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HSPG2 – Silverman-Handmaker type dyssegmental dysplasia

Dyssegmental dysplasia, Silverman-Handmaker type (DDSH) is an autosomal recessive, perinatally lethal skeletal dysplasia marked by anisospondyly and severe micromelic shortening. It results from biallelic loss-of-function variants in the perlecan gene, HSPG2, which compromises basement membrane integrity during vertebral segmentation.

Genetic studies have identified at least 4 unrelated probands homozygous or compound heterozygous for null HSPG2 alleles in lethal DDSH ([PMID:20542149]). Variant spectrum is dominated by nonsense and frameshift changes; for example, c.11750C>A (p.Ser3917Ter) represents a recurrent truncating allele. Mode of inheritance is autosomal recessive with no reported informative segregation beyond parental carrier status.

Functional modeling using morpholino-mediated knockdown in zebrafish recapitulates key DDSH features: abnormal mandibular jaw joint formation, reduced numbers of Sox10⁺ neural crest-derived chondrocytes and Col2a1a⁺ cartilage precursors, and decreased nkx3.2 expression in the mandibular region ([PMID:33678174]). These data support a loss-of-function mechanism for HSPG2 in cartilage development.

Allelic comparison with Schwartz-Jampel syndrome (SJS), a nonlethal HSPG2 hypomorphic disorder, further underscores a dosage effect: complete perlecan deficiency leads to lethal DDSH, whereas partial activity yields SJS neuromyotonia and chondrodysplasia. No studies have reported conflicting data or alternative genetic causes for classic DDSH.

In summary, biallelic null variants in HSPG2 are conclusively associated with DDSH, facilitating definitive molecular diagnosis, prenatal genetic counseling, and informing future therapeutic research on perlecan replacement or modulation.

References

  • European journal of medical genetics • 2010 • Phenotypic and molecular characterization of a novel case of dyssegmental dysplasia, Silverman-Handmaker type PMID:20542149
  • BMC developmental biology • 2021 • Knockdown of hspg2 is associated with abnormal mandibular joint formation and neural crest cell dysfunction in zebrafish PMID:33678174

Evidence Based Scoring (AI generated)

Gene–Disease Association

Moderate

4 unrelated probands with biallelic loss-of-function variants in lethal DDSH ([PMID:20542149]); consistent AR inheritance and variant type

Genetic Evidence

Moderate

Biallelic null HSPG2 variants in 4 probands, meeting criteria for autosomal recessive disease causation

Functional Evidence

Moderate

Zebrafish morpholino knockdown recapitulates cartilage and segmentation defects of DDSH ([PMID:33678174])