1p34.3

CRISTIN3,RSPO

Palmoplantar hyperkeratosis with a predisposition to squamous cell carcinoma of the skin and XX sex reversal.

Two families.

Mutations in the RSPO1 gene have been implicated in an autosomal recessive syndrome identified in an Italian family spanning three generations (Micali et al., 2005). The syndrome is characterized by: sclerodactyly, non-epidermolytic palmar plantar keratoderma (PPK) associated with multiple cutaneous squamous cell carcinomas, dental anomlies and early tooth loss due to chronic periodontal disease (in three out of five brothers), hypogenitalism with hypospadias, gynecomastia (in one brother), altered plasma sex hormone levels in the two brothers with abnormal genitalia and hypertriglyceridemia. Four out of the five affected brothers had an abnormal XX karyotype that was associated with the genital abnormalities. None of the five sisters, or their offspring, were affected.
The squamous cell carcinoma lesions found in these patients first developed in the hyperkeratotic skin of the hands and feet (PPK) and then metastasized to other parts of the body, indicating that a single gene is responsible for both the PPK and predisposition to SCC (Radi et al., 2005). However, the sex reversal can be considered to be non-penetrant in affected XY individuals. In this extended Italian family there are eleven 46,XX individuals in two sibships, all of the affected individuals have a male phenotype (two 46,XY and four 46,XX), while none of the seven genetic females with a female phenotype show any sign of the PPK/SCC phenotype or sexual ambiguity. This indicates that a single gene defect underlies both the PPK/SCC and sex reversal, rather than two independent mutations. The family is informative for linkage analysis for the PPK trait and allows linkage exclusion for the sex reversal trait.
Linkage analysis performed on this family detected positive LOD scores for two markers at 1p34-p35. Furthermore, an additional affected individual, also from Southern Italy, who presented with XX sex reversal, PPK and SCC, also showed linkage to 1p34, but with a different haplotype (Parma et al., 2006). Sequencing identified two homozygous RSPO1 mutations in the two families. A single nucleotide insertion in codon 36 results in a frame-shift and stop codon after ten amino acid residues, predicted to lead to abolition of all RSPO1 isoforms. However, the second mutation, a 2752 bp deletion including exon 4, leads to a shorter mRNA that may translate to a putative, shorter protein lacking the signal peptide and first furin domain.
In situ hybridization analysis has identified expression of mRspo1 in the urogenital ridge at E10.5, with sex-specific differences appearing at E12.5 inline with an increase in the somatic cells of the XX gonad. Furthermore, qPCR detected no differences in mRspo1 levels between XX and XY gonads at E10.5 and E11.5, by E12.5, however, there is a clear increase of expression in XX gonads which is five-fold higher than XY gonads by E14.5. Therefore, there is a sex-specific regulation of R spondin1 at a crucial time in sex determination (Parma et al., 2006). What is more, in the XX sex reversal patients, functional testes are present, but the individuals are sterile, indicating that R-spondin1 is not required for testis differentiation and function (Parma et al., 2006).
RT-PCR has shown that RSPO1 is not expressed in cultured keratinocytes, but it is expressed in fibroblasts. Furthermore, plantar keratinocytes from an affected individual did not differentiate in organotypic culture. Together, this data suggests that R-spondin1 might act as a paracrine signal from fibroblasts to keratinocytes, regulating keratinocyte proliferation and differentiation (Parma et al., 2006).

Syndromic true hermaphroditism with palmoplantar keratoderma, congenital bilateral corneal opacities, onychodystrophy and hearing impairment.

One patient