Musculocontractural Ehlers-Danlos Syndrome · mcEDS

Description

Musculocontractural Ehlers-Danlos syndrome, mcEDS, is an autosomal recessive connective tissue disorder defined by congenital multiple contractures, distinctive craniofacial features, and progressive skin and joint findings. The 2017 international classification (Malfait and colleagues, American Journal of Medical Genetics Part C, 2017) recognizes two molecular forms. The major form is caused by biallelic variants in CHST14, which encodes dermatan 4-O-sulfotransferase 1 and produces the dermatan sulfate chains that decorate proteoglycans in skin, joints, and vasculature. The minor form is caused by biallelic variants in DSE, which encodes dermatan sulfate epimerase. The CHST14 form was reported by Kosho and colleagues in the American Journal of Medical Genetics Part A in 2010, and the same group later showed that pathogenic CHST14 variants shift glycosaminoglycan composition from dermatan sulfate toward chondroitin sulfate (Miyake and colleagues, Human Mutation, 2010). The DSE form was reported by Muller and colleagues in Human Molecular Genetics in 2013.

The 2017 criteria require all three major findings present from birth: congenital multiple contractures characteristically including adducted thumbs and clubfoot, characteristic craniofacial features with large fontanelle, hypertelorism, short downslanting palpebral fissures, blue sclerae, and a small mouth, and characteristic cutaneous features with hyperextensibility, bruisability, fragility, atrophic scars, and increased palmar wrinkling. Minor criteria include progressive joint and skin findings, recurrent dislocations, ophthalmologic complications including glaucoma and refractive errors, and cardiovascular involvement most commonly mitral valve prolapse and ascending aortic dilation.

Confirmation is by gene sequencing of CHST14 or DSE with biallelic pathogenic variants. The original cohort was largely Japanese, and subsequent reports have expanded the geography to include families in Europe, the Middle East, South Asia, and the Americas. The total reported case count remains in the low hundreds.

Treatments to date

Care is supportive and multidisciplinary. There is no approved disease-modifying therapy, no enzyme replacement, and no gene therapy in clinical use.

Orthopedic management begins in infancy. Adducted thumbs and clubfoot are treated with serial casting and surgery as indicated. Recurrent large-joint dislocations are managed with bracing and physical therapy oriented toward stabilization rather than stretching. Spine surgery is considered for progressive kyphoscoliosis when bracing fails or pulmonary function declines. Tissue fragility complicates surgical exposure and fixation, and procedures are concentrated at centers experienced with connective tissue disease.

Cardiac surveillance is routine because of the documented frequency of mitral valve prolapse and reports of ascending aortic dilation and dissection. Baseline echocardiography is followed by periodic imaging on a schedule informed by individual findings. Ophthalmologic surveillance includes intraocular pressure monitoring for glaucoma, refraction, and retinal examination.

Skin care is conservative. Sun protection and gentle wound care reduce the burden of atrophic scarring, and contact sports are avoided because of bruising and laceration risk. Bowel and bladder diverticula and large subcutaneous hematomas have been reported and require imaging-guided assessment when symptomatic. Hearing and dental assessments are part of long-term follow-up.

No drug is approved by the FDA or EMA for mcEDS. Research has focused on the biology of dermatan sulfate and on cellular models that capture the glycosaminoglycan composition shift.