SH3PXD2B – Frank-ter Haar syndrome

Frank-ter Haar syndrome is a rare autosomal recessive disorder with multisystem involvement, including craniofacial dysmorphism such as brachycephaly (PMID:23140272) and hypertelorism (PMID:28694206). Multiple independent case reports and multi‐patient studies have established the association of pathogenic variants in SH3PXD2B with the syndrome, providing robust evidence from segregation analyses across several unrelated families, with additional affected relatives supporting the inheritance pattern (PMID:20137777).

Genetic evidence is substantial: several distinct mutational events including splice site, deletion, and missense variants have been reported. In particular, the variant c.806G>A (p.Trp269Ter) has been identified in a compound heterozygous state in affected individuals, and its occurrence in multiple cases underscores the variant spectrum involved in disease causation (PMID:28694206). Segregation evidence from consanguineous families further supports a recessive mode of inheritance, with extended analysis across affected relatives strengthening the gene–disease association (PMID:23140272).

Functional studies contribute to the understanding of the pathogenic mechanism: experiments demonstrate that loss-of-function mutations in SH3PXD2B lead to disruption of podosome formation, which in turn affects extracellular matrix remodeling and cell migration. These findings have been replicated both in in vitro cellular assays and in animal models, which recapitulate key features of Frank-ter Haar syndrome, including abnormal craniofacial development and cardiac anomalies (PMID:22829589).

Additional functional assessments using CRISPR/Cas9-mediated gene knockout in human embryonic stem cells have shown that disruption of SH3PXD2B perturbs mesenchymal differentiation and cell migration, establishing a direct link between the gene defect and the clinical phenotype (PMID:35955935). Furthermore, these experimental observations correlate with the multisystem clinical manifestations reported in patients, thereby reinforcing the proposed pathogenic mechanism of haploinsufficiency.

While some phenotypic overlaps with other syndromes have been noted in the literature, the convergence of genetic, segregation, and functional data has led multiple groups to conclude that the association between SH3PXD2B and Frank-ter Haar syndrome is strong. Notably, comprehensive reviews have aggregated data from over 40 patients spanning several families, providing significant weight to the clinical utility and diagnostic value of these findings (PMID:20137777).

Key take‑home sentence: The robust combination of genetic and functional evidence confirms that pathogenic variants in SH3PXD2B, including the recurrent c.806G>A (p.Trp269Ter) mutation, are highly predictive for Frank‑ter Haar syndrome, thereby significantly enhancing diagnostic accuracy and informing clinical management.

References

• BMC Medical Genetics • 2012 • Frank-ter Haar syndrome associated with sagittal craniosynostosis and raised intracranial pressure PMID:23140272
• Gene • 2017 • Identification of two novel SH3PXD2B gene mutations in Frank-Ter Haar syndrome by exome sequencing: Case report and review of the literature PMID:28694206
• American Journal of Human Genetics • 2010 • Disruption of the podosome adaptor protein TKS4 (SH3PXD2B) causes the skeletal dysplasia, eye, and cardiac abnormalities of Frank-Ter Haar Syndrome PMID:20137777
• The Journal of Biological Chemistry • 2012 • Frank-ter Haar syndrome protein Tks4 regulates epidermal growth factor-dependent cell migration PMID:22829589
• International Journal of Molecular Sciences • 2022 • A Novel Cell-Based Model for a Rare Disease: The Tks4-KO Human Embryonic Stem Cell Line as a Frank-Ter Haar Syndrome Model System PMID:35955935

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