Ehlers-Danlos Syndrome, Musculocontractural Type, 2

A number sign (#) is used with this entry because of evidence that Ehlers-Danlos syndrome musculocontractural type 2 (EDSMC2) is caused by homozygous mutation in the DSE gene (605942) on chromosome 6q22.

Description

The musculocontractural type of Ehlers-Danlos syndrome is characterized by progressive multisystem fragility-related manifestations, including joint dislocations and deformities; skin hyperextensibility, bruisability, and fragility, with recurrent large subcutaneous hematomas; cardiac valvular, respiratory, gastrointestinal, and ophthalmologic complications; and myopathy, featuring muscle hypoplasia, muscle weakness, and an abnormal muscle fiber pattern in histology in adulthood, resulting in gross motor developmental delay (summary by Muller et al., 2013).

For a discussion of genetic heterogeneity of the musculocontractural type of Ehlers-Danlos syndrome, see EDSMC1 (601776).

Clinical Features

Muller et al. (2013) studied a 2-year-old Indian boy, born of first-cousin parents, who exhibited facial dysmorphism consisting of frontal bossing, open anterior fontanel, downward-slanting palpebral fissures, telecanthus, bluish sclerae, high-arched palate, tent-shaped lips, dental crowding, brachycephaly, and prominent ears, as well as arachnodactyly, adducted thumbs, joint hyperlaxity, inguinal hernia, and congenital bilateral talipes equinovarus. Echocardiography showed a patent foramen ovale, and CT scan of the brain revealed generalized mild cerebral atrophy. After clubfoot surgery, the patient had delayed wound healing and atrophic scarring of the skin. Generalized muscle weakness was observed, suggestive of an underlying myopathy, and his gross motor development was delayed. His cognitive development was normal.

Syx et al. (2015) reported 2 Spanish sisters, aged 48 and 39 years, with hyperextensible and fragile skin, frequent hematomas after minor trauma with residual calcifications and pigmentation of the skin, and clubfeet; neither had adducted thumbs, and although fingers were long and slender, they did not show true arachnodactyly, and joint hypermobility was 'not obvious.' Muscle tone and strength were reduced, and both sisters experienced joint and muscle pain that limited daily activities. The older sister required mitral valve replacement due to severe regurgitation caused by a myxomatous prolapsing mitral valve with rupture of the chordae, but the younger sister had a normal echocardiogram without significant mitral valve anomalies. The older sister experienced uterine and bladder prolapse after 2 deliveries before age 40, and the younger sister had an eventration after gallbladder surgery. Neither sister had gastrointestinal or respiratory complications, and eye examination was unremarkable.

Molecular Genetics

In a 2-year-old Indian boy with the musculocontractural type of Ehlers-Danlos syndrome, who was negative for mutation in the CHST14 gene (608429), Muller et al. (2013) performed high-density SNP array genotyping, which revealed 25 homozygous regions exceeding 4 Mb. Sequencing of the functional candidate gene DSE (605942), located within the largest, 44.689-Mb region of homozygosity, revealed a homozygous missense mutation (S268L; 605492.0001). Both parents and a healthy brother were heterozygous for the mutation, which was not found in 300 Caucasian control DNA samples or in the 1000 Genomes Project, dbSNP, or NHLBI Exome Sequencing Project databases.

In 2 Spanish sisters with a musculocontractural type of Ehlers-Danlos syndrome, who were negative for mutation in the CHST14 gene, Syx et al. (2015) sequenced the candidate gene DSE and identified homozygosity for a missense mutation (R267G; 605942.0002) that segregated with disease in the family. The authors noted that EDSMC2 appeared to be a milder disorder than CHST14-associated EDSMC1 (601776), but that the limited number of reported patients with DSE mutations made it impossible as yet to clinically distinguish ESDMC2 from EDSMC1.