Acrokeratosis Verruciformis of Hopf

Updated: May 11, 2018
  • Author: Sarah Sweeney Pinney, MD; Chief Editor: William D James, MD  more...
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Overview

Background

Acrokeratosis verruciformis is a rare genodermatosis with an autosomal dominant mode of inheritance. Acrokeratosis verruciformis is a disorder of keratinization characterized by multiple flat-topped, skin-colored keratotic lesions resembling plane warts typically observed on the dorsum of the hands and feet. Hopf first suggested the name acrokeratosis verruciformis in 1931. [1] In 1947, Niedleman first published the largest series describing an Italian American family in which acrokeratosis verruciformis of Hopf occurred in 14 members. In the follow-up study in 1962, Niedleman and McKusick further described 24 cases in 4 generations of the same family. [2] The number and distribution of cases in the latter report suggested an autosomal dominant mode of transmission. [3]

Lesions identical to those of acrokeratosis verruciformis are also observed in many patients with acral Darier disease (also termed keratosis follicularis) or even in relatives of individuals with Darier disease. Considerable controversy surrounds the nature and relationship of acrokeratosis and Darier disease and whether they are manifestations of one genetic abnormality. Some authors suggest that acrokeratosis verruciformis of Hopf and Darier disease are distinct entities, while others maintain that they are variable expressions of the same disease, with the former being a mild expression or a forme fruste of the latter. [4, 5] Recent genetic studies review how these may be distinct entities that are allelic variants. [6]

Darier disease (keratosis follicularis) is the most important disorder to be distinguished from acrokeratosis. Darier disease, acrokeratosis verruciformis, epidermodysplasia verruciformis, plane warts, and seborrheic keratoses can be differentiated on the basis of histologic examination findings from biopsy samples from individual lesions. The hard nevus of Unna can be differentiated clinically on the basis of its late onset. [5, 7, 8]

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Pathophysiology

Acrokeratosis verruciformis has an autosomal dominant mode of inheritance. The close clinical and histological similarity of acrokeratosis verruciformis of Hopf to the acral lesions of keratosis follicularis (Darier disease) has been noted by Hopf and Darier themselves. The similarities led later observers to postulate a relationship between the 2 diseases. The exact relationship between acrokeratosis verruciformis and Darier disease is still controversial. A classic case of Darier disease poses no diagnostic problem. However, deciding whether a mild case of Darier disease represents, in fact, acrokeratosis verruciformis, remains difficult.

Although clinically similar, acrokeratosis verruciformis is thought to remain nondyskeratotic and nonacantholytic throughout life, whereas acral lesions of Darier disease show, upon careful histologic examination, various gradations of acantholytic dyskeratosis, especially in older lesions. Basically, the keratinization process in acrokeratosis verruciformis is exaggerated but normal, whereas in Darier disease, it is accentuated, altered, and faulty. [4]

A mutation in ATP2A2, a gene situated on band 12q23-q24 encoding for sarco(endo)plasmic reticulum Ca2+ ATPase2 (SERCA2), is the cause of Darier disease. [9] A total of 162 mutations in this gene have been reported to date that are thought to be associated with Darier disease. [10] SERCA2 is a calcium pump of sarcoplasmic/endoplasmic reticulum that plays a role in intracellular signaling. Although the relationship between these conditions is controversial, two distinct mutations in ATP2A2 have been found in acrokeratosis verruciformis that are not seen in Darier disease. [11, 12, 10] This finding suggests that the two diseases are allelic disorders with phenotypic expression of different severities. A more recent study provides evidence for genetic heterogeneity of acrokeratosis verruciformis and demonstrates that mutations in genes other than ATP2A2 are responsible for acrokeratosis verruciformis in some patients. [13, 14]

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Etiology

Acrokeratosis verruciformis of Hopf has an autosomal dominant mode of transmission. This has been suggested since 1962, in a large follow-up series by Niedleman and McKusick that described 24 cases in 4 generations in the same family. [2]

Sporadic cases can also occur. [15]

Acrokeratosis verruciformis and Darier disease are allelic disorders. ATP2A2 encoding the SERCA2 pump has been identified as the defective gene in Darier disease. In 2003, Dhitavat et al identified a heterozygous P602L mutation in the ATP2A2 gene in a family affected with acrokeratosis verruciformis for 6 generations. [11] This mutation predicts a nonconservative amino acid substitution in the ATP-binding domain of the molecule. The mutation segregates with the disease phenotype in the family and was not found in 50 controls. Moreover, functional analysis of the P602L mutant showed that it has lost its ability to transport Ca2+. This result demonstrates loss of function of the SERCA2 mutant in acrokeratosis verruciformis, thus providing evidence that acrokeratosis verruciformis and Darier disease are allelic disorders.

Exceptionally, a similar association with Hailey-Hailey disease has been reported. [16]

Acrokeratosis verruciformis of Hopf has been reported in a patient with nevoid basal cell carcinoma syndrome. [17]

The possible occurrence of squamous cell carcinoma in the context of the lesions of acrokeratosis verruciformis of Hopf has been rarely described, and one case report describes an association with keratoacanthomas. [18, 19]

This condition may also be associated with hypertrophic lichen planus and multiple steatocystomas. [20]

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Epidemiology

Frequency

Acrokeratosis verruciformis of Hopf is a rare genodermatosis.

Race

Acrokeratosis verruciformis has been described in individuals of many races.

Sex

No sex predilection has been reported for acrokeratosis verruciformis of Hopf.

Age

Acrokeratosis verruciformis is usually present at birth or manifests in early childhood. Onset may be delayed until the fifth decade of life.

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Prognosis

Lesions tend to persist throughout life and become more prominent following prolonged sun exposure.

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