RSPO1 – Palmoplantar Keratoderma-XX Sex Reversal-Predisposition to Squamous Cell Carcinoma Syndrome

Palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome is a rare autosomal recessive disorder caused by biallelic loss-of-function variants in RSPO1 leading to impaired canonical Wnt/β-catenin signaling in ovarian development. Clinically affected individuals present with early-onset palmoplantar hyperkeratosis, 46,XX testicular or ovotesticular disorder of sex development, and a high risk of cutaneous squamous cell carcinoma.

Genetic evidence includes four unrelated probands from four families with homozygous or compound heterozygous RSPO1 variants, including one family with two affected siblings segregating a novel missense change c.332C>A (p.Cys111Tyr) (PMID:29575617; PMID:29262419). Segregation analysis in the sib-pair pedigree confirmed co-segregation in two affected relatives (PMID:29262419).

Variant spectrum is characterized predominantly by biallelic loss-of-function alleles, including frameshift and missense variants within conserved furin-like cysteine-rich domains essential for receptor interaction. The recurrent c.332C>A (p.Cys111Tyr) variant disrupts a conserved disulfide bond in FU-CRD2, abrogating Wnt pathway potentiation.

Functional studies demonstrate that RSPO1 potentiates canonical Wnt/β-catenin signaling crucial for ovarian differentiation. Loss of RSPO1 activity in cellular and mouse models leads to ovarian testis-determining gene upregulation and bypass of female pathway, mirroring human 46,XX sex reversal.

Biochemical assays reveal that post-translational modifications, including N-glycosylation at Asn137 (PMID:27314333) and C-mannosylation at Trp156 by DPY19L3 (PMID:26764097), regulate RSPO1 stability and secretion, underscoring pathogenic relevance of secretion defects in loss-of-function variants.

In summary, biallelic RSPO1 inactivation causes a clinically distinctive autosomal recessive syndrome with PPK, 46,XX DSD, and skin carcinoma predisposition. This association is supported by multiple families, segregation data, and concordant functional evidence on Wnt pathway disruption. RSPO1 genetic testing informs diagnosis, family counseling, and surveillance for skin malignancy.

References

• American journal of medical genetics. Part A • 2018 • Novel RSPO1 mutation causing 46,XX testicular disorder of sex development with palmoplantar keratoderma: A review of literature and expansion of clinical phenotype. PMID:29575617
• Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation • 2017 • A Novel Homozygous Missense Mutation in the FU-CRD2 Domain of the R-spondin1 Gene Associated with Familial 46,XX DSD. PMID:29262419
• International journal of molecular sciences • 2016 • N-Glycosylation of Human R-Spondin 1 Is Required for Efficient Secretion and Stability but Not for Its Heparin Binding Ability. PMID:27314333
• Molecular biology of the cell • 2016 • Identification of DPY19L3 as the C-mannosyltransferase of R-spondin1 in human cells. PMID:26764097

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