young child should be disregarded.","\"At least two other major criteria\" is read as two major criteria other than the one used to satisfy the first clause. Encoded by requiring the first clause plus two of the three remaining majors, enumerated over both ways the first clause can be satisfied. The alternative reading, that any two majors count including the one already used, would make the rule satisfiable by three majors rather than effectively three distinct ones, and is the weaker reading; the stricter one is encoded.","Acrogeria and marfanoid facial features are named as minor criteria and have no HPO term. Both are assertable rather than mapped to an approximation.","The source lists \"skin hyperextensibility and fragility, abnormal scarring (wide or atrophic)\" as a single minor criterion. It is encoded as one item satisfied by any of those findings, since the source presents them as one criterion rather than as separate ones."],"curation":{"encoded_by":"claude-opus-5","notes":"Encoded from the GeneReviews chapter. Unlike the cEDS chapter, this one states the combination rule explicitly and unambiguously, so no conservative reading was needed for the logic. Malfait 2017 itself was not obtained and a Pass B curator should still reconcile the item wording.\nRECONCILED against the primary, 2026-09-18. The primary states the rule as \"Major criterion (1): severe and intractable periodontitis of early onset / OR major criterion (2): lack of attached gingiva / Plus / At least two other major criteria and one minor criterion\". This matches the encoding exactly, including the reading of \"two OTHER major criteria\" as excluding the one used to satisfy the gate.","reviews":[],"source_access":"primary","sources":[{"citation":{"authors":"Malfait F, Francomano C, Byers P, et al.","doi":"10.1002/ajmg.c.31552","journal":"Am J Med Genet C Semin Med Genet","pmid":"28306229","title":"","url":null,"year":2017},"note":"Obtained 2026-09-18 as the publisher PDF and read. This is now the source of record for the rule; the GeneReviews chapter below is retained because it was the basis of the original encoding and because the reconciliation against it is informative.","read":true,"role":"primary","title":"Malfait F, et al. The 2017 international classification of the Ehlers-Danlos syndromes"},{"citation":{"authors":"Kapferer-Seebacher I, van Dijk FS, Zschocke J","doi":null,"journal":"GeneReviews, University of Washington, Seattle","pmid":null,"title":"","url":"https://www.ncbi.nlm.nih.gov/books/n/gene/eds-pd/","year":2024},"note":"Reproduces the four major criteria, the eight minor criteria and an explicit \"Minimal criteria suggestive for pEDS\" combination rule, which is the rule encoded here. Co-authored by Kapferer-Seebacher, who leads the pEDS literature the criteria rest on. Read 2026-09-17.","read":true,"role":"reproduces","title":"GeneReviews: Periodontal Ehlers-Danlos Syndrome"}]},"disease":{"label":"Periodontal Ehlers-Danlos syndrome","mondo":"MONDO:0019566","omim":["130080","617174"],"ordo":"ORPHA:75392"},"id":"peds_malfait_2017","items":[{"hpo":["HP:0000166"],"id":"severe_early_periodontitis","label":"Severe periodontitis of early onset","paraphrase":"Severe and intractable periodontitis beginning in childhood or adolescence","rule":null,"source_ref":"Major criteria, item 1","type":"phenotypic","verify":"Confirm onset in childhood or adolescence, and that the periodontitis is severe and intractable. HPO carries severity but not age of onset."},{"hpo":["HP:6001467"],"id":"lack_of_attached_gingiva","label":"Generalized lack of attached gingiva","paraphrase":null,"rule":null,"source_ref":"Major criteria, item 2","type":"phenotypic","verify":"Confirm the lack is generalized. The source notes that a complete lack of attached gingiva is considered pathognomonic for pEDS."},{"hpo":["HP:0034517"],"id":"pretibial_plaques","label":"Pretibial plaques","paraphrase":"Pretibial plaques with haemosiderin deposition","rule":null,"source_ref":"Major criteria, item 3","type":"phenotypic","verify":null},{"hpo":[],"id":"family_history_peds","label":"Family history of pEDS in a first-degree relative","paraphrase":"A first-degree relative who meets these diagnostic criteria. The source notes that absence of a known family history does not preclude the diagnosis.","rule":null,"source_ref":"Major criteria, item 4","type":"assertable","verify":null},{"hpo":["HP:0000978"],"id":"easy_bruising","label":"Easy bruising","paraphrase":null,"rule":null,"source_ref":"Minor criteria, item 1","type":"phenotypic","verify":null},{"hpo":["HP:0001015","HP:0007394"],"id":"prominent_vasculature","label":"Prominent vasculature","paraphrase":null,"rule":null,"source_ref":"Minor criteria, item 2","type":"phenotypic","verify":null},{"hpo":["HP:0020152","HP:0001382"],"id":"distal_joint_hypermobility","label":"Joint hypermobility, mostly distal","paraphrase":null,"rule":null,"source_ref":"Minor criteria, item 3","type":"phenotypic","verify":"The source specifies hypermobility that is mostly distal. HP:0001382 is included because a profile recording only generic joint hypermobility should not silently miss the criterion; confirm the distribution."},{"hpo":["HP:0100790"],"id":"hernias","label":"Hernias","paraphrase":null,"rule":null,"source_ref":"Minor criteria, item 4","type":"phenotypic","verify":null},{"hpo":[],"id":"marfanoid_facial_features","label":"Marfanoid facial features","paraphrase":"No HPO term captures this; left assertable rather than approximated","rule":null,"source_ref":"Minor criteria, item 5","type":"assertable","verify":null},{"hpo":[],"id":"acrogeria","label":"Acrogeria","paraphrase":"An aged appearance of the extremities, particularly the hands. No HPO term; left assertable rather than approximated.","rule":null,"source_ref":"Minor criteria, item 6","type":"assertable","verify":null},{"hpo":["HP:0000974","HP:0001030","HP:0001075","HP:0031158"],"id":"skin_involvement","label":"Skin hyperextensibility and fragility, abnormal scarring","paraphrase":"Skin hyperextensibility and fragility, abnormal scarring (wide or atrophic)","rule":null,"source_ref":"Minor criteria, item 7","type":"phenotypic","verify":null},{"hpo":["HP:0002719"],"id":"increased_infections","label":"Increased rate of infections","paraphrase":null,"rule":null,"source_ref":"Minor criteria, item 8","type":"phenotypic","verify":null},{"hpo":[],"id":"one_minor_criterion","label":"At least one minor criterion","paraphrase":null,"rule":{"items":[{"item":"easy_bruising","kind":"item"},{"item":"prominent_vasculature","kind":"item"},{"item":"distal_joint_hypermobility","kind":"item"},{"item":"hernias","kind":"item"},{"item":"marfanoid_facial_features","kind":"item"},{"item":"acrogeria","kind":"item"},{"item":"skin_involvement","kind":"item"},{"item":"increased_infections","kind":"item"}],"kind":"any_of"},"source_ref":"Minimal criteria suggestive for pEDS, third clause","type":"composite","verify":null},{"hpo":[],"id":"clinically_suggestive","label":"Minimal criteria suggestive for pEDS","paraphrase":null,"rule":{"items":[{"items":[{"items":[{"item":"severe_early_periodontitis","kind":"item"},{"items":[{"item":"lack_of_attached_gingiva","kind":"item"},{"item":"pretibial_plaques","kind":"item"},{"item":"family_history_peds","kind":"item"}],"k":2,"kind":"n_of"}],"kind":"all_of"},{"items":[{"item":"lack_of_attached_gingiva","kind":"item"},{"items":[{"item":"severe_early_periodontitis","kind":"item"},{"item":"pretibial_plaques","kind":"item"},{"item":"family_history_peds","kind":"item"}],"k":2,"kind":"n_of"}],"kind":"all_of"}],"kind":"any_of"},{"item":"one_minor_criterion","kind":"item"}],"kind":"all_of"},"source_ref":"Minimal criteria suggestive for pEDS","type":"composite","verify":null},{"hpo":[],"id":"molecular_confirmation","label":"Pathogenic gain-of-function C1R or C1S variant","paraphrase":"A heterozygous pathogenic gain-of-function variant in C1R or C1S identified by molecular genetic testing","rule":null,"source_ref":"Establishing the Diagnosis","type":"assertable","verify":null}],"meta":{"citation":{"authors":"Malfait F, Francomano C, Byers P, et al.","doi":"10.1002/ajmg.c.31552","journal":"Am J Med Genet C Semin Med Genet","pmid":"28306229","title":"The 2017 international classification of the Ehlers-Danlos syndromes","url":null,"year":2017},"name":"2017 international classification of the Ehlers-Danlos syndromes, pEDS criteria","standing":"consensus","standing_note":"Published diagnostic criteria. GeneReviews (Periodontal Ehlers-Danlos Syndrome, NBK1533, last updated 2024) reproduces them as the \"minimal criteria suggestive for pEDS\" and refers to \"the publication of the diagnostic criteria for pEDS [Malfait et al 2017]\". Note the source's own caveat, recorded as an ambiguity below: the criteria are stated to be unsuitable for diagnosis in children under ten.","supersedes":"eds_villefranche_1998","version":"2017"},"source_path":"criteria/peds_malfait_2017.yaml","tests":[{"asserted":{"molecular_confirmation":true},"confirmed":["severe_early_periodontitis","lack_of_attached_gingiva"],"excluded":[],"expect":"met","expect_tier":"Periodontal EDS, molecularly confirmed","name":"gating major plus two others plus one minor, with a variant","present":["HP:0000166","HP:6001467","HP:0034517","HP:0000978"]},{"asserted":{"family_history_peds":true,"molecular_confirmation":true},"confirmed":["lack_of_attached_gingiva"],"excluded":["HP:0000166"],"expect":"met","expect_tier":"Periodontal EDS, molecularly confirmed","name":"gating major satisfied by lack of attached gingiva instead","present":["HP:6001467","HP:0034517","HP:0002719"]},{"asserted":{"family_history_peds":false,"molecular_confirmation":true},"confirmed":["severe_early_periodontitis"],"excluded":["HP:6001467"],"expect":"refuted","expect_tier":null,"name":"only one other major criterion is one below the boundary","present":["HP:0000166","HP:0034517","HP:0000978"]},{"asserted":{"acrogeria":false,"marfanoid_facial_features":false,"molecular_confirmation":true},"confirmed":["severe_early_periodontitis","lack_of_attached_gingiva"],"excluded":["HP:0000978","HP:0001015","HP:0007394","HP:0020152","HP:0001382","HP:0100790","HP:0000974","HP:0001030","HP:0001075","HP:0031158","HP:0002719"],"expect":"refuted","expect_tier":null,"name":"three major criteria but no minor criterion at all","present":["HP:0000166","HP:6001467","HP:0034517"]},{"asserted":{"family_history_peds":true},"confirmed":[],"excluded":["HP:0000166","HP:6001467"],"expect":"refuted","expect_tier":null,"name":"neither gating major criterion is present","present":["HP:0034517","HP:0000978"]},{"asserted":{"molecular_confirmation":false},"confirmed":["severe_early_periodontitis","lack_of_attached_gingiva"],"excluded":[],"expect":"met","expect_tier":"Clinically suggestive of periodontal EDS","name":"clinical criteria met, molecular testing not done","present":["HP:0000166","HP:6001467","HP:0034517","HP:0000978"]},{"asserted":{},"confirmed":["severe_early_periodontitis"],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"gating major present, the rest unassessed","present":["HP:0000166"]},{"asserted":{},"confirmed":[],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"empty profile","present":[]},{"asserted":{},"confirmed":["severe_early_periodontitis","lack_of_attached_gingiva"],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"two majors and a minor, third major open","present":["HP:0000166","HP:6001467","HP:0000978"]}],"verdicts":[{"label":"Periodontal EDS, molecularly confirmed","rule":{"items":[{"item":"clinically_suggestive","kind":"item"},{"item":"molecular_confirmation","kind":"item"}],"kind":"all_of"},"tier":0},{"label":"Clinically suggestive of periodontal EDS","rule":{"items":[{"item":"clinically_suggestive","kind":"item"}],"kind":"all_of"},"tier":1}]},{"ambiguity":["Table 1 heads the exclusion list \"Exclusion Criteria for typical RTT\", and the atypical requirements do not mention them. The exclusions are therefore applied to the typical tier only. This is the reading the table's own headings give, but it is the less conservative one, so a Pass B curator should confirm it against the body text.","\"Consider diagnosis when postnatal deceleration of head growth observed\" is a prompt to consider the diagnosis, not a criterion, and is not encoded as an item. HP:6001484 is the term a curator would use if a future revision promotes it.","The regression footnote describes a \"possible RTT\" label for individuals under 3 years with suggestive features who have not yet regressed. That is a provisional holding category rather than a diagnostic tier and is not encoded; encoding it would require an age model the schema deliberately does not have."],"curation":{"encoded_by":"claude-opus-5","notes":"Encoded from Table 1 of the primary publication and its footnotes. Pass A only.","reviews":[],"source_access":"primary","sources":[]},"disease":{"label":"Rett syndrome","mondo":"MONDO:0010726","omim":["312750"],"ordo":"ORPHA:778"},"id":"rett_neul_2010","items":[{"hpo":["HP:0002376"],"id":"regression","label":"A period of regression followed by recovery or stabilization","paraphrase":null,"rule":null,"source_ref":"Table 1, required criterion","type":"phenotypic","verify":"Confirm the regression was followed by recovery or stabilization"},{"hpo":["HP:6001482"],"id":"loss_of_hand_skills","label":"Partial or complete loss of acquired purposeful hand skills","paraphrase":null,"rule":null,"source_ref":"Table 1, main criterion 1","type":"phenotypic","verify":null},{"hpo":["HP:0002371"],"id":"loss_of_spoken_language","label":"Partial or complete loss of acquired spoken language","paraphrase":"Judged against best acquired spoken language skill; loss of babbling counts as loss of acquired language","rule":null,"source_ref":"Table 1, main criterion 2","type":"phenotypic","verify":null},{"hpo":["HP:0001288","HP:0002540"],"id":"gait_abnormalities","label":"Gait abnormalities","paraphrase":"Impaired (dyspraxic) gait or absence of the ability to walk","rule":null,"source_ref":"Table 1, main criterion 3","type":"phenotypic","verify":null},{"hpo":["HP:5200018"],"id":"stereotypic_hand_movements","label":"Stereotypic hand movements","paraphrase":null,"rule":null,"source_ref":"Table 1, main criterion 4","type":"phenotypic","verify":"Confirm the stereotypies are of the hands: wringing/squeezing, clapping/tapping, mouthing, or washing/rubbing automatisms"},{"hpo":[],"id":"brain_injury","label":"Brain injury, neurometabolic disease or severe infection","paraphrase":"Brain injury secondary to peri- or postnatal trauma, neurometabolic disease, or severe infection causing neurological problems, with clear evidence that the insult directly resulted in the neurological dysfunction","rule":null,"source_ref":"Table 1, exclusion criterion 1","type":"assertable","verify":null},{"hpo":[],"id":"grossly_abnormal_early_development","label":"Grossly abnormal psychomotor development in the first 6 months","paraphrase":"Abnormal to the point that normal milestones (head control, swallowing, social smile) are not met","rule":null,"source_ref":"Table 1, exclusion criterion 2","type":"assertable","verify":null},{"hpo":["HP:0005957"],"id":"breathing_disturbances","label":"Breathing disturbances when awake","paraphrase":null,"rule":null,"source_ref":"Table 1, supportive criterion 1","type":"phenotypic","verify":"Confirm the disturbance occurs when awake"},{"hpo":["HP:0003763"],"id":"bruxism","label":"Bruxism when awake","paraphrase":null,"rule":null,"source_ref":"Table 1, supportive criterion 2","type":"phenotypic","verify":"Confirm the bruxism occurs when awake"},{"hpo":["HP:0002360"],"id":"impaired_sleep","label":"Impaired sleep pattern","paraphrase":null,"rule":null,"source_ref":"Table 1, supportive criterion 3","type":"phenotypic","verify":null},{"hpo":["HP:0003808"],"id":"abnormal_muscle_tone","label":"Abnormal muscle tone","paraphrase":null,"rule":null,"source_ref":"Table 1, supportive criterion 4","type":"phenotypic","verify":null},{"hpo":[],"id":"peripheral_vasomotor_disturbances","label":"Peripheral vasomotor disturbances","paraphrase":"No HPO term captures peripheral vasomotor disturbance.","rule":null,"source_ref":"Table 1, supportive criterion 5","type":"assertable","verify":null},{"hpo":["HP:0002650","HP:0002808"],"id":"scoliosis_kyphosis","label":"Scoliosis or kyphosis","paraphrase":null,"rule":null,"source_ref":"Table 1, supportive criterion 6","type":"phenotypic","verify":null},{"hpo":["HP:0001510"],"id":"growth_retardation","label":"Growth retardation","paraphrase":null,"rule":null,"source_ref":"Table 1, supportive criterion 7","type":"phenotypic","verify":null},{"hpo":[],"id":"small_cold_hands_and_feet","label":"Small cold hands and feet","paraphrase":"The criterion conjoins size and temperature across both hands and feet. 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Every such item is marked with a verify string, so the engine reports it as provisionally met until a human confirms the measurement. Treat an unconfirmed NH-CSS count as an upper bound.","\"Molecular testing indicated (>=3/6)\" is a testing recommendation from Figure 1, not a diagnostic category. It is encoded as a weakest tier so the tool can say something useful below the diagnostic threshold, and labelled accordingly."],"curation":{"encoded_by":"claude-opus-5","notes":"Encoded from Table 1 of the primary publication and its footnotes, plus the testing thresholds in the body text. 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No HPO term captures this specifically; mapping it to a general neuronal migration abnormality would be a broadening of the criterion, so it is left assertable (section 5.2).","rule":null,"source_ref":"Table 2, major feature 6 (second limb)","type":"assertable","verify":null},{"hpo":[],"id":"tubers_or_migration_lines","label":"Multiple cortical tubers and/or radial migration lines","paraphrase":null,"rule":{"items":[{"item":"cortical_tubers","kind":"item"},{"item":"radial_migration_lines","kind":"item"}],"kind":"any_of"},"source_ref":"Table 2, major feature 6","type":"composite","verify":null},{"hpo":["HP:0009716"],"id":"subependymal_nodules","label":"Subependymal nodules","paraphrase":null,"rule":null,"source_ref":"Table 2, major feature 7","type":"phenotypic","verify":"Confirm at least 2 subependymal nodules"},{"hpo":["HP:0009718"],"id":"sega","label":"Subependymal giant cell astrocytoma","paraphrase":null,"rule":null,"source_ref":"Table 2, major feature 8","type":"phenotypic","verify":null},{"hpo":["HP:0009729"],"id":"cardiac_rhabdomyoma","label":"Cardiac rhabdomyoma","paraphrase":null,"rule":null,"source_ref":"Table 2, major feature 9","type":"phenotypic","verify":null},{"hpo":["HP:0012798"],"id":"lam","label":"Lymphangioleiomyomatosis","paraphrase":null,"rule":null,"source_ref":"Table 2, major feature 10","type":"phenotypic","verify":null},{"hpo":["HP:0006772"],"id":"angiomyolipomas","label":"Angiomyolipomas","paraphrase":null,"rule":null,"source_ref":"Table 2, major feature 11","type":"phenotypic","verify":"Confirm at least 2 angiomyolipomas"},{"hpo":["HP:0007449"],"id":"confetti_lesions","label":"Confetti skin lesions","paraphrase":null,"rule":null,"source_ref":"Table 2, minor feature 1","type":"phenotypic","verify":null},{"hpo":["HP:0009722"],"id":"dental_enamel_pits","label":"Dental enamel pits","paraphrase":null,"rule":null,"source_ref":"Table 2, minor feature 2","type":"phenotypic","verify":"Confirm at least 3 dental enamel pits"},{"hpo":[],"id":"intraoral_fibromas","label":"Intraoral fibromas","paraphrase":"Two or more intraoral fibromas. No HPO term for intraoral fibroma; left assertable rather than approximated.","rule":null,"source_ref":"Table 2, minor feature 3","type":"assertable","verify":null},{"hpo":[],"id":"retinal_achromic_patch","label":"Retinal achromic patch","paraphrase":"No HPO term captures a retinal achromic patch specifically.","rule":null,"source_ref":"Table 2, minor feature 4","type":"assertable","verify":null},{"hpo":["HP:0005562"],"id":"multiple_renal_cysts","label":"Multiple renal cysts","paraphrase":null,"rule":null,"source_ref":"Table 2, minor feature 5","type":"phenotypic","verify":null},{"hpo":[],"id":"nonrenal_hamartomas","label":"Nonrenal hamartomas","paraphrase":"The criterion is defined by exclusion of a site, which HPO cannot express; left assertable.","rule":null,"source_ref":"Table 2, minor feature 6","type":"assertable","verify":null},{"hpo":[],"id":"sclerotic_bone_lesions","label":"Sclerotic bone lesions","paraphrase":"Reinstated as a minor feature in the 2021 revision. HPO has only site-specific sclerosis terms, so a faithful single mapping is not available.","rule":null,"source_ref":"Table 2, minor feature 7","type":"assertable","verify":null},{"hpo":[],"id":"tsc_pathogenic_variant","label":"Pathogenic TSC1 or TSC2 variant","paraphrase":"A pathogenic variant in TSC1 or TSC2. Variants compatible with protein production should be considered with caution.","rule":null,"source_ref":"Table 2, genetic diagnosis","type":"assertable","verify":null}],"meta":{"citation":{"authors":"Northrup H, Aronow ME, Bebin EM, et al.","doi":"10.1016/j.pediatrneurol.2021.07.011","journal":"Pediatr Neurol","pmid":"34399110","title":"Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations","url":"https://www.pedneur.com/article/S0887-8994(21)00151-X/fulltext","year":2021},"name":"Updated International TSC Diagnostic Criteria","standing":"consensus","standing_note":"GeneReviews (Tuberous Sclerosis Complex) states: \"Consensus clinical diagnostic criteria for tuberous sclerosis complex (TSC) have been published [Northrup et al 2021]\". Evidence basis: that chapter, read 2026-09-18, plus the source's own title, which names it the updated International TSC diagnostic criteria.","supersedes":"tsc_northrup_2013","version":"2021"},"source_path":"criteria/tsc_northrup_2021.yaml","tests":[{"asserted":{},"confirmed":["cortical_tubers"],"excluded":[],"expect":"met","expect_tier":"Definite TSC","name":"definite via exactly two major features (at the boundary)","present":["HP:0009717","HP:0009729"]},{"asserted":{},"confirmed":[],"excluded":[],"expect":"met","expect_tier":"Definite TSC","name":"definite via one major and exactly two minor features","present":["HP:0009721","HP:0007449","HP:0005562"]},{"asserted":{"tsc_pathogenic_variant":true},"confirmed":[],"excluded":[],"expect":"met","expect_tier":"Definite TSC","name":"definite via genetic diagnosis 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definite","present":["HP:0012798","HP:0006772"]},{"asserted":{"fibrous_cephalic_plaque":false,"intraoral_fibromas":false,"nonrenal_hamartomas":false,"radial_migration_lines":false,"retinal_achromic_patch":false,"sclerotic_bone_lesions":false,"tsc_pathogenic_variant":false},"confirmed":[],"excluded":["HP:0009719","HP:0009720","HP:0009724","HP:0009721","HP:0009594","HP:0009717","HP:0009716","HP:0009718","HP:0009729","HP:0012798","HP:0006772","HP:0009722","HP:0005562"],"expect":"refuted","expect_tier":null,"name":"one minor feature only, everything else excluded (one below the two-minor boundary)","present":["HP:0007449"]},{"asserted":{"fibrous_cephalic_plaque":false,"intraoral_fibromas":false,"nonrenal_hamartomas":false,"radial_migration_lines":false,"retinal_achromic_patch":false,"sclerotic_bone_lesions":false,"tsc_pathogenic_variant":false},"confirmed":[],"excluded":["HP:0009719","HP:0009720","HP:0009724","HP:0009721","HP:0009594","HP:0009717","HP:0009716","HP:0009718","HP:0009729","HP:0012798","HP:0006772","HP:0007449","HP:0009722","HP:0005562"],"expect":"refuted","expect_tier":null,"name":"every feature excluded","present":[]},{"asserted":{},"confirmed":[],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"empty profile is indeterminate, not refuted","present":[]},{"asserted":{},"confirmed":[],"excluded":[],"expect":"indeterminate","expect_tier":null,"name":"one minor feature with nothing else assessed","present":["HP:0005562"]}],"verdicts":[{"label":"Definite TSC","rule":{"items":[{"item":"tsc_pathogenic_variant","kind":"item"},{"items":[{"items":[{"item":"hypomelanotic_macules","kind":"item"},{"item":"angiofibroma_or_plaque","kind":"item"},{"item":"ungual_fibromas","kind":"item"},{"item":"shagreen_patch","kind":"item"},{"item":"retinal_hamartomas","kind":"item"},{"item":"tubers_or_migration_lines","kind":"item"},{"item":"subependymal_nodules","kind":"item"},{"item":"sega","kind":"item"},{"item":"cardiac_rhabdomyoma","kind":"item"},{"item":"lam","kind":"item"},{"item":"angiomyolipomas","kind":"item"}],"k":2,"kind":"n_of"},{"items":[{"items":[{"item":"hypomelanotic_macules","kind":"item"},{"item":"angiofibroma_or_plaque","kind":"item"},{"item":"ungual_fibromas","kind":"item"},{"item":"shagreen_patch","kind":"item"},{"item":"retinal_hamartomas","kind":"item"},{"item":"tubers_or_migration_lines","kind":"item"},{"item":"subependymal_nodules","kind":"item"},{"item":"sega","kind":"item"},{"item":"cardiac_rhabdomyoma","kind":"item"}],"k":1,"kind":"n_of"},{"items":[{"item":"confetti_lesions","kind":"item"},{"item":"dental_enamel_pits","kind":"item"},{"item":"intraoral_fibromas","kind":"item"},{"item":"retinal_achromic_patch","kind":"item"},{"item":"multiple_renal_cysts","kind":"item"},{"item":"nonrenal_hamartomas","kind":"item"},{"item":"sclerotic_bone_lesions","kind":"item"}],"k":1,"kind":"n_of"}],"kind":"any_of"}],"kind":"all_of"},{"items":[{"items":[{"item":"hypomelanotic_macules","kind":"item"},{"item":"angiofibroma_or_plaque","kind":"item"},{"item":"ungual_fibromas","kind":"item"},{"item":"shagreen_patch","kind":"item"},{"item":"retinal_hamartomas","kind":"item"},{"item":"tubers_or_migration_lines","kind":"item"},{"item":"subependymal_nodules","kind":"item"},{"item":"sega","kind":"item"},{"item":"cardiac_rhabdomyoma","kind":"item"},{"item":"lam","kind":"item"},{"item":"angiomyolipomas","kind":"item"}],"k":1,"kind":"n_of"},{"items":[{"item":"confetti_lesions","kind":"item"},{"item":"dental_enamel_pits","kind":"item"},{"item":"intraoral_fibromas","kind":"item"},{"item":"retinal_achromic_patch","kind":"item"},{"item":"multiple_renal_cysts","kind":"item"},{"item":"nonrenal_hamartomas","kind":"item"},{"item":"sclerotic_bone_lesions","kind":"item"}],"k":2,"kind":"n_of"}],"kind":"all_of"}],"kind":"any_of"},"tier":0},{"label":"Possible TSC","rule":{"items":[{"items":[{"item":"hypomelanotic_macules","kind":"item"},{"item":"angiofibroma_or_plaque","kind":"item"},{"item":"ungual_fibromas","kind":"item"},{"item":"shagreen_patch","kind":"item"},{"item":"retinal_hamartomas","kind":"item"},{"item":"tubers_or_migration_lines","kind":"item"},{"item":"subependymal_nodules","kind":"item"},{"item":"sega","kind":"item"},{"item":"cardiac_rhabdomyoma","kind":"item"},{"item":"lam","kind":"item"},{"item":"angiomyolipomas","kind":"item"}],"k":1,"kind":"n_of"},{"items":[{"item":"confetti_lesions","kind":"item"},{"item":"dental_enamel_pits","kind":"item"},{"item":"intraoral_fibromas","kind":"item"},{"item":"retinal_achromic_patch","kind":"item"},{"item":"multiple_renal_cysts","kind":"item"},{"item":"nonrenal_hamartomas","kind":"item"},{"item":"sclerotic_bone_lesions","kind":"item"}],"k":2,"kind":"n_of"}],"kind":"any_of"},"tier":1}]},{"ambiguity":["SOURCE-QUALITY HAZARD, affecting how far this file should be trusted. The document read was a plain-text extraction of a three-column journal page, and the extractor interleaves the columns row by row. On the page carrying vEDS, text from cardiac-valvular EDS, vascular EDS and hypermobile EDS is interwoven line by line. Every item below was assigned to vEDS by reconstructing the column geometry and cross-checking the gene (COL3A1, not COL1A2) and the inheritance pattern (autosomal dominant, not recessive). That reconstruction is an inference about page layout, not a direct reading of a clean table. A curator with the publisher PDF should re-check the whole file against the printed vEDS box before it is promoted past draft.","Minor criteria 8 to 12 (hypermobility of small joints; tendon and muscle rupture; keratoconus; gingival recession and gingival fragility; early onset varicose veins) are the specific casualty of the scramble. In the extracted text they sit in a different column from minor criteria 1 to 7, immediately above the vEDS minimal-criteria bullet. They were assigned to vEDS because the cvEDS minor list is complete at four items and is closed by its own minimal-criteria bullet on the preceding page, and because hEDS, the only other subtype on the page, has no numbered minor-criteria list of this form. That leaves vEDS as the only possible owner of a list numbered 8 to 12. The reasoning is sound but it is reasoning, not reading.","The \"minimal criteria suggestive for vEDS\" paragraph names four index findings (a family history of the disorder; arterial rupture or dissection under 40 years of age; unexplained sigmoid colon rupture; spontaneous pneumothorax) and then qualifies them with \"in the presence of other features consistent with vEDS\". The qualifier can be read as attaching only to pneumothorax, or to all four findings. The conservative reading is encoded: every index finding must be accompanied by at least one other vEDS feature. Read the other way, a single index event would be enough on its own.","The same paragraph says testing should also be considered \"in the presence of a combination of the other minor clinical features\". The source gives no number for \"a combination\". Two is encoded, as the least a combination can mean, and only for the weakest verdict tier, which describes a band and does not assert that the criteria are met.","Major criterion 1 is a family history of vEDS with a documented causative COL3A1 variant. The minimal-criteria paragraph says only \"a family history of the disorder\", with no documentation requirement. The conservative reading is encoded: the single family-history item requires the documented variant, so an undocumented family history does not by itself trigger the suggestive tier.","Major criterion 2 is arterial rupture at a young age. The minimal-criteria paragraph widens this to arterial rupture or dissection under 40 years of age. Both are encoded, as separate items, with the dissection item marked as coming only from the minimal-criteria paragraph and not from the major criteria list. Age cannot be carried by an HPO term and is in the verify strings.","Major criterion 3 is spontaneous sigmoid colon perforation without known diverticular disease or other bowel pathology. HPO has no term for sigmoid colon perforation. HP:0031369 Colon perforation is mapped, which is broader than the criterion on site, spontaneity and the absence of other bowel pathology, and all three qualifiers are in the verify string so the item reports as provisionally met until a clinician confirms them. A profile carrying a colon perforation of any cause will light this item up, and the verify string is the only thing that stops that being an unqualified match.","Minor criterion 2 is thin, translucent skin with increased venous visibility. Only HP:0010648 Dermal translucency is mapped. HP:0000963 Thin skin was deliberately left out: it is not an ancestor or descendant of dermal translucency, it is common and non-specific, and mapping it here would let ordinary thin skin count towards a vEDS tier. The consequence is that a profile recording only thin skin will not satisfy this criterion automatically; such a case must be asserted explicitly.","Minor criterion 5 is acrogeria. HPO has no term for acrogeria, and HP:0007495 Prematurely aged appearance is a broader and different finding (generalised, not confined to the hands and feet), so the item is assertable rather than mapped.","Minor criterion 3 is a characteristic facial appearance. HPO has no term for the vEDS facial gestalt and HP:0001999 Abnormal facial shape is far too broad, so the item is assertable.","Minor criterion 11 joins gingival recession and gingival fragility with \"and\". It is encoded conservatively as requiring both, unlike the comma-separated lists elsewhere in this classification which are read as alternatives. If the intent was either finding alone, this file undercounts that one minor criterion.","Minor criterion 9 is tendon and muscle rupture. HP:0100551 does not exist for muscle rupture; HP:0100550 Tendon rupture carries \"Tendon/muscle rupture\" as a synonym and is the only mappable term, so it is used with muscle rupture named in the verify string.","The molecular-basis bullet says patients typically carry a heterozygous COL3A1 variant \"with the rare exception of\" three named arginine-to-cysteine substitutions in COL1A1, and the verification bullet says a panel should include COL1A1 to find them. The same paragraph also says those COL1A1 variants mimic COL3A1-vEDS and refers the reader to the companion paper on rare EDS types. It is therefore unclear whether a COL1A1 arginine-to-cysteine substitution confirms vEDS or a mimic. The conservative reading is encoded: the molecular item requires COL3A1, matching the source's explicit sentence that the diagnosis of vEDS rests on identifying a causative variant in one allele of COL3A1.","The strongest verdict tier is molecular confirmation alone, without any clinical requirement. This departs from the sibling cEDS and cvEDS files, which require the clinical criteria alongside the variant, and it is deliberate: the vEDS section states outright that the diagnosis rests on the identification of a causative COL3A1 variant. It also means a confirmed variant carrier with no findings reports as met, which is the clinically correct behaviour for this subtype."],"curation":{"encoded_by":"claude-opus-5","notes":"Pass A only. The source for vEDS does not state a countable clinical rule of the kind cEDS and cvEDS carry. It gives five major criteria, twelve minor criteria, a narrative \"minimal criteria suggestive\" paragraph that names the findings which should trigger diagnostic studies, and an explicit statement that the diagnosis rests on identifying a causative variant in one allele of COL3A1. The verdict tiers encode exactly that and nothing more: no \"two major criteria\" or similar threshold was invented, because the source states none.\nThe MONDO and Orphanet identifiers are not in the paper; only the OMIM number (130050) is. They were supplied from identifier knowledge and should be re-checked by Pass B.","reviews":[],"source_access":"primary","sources":[{"citation":{"authors":"Malfait F, Francomano C, Byers P, et al.","doi":"10.1002/ajmg.c.31552","journal":"Am J Med Genet C Semin Med Genet","pmid":"28306229","title":"","url":null,"year":2017},"note":"Read 2026-09-19 as a plain-text extraction of the publisher PDF. The vEDS section, its major and minor criteria, its minimal-criteria paragraph and its molecular-basis and verification bullets were all read directly. The extraction is column-scrambled; see the first ambiguity entry for what that cost.","read":true,"role":"primary","title":"Malfait F, et al. The 2017 international classification of the Ehlers-Danlos syndromes"}]},"disease":{"label":"Vascular Ehlers-Danlos syndrome","mondo":"MONDO:0007524","omim":["130050"],"ordo":"ORPHA:286"},"id":"veds_malfait_2017","items":[{"hpo":[],"id":"family_history_veds","label":"Family history of vEDS with a documented causative COL3A1 variant","paraphrase":"An affected relative in whom a causative COL3A1 variant has been documented","rule":null,"source_ref":"vEDS major criterion 1","type":"assertable","verify":null},{"hpo":["HP:0025019"],"id":"arterial_rupture","label":"Arterial rupture at a young age","paraphrase":null,"rule":null,"source_ref":"vEDS major criterion 2","type":"phenotypic","verify":"Confirm the rupture occurred at a young age. HPO cannot carry age. The minimal-criteria paragraph puts the threshold at under 40 years."},{"hpo":["HP:0031369"],"id":"sigmoid_colon_perforation","label":"Spontaneous sigmoid colon perforation","paraphrase":"Spontaneous perforation of the sigmoid colon with no known diverticular disease or other bowel pathology","rule":null,"source_ref":"vEDS major criterion 3","type":"phenotypic","verify":"Confirm all three qualifiers the mapped term cannot carry: that the perforation was of the sigmoid colon, that it was spontaneous, and that there is no known diverticular disease or other bowel pathology to explain it."},{"hpo":["HP:0100718"],"id":"uterine_rupture","label":"Uterine rupture in the third trimester","paraphrase":null,"rule":null,"source_ref":"vEDS major criterion 4","type":"phenotypic","verify":"Confirm the rupture was in the third trimester, with no previous Caesarean section and no severe peripartum perineal tearing."},{"hpo":["HP:0031157"],"id":"carotid_cavernous_fistula","label":"Carotid-cavernous sinus fistula","paraphrase":null,"rule":null,"source_ref":"vEDS major criterion 5","type":"phenotypic","verify":"Confirm the fistula formed in the absence of trauma."},{"hpo":["HP:0000978"],"id":"bruising","label":"Bruising unrelated to trauma or in unusual sites","paraphrase":null,"rule":null,"source_ref":"vEDS minor criterion 1","type":"phenotypic","verify":"Confirm the bruising is unrelated to identified trauma, or is in unusual sites such as the cheeks and back. HPO carries neither qualifier, and ordinary easy bruising does not meet this criterion."},{"hpo":["HP:0010648"],"id":"thin_translucent_skin","label":"Thin, translucent skin with increased venous visibility","paraphrase":null,"rule":null,"source_ref":"vEDS minor criterion 2","type":"phenotypic","verify":"Confirm the skin is thin and translucent with increased venous visibility. Thin skin alone is not mapped here; assert this item explicitly if that is all that was recorded."},{"hpo":[],"id":"characteristic_facial_appearance","label":"Characteristic vEDS facial appearance","paraphrase":"HPO has no term for the vEDS facial gestalt, so this is never resolved from a profile","rule":null,"source_ref":"vEDS minor criterion 3","type":"assertable","verify":null},{"hpo":["HP:0002108"],"id":"spontaneous_pneumothorax","label":"Spontaneous pneumothorax","paraphrase":null,"rule":null,"source_ref":"vEDS minor criterion 4","type":"phenotypic","verify":null},{"hpo":[],"id":"acrogeria","label":"Acrogeria","paraphrase":"Prematurely aged, thin skin of the hands and feet. HPO has no term for acrogeria and the nearest term is broader and different, so this is not resolved from a profile.","rule":null,"source_ref":"vEDS minor criterion 5","type":"assertable","verify":null},{"hpo":["HP:0001762"],"id":"talipes_equinovarus","label":"Talipes equinovarus","paraphrase":null,"rule":null,"source_ref":"vEDS minor criterion 6","type":"phenotypic","verify":null},{"hpo":["HP:0001374"],"id":"congenital_hip_dislocation","label":"Congenital hip dislocation","paraphrase":null,"rule":null,"source_ref":"vEDS minor criterion 7","type":"phenotypic","verify":null},{"hpo":["HP:0430046"],"id":"small_joint_hypermobility","label":"Hypermobility of small joints","paraphrase":null,"rule":null,"source_ref":"vEDS minor criterion 8","type":"phenotypic","verify":null},{"hpo":["HP:0100550"],"id":"tendon_or_muscle_rupture","label":"Tendon and muscle rupture","paraphrase":null,"rule":null,"source_ref":"vEDS minor criterion 9","type":"phenotypic","verify":"HPO has no separate term for muscle rupture; the mapped term carries \"tendon/muscle rupture\" as a synonym. Confirm directly if the rupture was muscular rather than tendinous."},{"hpo":["HP:0000563"],"id":"keratoconus","label":"Keratoconus","paraphrase":null,"rule":null,"source_ref":"vEDS minor criterion 10","type":"phenotypic","verify":null},{"hpo":["HP:0030816"],"id":"gingival_recession","label":"Gingival recession","paraphrase":null,"rule":null,"source_ref":"vEDS minor criterion 11, first half","type":"phenotypic","verify":null},{"hpo":["HP:0034518"],"id":"gingival_fragility","label":"Gingival fragility","paraphrase":null,"rule":null,"source_ref":"vEDS minor criterion 11, second half","type":"phenotypic","verify":null},{"hpo":[],"id":"gingival_recession_and_fragility","label":"Gingival recession and gingival fragility","paraphrase":null,"rule":{"items":[{"item":"gingival_recession","kind":"item"},{"item":"gingival_fragility","kind":"item"}],"kind":"all_of"},"source_ref":"vEDS minor criterion 11","type":"composite","verify":null},{"hpo":["HP:0002619"],"id":"early_onset_varicose_veins","label":"Early onset varicose veins","paraphrase":null,"rule":null,"source_ref":"vEDS minor criterion 12","type":"phenotypic","verify":"Confirm onset under 30 years of age, and, in a woman, that she is nulliparous. HPO carries neither qualifier."},{"hpo":[],"id":"molecular_confirmation","label":"Causative variant in one allele of COL3A1","paraphrase":"The source states the diagnosis of vEDS rests on identifying a causative variant in one allele of COL3A1. Biallelic COL3A1 variants are noted as a very rare alternative and also satisfy this item.","rule":null,"source_ref":"vEDS verification of clinical diagnosis, and molecular basis","type":"assertable","verify":null},{"hpo":["HP:0005294"],"id":"arterial_dissection","label":"Arterial dissection under 40 years of age","paraphrase":"Named in the minimal-criteria paragraph, not in the major criteria list","rule":null,"source_ref":"vEDS minimal criteria suggestive, index findings","type":"phenotypic","verify":"Confirm the dissection occurred under 40 years of age. HPO cannot carry age."},{"hpo":[],"id":"arterial_rupture_or_dissection","label":"Arterial rupture or dissection under 40 years of age","paraphrase":null,"rule":{"items":[{"item":"arterial_rupture","kind":"item"},{"item":"arterial_dissection","kind":"item"}],"kind":"any_of"},"source_ref":"vEDS minimal criteria suggestive, index findings","type":"composite","verify":null},{"hpo":[],"id":"index_finding_other_than_pneumothorax","label":"An index finding other than spontaneous pneumothorax","paraphrase":null,"rule":{"items":[{"item":"family_history_veds","kind":"item"},{"item":"arterial_rupture_or_dissection","kind":"item"},{"item":"sigmoid_colon_perforation","kind":"item"}],"kind":"any_of"},"source_ref":"vEDS minimal criteria suggestive, index findings","type":"composite","verify":null},{"hpo":[],"id":"other_veds_feature","label":"At least one other feature consistent with vEDS","paraphrase":null,"rule":{"items":[{"item":"uterine_rupture","kind":"item"},{"item":"carotid_cavernous_fistula","kind":"item"},{"item":"bruising","kind":"item"},{"item":"thin_translucent_skin","kind":"item"},{"item":"characteristic_facial_appearance","kind":"item"},{"item":"spontaneous_pneumothorax","kind":"item"},{"item":"acrogeria","kind":"item"},{"item":"talipes_equinovarus","kind":"item"},{"item":"congenital_hip_dislocation","kind":"item"},{"item":"small_joint_hypermobility","kind":"item"},{"item":"tendon_or_muscle_rupture","kind":"item"},{"item":"keratoconus","kind":"item"},{"item":"gingival_recession_and_fragility","kind":"item"},{"item":"early_onset_varicose_veins","kind":"item"}],"kind":"any_of"},"source_ref":"vEDS minimal criteria suggestive, qualifying clause","type":"composite","verify":null},{"hpo":[],"id":"other_veds_feature_excluding_pneumothorax","label":"At least one other feature consistent with vEDS, pneumothorax aside","paraphrase":"Used only where spontaneous pneumothorax is itself serving as the index finding, so that a single pneumothorax cannot satisfy both halves of the rule","rule":{"items":[{"item":"uterine_rupture","kind":"item"},{"item":"carotid_cavernous_fistula","kind":"item"},{"item":"bruising","kind":"item"},{"item":"thin_translucent_skin","kind":"item"},{"item":"characteristic_facial_appearance","kind":"item"},{"item":"acrogeria","kind":"item"},{"item":"talipes_equinovarus","kind":"item"},{"item":"congenital_hip_dislocation","kind":"item"},{"item":"small_joint_hypermobility","kind":"item"},{"item":"tendon_or_muscle_rupture","kind":"item"},{"item":"keratoconus","kind":"item"},{"item":"gingival_recession_and_fragility","kind":"item"},{"item":"early_onset_varicose_veins","kind":"item"}],"kind":"any_of"},"source_ref":"vEDS minimal criteria suggestive, qualifying clause","type":"composite","verify":null},{"hpo":[],"id":"clinically_suggestive","label":"Minimal criteria suggestive for vEDS","paraphrase":null,"rule":{"items":[{"items":[{"item":"index_finding_other_than_pneumothorax","kind":"item"},{"item":"other_veds_feature","kind":"item"}],"kind":"all_of"},{"items":[{"item":"spontaneous_pneumothorax","kind":"item"},{"item":"other_veds_feature_excluding_pneumothorax","kind":"item"}],"kind":"all_of"}],"kind":"any_of"},"source_ref":"vEDS minimal criteria suggestive","type":"composite","verify":null},{"hpo":[],"id":"combination_of_minor_features","label":"A combination of at least two minor features","paraphrase":null,"rule":{"items":[{"item":"bruising","kind":"item"},{"item":"thin_translucent_skin","kind":"item"},{"item":"characteristic_facial_appearance","kind":"item"},{"item":"spontaneous_pneumothorax","kind":"item"},{"item":"acrogeria","kind":"item"},{"item":"talipes_equinovarus","kind":"item"},{"item":"congenital_hip_dislocation","kind":"item"},{"item":"small_joint_hypermobility","kind":"item"},{"item":"tendon_or_muscle_rupture","kind":"item"},{"item":"keratoconus","kind":"item"},{"item":"gingival_recession_and_fragility","kind":"item"},{"item":"early_onset_varicose_veins","kind":"item"}],"k":2,"kind":"n_of"},"source_ref":"vEDS minimal criteria suggestive, final sentence","type":"composite","verify":null}],"meta":{"citation":{"authors":"Malfait F, Francomano C, Byers P, et al.","doi":"10.1002/ajmg.c.31552","journal":"Am J Med Genet C Semin Med Genet","pmid":"28306229","title":"The 2017 international classification of the Ehlers-Danlos syndromes","url":null,"year":2017},"name":"2017 international classification of the Ehlers-Danlos syndromes, vEDS criteria","standing":"consensus","standing_note":"Part of the 2017 international classification, the consensus nosology for the Ehlers-Danlos syndromes, which defines vEDS with its own major and minor criteria and states that the diagnosis rests on molecular confirmation.","supersedes":"eds_villefranche_1998","version":"2017"},"source_path":"criteria/veds_malfait_2017.yaml","tests":[{"asserted":{"molecular_confirmation":true},"confirmed":["arterial_rupture","thin_translucent_skin","bruising"],"excluded":[],"expect":"met","expect_tier":"Vascular EDS, confirmed by a causative COL3A1 variant","name":"arterial rupture in the twenties with translucent skin and atypical bruising, COL3A1 variant found","present":["HP:0025019","HP:0010648","HP:0000978"]},{"asserted":{"molecular_confirmation":true},"confirmed":[],"excluded":[],"expect":"met","expect_tier":"Vascular EDS, confirmed by a causative COL3A1 variant","name":"a confirmed COL3A1 variant alone is the diagnosis, per the source","present":[]},{"asserted":{"acrogeria":false,"characteristic_facial_appearance":false,"family_history_veds":false,"molecular_confirmation":false},"confirmed":["sigmoid_colon_perforation"],"excluded":["HP:0025019","HP:0005294","HP:0100718","HP:0031157","HP:0000978","HP:0010648","HP:0002108","HP:0001762","HP:0001374","HP:0430046","HP:0100550","HP:0030816","HP:0034518","HP:0002619"],"expect":"met","expect_tier":"Clinically suggestive of vascular EDS (an index finding with at least one other consistent feature)","name":"index finding plus exactly one other feature (at the boundary), no testing done","present":["HP:0031369","HP:0000563"]},{"asserted":{"acrogeria":false,"characteristic_facial_appearance":false,"family_history_veds":false,"molecular_confirmation":false},"confirmed":["early_onset_varicose_veins"],"excluded":["HP:0025019","HP:0005294","HP:0031369","HP:0100718","HP:0031157","HP:0000978","HP:0010648","HP:0002108","HP:0001762","HP:0001374","HP:0430046","HP:0100550","HP:0030816","HP:0034518"],"expect":"met","expect_tier":"Two or more minor features, below the index findings the source requires for the suggestive threshold","name":"exactly two minor features and no index finding reaches only the lowest 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profile","present":[]},{"asserted":{"acrogeria":false,"characteristic_facial_appearance":false,"family_history_veds":false,"molecular_confirmation":false},"confirmed":["arterial_rupture"],"excluded":["HP:0034518","HP:0005294","HP:0031369","HP:0100718","HP:0031157","HP:0000978","HP:0010648","HP:0002108","HP:0001762","HP:0001374","HP:0430046","HP:0100550","HP:0002619","HP:0000563"],"expect":"refuted","expect_tier":null,"name":"gingival recession without fragility does not satisfy minor criterion 11","present":["HP:0030816","HP:0025019"]}],"verdicts":[{"label":"Vascular EDS, confirmed by a causative COL3A1 variant","rule":{"items":[{"item":"molecular_confirmation","kind":"item"}],"kind":"all_of"},"tier":0},{"label":"Clinically suggestive of vascular EDS (an index finding with at least one other consistent feature)","rule":{"items":[{"item":"clinically_suggestive","kind":"item"}],"kind":"all_of"},"tier":1},{"label":"Two or more minor features, below the index findings the source requires for the suggestive threshold","rule":{"items":[{"item":"combination_of_minor_features","kind":"item"}],"kind":"all_of"},"tier":2}]}]}