A number sign (#) is used with this entry because of evidence that Ehlers-Danlos syndrome spondylodysplastic type 2 (EDSSPD2) is caused by compound heterozygous or homozygous mutation in the B3GALT6 gene (615291) on chromosome 1p36.

Mutation in the B3GALT6 gene can also cause spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMDJL1; 271640) and Al-Gazali syndrome (ALGAZ; 609465), which have overlapping features with EDSSPD2.

The features of Ehlers-Danlos syndrome spondylodysplastic type 2 (EDSSPD2) include an aged appearance, developmental delay, short stature, craniofacial disproportion, generalized osteopenia, defective wound healing, hypermobile joints, hypotonic muscles, and loose but elastic skin (Okajima et al., 1999).

For a discussion of genetic heterogeneity of the spondylodysplastic type of Ehlers-Danlos syndrome, see 130070.

Van Damme et al. (2018) reported clinical and molecular data on 12 patients with EDSSPD2, all of whom had findings of both a severe form of Ehler-Danlos syndrome and spondyloepimetaphyseal dysplasia. Prenatal ultrasound findings were described in 4 pregnancies and included features of severe skeletal dysplasia. Among the 10 liveborn patients, 5 were born at term; gestational age was not mentioned for the other patients. Anthropometric measurements were within normal limits at birth, but postnatal growth restriction was severe in all patients. Progressive and severe kyphoscoliosis, multiple joint contractures of small and large joints, and joint hypermobility with multiple dislocations of small and large joints were seen in all patients. Four patients had congenital hip dysplasia, and 3 had cervical spine instability. Hypotonia was reported in 5 patients. Skin was hyperextensible in 7 of 10 patients and soft with a doughy texture in 9 of 10 patients. Skin was described as thin and translucent in 4 patients, and as having a cutis laxa-like aspect in 5. Atrophic scarring was reported in 5 patients, but easy bruisability was described in only 2. Most patients had recognizable facies, including midfacial hypoplasia, frontal bossing, low-set and posteriorly rotated ears, depressed nasal bridge, prominent eyes, blue sclerae, short nose with anteverted nares, and a long philtrum. Delayed motor development ranging from mild to severe was reported in 5 patients, and speech was delayed in 2 patients. One patient had an intracranial hemorrhage following vaginal delivery and had a dilated aortic root and mild prolapse of the mitral valve. This patient also had recurrent spontaneous pneumothoraces. Another patient had perforated diverticulitis at age 33 years, a cerebral vascular accident at age 35 years, and dilatation of the thoracic aorta diagnosed at age 37 years. Radiographic findings included moderate to severe spondyloepimetaphyseal dysplasia. All patients showed widening of the metaphyses of long bones, relative narrowing and bowing of the diaphysis of long bones, hypoplasia of the iliac bones, and changes in the shape of the vertebral bodies. All but one patient had moderate to severe acetabular dysplasia and femoral head dysplasia. Osteopenia was seen in 8 patients.

In 4 patients from 3 families with a progeroid form of EDS who did not have mutations in the B4GALT7 gene, Nakajima et al. (2013) performed Sanger sequencing of the B3GALT6 gene and found that all 4 patients were compound heterozygous for a frameshift and a missense mutation (615291.0007-615291.0011). Nakajima et al. (2013) showed that the GalT-II activities of a missense mutation that was common to 2 of the families (S309T; 615291.0008) were significantly decreased compared to wildtype, suggesting loss of function. The mutations were not detected in more than 200 ethnically matched controls or in public databases, including the 1000 Genomes Project Database.

Using whole-exome, panel, and direct gene sequencing of 12 patients from 9 families with EDSSPD2, Van Damme et al. (2018) identified 8 compound heterozygous mutations and 1 homozygous (615291.0015) mutation in the B3GALT6 gene, including 11 missense variants, 2 frameshift variants, a deletion of 19 amino acids, and a start codon alteration. Most mutations were located in the luminal domain. In families in whom parental DNA was available, mutations segregated as expected. Studies in fibroblasts showed that these mutations reduced the amount and activity of B3GALT6, which in turn reduced glycosaminoglycan synthesis and produced ultrastructural abnormalities in collagen fibril organization.