Skeletal Dysplasias Curation Project

Overview

Comprehensive curation of skeletal dysplasias for the dismech knowledge base, prioritizing genetic skeletal disorders with defined molecular pathogenesis and clear genotype-phenotype correlations. This project focuses on disorders where: 1. Single-gene or well-defined genetic drivers are established 2. Molecular mechanisms affecting bone/cartilage development are understood 3. Phenotypic severity correlates with mutation type or location 4. Progressive skeletal manifestations are documented

The 2023 Nosology of Genetic Skeletal Disorders classifies over 770 disorders into 42 groups. This project prioritizes paradigmatic examples from key groups with therapeutic implications or strong mechanistic understanding.

Selection Criteria

Skeletal dysplasias are prioritized based on: - Genetic clarity: Single-gene mutations with defined pathogenic mechanisms - Pathway understanding: Well-characterized signaling cascades (FGFR, TGF-β, Hedgehog, WNT) - Therapeutic relevance: Emerging or approved targeted therapies (e.g., vosoritide for achondroplasia) - Educational value: Paradigmatic examples of developmental bone biology (e.g., type II collagenopathies spectrum)

Existing Related Entries in KB (7)

Skeletal Dysplasias to Curate

Tier 1: Paradigmatic FGFR3-Related Disorders (Highest Priority)

The FGFR3 disorders represent a clinical spectrum with the same gene but different mutations/severity. Therapeutically relevant with vosoritide FDA approval.

Tier 2: Type II Collagenopathies Spectrum (High Priority)

COL2A1 mutations cause a spectrum from lethal to mild, demonstrating genotype-phenotype correlation.

Tier 3: Other FGFR-Related Disorders (High Priority)

FGFR1, FGFR2, and FGFR3 mutations in craniosynostosis and other skeletal phenotypes.

Tier 4: Osteogenesis Imperfecta Spectrum (High Priority)

"Brittle bone disease" - primarily type I collagen defects with broad phenotypic spectrum.

Tier 5: RASopathies with Skeletal Features (Medium Priority)

RAS-MAPK pathway disorders with significant skeletal manifestations.

Tier 6: TGF-β/BMP Pathway Disorders (Medium Priority)

Signaling pathway disorders affecting bone and connective tissue.

Tier 7: Ciliopathies with Skeletal Features (Medium Priority)

Primary cilia dysfunction affecting skeletal development.

Tier 8: Metabolic Bone Disorders (Medium Priority)

Enzyme deficiencies and metabolic disorders affecting bone.

Tier 9: Limb Development Disorders (Medium Priority)

Primary limb patterning and development defects.

Tier 10: Sclerosing Bone Dysplasias (Lower Priority)

Disorders of increased bone density.

Key Pathways to Document

Growth Plate Signaling

1. FGFR3 pathway - Negative regulator of endochondral ossification
2. IHH/PTHrP loop - Chondrocyte proliferation/differentiation balance
3. WNT/β-catenin - Osteoblast differentiation
4. BMP signaling - Bone induction and maintenance
5. Notch signaling - Somitogenesis and vertebral patterning

Extracellular Matrix

1. Type II collagen - Cartilage ECM (COL2A1 spectrum)
2. Type I collagen - Bone ECM (OI spectrum)
3. Proteoglycans - Aggrecan, perlecan mutations
4. Fibrillin/TGF-β - Connective tissue homeostasis

Bone Remodeling

1. RANKL/OPG/RANK - Osteoclastogenesis
2. Sclerostin/WNT - Bone formation regulation
3. Cathepsin K - Bone resorption

Therapeutic Landscape (2024-2026)

Research Sources

• 2023 Nosology of Genetic Skeletal Disorders: AJMG Part A (10.1002/ajmg.a.63132)
• FGFR3 in skeletal disorders: Nature Reviews Endocrinology 2024
• Vosoritide mechanism and trials: PMID:34283177 (NEJM 2021)
• Type II collagenopathies review: Orphanet Journal of Rare Diseases 2021
• OI genetics and therapy: PMID:31078423

STATUS

Tier 1: FGFR3-Related Disorders (5/5) ✓

• [x] Achondroplasia - Created 2026-01-30, 65.8% compliance
• [x] Hypochondroplasia - Created 2026-01-30
• [x] Thanatophoric Dysplasia Type I - Created 2026-01-30
• [x] Thanatophoric Dysplasia Type II - Created 2026-01-30
• [x] SADDAN - Created 2026-01-30

Tier 2: Type II Collagenopathies (6/6) ✓

• [x] Achondrogenesis Type II - Created 2026-02-04, 76.7% compliance
• [x] Hypochondrogenesis - Created 2026-02-04, 75.0% compliance
• [x] Spondyloepiphyseal Dysplasia Congenita - Created 2026-02-04, 69.4% compliance
• [x] Kniest Dysplasia - Created 2026-02-04, 69.7% compliance
• [x] Stickler Syndrome Type 1 - Created 2026-02-04, 71.0% compliance
• [x] SEMD Strudwick Type - Created 2026-02-04, 69.7% compliance

Tier 3: Other FGFR Craniosynostosis (6/6) ✓

• [x] Jackson-Weiss Syndrome - Created 2026-02-04, 86.4% compliance
• [x] Muenke Syndrome - Created 2026-02-04, 85.7% compliance
• [x] Pfeiffer Syndrome - Created 2026-02-04, 79.2% compliance
• [x] Crouzon Syndrome - Created 2026-02-04, 77.3% compliance
• [x] Apert Syndrome - Created 2026-02-04, 71.9% compliance
• [x] Crouzon with Acanthosis Nigricans - Created 2026-02-04, 69.6% compliance

Tier 4: Osteogenesis Imperfecta (6/6) ✓

• [x] OI Type I - Created 2026-02-04, 65.4% compliance
• [x] OI Type II - Created 2026-02-04, 62.5% compliance
• [x] OI Type III - Created 2026-02-04, 56.2% compliance
• [x] OI Type IV - Created 2026-02-04, 57.7% compliance
• [x] OI Type V - Created 2026-02-04, 60.7% compliance
• [x] OI Type VII (CRTAP) - Created 2026-02-04, 56.7% compliance

Tier 5: RASopathies (4/4) ✓

• [x] Noonan Syndrome - Already in KB, 68.3% compliance
• [x] Costello Syndrome - Created 2026-02-04, 63.9% compliance (enhanced with deep research)
• [x] Cardiofaciocutaneous Syndrome - Created 2026-02-04, 68.4% compliance (enhanced with deep research)
• [x] Neurofibromatosis Type 1 - Already in KB, 51.2% compliance

Tier 6: TGF-β/BMP Pathway (5/5) ✓

• [x] Loeys-Dietz Syndrome - Created 2026-02-09, 82.8% compliance
• [x] Shprintzen-Goldberg Syndrome - Created 2026-02-09, 77.4% compliance
• [x] Camurati-Engelmann Disease - Created 2026-02-09, 82.9% compliance
• [x] Fibrodysplasia Ossificans Progressiva - Already in KB
• [x] Multiple Synostoses Syndrome - Created 2026-02-09, 73.1% compliance

Tier 7: Ciliopathies (4/4) ✓

• [x] Jeune Asphyxiating Thoracic Dystrophy - Created 2026-02-09, 88.6% compliance
• [x] Short-Rib Polydactyly Syndrome - Created 2026-02-09, 92.3% compliance
• [x] Ellis-van Creveld Syndrome - Created 2026-02-09, 94.1% compliance
• [x] Orofaciodigital Syndrome Type I - Created 2026-02-09, 92.6% compliance

Tier 8: Metabolic Bone (4/4) ✓

• [x] Hypophosphatasia - Created 2026-02-09, 85.7% compliance
• [x] X-Linked Hypophosphatemia - Created 2026-02-09, 96.3% compliance
• [x] Mucopolysaccharidosis - Created 2026-02-09, 86.7% compliance
• [x] Gaucher Disease - Already in KB with skeletal coverage

Tier 9: Limb Development (6/6) ✓

• [x] Holt-Oram Syndrome - Created 2026-02-09, 78.9% compliance
• [x] Ulnar-Mammary Syndrome - Created 2026-02-09, 88.9% compliance
• [x] Hand-Foot-Genital Syndrome - Created 2026-02-09, 90.0% compliance
• [x] Greig Cephalopolysyndactyly - Created 2026-02-09, 82.4% compliance
• [x] Pallister-Hall Syndrome - Created 2026-02-09, 81.2% compliance
• [x] Brachydactyly Type A1 - Created 2026-02-09, 92.3% compliance

Tier 10: Sclerosing Bone Dysplasias (5/5) ✓

• [x] Osteopetrosis (CLCN7) - Created 2026-02-09, 88.9% compliance
• [x] Osteopetrosis (TCIRG1) - Created 2026-02-09, 81.2% compliance
• [x] Pycnodysostosis - Created 2026-02-09, 88.9% compliance
• [x] Sclerosteosis - Created 2026-02-09, 88.2% compliance
• [x] Van Buchem Disease - Created 2026-02-09, 88.9% compliance

Progress Summary

• Total planned: 51 skeletal dysplasias
• Already in KB: 4 (FOP, Noonan, NF1, reused for Tier 5)
• Completed: 51/51 (100%) ✓
• Remaining: 0

Priority Rationale

1. Tier 1 (FGFR3): Therapeutically most relevant - vosoritide approved, infigratinib in trials
2. Tier 2 (COL2A1): Best example of allelic series showing genotype-phenotype correlation
3. Tier 3 (FGFR craniosynostosis): Common, surgically managed, shared pathway with Tier 1
4. Tier 4 (OI): Common, therapeutics in development (setrusumab), classic genetics
5. Tier 5-10: Ordered by therapeutic relevance and mechanistic clarity

NOTES

2026-02-09 (Tier 9 + Tier 10 Completion - PROJECT COMPLETE)

6 Tier 9 disorders curated (Limb Development):

13. Holt-Oram Syndrome (MONDO:0007732) - 78.9% compliance

    • TBX5 haploinsufficiency: anterior/radial limb + cardiac
    • Key refs: PMID:8988165, 11572777, 15096952, 16183809, 30552424
    • 5 phenotypes, 74% mutation detection with strict criteria

14. Greig Cephalopolysyndactyly (MONDO:0008287) - 82.4% compliance

    • GLI3 haploinsufficiency disrupting Hedgehog signaling
    • Key refs: PMID:15739154, 20672375, 24736735, 28224613, 10693759
    • 5 phenotypes, robust genotype-phenotype correlation

15. Pallister-Hall Syndrome (MONDO:0007804) - 81.2% compliance

    • GLI3 middle-third truncations → constitutive repressor
    • Key refs: PMID:15739154, 10375510, 10693759, 24736735
    • 4 phenotypes: hypothalamic hamartoma pathognomonic

16. Ulnar-Mammary Syndrome (MONDO:0008411) - 88.9% compliance

    • TBX3 haploinsufficiency: posterior/ulnar limb + apocrine
    • Complementary to TBX5/Holt-Oram (anterior vs posterior)
    • Key refs: PMID:9207801, 10330342, 16530712
    • 4 phenotypes, T-domain mutations → more severe limb defects

17. Hand-Foot-Genital Syndrome (MONDO:0007698) - 90.0% compliance

    • HOXA13 loss-of-function: distal limb + Mullerian duct
    • Multiple mutation types: nonsense, polyalanine expansion, missense
    • Key refs: PMID:9020844, 10839976, 19591980
    • 5 phenotypes including bicornuate uterus and hypospadias

18. Brachydactyly Type A1 (MONDO:0007215) - 92.3% compliance

    • IHH missense mutations: multi-level Hedgehog signaling disruption
    • First recorded Mendelian autosomal dominant trait (Farabee 1903)
    • Key refs: PMID:11455389, 12525541, 21537345
    • Patched1 binding, protein stability, heparan sulfate interaction

5 Tier 10 disorders curated (Sclerosing Bone Dysplasias):

19. ADO Type II (MONDO:0008156) - 88.9% compliance

    • CLCN7 dominant negative: dimeric chloride channel disruption
    • 66% penetrance, allelic with recessive osteopetrosis
    • 84% fractures, 19% visual loss, 16% osteomyelitis (94-patient cohort)
    • Key refs: PMID:11741829, 12929941, 17164308

20. ARO (TCIRG1) (MONDO:0009816) - 81.2% compliance

    • TCIRG1 vacuolar proton pump deficiency: osteoclast acidification failure

    • 50% of infantile malignant osteopetrosis, fatal if untreated

    • HSCT only curative treatment
    • Key ref: PMID:10888887

21. Pycnodysostosis (MONDO:0009940) - 88.9% compliance

    • CTSK cathepsin K deficiency: collagen degradation failure
    • 33 mutations in 59 families, hotspot exons 6/7
    • Short stature, osteosclerosis, open fontanelles characteristic
    • Key refs: PMID:8703060, 21569238

22. Sclerosteosis (MONDO:0017838) - 88.2% compliance

    • SOST loss-of-function: unopposed Wnt-mediated bone formation
    • Afrikaner founder effect, hand malformations distinguish from VBD
    • Led to romosozumab development for osteoporosis
    • Key refs: PMID:11181578, 11179006

23. Van Buchem Disease (MONDO:0009395) - 88.9% compliance

    • 52-kb SOST enhancer deletion: regulatory vs coding SOST disruption
    • ECR5 bone-specific enhancer identified (PMID:15965026)
    • First human disease from distant regulatory element deletion
    • Key refs: PMID:11836356, 15965026

PROJECT COMPLETE: 51/51 skeletal dysplasias curated across 10 tiers.

Key pathway themes covered: - FGFR3 gain-of-function spectrum (Tier 1) - Type II collagen allelic series (Tier 2) - FGFR craniosynostosis (Tier 3) - Type I collagen/OI spectrum (Tier 4) - RAS-MAPK pathway (Tier 5) - TGF-β/BMP signaling (Tier 6) - Primary cilia/Hedgehog (Tier 7) - Metabolic bone (Tier 8) - Limb patterning transcription factors (Tier 9) - Osteoclast/osteoblast regulation (Tier 10)

2026-02-09 (Tier 6 + Tier 7 Curation Session)

3 new disorders curated across Tier 6 (TGF-β/BMP) and Tier 7 (Ciliopathies):

1. Loeys-Dietz Syndrome (MONDO:0018954) - 82.8% compliance - 5 subtypes (LDS types 1-5: TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3) - Paradoxical TGF-β signaling mechanism documented (loss-of-function mutations → tissue hyperactivation) - Key refs: PMID:16928994 (Loeys 2006 NEJM), PMID:24577266 (MacCarrick 2014 guidelines), PMID:35662564 (Gouda 2022 systematic review) - 15 phenotypes with HPO terms including aortic aneurysm, hypertelorism, bifid uvula - ERK/JNK noncanonical signaling pathway documented (PMID:21493862) - Losartan treatment evidence from Marfan mouse model (PMID:16601194)

2. Camurati-Engelmann Disease (MONDO:0007542) - 82.9% compliance - TGFB1 LAP domain mutations (R218H, R218C, C225R) causing constitutive TGF-β1 activation - Key refs: PMID:15894597 (Janssens 2006, 100 patients), PMID:11278244 (Saito 2001, mechanism) - 9 phenotypes with frequencies from 100-patient cohort (limb pain 68%, waddling gait 48%, muscle weakness 39%) - Losartan treatment evidence (PMID:25140400) - 6 PMIDs, 20 evidence items

3. Ellis-van Creveld Syndrome (MONDO:0009162) - 94.1% compliance - EVC/EVC2 mutations disrupting Hedgehog signaling at primary cilium - Key refs: PMID:10700184 (Ruiz-Perez 2000 EVC), PMID:12571802 (Ruiz-Perez 2003 EVC2), PMID:23026747 (Caparros-Martin 2013 Smo interaction) - 3 pathophysiology mechanisms: Hedgehog disruption, cilium dysfunction, cardiac septation - Cardiac phenotype detailed with 32-case series (PMID:21533779): 88% endocardial cushion defects - EFCAB7-IQCE tethering mechanism at cilia base (PMID:24582806) - 6 PMIDs, 25 evidence items

All 3 files pass schema + term + reference validation.

2026-02-09 (Tier 6 + Tier 7 Curation Session, Part 2)

3 additional disorders curated, completing Tier 6:

4. Shprintzen-Goldberg Syndrome (MONDO:0008426) - 77.4% compliance - SKI mutations in R-SMAD binding domain; 73% in 5-residue hotspot (p.Ser31-Pro35) - Enhanced TGF-β signaling mechanism (loss of SKI repression) - Key refs: PMID:23023332 (Doyle 2012 Nat Genet, SKI discovery), PMID:23103230 (Carmignac 2012 AJHG), PMID:24736733 (Schepers 2015 EJHG, mutational hotspot) - 10 phenotypes: craniosynostosis, intellectual disability, aortic aneurysm, cervical vertebral anomalies - Distinguished from MFS/LDS by craniosynostosis + intellectual disability - 4 PMIDs, 14 evidence items

5. Multiple Synostoses Syndrome (MONDO:0017923) - 73.1% compliance - NOG (SYNS1) and GDF5 (SYNS2) mutations converging on BMP signaling dysregulation - NOG: hypomorphic alleles reducing functional noggin dimer secretion - GDF5: gain-of-function via noggin resistance (S94N mutation) - Key refs: PMID:10080184 (Gong 1999 Nat Genet, NOG discovery), PMID:16532400 (Dawson 2006 AJHG, GDF5), PMID:21976273 (Schwaerzer 2012, molecular mechanism) - 6 phenotypes: symphalangism, carpal/tarsal fusions, conductive hearing loss - 4 PMIDs, 14 evidence items

6. Jeune Asphyxiating Thoracic Dystrophy (MONDO:0018770) - 88.6% compliance - Genetically heterogeneous ciliopathy: DYNC2H1 (33-59%), IFT80 (5%), IFT140, WDR19 - DYNC2H1 genotype-phenotype: primarily skeletal, lacks extra-skeletal involvement - Clinical frequencies: pulmonary insufficiency 60%, retinal 50% (>5y), liver 22%, renal 17% - Key refs: PMID:17468754 (Beales 2007, IFT80 first IFT-disease link), PMID:23456818 (Schmidts 2013, DYNC2H1 41%), PMID:23339108 (Baujat 2013, 39-family clinical review) - VEPTR treatment: 68% survival vs 70-80% untreated mortality (PMID:25575358) - 8 phenotypes, 5 PMIDs, 22 evidence items

All 3 files pass schema + term + reference validation. Tier 6 now complete (5/5).

2026-02-09 (Tier 7 Completion + Tier 8 Start)

3 more disorders curated, completing Tier 7 (Ciliopathies) and starting Tier 8 (Metabolic Bone):

7. Short-Rib Polydactyly Syndrome (MONDO:0015461) - 92.3% compliance - Lethal skeletal ciliopathy spectrum: DYNC2H1, NEK1, WDR34, IFT80 mutations - ATD-SRP spectrum continuum established (PMID:19442771) - NEK1 discovery for Majewski type (PMID:21211617); digenic NEK1+DYNC2H1 inheritance noted - WDR34 mutations reveal NF-κB pathway role in ciliopathies (PMID:24183449) - IFT80 extends Jeune-Verma-Naumoff spectrum (PMID:19648123) - 7 phenotypes, 4 genetic entries, 5 PMIDs, 20 evidence items

8. Orofaciodigital Syndrome Type I (MONDO:0010702) - 92.6% compliance - X-linked dominant ciliopathy, OFD1 mutations, male lethal - OFD1 centrosomal/basal body protein disrupts Shh and Wnt signaling (PMID:19876934) - Oral features most reliable diagnostic criteria (PMID:23033313) - 30-family mutation study: 22 novel mutations, hotspot exons 3/8/9/13/16 (PMID:23033313, PMID:16397067) - Renal cystic disease progressive → dialysis by age 35 (PMID:9482645) - Brain MRI spectrum: ACC, interhemispheric cysts, vermis hypoplasia - 7 phenotypes, 2 pathophysiology mechanisms, 4 PMIDs, 24 evidence items

9. Hypophosphatasia (MONDO:0018570) - 85.7% compliance - ALPL mutations → TNSALP deficiency → PPi accumulation → mineralization failure - Genetic nosology from 424-patient cohort: severe (recessive), moderate (recessive/dominant), mild (dominant, very common) (PMID:32973344) - DNE vs haploinsufficiency mechanisms in dominant forms; 60% adults heterozygous without DNE - Asfotase alfa: 95% vs 42% survival at 1 year (PMID:26529632) - PLP/B6 metabolism: ectoenzyme role, seizure mechanism (PMID:20392236) - PPi mineralization: crystals form in matrix vesicles but fail to enlarge (PMID:20392236) - 8 phenotypes, 2 pathophysiology, 4 PMIDs, 24 evidence items

All 3 files pass schema + term + reference validation. Tier 7 now complete (4/4).

2026-02-09 (Tier 8 Completion)

3 more disorders curated (+ 1 already in KB), completing Tier 8 (Metabolic Bone Disorders):

10. X-Linked Hypophosphatemia (MONDO:0010619) - 96.3% compliance

    • PHEX loss-of-function → FGF23 excess → renal phosphate wasting → rickets/osteomalacia
    • Two pathophysiology mechanisms: FGF23-mediated phosphate wasting + defective bone mineralization
    • Key refs: PMID:7550339 (HYP Consortium 1995, PHEX cloning), PMID:11062477 (ADHR Consortium 2000, FGF23 discovery), PMID:29947083 (Insogna 2018, adult burosumab phase 3), PMID:31104833 (Imel 2019, pediatric burosumab phase 3), PMID:29460029 (Chesher 2018, adult clinical features)
    • Burosumab: 94.1% phosphate normalization vs 7.6% placebo; 16.8x fracture healing odds
    • Dental disease 63%, nephrocalcinosis 42% in adult cohort
    • 7 phenotypes, 5 PMIDs, 28 evidence items

11. Mucopolysaccharidosis (MONDO:0019249) - 86.7% compliance

    • Overview entry covering MPS I/II/IV subtypes
    • Two pathophysiology mechanisms: lysosomal GAG accumulation + TLR4-mediated inflammatory response
    • Key refs: PMID:32780955 (Hampe 2020, dysostosis multiplex), PMID:30442189 (Concolino 2018, ERT review), PMID:25624320 (Aldenhoven 2015, 217 HCT patients), PMID:35216110 (Mandolfo 2022, innate immunity)
    • HSCT gold standard for severe MPS I-H; early transplantation critical for cognitive outcomes
    • ERT limitations: no BBB crossing, poor bone/cartilage penetration
    • 8 phenotypes, 3 genetic entries, 4 PMIDs, 24 evidence items

12. Gaucher Disease - Already in KB with good skeletal coverage

    • Bone crises, pathologic fractures, Erlenmeyer flask deformities
    • ERT/SRT evidence already documented (PMIDs: 28218669, 19047232, 22010032, 25688781)

All new files pass schema + term + reference validation. Tier 8 now complete (4/4).

2026-02-04 (Tier 5 Curation Session)

Tier 5 Complete - All 4 RASopathies with skeletal features covered:

1. Noonan Syndrome (MONDO:0018997) - Already in KB, 68.3% compliance - PTPN11, SOS1, RAF1, RIT1 mutations in RAS-MAPK pathway - Short stature, pectus deformities, CHD, developmental delay

2. Costello Syndrome (HRAS, MONDO:0009026) - 63.9% compliance - HRAS G12S mutations (~80%), constitutive RAS activation - Key refs: PMID:16443854 (Kerr 2006 genotype-phenotype), PMID:38415356 (Rodriguez 2024 MAT mechanism) - ~17% lifetime malignancy risk, G12A genotype-cancer correlation - Added: Multifocal atrial tachycardia phenotype (50% prevalence) - Added: Atrial cardiomyocyte pacemaker-nodal reprogramming mechanism

3. Cardiofaciocutaneous Syndrome (BRAF/MEK, MONDO:0015280) - 68.4% compliance - BRAF (~81%), MEK1 (~14%), MEK2 (~5%) mutations - Key refs: PMID:16439621 (Rodriguez-Viciana 2006 discovery), PMID:38136934 (Scorrano 2023 review), PMID:36308388 (Jelin 2023 prenatal) - Most severe cognitive impairment in RASopathy spectrum - Added: Seizures phenotype with gene-specific frequencies (57% BRAF, 61% MEK1, 30% MEK2) - Added: Polyhydramnios as prenatal manifestation - Added: MEK inhibitor therapy evidence from zebrafish models

4. Neurofibromatosis Type 1 (NF1, MONDO:0007902) - Already in KB, 51.2% compliance - NF1 loss → RAS-MAPK hyperactivation - Skeletal: scoliosis, tibial pseudarthrosis, sphenoid dysplasia

All files pass schema + term + reference validation.

2026-02-04 (Tier 4 Curation Session)

Tier 4 Complete - All 6 Osteogenesis Imperfecta spectrum disorders curated:

1. OI Type I (mild, MONDO:0008146) - 65.4% compliance - COL1A1 haploinsufficiency mechanism (null mutations → 50% collagen) - Key refs: PMID:1353940 (Willing 1992), PMID:23529829 (Ben Amor 2013) - Blue sclerae, near-normal stature (-1.1 Z-score), hearing loss

2. OI Type II (perinatal lethal, MONDO:0008147) - 62.5% compliance - Dominant-negative glycine substitutions in Gly-X-Y repeat - Key ref: PMID:7643358 (Cole & Dalgleish 1995 review) - 7% recurrence risk due to gonadal mosaicism

3. OI Type III (severe progressive, MONDO:0009804) - 56.2% compliance - Most severe non-lethal form, progressive deformity - Key ref: PMID:7643358 (genotype-phenotype correlation)

4. OI Type IV (moderate, MONDO:0008148) - 57.7% compliance - Intermediate severity, normal sclerae distinguishing from type I - Key ref: PMID:7643358

5. OI Type V (IFITM5, MONDO:0012591) - 60.7% compliance - Single recurrent c.-14C>T mutation adds MALEP to N-terminus - Key ref: PMID:22863190 (Cho 2012 discovery paper) - Hyperplastic callus, radioulnar synostosis pathognomonic

6. OI Type VII (CRTAP, MONDO:0012536) - 56.7% compliance - Autosomal recessive, prolyl 3-hydroxylation deficiency - Key ref: PMID:17055431 (Morello 2006 Cell paper) - Rhizomelia distinguishes from dominant OI

All 6 files pass schema + term validation.

2026-02-04 (Tier 2 Curation Session)

Tier 2 Complete - All 6 Type II Collagenopathies (COL2A1 spectrum) curated:

1. Achondrogenesis Type II (lethal, MONDO:0008702) - 76.7% compliance - Severe end of spectrum, glycine substitutions in Gly-X-Y repeat - Key refs: PMID:7829510 (collagen replacement), PMID:10745044 (phenotypic continuum) - Documents complete absence of type II collagen, replacement by types I/III

2. Hypochondrogenesis (usually lethal, MONDO:0019669) - 75.0% compliance - Intermediate severity between ACG2 and SEDC - Key refs: PMID:6641761 (original description), PMID:2572591 (Gly943Ser mutation) - Added ER stress and chondrocyte apoptosis pathway (PMID:25187577)

3. Spondyloepiphyseal Dysplasia Congenita (MONDO:0008471) - 69.4% compliance - Short-trunk dwarfism, myopia, hearing loss, odontoid hypoplasia - Key refs: PMID:1971141 (landmark COL2A1 linkage), PMID:7550321 (spectrum) - Added cleft palate phenotype with evidence (PMID:11878179)

4. Kniest Dysplasia (MONDO:0007987) - 69.7% compliance - Dumbbell-shaped bones, enlarged joints, "Swiss cheese" cartilage - Key refs: PMID:8723084 (histopathology), PMID:7981752 (exon-skipping mutations) - Characteristically caused by exon-skipping/in-frame deletions

5. Stickler Syndrome Type 1 (MONDO:0007160) - 71.0% compliance - Mildest form, haploinsufficiency mechanism - Key refs: PMID:20179744 (100-patient series), PMID:17675240 (prophylaxis efficacy) - Membranous vitreous pathognomonic, 73%→8% RD reduction with cryotherapy

6. SEMD Strudwick Type (MONDO:0008476) - 69.7% compliance - Distinguished by "dappled" metaphyseal changes - Key refs: PMID:7550321 (biochemical characterization), PMID:12925722 (Gly262Asp) - Added early-onset osteoarthritis phenotype

All 6 files pass schema + term + reference validation.

2026-01-30 (Tier 1 Curation Session)

Tier 1 Complete - All 5 FGFR3-related disorders curated:

1. Achondroplasia (FGFR3 G380R) - 65.8% compliance - Paradigmatic FGFR3 disorder, most common skeletal dysplasia - Key refs: PMID:7913883 (Shiang 1994 discovery), PMID:7847369 (Bellus G380R confirmation) - Evidence added for FGFR3 pathophysiology, vosoritide treatment (PMID:31269546) - Covers gain-of-function signaling, growth plate dysfunction

2. Hypochondroplasia (FGFR3 N540K) - Mild end of FGFR3 spectrum - ~50-70% have N540K mutation; genetic heterogeneity noted

3. Thanatophoric Dysplasia Type 1 (FGFR3 R248C and others) - Lethal skeletal dysplasia, curved femurs characteristic - Extracellular domain mutations causing ligand-independent dimerization

4. Thanatophoric Dysplasia Type 2 (FGFR3 K650E) - Lethal, straight femurs, frequent cloverleaf skull - K650E in kinase activation loop, severe constitutive activation

5. SADDAN (FGFR3 K650M) - Intermediate severity, developmental delay + acanthosis nigricans - Same codon as TD2 but different amino acid → different phenotype

All 5 files pass schema + term validation.

2026-01-30 (Project Created)

Initial project file for skeletal dysplasias curation. Structure modeled on CANCER.md project.

Scope decisions: - Focus on genetic skeletal disorders per 2023 Nosology classification - Prioritize disorders with therapeutic implications or strong mechanistic understanding - Include allelic series (FGFR3, COL2A1, COL1A1) to demonstrate genotype-phenotype correlations - Exclude purely metabolic bone disease covered elsewhere (osteoporosis) unless there's specific genetic overlap

Key pathways to emphasize: 1. FGFR3 signaling and CNP/natriuretic peptide pathway (achondroplasia therapy) 2. Collagen biosynthesis and quality control (OI, type II collagenopathies) 3. TGF-β superfamily signaling (LDS, FOP, Marfan connections) 4. Primary cilia and Hedgehog signaling (ciliopathies) 5. RANKL/OPG bone remodeling axis (sclerosing dysplasias)

Related entries already in KB: - Marfan Syndrome (FBN1/TGF-β) - connects to Tier 6 - EDS (collagen) - connects to OI spectrum - FOP (ACVR1/BMP) - Tier 6 complete - NF1 - in KB but could enhance skeletal aspects

Recommended curation order: Start with Achondroplasia as the paradigmatic FGFR3 disorder with FDA-approved therapy demonstrating mechanism-based treatment.