Dyssegmental Dysplasia, Silverman-Handmaker Type

A number sign (#) is used with this entry because the Silverman-Handmaker type of dyssegmental dysplasia (DDSH) is caused by homozygous or compound heterozygous mutation in the gene encoding perlecan (HSPG2; 142461) on chromosome 1p36.

See also Schwartz-Jampel syndrome type 1 (SJS1; 255800), an allelic disorder with a less severe but overlapping phenotype.

Clinical Features

The dyssegmental dysplasias are lethal forms of neonatal short-limbed dwarfism. Handmaker et al. (1977) coined the term 'dyssegmental dysplasia' because of the marked differences in size and shape of the vertebral bodies (anisospondyly), which he attributed to errors in segmentation. Fasanelli et al. (1985) proposed that there are different forms of dyssegmental dwarfism, a lethal Silverman type and a less severe Rolland-Desbuquois type (224400).

Aleck et al. (1987) found reports of 18 cases, including 3 reports of affected sibs, and reported 8 additional cases. The authors presented further evidence for the existence of 2 forms of dyssegmental dysplasia.

Molecular Genetics

In a pair of sibs with DDSH born to consanguineous parents, Arikawa-Hirasawa et al. (2001) identified a homozygous 89-bp duplication in exon 34 of the HSPG2 gene (142461.0003). A third unrelated patient was compound heterozygous for 2 truncating mutations (142461.0004; 142461.0005). The cartilage matrix from these patients stained poorly with antibody specific for perlecan, but there was staining of intracellular inclusion bodies. Truncated perlecan was not secreted by patient fibroblasts, but was degraded into smaller fragments within the cells. Thus, the Silverman-Handmaker type of dyssegmental dysplasia is caused by a functional null mutation of HSPG2. Arikawa-Hirasawa et al. (2001) concluded that their findings demonstrate the critical role of perlecan in cartilage development.