CDC42 – macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome

Takenouchi-Kosaki syndrome (TKS; MONDO:0014757) is an autosomal dominant multisystem disorder characterized by congenital macrothrombocytopenia, dysmorphic facial features, growth retardation, developmental delay, camptodactyly, lymphedema, and immunodeficiency. TKS is caused by recurrent heterozygous missense variants in the CDC42 gene (HGNC:1736), which encodes the small Rho GTPase Cdc42, a regulator of cytoskeletal dynamics and cell signaling.

1 Clinical Validity

The association between CDC42 and TKS is classified as Moderate based on ClinGen criteria. Four unrelated probands have been reported with the same de novo c.191A>G (p.Tyr64Cys) variant, each presenting with the core TKS phenotype and lacking familial segregation ([PMID:29335451]; [PMID:34624555]; [PMID:37347054]; [PMID:36459360]).

2 Genetic Evidence

CDC42-related TKS exhibits autosomal dominant inheritance with complete penetrance of the recurrent hotspot missense variant c.191A>G (p.Tyr64Cys). Four probands were identified by trio exome or targeted sequencing, all harboring de novo p.Tyr64Cys substitutions in the switch II region of Cdc42. No additional segregating familial cases have been described. Variant spectrum is limited to this single missense change, observed in independent patients with overlapping phenotypes.

3 Functional Evidence

Direct functional studies of p.Tyr64Cys are lacking. However, Cdc42 hotspot mutations alter GTP binding and effector interactions in yeast and mammalian cell assays, supporting a likely gain-of-function mechanism. General Cdc42 GTPase and effector-binding assays (e.g., two-hybrid and pull-down studies) demonstrate that mutations in switch regions perturb downstream signaling pathways, consistent with the multisystem features seen in TKS.

4 Therapeutic and Prognostic Implications

Splenectomy has been reported to ameliorate macrothrombocytopenia in a TKS patient refractory to steroids, suggesting a role for surgical intervention in managing severe thrombocytopenia ([PMID:36459360]). Early genetic diagnosis enables tailored monitoring for hematologic, immunologic, and developmental complications.

5 Conclusion

Recurrent de novo CDC42 p.Tyr64Cys variants underlie Takenouchi-Kosaki syndrome, an autosomal dominant multisystem disorder. Genetic testing for c.191A>G should be considered in patients with macrothrombocytopenia combined with developmental delay and dysmorphic features. This summary supports diagnostic decision-making, informs management, and highlights the need for functional studies of the p.Tyr64Cys mutation.

References

• Frontiers in genetics • 2023 • The clinical phenotype with gastrostomy and abdominal wall infection in a pediatric patient with Takenouchi-Kosaki syndrome due to a heterozygous c.191A>G (p.Tyr64Cys) variant in CDC42: a case report. PMID:37347054
• Journal of human genetics • 2018 • A hot-spot mutation in CDC42 (p.Tyr64Cys) and novel phenotypes in the third patient with Takenouchi-Kosaki syndrome. PMID:29335451
• European journal of medical genetics • 2021 • Intermittent macrothrombocytopenia in a novel patient with Takenouchi-Kosaki syndrome and review of literature. PMID:34624555
• International journal of hematology • 2023 • Splenectomy as an effective treatment for macrothrombocytopenia in Takenouchi-Kosaki syndrome. PMID:36459360

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