Are You Confident of the Diagnosis?
Acrokeratosis verruciformis of Hopf is a rare genodermatosis best characterized within the disorders of keratinization. It is inherited in an autosomal dominant mode of transmission.
Characteristic findings on physical examination
Findings include multiple flat-topped skin-colored keratotic papules akin to verruca planae ( flat warts). A localized distribution favors the dorsum of the hands and feet but can occur elsewhere. There can be punctate keratoses on the palms and soles. There can be variable nail involvement including longitudinal striations, brittleness, and subungual hyperkeratosis.
The key to the distinct diagnosis of acrokeratosis verruciformis has been to pathologically differentiate it from the acral lesions of Darier’s disease (keratosis follicularis) by lesional skin biopsy. Other diagnostic considerations in the differential diagnosis include epidermodysplasia verruciformis, plane warts, and seborrheic and stucco keratoses. These latter entities can typically be distinguished clinically and pathologically without great difficulty.
The pathologic findings of nondyskeratosis and nonacantholysis within the hyperkeratosis, hypergranulosis and regular acanthosis of the papillomatous epidermis and the typical intermittent “church spire” epidermal elevations are different from the pathologic changes of dyskeratosis and acantholysis seen in Darier’s disease.
Who is at Risk for Developing this Disease?
As a genodermatosis, acrokeratosis verruciformis is typically present at birth or early in life but cases have been described where the onset of the disease is delayed into the fifth decade of life. Given the autosomal dominant nature of the inheritance, there is no predilection for either sex. The distribution is worldwide and does not have any apparent racial pattern.
What is the Cause of this Disease?
The genetic nature of the entity with autosomal dominant transmission was established by Niedleman and McKusick in the definitive analysis of multiple generations of the same family with 24 cases within the kindred. Not withstanding the reports of mixed pedigrees that have some clinical features of Darier’s disease, there are pure pedigrees with features only of acrokeratosis verruciformis of Hopf. There have been other sporadic cases attributed to spontaneous mutations.
Historically, there was an ongoing controversy as to the possible relationship between acrokeratosis verruciformis and Darier’s disease. The clinical similarities and variable clinical findings in patients who were originally classified as having acrokeratosis verruciformis but whose condition later in life was felt to better fit a diagnosis of Darier’s disease made classification difficult.
Recent investigations have established that a defect in the Ca++ pump of sarcoplasmic/endoplasmic reticulum is the cause of Darier’s disease. This mutation has been isolated to the gene ATP2A2 situated on the band 12q23-q24. It encodes for the sarco(endo)-plasmic reticulum Ca++ATPase pump (SERCA2).
Molecular studies have now demonstrated that a missense heterozygous P602L mutation in ATP2A2 occurs in acrokeratosis verruciformis as well. It is felt that this shared pathophysiology establishes acrokeratosis verruciformis and Darier’s disease as allelic disorders. This is felt to be an example of variable clinical phenotypic expression due to the shared loss of SERCA2 pump function leading to impared Ca++ transport across cellular membranes. A subsequent study from China failed to confirm this specific defect.
Systemic Implications and Complications
There have been isolated case reports of malignant epidermal degeneration in patients with acrokeratosis verruciformis. These include squamous cell carcinoma and keratoacanthomas. A clinical response to oral retinoids was suggested. Long-term clinical follow up by dermatology is necessary in this context.
Often overlooked as a nontherapy but an important option in genodermatosis, where no permanent cure is available. It may be the best treatment option in cases of limited acrokeratosis verruciformis.
Moisturizers such as over-the-counter alpha hydroxy acids and ammoniated lactate formulations are readily available and have a rational adjunctive role in the hyperkeratotic lesions.
These topical vitamin A derivatives are available in many strengths and bases and have the demonstated ability to alter the differentiation and maturation of keratinocytes. As such they have a major role in the diverse disorders of keratinization.
The frequency of use is titrated to the therapeutic benefit of thinning of the keratoses vs the side effects of retinoid dermatitis manifested by erythema, scaling and irritation. The concentration of tretinoin cream at 0.025 % daily or every other day is a reasonable place to begin. Other retinoids such as adapalene or tazarotene are equally rational interventions especially were there is disease resistance.
Broad-spectrum UVA/UVB sunscreens have a rational role in attempting to prevent the hyperpigmentation often reported after sun exposure.
Systemic retinoids have been the most effective treatment for the generalized disorders of keratinization since their introduction in the early 1980s.The effectiveness was tempered by the rapid recurrence of the entity on discontinuation of the oral retinoids and the side effect profile that is both dose dependant and cumulative. Isotetinoin (1mg/kg daily) and Acitretin (titrated to side effects beginning at 0.5mg/kg) are available in the US.
As acrokeratosis verruciformis is typically in a less generalized limited distribution, the role of oral agents is even further tempered and limited to unique clinical situations. The known teratogenicity of these agents further limits their use in women of child bearing potential and restrictive registry programs for isotretinoin limit the clinical availability. Two forms of birth control are mandatory in this setting.
It can not be emphasized too strongly that the use of these agents should be utilized only by experienced physicians who are well versed in the multiple side effects. The cumulative effects on bone and tendons play a greater role in long-term exposure and need to be recognized and monitored especially in the disorders of keratinization.
Oral birth control has an obvious role in the prevention of generational transmission of an autosomal dominant entity.
Cryotherapy (with liquid nitrogen for focal lesions)
Superficial dermabrasion. But limited by the repopulation of the defective epidermis from infundibular and adnexal components.
Ablative lasers. The use of destructive lasers such as “non fractionated” carbon dioxide or Nd:YAG is another surgical consideration in the hands of experienced clinicians.
Optimal Therapeutic Approach for this Disease
Longitudinal observation is the most rational course, followed by topical retinoids. Limited cryotherapy has a place in difficult lesions. The use of systemic retinoids and ablative lasers is are limited to severe situations and requires clinicians with experience in both the underlying disease entity and the specialized therapeutic interventions.
The key to patient management in acrokeratosis verruciformis is longitudinal observation by experienced clinicians. The literature emphasizes that the initial manifestations may alter over time, to the extent that the original diagnosis of acrokeratosis verruciformis may be changed to Darier’s disease both clinically and by the alteration of the pathology findings, especially on repetitive biopsies and serial sectioning for acantholysis and dyskeratosis.
The isolated case reports of malignant transformation speak to the necessity of long-term follow up and biopsy of any atypical clinical lesions. As in any genodermatosis, the role of genetic counseling should not be forgotten and a coordinated approach with both dermatologists and geneticists working in conjunction would serve to give the patient and their family the most useful information.
A sensitivity to the adolecent years, with the attendant importance of socialization and peer interaction, may require an alteration in the conservative approach to acrokeratosis verruciformis. This need alone can tip the risk-benefit ratio to more aggressive therapies for a limited period of time. Repetitive discussions and reasonable expectations play an important role in this family dynamic.
The future of genetic science and manipulation of specific genetic defects are events to look forward to as further progress is made in these fields.
Unusual Clinical Scenarios to Consider in Patient Management
The differentiation of acrodermatitis verruciformis from Darier’s disease needs to be considered over time and additional clinical manifestations need to be sought and recognized. The rare development of cutaneous malignancy is worth noting but not expected in all patients. The linkage to a case of basal cell nevus syndrome to acrokeratosis verruciformis is another unusual clinical situation to be aware of. Long-term use of therapeutic retinoids requires monitoring by experienced clinicians.
What is the Evidence?
Hopf, G. “Uber eine bisher nicht beschriebene disseminierte Keratose (Akreokeratosis verruciformis)”. Dermatol Z. vol. 60. 1931. pp. 227-50. (Original report.)
Niedleman, ML, McKusick, VA. “Acrokeratosis verruciformis (Hopf) . A follow up study”. Arch Dermatol. vol. 86. 1962. pp. 779-82. (Definitive analysis of 24 cases in four generations of the same family confirming the autosomal dominant nature of the genetic transmission.)
Panja, RK. “Acrokeratosis verruciformis: (Hopf) — A clinical entity?”. Br J Dermatol. vol. 96. 1977. pp. 643-52. (The controversy as to whether acrokeratosis verruciformis is a specific entity or just a forme fruste of Darier’s disease is reviewed and the comments on the relationship of these diseases are assessed by the original authors.)
Dhitavat, J, Macfarlane, S, Dode, L. “Acrodermatitis verruciformis of Hopf is caused by Mutation in ATP2A2: Evidence that it is allelic to Darier’s Disease”. J Invest Dermatol. vol. 120. 2003. pp. 229-32. (Molecular analysis by the British team that defined the gene defect in Darier’s Disease. The role of the defect in Ca++ pump metabolism due to a heterozygous P602L mutation in the ATP2A2 gene is explored and the variable phenotypic expression of the two diseases is discussed. A definitive paper.)
Wang, PG, Gao, M, Lin, GS. “Genetic heterogenicity in acrokeratosis verruciformis of Hopf”. Clin Exp Dermatol. vol. 31. 2006. pp. 558-63. (The controversy continues as this Chinese group could not confirm the same specific defect in ATP2A2 and favors the distinct entity hypothesis.)
Farro, P, Zalaudek, I, Ferrara, G. “Unusual association between acrodermatitis verruciformis of Hopf and multiple keratoacanthomas. Successful treatment with acitretin”. J Dtsch Dermatol Ges. vol. 2. 2004. pp. 440-2. (An example of the role of systemic retinoid therapy in a unique clinical setting.)
Humbert, P, Laurent, R, Faivre, B. “Nevoidal basal cell syndrome and acrokeratosis verruciformis. Occurence of two rare inherited autosomal dominant conditions in the same patient”. Dermatologica. vol. 180. 1990. pp. 163-70. (A single case report of an association of two different types of mutation in the same patient.)
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