Alternative titles; symbols
SNOMEDCT: 765204000, 93132001; ORPHA: 1865; DO: 0090032;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p36.12 | Dyssegmental dysplasia, Silverman-Handmaker type | 224410 | Autosomal recessive | 3 | HSPG2 | 142461 |
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.
Silverman-Handmaker dyssegmental dysplasia (DDSH) is a lethal autosomal recessive skeletal dysplasia with anisospondyly and micromelia. Individuals with DDSH also have a flat face, micrognathia, cleft palate and reduced joint mobility, and frequently have an encephalocele. The endochondral growth plate is short, the calcospherites (spherical calcium-phosphorus crystals produced by hypertrophic chondrocytes) are unfused, and there is mucoid degeneration of the resting cartilage (summary by Arikawa-Hirasawa et al., 2001).
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.
The pattern of transmission of DDSH in the family studied by Arikawa-Hirasawa et al. (2001) was consistent with autosomal recessive inheritance.
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.
Aleck, K. A., Grix, A., Clericuzio, C., Kaplan, P., Adomian, G. E., Lachman, R., Rimoin, D. L. Dyssegmental dysplasias: clinical, radiographic, and morphologic evidence of heterogeneity. Am. J. Med. Genet. 27: 295-312, 1987. [PubMed: 3605216] [Full Text: https://doi.org/10.1002/ajmg.1320270208]
Arikawa-Hirasawa, E., Wilcox, W. R., Le, A. H., Silverman, N., Govindraj, P., Hassell, J. R., Yamada, Y. Dyssegmental dysplasia, Silverman-Handmaker type, is caused by functional null mutations of the perlecan gene. Nature Genet. 27: 431-434, 2001. [PubMed: 11279527] [Full Text: https://doi.org/10.1038/86941]
Fasanelli, S., Kozlowski, K., Reiter, S., Sillence, D. Dyssegmental dysplasia (report of two cases with a review of the literature). Skeletal Radiol. 14: 173-177, 1985. [PubMed: 4059934] [Full Text: https://doi.org/10.1007/BF00355557]
Handmaker, S. D., Robinson, L. D., Campbell, J. A., Chinwah, O., Gorlin, R. J. Dyssegmental dwarfism: a new syndrome of lethal dwarfism. Birth Defects Orig. Art. Ser. XIII(3D): 79-90, 1977.