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Fanconi anemia phenotype coverage against the FCF-guideline HPO profile

Date: 2026-08-08 Entry: kb/disorders/Fanconi_Anemia.yaml PR: monarch-initiative/dismech#8190 Feedback to profile authors / schema issue: monarch-initiative/dismech#8179 Trigger: Connelly et al., A custom phenotypic profile for Fanconi anemia: Addressing gaps in existing disease annotations (manuscript; profile published at https://github.com/ehurwitz/FA-custom-profile).

What prompted this

The Connelly manuscript reports a 264-term HPO profile for Fanconi anemia (FA) extracted from the complete Fanconi Cancer Foundation Clinical Care Guidelines (5th ed., 2020) with OntoGPT + manual curation. 161 of those terms (61%) are absent from both OMIM (215 terms across 22 complementation-group entries) and Orphanet (106 terms, ORPHA:84), which themselves share only 36 terms.

The question asked was whether the dismech FA entry already accounted for those phenotypes. It did not: the gap fell almost exactly where the manuscript says the guideline-derived novelty lies.

Method

The manuscript names only ~29 HPO terms inline, so the comparison was run against the full profile (FA-custom-profile.hpoa, 264 terms) from the repository the paper's data availability statement points to. Coverage was assessed by HPO closure, not string matching: for each profile term absent from the entry, we asked whether the entry asserts an ancestor (we cover it, less specifically), a descendant (we cover it, more specifically), or nothing at all.

                     before   after
exact match             78     116
parent-only             56      50
child-only              21      22
not represented        109      76

(Initial figures were 118/52/21/73; the four-term difference is the review pass described under "Corrections after review" below.)

Evidence policy for this pass

The paper and its .hpoa were used only to identify gaps — never as evidence. Every phenotype added here carries an independent primary-literature citation with a snippet verified against the cached PubMed abstract (just count-verified-snippets: 388/388). Where the literature would only support a treatment sequela rather than a disease phenotype, the term was left uncurated (see "Deliberately not added").

What was added (41 phenotype blocks)

This table reflects the final state after the review pass; two terms curated in the first draft (recurrent aphthous stomatitis, narrow palpebral fissure) were withdrawn and the moyamoya and microcornea sources were replaced. See "Corrections after review" below.

Domain Terms Key sources
Oral / dental gingivitis, gingival overgrowth, periodontitis, microdontia, tooth agenesis, tooth malposition, hyposalivation, oral ulcer, oral leukoplakia PMID:17688024, PMID:11759873, PMID:16169820, PMID:18543739, PMID:15139958, PMID:36054728
Psychiatric anxiety, depression, diminished mental health PMID:40272053
Endocrine / metabolic osteoporosis, insulin resistance, GH deficiency PMID:17426088, PMID:32529760, PMID:25575015
Immune recurrent infections, reduced NK cell count PMID:21542827, PMID:24240977, PMID:31990462, PMID:15139958
Haematologic marrow hypocellularity, neutropenia, petechiae, bruising, transfusional iron overload PMID:37303314, PMID:39559288, PMID:31990462, PMID:22510772
Cellular crosslinker-induced chromosomal breakage, DNA repair defect, radiosensitivity PMID:20301575, PMID:25827349, PMID:21930984
Neoplasm AML, basal cell carcinoma, oral/oropharyngeal SCC, medulloblastoma, nephroblastoma PMID:20301575, PMID:38907138, PMID:26484938, PMID:40478605, PMID:26691948
Skeletal / limb abnormal rib morphology, scapular hypoplasia, radial ray anomaly spectrum, thumb duplication (preaxial polydactyly) PMID:17006268, PMID:35360980
Ocular microcornea PMID:20022637, PMID:23648176
Dermatologic freckling PMID:32822789
Other pulmonary fibrosis, ectopic kidney, moyamoya phenomenon, holoprosencephaly, feeding difficulties PMID:9096763, PMID:35197271, PMID:38510908, PMID:25719591, PMID:29278735, PMID:20301575

Three added terms (HP:0002745 oral leukoplakia, HP:0000882 hypoplastic scapulae, HP:0040218 reduced total NK cell count) are not in the Connelly profile. They were added because they are what the located evidence actually supports — the profile's HP:0000912 Sprengel anomaly, for instance, is not what PMID:17006268 describes (bilateral scapular hypoplasia with winging), and HP:0012178 is obsolete in current HPO.

Deliberately not added

  • Keratoconjunctivitis sicca (HP:0001097) — the one FA cohort that quantifies it (PMID:34774576) attributes it to ocular GVHD after HSCT. That is a transplant sequela, which the Connelly profile's own inclusion rule excludes.
  • Verrucae (HP:0200043) — the available FA case (PMID:31718429) describes genital warts arising three years post-HSCT under multiple immunosuppressants.
  • Melanoma (HP:0002861) — no FA-specific primary source located. The NCI non-melanoma skin cancer study (PMID:38907138) is explicitly non-melanoma.
  • Frequency bands were assigned only where a cited percentage maps cleanly onto a FrequencyEnum band, per docs/frequency-evidence-guidelines.md. Osteoporosis carries no band: the block now quotes the phenotype-expansion sentence from PMID:17426088, which states no rate at all, and the 92% figure in the same paper covers osteopenia or osteoporosis in patients aged ≥18 rather than osteoporosis across the population.

Corrections after review (PR #8190)

The automated reviewer raised eight items on the first pass; all were accepted, four of them changing what is asserted:

  • HP:0045025 Narrow palpebral fissure — block removed. The supporting sentence measures palpebral fissure length, which is HP:0012745 Short palpebral fissure (already asserted in this entry), not fissure height. The two terms are not ontologically related, so this was a straight term error. HP:0045025 returns to the unevidenced list.
  • HP:0011107 Recurrent aphthous stomatitis — block removed. The quoted sentence (ulcer healing after transfusion) supports neither recurrence nor stomatitis, and the block was redundant with Oral Ulceration from the same source.
  • HP:0011834 Moyamoya phenomenon — evidence replaced. The original citation (PMID:35978939) is an alpha-thalassemia case report naming FA only in a background list, which fails this pass's own evidence policy. Replaced with two FA-specific cases (PMID:38510908, PMID:25719591), and the category corrected from Cardiac to Neurologic.
  • HP:0000482 Microcornea — evidence replaced. The original snippet was truncated to dodge a bracket-stripping interaction in the validator and fell below the minimum snippet length. Replaced with the NCI ophthalmic cohort (PMID:20022637, microcornea in 55% of 22 patients) and an independent series (PMID:23648176).

references_cache/PMID_34774576.md and PMID_35978939.md were removed with the evidence that cited them; PMID:34774576 is still referenced in prose above as the source for the keratoconjunctivitis-sicca exclusion, so re-fetch it with just fetch-reference if that term is ever curated.

Two further items were term-precision fixes that preserve profile coverage by closure: HP:0000782 → HP:0000882 Hypoplastic scapulae (exact match to the quoted finding), and HP:0010442 → HP:0001177 Preaxial hand polydactyly (a descendant, so HP:0010442 stays covered). Three were name collisions with pre-existing blocks, resolved by renaming rather than deleting (Reduced Circulating Growth Hormone Concentration, Early-Onset Osteoporosis, Radial Ray Anomaly Spectrum), with the osteoporosis block also re-quoted so it no longer reuses a snippet already carried elsewhere in the entry.

Remaining worklist

The largest surviving cluster is fine-grained hand/upper-limb radiographic detail (absent/small scaphoid and trapezium, carpal bone hypoplasia, forearm bowing, humeral anomalies, wrist/elbow motion limits). PMID:35360980 characterises the radial ray spectrum but its abstract does not enumerate individual carpal bones; resolving these needs the full text of a radiographic series.

The second cluster is gastrointestinal symptomatology (GERD, dysphagia, odynophagia, nausea, constipation, diarrhoea, gastroparesis, malabsorption, abdominal pain). These are prominent in the FCF guidelines but repeated PubMed searches found no FA-specific primary study quantifying them; the one cohort that reports a GI figure (PMID:31990462) gives only "gastrointestinal system abnormality was 5.7%", i.e. structural anomalies, not symptoms. This looks like a genuine primary-literature gap rather than a search failure, and is worth flagging back to the profile authors.

Not represented at all (76)

Abnormality of limbs (18)

  • HP:0031095 Abnormal humerus morphology
  • HP:0011835 Absent scaphoid
  • HP:0004253 Absent trapezium
  • HP:0001166 Arachnodactyly
  • HP:0005743 Avascular necrosis of the capital femoral epiphysis
  • HP:0003956 Bowed forearm bones
  • HP:0001156 Brachydactyly
  • HP:0001498 Carpal bone hypoplasia
  • HP:0034681 Finger joint contracture
  • HP:0002996 Limited elbow movement
  • HP:0006248 Limited wrist movement
  • HP:0100559 Lower limb asymmetry
  • HP:0006190 Radially deviated wrists
  • HP:0005792 Short humerus
  • HP:0001238 Slender finger
  • HP:0004247 Small scaphoid
  • HP:0004255 Small trapezium
  • HP:0003031 Ulnar bowing

Abnormality of the digestive system (15)

  • HP:0002027 Abdominal pain
  • HP:0005912 Biliary atresia
  • HP:0002607 Bowel incontinence
  • HP:0002019 Constipation
  • HP:0002014 Diarrhea
  • HP:0002015 Dysphagia
  • HP:0040183 Encopresis
  • HP:0002020 Gastroesophageal reflux
  • HP:0002578 Gastroparesis
  • HP:0005214 Intestinal obstruction
  • HP:0002024 Malabsorption
  • HP:0004395 Malnutrition
  • HP:0030996 Megaduodenum
  • HP:0002018 Nausea
  • HP:0032043 Odynophagia

Abnormality of head or neck (8)

  • HP:0032154 Aphthous ulcer
  • HP:0011109 Chronic sinusitis
  • HP:0001363 Craniosynostosis
  • HP:0001097 Keratoconjunctivitis sicca
  • HP:0045025 Narrow palpebral fissure
  • HP:0002691 Platybasia
  • HP:0011107 Recurrent aphthous stomatitis
  • HP:0000506 Telecanthus

Abnormality of the integument (7)

  • HP:0025127 Actinic keratosis
  • HP:0000958 Dry skin
  • HP:0025474 Erythematous plaque
  • HP:0040189 Scaling skin
  • HP:0200036 Skin nodule
  • HP:0001072 Thickened skin
  • HP:0200043 Verrucae

Abnormality of the nervous system (6)

  • HP:0001331 Absent septum pellucidum
  • HP:0009592 Astrocytoma
  • HP:0002308 Chiari malformation
  • HP:5200320 Diminishment of relationship seeking
  • HP:0012174 Glioblastoma multiforme
  • HP:0003006 Neuroblastoma

Abnormality of the musculoskeletal system (5)

  • HP:0010305 Absence of the sacrum
  • HP:0008839 Hypoplastic pelvis
  • HP:0004590 Hypoplastic sacrum
  • HP:0000912 Sprengel anomaly
  • HP:0025261 Stiff finger

Abnormality of the cardiovascular system (5)

  • HP:0031640 Abnormal radial artery morphology
  • HP:0001650 Aortic valve stenosis
  • HP:0011590 Double aortic arch
  • HP:0004935 Pulmonary artery atresia
  • HP:0001642 Pulmonic stenosis

Growth abnormality (3)

  • HP:0001508 Failure to thrive
  • HP:0025502 Overweight
  • HP:0001518 Small for gestational age

Abnormality of the ear (3)

  • HP:0001963 Abnormal speech discrimination
  • HP:0040090 Abnormal tympanic membrane morphology
  • HP:0034585 Cochlear nerve hypoplasia

Neoplasm (1)

  • HP:0002861 Melanoma

Abnormality of the genitourinary system (1)

  • HP:0008661 Urethral stenosis

Abnormality of the endocrine system (1)

  • HP:0012285 Abnormal hypothalamus physiology

Abnormality of prenatal development or birth (1)

  • HP:0034057 Fetal anomaly

Abnormality of the immune system (1)

  • HP:0410028 Recurrent oral herpes

Constitutional symptom (1)

  • HP:6000064 Excessive eructation

Represented only by a broader parent term (50)

  • HP:0010704 1-2 finger cutaneous syndactyly — entry has HP:0006101 Finger syndactyly
  • HP:0006482 Abnormal dental morphology — entry has HP:0000164 Abnormality of the dentition
  • HP:0010461 Abnormality of the male genitalia — entry has HP:0000078 Abnormality of the genital system
  • HP:0000140 Abnormality of the menstrual cycle — entry has HP:0000078 Abnormality of the genital system
  • HP:0003974 Absent radius — entry has HP:0006501 Aplasia/Hypoplasia of the radius
  • HP:0010469 Absent testis — entry has HP:0000035 Abnormal testis morphology, HP:0000078 Abnormality of the genital system
  • HP:0000141 Amenorrhea — entry has HP:0000078 Abnormality of the genital system
  • HP:0009892 Anotia — entry has HP:0000377 Abnormal pinna morphology
  • HP:0003982 Aplasia of the ulna — entry has HP:0006495 Aplasia/Hypoplasia of the ulna
  • HP:0000151 Aplasia of the uterus — entry has HP:0000078 Abnormality of the genital system, HP:0000130 Abnormality of the uterus
  • HP:0003250 Aplasia of the vagina — entry has HP:0000078 Abnormality of the genital system
  • HP:0001915 Aplastic anemia — entry has HP:0001876 Pancytopenia
  • HP:0001638 Cardiomyopathy — entry has HP:0001627 Abnormal heart morphology
  • HP:0004602 Cervical C2/C3 vertebral fusion — entry has HP:0002949 Fused cervical vertebrae
  • HP:0030079 Cervix cancer — entry has HP:0000078 Abnormality of the genital system, HP:0000130 Abnormality of the uterus
  • HP:0000041 Chordee — entry has HP:0000078 Abnormality of the genital system
  • HP:0012622 Chronic kidney disease — entry has HP:0000083 Renal insufficiency
  • HP:0001374 Congenital hip dislocation — entry has HP:0001385 Hip dysplasia, HP:0002827 Hip dislocation
  • HP:0000144 Decreased fertility — entry has HP:0000078 Abnormality of the genital system
  • HP:0000868 Decreased fertility in females — entry has HP:0000078 Abnormality of the genital system
  • HP:0008734 Decreased testicular size — entry has HP:0000035 Abnormal testis morphology, HP:0000078 Abnormality of the genital system
  • HP:0000696 Delayed eruption of permanent teeth — entry has HP:0000164 Abnormality of the dentition
  • HP:0009603 Deviation of the thumb — entry has HP:0001172 Abnormal thumb morphology
  • HP:0000819 Diabetes mellitus — entry has HP:0011014 Abnormal glucose homeostasis
  • HP:0009942 Duplication of thumb phalanx — entry has HP:0001172 Abnormal thumb morphology
  • HP:0003241 External genital hypoplasia — entry has HP:0000078 Abnormality of the genital system
  • HP:0000085 Horseshoe kidney — entry has HP:0012210 Abnormal renal morphology, HP:0100542 Abnormal localization of kidney
  • HP:0000126 Hydronephrosis — entry has HP:0012210 Abnormal renal morphology
  • HP:0003074 Hyperglycemia — entry has HP:0011014 Abnormal glucose homeostasis
  • HP:0000013 Hypoplasia of the uterus — entry has HP:0000078 Abnormality of the genital system, HP:0000130 Abnormality of the uterus
  • HP:0040270 Impaired glucose tolerance — entry has HP:0011014 Abnormal glucose homeostasis
  • HP:0000858 Irregular menstruation — entry has HP:0000078 Abnormality of the genital system
  • HP:0000132 Menorrhagia — entry has HP:0000078 Abnormality of the genital system
  • HP:0030260 Microphallus — entry has HP:0000078 Abnormality of the genital system
  • HP:0000876 Oligomenorrhea — entry has HP:0000078 Abnormality of the genital system
  • HP:0009944 Partial duplication of thumb phalanx — entry has HP:0001172 Abnormal thumb morphology
  • HP:0001741 Phimosis — entry has HP:0000078 Abnormality of the genital system, HP:0100587 Abnormal preputium morphology
  • HP:0002718 Recurrent bacterial infections — entry has HP:0002719 Recurrent infections
  • HP:0002841 Recurrent fungal infections — entry has HP:0002719 Recurrent infections
  • HP:0004429 Recurrent viral infections — entry has HP:0002719 Recurrent infections
  • HP:0000104 Renal agenesis — entry has HP:0008678 Renal hypoplasia/aplasia, HP:0012210 Abnormal renal morphology
  • HP:0000110 Renal dysplasia — entry has HP:0012210 Abnormal renal morphology
  • HP:0000089 Renal hypoplasia — entry has HP:0008678 Renal hypoplasia/aplasia, HP:0012210 Abnormal renal morphology
  • HP:0004712 Renal malrotation — entry has HP:0012210 Abnormal renal morphology
  • HP:0009660 Short phalanx of the thumb — entry has HP:0001172 Abnormal thumb morphology, HP:0006265 Aplasia/Hypoplasia of fingers
  • HP:0009778 Short thumb — entry has HP:0001172 Abnormal thumb morphology, HP:0006265 Aplasia/Hypoplasia of fingers
  • HP:0034231 Sigmoid kidney — entry has HP:0000086 Ectopic kidney, HP:0012210 Abnormal renal morphology
  • HP:0011069 Supernumerary tooth — entry has HP:0000164 Abnormality of the dentition
  • HP:0000029 Testicular atrophy — entry has HP:0000035 Abnormal testis morphology, HP:0000078 Abnormality of the genital system
  • HP:6000942 Thumb hypoplasia grade 4 — entry has HP:0001172 Abnormal thumb morphology, HP:0006265 Aplasia/Hypoplasia of fingers