SOST – Craniodiaphyseal Dysplasia

Craniodiaphyseal dysplasia (CDD) is an exceptionally rare sclerosing bone dysplasia characterized by progressive craniofacial hyperostosis leading to "leontiasis ossea," intracranial hypertension, and cranial nerve compression. SOST (HGNC:13771) encodes sclerostin, a secreted glycoprotein that antagonizes Wnt/β-catenin signaling via LRP5/6, critically regulating bone formation. Pathogenic SOST variants extend the spectrum of sclerosing bone dysplasias to include CDD, complementing its established role in sclerosteosis and Van Buchem disease.

Genetic Evidence

CDD due to SOST variants manifests predominantly as an autosomal dominant disorder. Two unrelated probands harboring heterozygous signal peptide mutations, c.61G>T (p.Val21Leu) and c.61G>A (p.Val21Met), were identified in independent families with CDD (PMID:21221996). An additional consanguineous family presented with two affected siblings carrying a homozygous truncating SOST variant, c.327C>A (p.Cys109Ter) (PMID:40605263). Segregation of the homozygous allele in one affected sibling supports pathogenicity.

Functional Evidence

In cell-based assays, signal peptide mutants (p.Val21Leu, p.Val21Met) exhibited markedly reduced sclerostin secretion in 293E cells (PMID:21221996). The truncating p.Cys109Ter variant abrogated SOST RNA and protein expression and produced a truncated, non-secreted protein in HEK293T cells (PMID:40605263). These concordant loss-of-function effects recapitulate the severe CDD phenotype.

Mechanism of Pathogenicity

Autosomal dominant SOST variants act via a dominant-negative mechanism: missecreted sclerostin disrupts extracellular antagonism of Wnt signaling, driving excessive bone deposition. Homozygous truncations further confirm that complete loss of sclerostin precipitates the most severe craniofacial hyperostosis.

Clinical Utility & Recommendations

Given the high penetrance and clear functional impact of SOST variants in CDD, targeted sequencing of SOST is recommended in patients with early-onset craniofacial hyperostosis. Functional assays of secretion can support variant interpretation. This association informs diagnostic algorithms, genetic counseling, and the development of sclerostin-modulating therapies.

Key Take-home: Pathogenic SOST variants cause craniodiaphyseal dysplasia via impaired sclerostin secretion, and SOST testing is critical for accurate diagnosis and management of this severe sclerosing bone dysplasia.

References

• Human Genetics • 2011 • Identification of signal peptide domain SOST mutations in autosomal dominant craniodiaphyseal dysplasia. PMID:21221996
• Molecular Genetics & Genomic Medicine • 2025 • Novel Loss of Function Variant in SOST From Chinese Family Results in Sclerosteosis 1. PMID:40605263

Evidence Based Scoring (AI generated)