Acrokeratosis verruciformis of Hopf (or simply acrokeratosis verruciformis: AKV) is a rare genodermatosis characterized by keratotic lesions on the dorsum of the hands and feet. AKV most commonly develops during early childhood, but occasionally develops as late as the fifth decade.[1] The natural history of the disease is a chronic course without spontaneous remission. It exhibits an autosomal dominant inheritance pattern and shows incomplete penetrance. Because of this, there may not always be a family history. There is no gender predilection.

Hopf first described AKV in 1931.[1] The probable etiology is a mutation in the ATP2A2 gene located on chromosome 12q24,[1], which is the same gene affected in Darier disease.[2] The diseases are distinct but may coexist in the same patient.[2][3][4]

Clinically acrokeratosis verruciformis of Hopf appears as flat-topped keratotic papules and plaques on the dorsum of the hands and feet. Less frequently, the lesions may occur on the legs or arms. The disease spares sebaceous areas, like the frontal scalp, flexural surfaces, and oral mucosa. There are associated nail changes to include thickening of the nail plate, leukonychia, and longitudinal ridges.[1]

Histopathologically, the lesions will have papillomatosis, acanthosis, hyperkeratosis, and hypergranulosis. The lesions will not have parakeratosis.[1]

Acrokeratosis verruciformis of Hopf results from a single genetic defect to the ATP2A2 gene on chromosome 12q24. It is a heterozygous pro602Leu mutation, which is the same gene affected in Darier disease, but there are multiple different mutations.[5] This mutation has an autosomal dominant pattern of inheritance but incomplete penetrance, which means a patient will not always have a family history.[1] If a family history of the disease exists, it may span many generations.[6][7]

AKV is a rare genodermatosis without gender predilection. It occurs most commonly in children during early childhood but can occur later in life.[1][8] The disease can also be present at birth.[8]

The P602L mutation in ATP2A2 leads to an inability to transport calcium in the sarcoendoplasmic reticulum calcium ATPase.[1] This defect causes disordered keratinization and will lead to a genodermatosis with multiple verrucous plaques and papules on the hands and feet.[8] Since this is a dominant mutation, the disease follows a chronic course without remission.[1] The lesions can rarely undergo malignant transformation to squamous cell carcinoma.[1]

The same gene is effected in Darier disease.[2]  While there is some histologic and clinical overlap between the two diseases, genetic testing has shown that AKV is an allelic variant of Darier disease and is a distinct clinical entity. 

Recently patients with Darier disease and acrokeratosis verruciformis of Hopf have had lesions evaluated with a polymerase chain reaction. HPV-17 is detectable in the lesions, and the L1 capsid showed expression in the cytoplasm in areas of hypergranulosis, which suggests susceptibility to HPV in these patients.[3]

This histopathology has several defining features. These include papillomatosis (circumscribed epidermal elevations that resemble church spires), acanthosis (epidermal thickening), hyperkeratosis (thickening of the stratum corneum), and hypergranulosis (thickening of the stratum granulosum).[1][9]

Cytologically, AKV has overlapping features with Darier disease, stemming from the fact that the diseases originate from mutations in the same gene.[2] These overlapping cytologic features can only appear on rarely performed cytologic specimens like split-skin smear tests. The overlapping features include the presence of acantholytic keratinocytes and dyskeratotic keratinocytes, called corps ronds and grains.[2] Since there is not routinely acantholysis (epidermal splitting) histologically in acrokeratosis verruciformis of Hopf on histopathology, a biopsy would differentiate these two diagnoses.[2]