Continuing Education Activity

Acrokeratosis verruciformis is a rare genodermatosis that usually develops in childhood and is characterized by verrucous papules on the dorsum of the hands and feet. Aside from any cosmetic concerns, this condition is generally benign. However, there have been cases of malignant transformation, so referral to a dermatologist is recommended. This activity reviews the evaluation and management of this condition and highlights the role of the interprofessional team in caring for affected patients.

Objectives:

• Describe the typical presentation of a patient with acrokeratosis verruciformis.
• Explain the histopathological findings that characterize acrokeratosis verruciformis.
• Outline the management and treatment options of acrokeratosis verruciformis.
• Review how the interprofessional team approach in caring for patients affected by acrokeratosis verruciformis will improve outcomes.

Introduction

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]

Etiology

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]

Epidemiology

AKV is a rare genodermatosis without race or 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]

Pathophysiology

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 affected 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]

Histopathology

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]

History and Physical

Acrokeratosis verruciformis of Hopf presents as multiple flat-topped and polygonal papules and verrucous plaques. These lesions are skin-colored and firm. Friction on the surrounding skin can produce vesicles. These lesions' predominant locations are on the dorsal surfaces of the hands and the feet. Less commonly, the lesions can occur on the legs, knees, arms, and elbows. Additional findings can include thickening of the nail plate, leukonychia, and longitudinal ridges in the nails.[1]

Acrokeratosis verruciformis of Hopf has no predilection for follicular areas and does not involve the oral mucosa and sebaceous regions, which can help differentiate the disease from Darier disease.[2]

Dermoscopy will show irregular white homogenous areas with a cobblestone appearance.[9]

Evaluation

Clinically, AKV can resemble flat warts, seborrheic keratosis, epidermodysplasia verruciform, and Darier disease. Biopsy should be performed to confirm the diagnosis. The immediate family members should be evaluated for the presence of similar lesions, which may indicate an autosomal dominant genodermatosis like acrokeratosis verruciformis of Hopf, though this is not always the case.[1]

Treatment / Management

Superficial ablation is known to be effective in acrokeratosis verruciformis of Hopf.[1] Other methods of treatment include cryotherapy, laser therapy, keratolytic solutions, and surgical excision.[10] However, recurrence may be more frequent with these methods.[1]

Differential Diagnosis

The differential diagnosis of acrokeratosis verruciformis of Hopf includes epidermodysplasia verruciformis, stucco keratosis, verruca vulgaris, and Darier disease.[1] While the lesion may resemble these other entities clinically, a biopsy will lead to a definitive diagnosis. There are several other pieces of information that can be helpful in the differential diagnosis. Lesions can be evaluated cytologically to rule out epidermodysplasia verruciformis. A family history of similar lesions can undergo an evaluation to determine if there is a genetic component that Darier and acrokeratosis verruciformis of Hopf more likely and stucco keratosis and verruca vulgaris less likely. The presence of nail changes and onset during childhood may also point to acrokeratosis verruciformis of Hopf.[1][2] Ultimately, a biopsy and histologic evaluation will be most beneficial in diagnosing this condition.

Prognosis

Acrokeratosis verruciformis of Hopf has a chronic course with frequent recurrence due to the underlying autosomal defect in ATP2A2 but usually has a benign disease course. Acrokeratosis verruciformis of Hopf may rarely transform to squamous cell carcinoma.[1]

Complications

 Acrokeratosis verruciformis of Hopf may rarely transform to squamous cell carcinoma.[1]

Deterrence and Patient Education

Patients with acrokeratosis verruciformis of Hopf should receive the information that this is an autosomal dominant disease so it may affect their children. They should have frequent monitoring by a dermatologist as the lesions can undergo malignant transformation to squamous cell carcinoma.[1]

Pearls and Other Issues

• Acrokeratosis verruciformis of Hopf may rarely transform to squamous cell carcinoma.[1]
• Acrokeratosis verruciformis of Hopf is a rare genodermatosis that has a mutation in the same gene as Darier disease.[2]
• Superficial ablation is known to be effective in acrokeratosis verruciformis of Hopf.[1][10]
• Acrokeratosis verruciformis of Hopf results from a single genetic defect to the ATP2A2 gene on chromosome 12q24.[2]

Enhancing Healthcare Team Outcomes

Acrokeratosis verruciformis of Hopf may rarely transform to squamous cell carcinoma [1], so patients should regularly follow up with specialty trained dermatology nurses and dermatology clinicians for monitoring.[1] An interprofessional team approach results in the best care. [Level 5]

Suspected AKV should undergo a histopathological evaluation to confirm the diagnosis.[2]