Palmoplantar Carcinoma, Multiple Self-Healing

A number sign (#) is used with this entry because of evidence that multiple self-healing palmoplantar carcinoma (MSPC) is caused by heterozygous mutation in the NLRP1 gene (606636) on chromosome 17p13.

Description

Multiple self-healing palmoplantar carcinoma (MSPC) is characterized by recurrent keratoacanthomas in palmoplantar skin as well as in conjunctival and corneal epithelia. In addition, patients experience a high susceptibility to malignant squamous cell carcinoma (summary by Zhong et al., 2016).

Clinical Features

Soler et al. (2013) described a Caucasian French mother and son who had corneal intraepithelial dyskeratosis and palmoplantar hyperkeratosis. At 27 years of age, the mother presented with unilateral keratopathy with neovascularization and complete corneal opacification. In addition, she had palmoplantar hyperkeratosis, dyshidrosis, and maxillary decalcification with alveolysis and tooth loss. Her son presented at age 2 years with corneal dyskeratosis characterized by bilateral inferior corneolimbal infiltrates, limbal thickening, neovascularization, and keratin deposits. Despite topical corticosteroid therapy, he developed bilateral centripetal evolution of the infiltrates resulting in bilateral vision impairment that required multiple surgical interventions. He also had pruritic hyperkeratotic scars, palmoplantar hyperkeratosis, chronic rhinitis, and a raspy voice. His nails were dystrophic with prominent thickening of the nail beds, and he exhibited dysmorphism, with long philtrum, short neck, and bulging chest, and also had finger joint hypermobility. Histopathologic findings of the son's excised cornea showed acanthosis, parakeratosis, and dyskeratotic keratinization involving most of the corneal epithelium except the basal layers, with absence of the Bowman layer and presence of a stromal inflammatory infiltrate. A vocal cord biopsy showed similar features, including epithelial hyperplasia with dyskeratosis and parakeratosis. His maternal grandparents were unaffected, and he had an unaffected brother. Soler et al. (2013) stated that the histopathologic findings were consistent with those reported in hereditary benign intraepithelial dyskeratosis (HBID; 127600).

Mamai et al. (2015) reported a large 5-generation Tunisian family segregating autosomal dominant palmoplantar keratoacanthoma. The development of skin lesions began with the progressive appearance of multiple ulcerative/nodular tumors on plantar skin. The average age of onset was 8.8 years for the 15 affected family members studied, with a range from 1 year to 25 years of age. The palmoplantar tumors, which were 5 to 15 mm in diameter and 8 to 12 in number, grew over a period of 3 months and regressed spontaneously after 6 months, leaving atrophic scars consistent with keratoacanthoma. Histologic examination of a primary plantar lesion showed massive epidermal hyperkeratosis overlying an endophytic squamoproliferative tumor with prominent keratin cyst formation and crypt abscesses and a dense stromal inflammatory infiltrate at the base. Mamai et al. (2015) noted that the granular layer, normally prominent in the palmoplantar epidermis, was nearly absent. They also stated that the histologic findings were suggestive of verrucous carcinoma, a form of low-grade squamous cell carcinoma (SCC). In addition to palmoplantar tumors, 80% of the studied family members also developed conjunctival lesions, which appeared in the second decade of life. All were surgically removed, and histologic examination showed squamous epithelial lobules with a dyskeratotic center, suggestive of conjunctival keratoacanthoma. Despite the use of retinoids to halt the progression of palmoplantar tumors, 5 (33%) of 15 patients with available medical records had developed malignant tumors, including tumors in the lungs, head and neck, SCC on the nose, and SCC with bone metastases. The authors designated this disorder 'multiple self-healing palmoplantar carcinoma (MSPC).'

Zhong et al. (2016) restudied the families reported by Soler et al. (2013) and Mamai et al. (2015) and concluded that both families had MSPC. Zhong et al. (2016) stated that in addition to characteristic palmoplantar keratoacanthomas, a subset of patients with MSPC displayed irregular and thickened nails and hyperkeratosis pilaris.

Zhong et al. (2016) reported a consanguineous family in which a sister and brother had clinical features of MSPC as well as multiple discrete and semiconfluent lichenoid papules on the arms, legs, and lower trunk. Both parents also displayed noticeable but less severe skin phenotypes, including plantar keratosis, follicular hyperkeratosis, and macular amyloidosis. The authors diagnosed these patients with familial keratosis lichenoides chronica (Nekam disease).

Inheritance

The transmission pattern of MSPC in the families reported by Soler et al. (2013) and Mamai et al. (2015) was consistent with autosomal dominant inheritance.

Mapping

Using DNA from 11 affected and 5 unaffected members of a large 5-generation Tunisian family segregating autosomal dominant palmoplantar keratoacanthoma, Mamai et al. (2015) performed SNP genotyping and identity-by-descent mapping. A single 11.4-Mb region on chromosome 17p13.3-p12, between SNPs rs8065368 and rs2322788, was shared by all affected individuals and none of the unaffected family members. Parametric and nonparametric linkage analysis yielded maximum lod scores of 1.69 and 4.21, respectively.

Molecular Genetics

In an affected mother and son from a Caucasian French family originally diagnosed with corneal intraepithelial dyskeratosis and ectodermal dysplasia, but later diagnosed with MSPC by Zhong et al. (2016), Soler et al. (2013) excluded duplication at chromosome 4q35. Filtered exome sequencing followed by Sanger sequencing identified a heterozygous missense mutation in the NLRP1 gene (M77T; 606636.0002) that appeared de novo in the mother, segregated with disease in the family, and was not found in 672 controls or in 61 exome-sequenced subjects' DNA.

In a large 5-generation Tunisian family segregating autosomal dominant MSPC, originally studied by Mamai et al. (2015), Zhong et al. (2016) performed whole-exome sequencing and identified a heterozygous missense mutation in exon 1 of the NLRP1 gene (A54T; 606636.0003) that segregated with disease in 16 family members. By Sanger sequencing of NLRP1 exon 1 in another 4-generation kindred with MSPC, Zhong et al. (2016) identified heterozygosity for a different missense mutation (A66V; 606636.0004) that segregated with disease in that family. Both families were negative for mutation in the TGFBR1 gene (190181). The authors noted that 1 member of the Tunisian family was reported to be asymptomatic despite being a carrier of the A54T mutation, suggesting the existence of possible modifier alleles. Functional analysis demonstrated that all 3 MSPC-associated mutations are gain-of-function variants that cause increased inflammasome activation.

In 2 sibs in a consanguineous family with features of MSPC as well as multiple discrete and semiconfluent lichenoid papules, Zhong et al. (2016) identified homozygosity for an in-frame deletion in the NLRP1 gene (606636.0005).