Palmoplantar Hyperkeratosis With Squamous Cell Carcinoma Of Skin And 46,xx Sex Reversal

A number sign (#) is used with this entry because of evidence that this syndrome is caused by homozygous mutation in the gene encoding R-spondin-1 (RSPO1; 609595) on chromosome 1p34.

Clinical Features

Guerriero et al. (2000) reported a 60-year-old man with familial scleroatrophic syndrome of Huriez (181600) who had developed squamous cell carcinomas on the affected skin of the right palm. Immunohistochemical analysis showed a marked reduction in the number of CD1a+, Lag+, and S100+ epidermal Langerhans cells (see 604856), but not of CD1b+ and factor XIIIa+ dermal dendritic cells, limited to palmoplantar skin. The Langerhans cell depletion was not associated with an abnormal skin content of mRNA for factors involved in Langerhans cell development or recruitment in the epidermis, including granulocyte/macrophage colony-stimulating factor (138960), transforming growth factor-beta-1 (190180), and macrophage inflammatory protein-3-alpha (601960).

Radi et al. (2005) and Micali et al. (2005) described a large consanguineous Italian family, including the patient described by Guerriero et al. (2000), with four 46,XX SRY (480000)-negative brothers. Palmoplantar hyperkeratosis (PPK) and predisposition to squamous cell carcinoma of the skin (SCC) segregated as recessive traits. All members of the family with PPK were phenotypic males (46,XY or 46,XX), whereas 7 XX sibs were healthy phenotypic females with no signs of PPK. The proband in the report of Micali et al. (2005), a Sicilian fisherman, was found to have laryngeal carcinoma in his early forties and nodular testicular hyperplasia of Leydig cells. Hypospadias, testicular hypoplasia, ambiguous external genitalia, and gynecomastia were present. The combination of the XX sex reversal phenotype with PPK and SCC was described in another individual by Vernole et al. (2000) and Riggio et al. (2005). Both this patient and the family described by Radi et al. (2005) and Micali et al. (2005) were from southern Italy.

Palmoplantar Keratoderma and True Hermaphroditism

Tomaselli et al. (2008) described a 40-year-old 46,XX SRY-negative woman with clitoral enlargement noted at birth and reared as a female. Later she was found to have bilateral corneal opacities, strabismus, and bilateral sensorineural hypoacusis. Puberty began at age 9 to 10 years, with appearance of pubic hair and breast development; menarche occurred at 11 years of age. At age 27 years, a right groin mass was surgically removed and found to be a seminoma. Hormonal profile at that time was indicative of a functional ovary; 1 year later, the endocrine profile was consistent with premature menopause. At age 35, laparoscopy showed an apparently normal uterus, left fallopian tube, and left gonad; gonadal biopsy showed both testicular and ovarian structures, and histology after left gonadectomy revealed another seminoma. She was also noted to have dystrophic nails and palmoplantar keratoderma. Her parents were first cousins, and her brother, the father of 3 children, reportedly had similar dermatologic lesions, but was unavailable for evaluation.

Mapping

In genetic analysis of the families described by Radi et al. (2005) and Micali et al. (2005), Parma et al. (2006) proposed that homozygosity for a single mutational event caused both PPK and SCC in XY and XX individuals and sex reversal in XX individuals. The family was highly informative for linkage analysis for the PPK trait and allowed exclusion for the sex reversal trait. Thus, Parma et al. (2006) used linkage against the PPK trait as a means to 'hitchhike' to find the mutation causing the sex reversal trait. Radi et al. (2005) had shown that 24 loci potentially involved in the sex reversal or PPK etiology were not implicated in the phenotype of this family. Although these loci were firmly excluded, Parma et al. (2006) detected positive lod scores for 2 markers at 1p35-p34, in the region containing the WNT4 gene (603490) and the erythrokeratodermia variabilis (EKV; 133200) locus. By using markers mapping to the adjacent regions, Parma et al. (2006) confirmed the linkage and found that a region proximal to WNT4-EKV, spanning approximately 15 cM at 1p34, was homozygous by descent in all members of the family with PPK and SCC and in all sex-reversed members (maximum 2-point lod of 5.6 for the PPK trait and 3.3 for the sex reversal trait). The critical region spanned from D1S516 to D1S232 and contained approximately 190 genes.

Molecular Genetics

Parma et al. (2006) identified a homozygous single-nucleotide insertion in R-spondin-1 (RSPO1; 609595.0001), the 90th gene tested, in the affected members of the family described by Micali et al. (2005). Proof that mutations in RSPO1 were responsible for both sex reversal and PPK/SCC came from the identification of a homozygous deletion of 2,752 bp, including exon 4 and part of the adjacent introns, in the sporadic and genetically independent individual studied by Vernole et al. (2000) (609595.0002). Using combined microsatellite SNP analysis, Parma et al. (2006) demonstrated that the haplotype in affected individuals in the 2 families differed, suggesting that the 2 mutations were independent or that a single mutation occurred in a very distant common ancestor.

As pointed out by Capel (2006), female-to-male sex reversal is a very rare and puzzling phenomenon. The identification of mutations in the RSPO1 gene in XX sex-reversed individuals suggested that antagonistic pathways in the bipotential gonad regulate sex determination. It has been suggested that a parsimonious explanation for the XX female-to-male sex reversal puzzle is that SRY represses a repressor of male development, 'Z.' Based on this paradigm, mutations in 'Z' could lead to derepression of the male pathway in XX gonads (McElreavey et al., 1993). The findings that both WNT4 and RSPO1 have essential roles in ovary determination suggested a refinement and elaboration of this view.

Parma et al. (2006) showed that adhesion properties of keratinocytes are disrupted by mutations in RSPO1. Capel (2006) suggested that how this cellular phenotype comes about may be important for understanding how different morphologies arise in the gonad as testis and ovary development pathways diverge.

In a 40-year-old 46,XX SRY-negative woman with true hermaphroditism and palmoplantar keratoderma, whose parents were first cousins, Tomaselli et al. (2008) identified homozygosity for a splice site mutation in the RSPO1 gene (609595.0003). The authors stated that this was the first patient in whom XX true hermaphroditism was associated with a single gene alteration in the absence of SRY.