Hereditary Palmoplantar (Epidermolytic) Keratoderma: Illustration Through a Familial Report

Virendra N. Sehgal, MD; Kabir Sardana, MD; Sonal Sharma, MD; Dharmendra Raut, MBBS


Skinmed. 2004;3(6) 

In This Article

Clinical Repercussions

PPKs constitute a heterogeneous group of disorders characterized by thickening of the palms and soles. The condition may either be hereditary or acquired and in the form of associated syndrome(s), PPK being its predominant component. Hereditary forms may be localized to the hands and feet or associated with more generalized skin disorders.

Diffuse nonepidermolytic palmoplantar keratoderma (NEPPK), Thost-Unna disease, and PPK diffusa circumscripta were first described by Thost[2] and Unna[3] and later delineated into clinical variants by Greither.[4] NEPPK is characterized by diffuse hyperkeratosis of the palms and soles that usually becomes apparent between ages 3 months and 12 months. This autosomal dominant condition presents with thick, diffuse hyperkeratosis with an erythematous border affecting the palms and soles.[2,3] Aberrant keratotic lesions may appear on the dorsum of the hands, feet, knees, and elbows.[3,4] Hyperhidrosis,[2,3] thickened nails,[2] clinodactyly,[15] low serum Vitamin A,[2] dermatophytosis,[16] cutaneous horns,[17] contractures,[10] and dyskeratosis congenita[18] are its other associated features. The incidence of dermatophytosis was found to be 35% with an almost complete therapeutic resistance, especially in Trichophyton rubrum.[16] Histology was marked by nonspecific changes, such as orthokeratotic hyperkeratosis, hypergranulosis/normogranulosis, and associated moderate acanthosis.[2,3,19] Linkage to type II keratin locus on 12q11-13 has been reported with K1 gene mutation in a single family.[19] The residue involved, K741, is the most frequently found in the cross-linking of the cornified cell envelope.[19] Significantly, other families with NEPPK have been mapped outside the keratin cluster 12q11-13.[19]

Diffuse epidermolytic PPK (Vorner disease, PPK cum degeneration granulosa) is the most common type of hereditary PPK.[20,21] Localized epidermolytic hyperkeratosis, first described by Vorner[22] and Klaus et al.,[23] demonstrated dominant inheritance and male-to-male transmission, which was later substantiated,[11,24,25] although the inheritance is said to be autosomal dominant. Some researchers[26] suggested the existence of an autosomal recessive form, but because of the high background frequency of consanguinity in Kuwait where the patients were observed and because of the possibility of gonadal mosaicism, the evidence for recessive inheritance is not strong in this small family. Epidermolytic PPK is probably one of the most common keratin diseases, with an incidence of at least 4.4 per 100,000 in Northern Ireland.[19] The condition presents in the first year of life and is phenotypically similar to NEPPK.[21] Histology of the condition reveals epidermolytic hyperkeratosis, which was thought to differentiate it from NEPPK.[20]

In a large family with epidermolytic PPK of the Vorner-Unna-Thost type, one group[27] mapped the gene to 17q11-q23. Other groups[28,29] concluded by linkage analysis that the disease mutation maps to the same region as the type 1 (acidic) keratin gene cluster. One acidic keratin, keratin 9 (KRT9), is expressed only in the terminally differentiated epidermis of palms and soles; thus, the KRT9 gene is the most probable site of the mutation in epidermolytic PPK and this gene has been mapped to a chromosome.[27,28,29] Five different KRT9 gene mutations (the R162W mutation) were found in five other apparently unrelated epidermolytic PPK families.[20,29] All of these mutations are localized in the highly conserved coil-1A region of the rod domain, which is thought to be relevant for dimer formation in intermediate filaments.[20,29] The R162W mutation is in the residue corresponding to that which is altered in keratins, KRT14 and KRT10 in epidermolysis bullosa simplex and epidermolytic hyperkeratosis, respectively.[20,28,29] Researchers[30] refined the assignment of the KRT9 gene to 17q21.1-q21.2 by fluorescence in situ hybridization. Experimental evidence was obtained that the arg162-to-gln point mutation observed in patients with epidermolytic HPPK has a dominant-negative effect on keratin network formation.[31] The same author group[31] also summarized published reports of mutations in KRT9 associated with epidermolytic PPK and commented that amino acid residues 156-171, which correspond to the head of the KRT9 alpha-helical domain, may be crucial for keratin filament assembly and intermediate filament network formation.[31] Four Northern Irish kindreds with epidermolytic PPK were studied, and heterozygous missense mutations in exon 1 of KRT9 was found in all of the families.[32]

Recently, a novel mutation in the exon 6 splice donor site of keratin 1 (G4134A) has been noticed in three kindreds.[33] This mutation appears to have a milder effect than previously described mutations in the helix initiation and termination sequence on the function of the rod domain, with regard to filament assembly and stability. Affected persons displayed only mild focal epidermolysis in the spinous layer of palmoplantar epidermis. A follow-up study[34] of the family originally seen by Vorner in 1901 with clinical, histopathologic, and molecular investigations, revealed the typical features of the condition and a novel mutation in KRT9, N160I. The mutation in the coil-1A domain is thought to have a dominant negative effect on the assembly of keratin intermediate filaments, explaining the dominant inheritance of the phenotype.[31,34] The various allelic types of epidermolytic PPK are indexed in Table I .

Associations of epidermolytic PPK include raised serum IgE,[26] knuckle pads,[35] clubbing,[36] epidermolytic hystric nevus,[37] Ehlers-Danlos syndrome,[38] nail changes and periodontosis,[39] malignancy,[40] Beckwith-Wiedemann syndrome, Birt-Hogg-Dube syndrome, familial atypical multiple mole melanoma syndrome, hereditary tylosis, incontinentia pigmenti, supernumerary nipples,[41] hereditary motor and sensory neuropathy,[42] hereditary callosities with blisters,[43] and adenocarcinoma of the colon.[44]


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