Spondyloepiphyseal Dysplasia with Congenital Joint Dislocations (SEDCJD) - OMIM #143095

Overview

Synonyms and Alternate Names

Genetics and Molecular Basis

• CHST3 spans >20 kb with three exons
• C6ST-1 catalyzes the transfer of sulfate to the C-6 position of galactose in chondroitin sulfate (CS) and keratan sulfate (KS) proteoglycans
• Loss-of-function mutations result in undersulfation of chondroitin sulfate proteoglycans in cartilage and extracellular matrix
• Undersulfated CS disrupts cartilage matrix integrity, joint morphogenesis, vertebral development, and ligament structure
• Mutations found include missense, nonsense, splice-site, and small deletions; the variant spectrum continues to expand
• Notable recent mutations include c.601T>A; p.(Tyr201Asn), c.626C>A; p.(Pro209Gln), c.1343T>G and c.761C>G (compound heterozygotes)
• Inheritance: Autosomal recessive - consanguineous families are overrepresented in reported cases; carriers are asymptomatic
• No convincing genotype-phenotype correlation has been established (Liang et al., 2023)

Clinical Features

1. Joint Involvement

• Large joint dislocations at birth or infancy: hip (bilateral), knee, and elbow joints most commonly affected
• Shoulder and wrist subluxations also reported
• Equinovarus or equinovalgus foot deformities (clubfoot)
• Progressive joint pain and restricted extension of elbows and knees
• Early-onset osteoarthritis, particularly of hip and spine
• Dislocations worsen year by year; joint symptoms often force wheelchair use by the second decade

2. Spinal Disease

• Severe progressive kyphoscoliosis - a hallmark feature
• Cervical kyphosis and atlantoaxial instability (risk of spinal cord compression)
• Platyspondyly and vertebral irregularities on imaging
• Intervertebral disc degeneration, trunk shortening
• Rigid lumbar spine in adulthood

3. Short Stature

• Disproportionate short stature with rhizomelic limbs (proximal limb shortening)
• Significant height deficit (height Z-score of -4.94 reported in one series)
• Adult height typically in the 110-140 cm range

4. Craniofacial Features

• Hypertelorism, depressed/broad nasal bridge, broad nasal tip
• Broad high forehead (frontal bossing)
• Prominent philtrum, flattened midface
• Cleft palate in a subset
• Note: typical Larsen-type facial features are usually absent or mild in SEDCJD

5. Additional Features

Radiological Features

• Epiphyseal dysplasia of multiple joints (carpal, tarsal, femoral head)
• Platyspondyly (flat vertebral bodies)
• Cervical kyphosis with odontoid hypoplasia
• Enlargement and deformity of elbow and knee joints
• Hip subluxation/dislocation; femoral head avascular necrosis may develop
• Carpal and tarsal bone hypoplasia/irregularity
• Trabecular bone microarchitecture may be abnormal (reduced volumetric BMD on HR-pQCT)
• Compression fractures (lumbar) in the second decade

Natural History

• Evident at birth with joint dislocations
• Progressive: joint pain and restricted motion increase through childhood
• Wheelchair dependence common by the second decade
• Spinal rigidity and kyphoscoliosis worsen with age
• Early-onset degenerative joint disease requiring surgical intervention
• One reported patient underwent femoral head osteonecrosis treatment at age 19 (bone flap with cannulated screw fixation)

Diagnosis

• Larsen syndrome (FLNB, AD) - dominant inheritance, classic facial features, frontal bossing, cylindrical fingers
• Desbuquois dysplasia (CANT1)
• Spondyloepimetaphyseal dysplasia with joint laxity (KIF22/B3GALT6)
• SEDC (COL2A1) - no major joint dislocations at birth
• Ehlers-Danlos syndrome, arthrochalasia type (COL1A1/1A2)

Management

Epidemiology

• Very rare; exact prevalence unknown
• First reported in Omani families (consanguineous)
• Subsequently described in South Asian (Pakistani, Indian), Chinese, and European populations
• The 2023 systematic review by Liang et al. (PMID 36729370) remains the most comprehensive summary of published cases

Key Points Summary

1. SEDCJD (OMIM #143095) = CHST3 biallelic mutations, autosomal recessive
2. CHST3 encodes C6ST-1, required for chondroitin sulfate 6-O-sulfation
3. Cardinal features: congenital large joint dislocations + progressive kyphoscoliosis + short stature + normal intelligence
4. Progressive course - joint pain worsens, spinal disease advances, early osteoarthritis
5. Management is entirely supportive/surgical; no enzyme replacement or gene therapy available
6. No genotype-phenotype correlation established
7. Distinct from (but phenotypically overlaps with) autosomal dominant Larsen syndrome (FLNB)

• Liang et al. 2023 - Systematic Review, Endocrine (PMID 36729370)
• Mughal et al. 2024 - Novel CHST3 variant, Mol Syndromol (PMID 39359945)
• Yan et al. 2017 - Chinese case, Annals of Joint
• NCBI MedGen entry for SEDCJD
• Rheumatology 2-Volume Set (2022, Elsevier), Ch. 216 - Skeletal Dysplasias