Palmoplantar Keratoderma, Punctate Type Ia

A number sign (#) is used with this entry because of evidence that punctate palmoplantar keratoderma type IA (PPKP1A) is caused by heterozygous mutation in the AAGAB gene (614888) on chromosome 15q23.

Description

Punctate palmoplantar keratoderma type I, also called keratosis punctate palmoplantaris type Buschke-Fisher-Brauer, is a rare autosomal dominant hereditary skin disease characterized by multiple hyperkeratotic centrally indented papules that develop in early adolescence or later and are irregularly distributed on the palms and soles. In mechanically irritated areas, confluent plaques can be found. Interfamilial and intrafamilial severity shows broad variation. There have been reports of an association between PPKP and the development of early- and late-onset malignancies, including squamous cell carcinoma (summary by Giehl et al., 2012).

Another form of PPKP type I has been mapped to chromosome 8q24 (PPKP1B; 614936).

Other forms of punctate palmoplantar keratoderma include a porokeratotic type (PPKP2; 175860) and focal acrohyperkeratosis (PPKP3; 101850).

For a general phenotypic description and a discussion of genetic heterogeneity of palmoplantar keratoderma (PPK), see epidermolytic PPK (144200).

Clinical Features

In 14 families with keratosis palmoplantaris papulosa reported by Schirren and Dinger (1965), direct transmission was observed. Females were less severely affected. Salamon et al. (1982) studied a family with 8 cases including instances of male-to-male transmission. Onset in the proband was at age 20 years. Useful clinical photographs were provided. Comparison of the histologic findings with those reported by others suggested to Salamon et al. (1982) that keratodermia palmoplantaris papulosa is genetically heterogeneous.

Stevens et al. (1994, 1996) reported a large family in which 38 persons in 4 generations had keratosis punctata. Ten of 34 affected adults developed different malignancies (Hodgkin disease and renal, breast, pancreatic, and colonic adenocarcinomas). In 5 persons malignancies developed before the age of 50. Stevens et al. (1994) proposed that in this family mutation in the type I acidic keratin gene cluster at 17q12-q21 (see, e.g., KRT9, 607606) might be related to pathology of tumor suppressor gene(s) in the region of 17q21 (see, e.g., BRCA1, 113705). In a Table, Stevens et al. (1996) stated that the characteristics in this family were onset between ages 12 and 30 years, multiple tiny punctate keratoses over the entire palmoplantar surfaces, coalescence of the punctate keratoses into a more diffuse pattern over the pressure points of the soles, and variable nail changes.

In 3 ethnically diverse, 4-generation families segregating punctate palmoplantar keratoderma type I (PPKP1), Martinez-Mir et al. (2003) found that all affected family members had typical features without nail involvement. No increased prevalence of cancer was found in the families.

Giehl et al. (2012) studied 3 families with PPKP, 2 of Croatian origin and 1 of German origin. In the 14 affected individuals, keratoses on the soles were more severe than those on the palms, especially over pressure points. Histology showed marked hyperkeratosis with focal parakeratosis and prominent hypergranulosis, consistent with PPKP1. Phenotypic variability was observed between as well as within the families.

Pohler et al. (2012) studied a collection of 18 PPKP1 kindreds from Scotland, Ireland, Japan, and Tunisia, 11 of which had a family history consistent with autosomal dominant inheritance. In all families the onset was typically in the first to second decades of life, with the appearance of small circumscribed lesions on the palms and soles that consistently increased in number with advancing age and later coalesced to form larger lesions. However, there was considerable phenotypic variation between families, with lesions remaining subtle in some, whereas in others the phenotype resembled human papillomavirus (HPV)-induced lesions and was much more severe, painful, and debilitating. Histology of affected palmar epidermis from 3 unrelated kindreds of different ethnicities showed very similar findings, involving a well-defined central epidermal depression associated with hypergranulosis and a prominent layer of overlying orthokeratosis. Immunohistochemical staining for the cell proliferation marker Ki67 showed continuous staining of the proliferative basal cell compartment of the epidermis beneath the hyperkeratotic lesions, indicative of a hyperproliferative form of hyperkeratosis rather than a retention hyperkeratosis due to defective desquamation. Ultrastructural analysis of affected plantar skin showed mild acanthosis, a reduction in the granular cell layer, and compact orthokeratosis. In basal keratinocytes, there was a large increase in the number of small vesicles close to the cell membrane and prominent dilatation of the Golgi apparatus in affected epidermis compared to control skin. Pohler et al. (2012) noted that the ultrastructural findings were compatible with a defect in vesicle transport.

Mapping

In 3 ethnically diverse, 4-generation families segregating punctate palmoplantar keratoderma type I, Martinez-Mir et al. (2003) found linkage of the disorder to a 9.98-cM interval flanked by markers D15S534 and D15S818 on chromosome 15q22-q24 (maximum 2-point lod score of 4.93 at theta = 0.0 for D15S988).

In a large 7-generation Tunisian PPKP kindred that originated from Saudi Arabia and was previously reported by El Amri et al. (2010), Pohler et al. (2012) found linkage to the previously reported 15q22 locus, obtaining a maximum 2-point lod score of 8.18 at theta = 0.0 for the marker D15S983. A 6.24-Mb critical interval was defined by recombination events.

Exclusion Studies

Kelsell et al. (1995) excluded linkage of a form of PPKP to the keratin gene clusters on 12q and 17q.

Molecular Genetics

In 2 Croatian families and a German family with PPKP1, Giehl et al. (2012) performed whole-exome sequencing followed by filtering and identified 2 heterozygous nonsense mutations in the AAGAB gene, R161X (614888.0001) and R124X (614888.0002), that segregated fully with disease in the respective families. Haplotype analysis of the 2 Croatian families indicated that the R161X mutation was inherited by descent from a common ancestor.

By whole-exome sequencing in the proband from a 4-generation Scottish family with PPKP1, Pohler et al. (2012) identified heterozygosity for the R161X mutation in the AAGAB gene, which was confirmed by conventional sequencing to segregate with disease in the family and was not found in the current dbSNP or 1000 Genomes databases. Sequencing of AAGAB in a large 7-generation Tunisian pedigree with PPKP mapping to 15q22 revealed a heterozygous 2-bp deletion (614888.0003) that segregated with disease in the family, as well as in 2 additional Tunisian families. Sequencing of another 14 PPKP kindreds of Scottish, Irish, Japanese, and Tunisian backgrounds, respectively, revealed another 6 mutations in the AAGAB gene, including 1 splice site, 1 nonsense, and 4 frameshift mutations (see, e.g., 614888.0004-614888.0006).