Acrokeratosis Verruciformis of Hopf


Article Author:
Grant Williams


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Mark Lincoln


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Sandeep Sekhon


Updated:
11/4/2019 3:34:57 PM

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 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 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]

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 back 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 family history should undergo evaluation for 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.s 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 the definitive diagnosis. There are several other pieces of information that can help parse 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 have frequent monitoring by a dermatologist since 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 V]

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


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Acrokeratosis Verruciformis of Hopf - Questions

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Which of the following are histologic features of acrokeratosis verruciformis of Hopf?



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A defect in which gene is responsible for acrokeratosis verruciformis of Hopf?



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What is the clinical appearance of Acrokeratosis verruciformis of Hopf?



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A 14-year-old girl with multiple flat-topped, skin-colored keratotic lesions that have been present for years presents to the clinic. The defective gene alters the effect of which protein in the keratinocyte?



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A 10-year-old presents with flat-topped keratotic lesions on the dorsum of the hands and feet. The patient's father has similar lesions. What is the most likely clinical course?



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20-year-old librarian presents in dermatology clinic with multiple flat-topped keratotic papules and plaques on his extremities that spare his sebaceous areas. He states they have been present since childhood and are refractory to topical treatment. He is in a monogamous sexual relationship with his girlfriend and smokes marijuana occasionally. However malodor from his skin lesion is causing him significant distress and he thinks he may lose his girlfriend. The patient wants to know if there is a permanent cure for his condition. What should be the response of clinician?



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A 15-year-old male presents with flat-topped keratotic lesions on the dorsum of the hands and feet. The patient's father has similar lesions that initially responded to treatment, but they have returned. What histologic changes are likely to be seen on biopsy of any of the lesions?



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Acrokeratosis Verruciformis of Hopf - References

References

Acrokeratosis verruciformis of Hopf - Case report., Andrade TC,Silva GV,Silva TM,Pinto AC,Nunes AJ,Martelli AC,, Anais brasileiros de dermatologia, 2016 Sep-Oct     [PubMed]
Acrokeratosis verruciformis of Hopf exhibiting Darier disease-like cytological features., Harman M,Durdu M,İbiloğlu I,, Clinical and experimental dermatology, 2016 Oct     [PubMed]
Matsumoto A,Gregory N,Rady PL,Tyring SK,Carlson JA, Brief Report: HPV-17 Infection in Darier Disease With Acrokeratosis Verrucosis of Hopf. The American Journal of dermatopathology. 2017 May     [PubMed]
Hafner O,Vakilzadeh F, [Acrokeratosis verruciformis-like changes in Darier disease]. Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete. 1997 Aug     [PubMed]
Bergman R,Sezin T,Indelman M,Helou WA,Avitan-Hersh E, Acrokeratosis verruciformis of Hopf showing P602L mutation in ATP2A2 and overlapping histopathological features with Darier disease. The American Journal of dermatopathology. 2012 Aug     [PubMed]
Dhitavat J,Macfarlane S,Dode L,Leslie N,Sakuntabhai A,MacSween R,Saihan E,Hovnanian A, Acrokeratosis verruciformis of Hopf is caused by mutation in ATP2A2: evidence that it is allelic to Darier's disease. The Journal of investigative dermatology. 2003 Feb     [PubMed]
NIEDELMAN ML, Acrokeratosis verruciformis (Hopf) report of 14 cases in one family in four generations, with a review of the literature. Archives of dermatology and syphilology. 1947 Jul     [PubMed]
Bang CH,Kim HS,Park YM,Kim HO,Lee JY, Non-familial Acrokeratosis Verruciformis of Hopf. Annals of dermatology. 2011 Sep     [PubMed]
Behera B,Prabhakaran N,Naveed S,Kumari R,Thappa DM,Gochhait D, Dermoscopy of acrokeratosis verruciformis of Hopf. Journal of the American Academy of Dermatology. 2017 Aug     [PubMed]
DeFelice T,Robinson M,Patel R,Kamino H, Acrokeratosis verruciformis. Dermatology online journal. 2012 Dec 15     [PubMed]

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