Porokeratosis 1, Multiple Types

A number sign (#) is used with this entry because of evidence that multiple types of porokeratosis (POROK1) are caused by heterozygous mutation in the PMVK gene (607622) gene on chromosome 1q21.

Description

Porokeratosis is a rare skin disorder characterized by one or more annular plaques with a surrounding raised horny border that spreads centrifugally. Variants of porokeratosis have been described that differ in morphologic shapes, distribution, and clinical course (Schamroth et al., 1997). However, as noted by Sybert (2010), several families with expression of more than one variant of porokeratosis among members, and several individuals expressing more than one variant, have been reported, suggesting that the distinctions among these variants may be artificial.

Mutations in the MVK gene have been found to cause multiple types of porokeratosis, which have been described as porokeratosis of Mibelli, porokeratoma, genital porokeratosis, hyperkeratotic porokeratosis, and linear porokeratosis.

The preferred title of this entry was formerly 'Porokeratosis 1, Mibelli Type; POROK1.'

Genetic Heterogeneity of Porokeratosis

Also see porokeratosis-2 (POROK2; 175850), mapped to chromosome 12q24; POROK3 (175900), caused by mutation in the MVK gene (251170) on chromosome 12q24; POROK4 (607728), mapped to chromosome 15q25-q26; POROK5 (612293), mapped to chromosome 1p31; POROK6 (612353), mapped to chromosome 1p31; POROK7 (614714), caused by mutation in the MVD gene (603236) on chromosome 16q24; POROK8 (616063), caused by mutation in the SLC17A9 gene (612107) on chromosome 20q13; and POROK9 (616631), caused by mutation in the FDPS gene (134629) on chromosome 1q22.

A palmoplantar form of punctate porokeratosis has also been described (PPKP2; 175860).

Genotype/Phenotype Correlations

Zhang et al. (2015) screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified mutations in the MVK, MVD, PMVK, and FDPS genes in 113 patients. The authors noted that giant plaque-type porokeratosis ptychotropica with lesion diameters of at least 5 cm appeared to be uniquely associated with mutation in MVK; it was observed in 19 (50%) of 38 MVK probands, but not in patients with mutations in any of the other 3 genes or in the 21 probands in whom no mutation was found. MVK patients also showed the widest range in terms of the number and size of lesions, as well as presence of porokeratosis subtypes. In patients with MVD mutations, the age of onset ranged from 5 to 70 years, and lesion diameters were generally less than 2 cm. In addition, 6 of the 62 MVD probands exhibited solar facial porokeratosis, which was not seen in any other patients. Localized genital porokeratosis and porokeratoma appeared to be uniquely associated with mutation in the PMVK gene, whereas patients with mutations in the FDPS gene had more than 500 lesions, all with diameters of 1 cm or less.

Clinical Features

Bloom and Abramowitz (1943) described porokeratosis of Mibelli in an Italian man and his 2 sons. The grandfather was said to be affected. Examination of the father and sons showed that one had only annular lesions, and the 2 others had in addition the linear and gyrate plaque lesions. The most conspicuous histologic feature in all of the lesions was a cornoid lamella.

MacMillan and Roberts (1974) reported that quiescent lesions become active and extensive after immunosuppression for renal transplantation.

Goerttler and Jung (1975) stated that about 7% of patients eventually develop skin cancer, usually on the extremities.

Machino et al. (1984) described a Japanese patient with porokeratosis of Mibelli who also had features of Werner syndrome (277700), a relatively frequent disorder in Japan. He died of metastatic squamous carcinoma which developed in a lesion on the foot. Several carcinomas-in-situ were found in other lesions, and at autopsy adenocarcinoma of the descending colon was also found. The patient's father and 2 sibs had porokeratosis of Mibelli.

Schamroth et al. (1997) provided a review of porokeratosis of Mibelli, noting that onset is usually in childhood, with lesions that range from solitary to multiple and that may be linear or punctate.

Inheritance

Male-to-male transmission in the family reported by Bloom and Abramowitz (1943) is consistent with autosomal dominant inheritance.

The male:female ratio of patients with this disorder is said to be 3 to 1 (Goerttler and Jung, 1975).

The existence of a nonfamilial form has been proposed (Bhutani et al., 1977).

Cytogenetics

Taylor et al. (1973, 1973) found a high proportion of cultured fibroblasts exhibiting a variety of chromosomal aberrations with no specific aberration consistently present.

Scappaticci et al. (1989) found clonal chromosomal abnormalities with preferential involvement of chromosome 3 in 3 sibs and 1 sporadic case with this disorder. Region 3p14-p12, which includes the most common fragile site in humans, was particularly involved. Scappaticci et al. (1989) concluded that porokeratosis of Mibelli is associated with chromosomal instability and that this in turn may predispose to malignancy.

Molecular Genetics

From a cohort of 134 Chinese probands with porokeratosis who were screened for mutations in isoprenoid genes, Zhang et al. (2015) identified 6 heterozygous mutations in the PMVK gene in 9 probands (see, e.g., 607622.0001 and 607622.0002). The mutations segregated with disease in all pedigrees for which DNA was available, and were not found in 270 ethnically matched controls. Although all 9 patients had porokeratotic lesions of the Mibelli type, they also exhibited other porokeratosis subtypes: 5 had porokeratoma, 4 had genital porokeratosis, 3 had hyperkeratotic porokeratosis, and 1 showed linear porokeratotic lesions. None of the patients had more than 100 lesions (4 of them had 10 or fewer), and the lesions ranged in size from 5 mm to 5 cm in diameter. Zhang et al. (2015) observed that even within families, affected individuals carrying the same mutation showed different clinical manifestations and varying degrees of severity. All examined lesional tissue showed cornoid lamella, a histologic hallmark of porokeratosis with vertical columns of parakeratosis overlying an area of hypogranulosis with dyskeratotic cells.

History

The prefix 'poro' comes from the Greek for 'hole.' Mibelli (1860-1910), who described this condition, was an Italian dermatologist. His cases came from the province of Parma. He called the disorder porokeratosis because he believed it started from sweat glands.