Dermatology Online Journal

Acrokeratosis verruciformis of Hopf (Hopf disease): case report and review of the literature
MAJ E Rallis, A Economidi, MAJ P Papadakis, LTC C Verros
Dermatology Online Journal 11 (2): 10

Department of Dermatology, 401 General Military Hospital of Athens, Athens, Greece. cverros@vip.gr

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Abstract

Acrokeratosis verruciformis of Hopf is an autosomal dominant genodermatosis usually presenting with multiple planar wart-like lesions, typically observed on the dorsum of the hands and feet. The disease is very rare and the pathogenesis remains unknown. Considerable controversy surrounds the nature and relationship of acrokeratosis and Darier disease and whether they are manifestations of one genetic abnormality. We describe the case of a 19-year-old man seen in our clinic with skin-coloured, flat, warty papules localized to the dorsum of the hands and feet. Both clinical and histological findings were compatible with acrokeratosis verruciformis. We also review the disease, particularly its relation with Darier Disease and therapeutical options.

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Introduction

Acrokeratosis verruciformis is a very rare, heritable hyperkeratotic dermatosis that was originally described by Hopf in 1931 [1]. It is characterized by multiple, localized, symmetrical, flat, skin-colored, wart-like lesions, typically observed on the dorsum of the hands and feet. Small groups or isolated papules may develop on the knees, elbows, forearms, and also on other parts of the body [2]. The forehead, scalp, flexures, and the oral mucosa are never affected [3]. The lesions are usually present at birth, but they may appear later in infancy as papules or at puberty as ichthyosis. In some cases, onset may be delayed until the fifth decade of life [2].

Clinical synopsis

A 19-year-old man was referred to our clinic because of the presence of skin-colored, warty hyperkeratotic lesions that were located mainly on the dorsum of the hands and feet (Figs. 1 and 2).

Figure 1	Figure 2

Clinical examination also revealed similar, discrete lesions on the elbows, knees, and forearms, as well as punctuate keratoses on the palms (Fig. 3) and the soles (Fig. 4). Dermatophytosis of the feet was also present.

Figure 3	Figure 4

According to patient, the lesions were present at birth and increased in number since then. Nine more members of his family, including his father and his uncle (father's brother), had similar skin lesions and some of them also reported varying degrees of nail involvement. His father, among other findings, had Darier-like, thickened nails with V-shaped nicks at their free margins. Leuconychia and longitudinal grooves were also seen in some nails (Figs. 5, 6, 7). All his family is currently under investigation. Fig. 8) shows the son's and father's hands side by side.

Figure 5	Figure 6

Figure 7	Figure 8

Figure 9

Skin biopsy was performed and histological examination showed mild acanthosis with slight papillomatosis. There was also hyperkeratosis, most marked at the edges of the lesion, with moderate hypergranulosis and a thin layer of orthokeratosis (Fig. 9). The dermis was infiltrated with a few inflammatory cells surrounding the vessels. Both clinical and laboratory findings were compatible of acrokeratosis verruciformis of Hopf.

Discussion

Acrokeratosis verruciformis of Hopf is an autosomal dominant genodermatosis of unknown etiology, with no sexual predilection. Apart from the typical skin-colored, flat, warty papules on the dorsum of the hands and feet, examination may reveal thickening of palmar skin and punctate keratoses on the palms and the soles [2]. Interruptions of the dermal ridges in the finger pads and palms, identical to those seen in Grover, Galli-Galli, and Darier diseases, is another rather common finding in acrokeratosis verruciformis [4]. Nails may be whitish and thickened, and have longitudinal ridges breaking at the distal edge [3].

Skin biopsy is required to confirm the diagnosis. Histological examination of the wart-like papules usually shows considerable hyperkeratosis, an increase in thickness of the granular layer, acanthuses and slight papillomatosis, and is frequently (but not always) associated with circumscribed epidermal elevations resembling church spires. The rete ridges are slightly elongated and extend to a uniform level [5]. No parakeratosis or vacuolization is seen. The process is essentially epidermal in nature, but there might be a banal dermal infiltrate [6].

Lesions identical to those of acrokeratosis verruciformis can also be observed in patients with acral Darier disease or even in relatives of such patients [2]. A possible relationship between acrokeratosis verruciformis of Hopf and Darier disease has been suggested, nevertheless they are still considered to be distinct both genetically and histologically [7].

The two diseases may be similar clinically, but the acral lesions in Darier disease, though initially non-dyskeratotic, have every likelihood of developing dyskeratosis at a later age, whereas acrokeratosis verruciformis remains non-dyskeratotic and non-acantholytic throughout life. Basically, the keratinization process in acrokeratosis verruciformis is exaggerated but normal, whereas in Darier disease it is accentuated, altered and faulty [3].

Considering the possible genetic relationship between the two diseases, a recent report has shown that acrokeratosis verruciformis can arise from a missence mutation in ATP2A2, encoding the sarcoendoplasmic reticulum Ca2+ ATPase2 pump, which is also defective in Darier disease [8]. This could lead to the belief that the two diseases are allelic disorders with phenotypic expression of different severities [8]. However, further studies will have to be undertaken, for a final conclusion to be made.

Other skin disorders that should be included in the clinical differential diagnosis of Hopf disease are epidermodysplasia verruciformis, planar warts, and seborrheic keratosis; these can be distinguished by histological features. The hard nevus of Unna can be differentiated clinically by its late onset.

The only treatment considered effective for acrokeratosis verruciformis is superficial ablation. Although in general, treatment is not recommended, several medical and surgical treatments have been suggested. Applications of retinoic acid have been helpful for some affected individuals, and cryotherapy or destructive lasers such as CO2 or Nd:YAG have been tried. Lesions tend to persist throughout life and become more prominent after prolonged sun exposure [2]. Transformation to squamous cell carcinoma has been reported in two cases [3, 9] and there is one report that suggests a possible linkage of acrokeratosis verruciformis and nevoidbasal cell carcinoma syndrome [7].

References

1. Hopf G. Ueber eine bisher nicht beschriebene disseminierte Keratose (Akrokeratosis verruciformis). Dermatologische Zeitschrift 1931; 60: 227

2. Mohsin Ali. Acrokeratosis verruciformis of Hopf. In: http//www. emedicine.com/derm/topic7.htm. March 2, 2004

3. Panja RK. Acrokeratosis verruciformis (Hopf)-a clinical entity? Br J Dermatol. 1977; 96: 643-652

4. Raff M, Szilvassy J. Specific dermatoglyphic patterns: A characteristic manifestation of acantholytic dyskeratotic dermatoses. J Am Acad Dermatol. 1989; 21(5 Pt): 958-960

5. Johnson B Jr, Honig P. Congenital Diseases (Genodermatoses). In: Elder D, Elenitsas R, Jaworsky C, Johnson B Jr, Lever's Histopathology of the Skin, 8th edn, Lippincott-Raven, Philadelphia-New York, 1992, p117-150

6. Schueller WA. Acrokeratosis verruciformis of Hopf. Arch Dermatol. 1972; 106(1): 81-83

7. Humbert P, Laurent R, Faivre B et al. Nevoid Basal Cell Carcinoma Syndrome and Acrokeratosis Verruciformis. Occurrence of two rare inherited autosomal dominant conditions in the same patient. Dermatologica 1990; 180(3): 169-170

8. 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. J Invest Dermatol. 2003 Feb;120(2):229-32. PubMed

9. Dogliotti M, Schmaman A. Acrokeratosis verruciformis: malignant transformation. Dermatologica 1971; 143(2): 95-99

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