AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Acrokeratosis verruciformis is an autosomal dominant genodermatosis characterized by multiple warty lesions resembling plane warts typically observed on the dorsum of the hands and feet. Hopf first suggested the name acrokeratosis verruciformis in 1931. In 1947, Niedleman first published the largest series describing an Italian American family in which acrokeratosis verruciformis of Hopf occurred in 14 members. In the follow-up study in 1962, Niedleman and McKusick further described 24 cases in 4 generations of the same family. The number and distribution of cases in the latter report suggested an autosomal dominant mode of transmission.

Lesions identical to those of acrokeratosis verruciformis are also observed in many patients with acral Darier disease (also termed keratosis follicularis). To complicate matters further, lesions of acrokeratosis verruciformis have been reported in relatives of individuals with Darier disease. Considerable controversy surrounds the nature and relationship of acrokeratosis and Darier disease and whether they are manifestations of one genetic abnormality. Acrokeratosis verruciformis and acral Darier disease have been distinguished as 2 distinct entities in the literature. Although clinically similar, acrokeratosis verruciformis is thought to remain nondyskeratotic throughout life, whereas acral lesions of Darier disease show, upon careful histologic examination, various gradations of benign acantholytic dyskeratosis.

Darier disease (keratosis follicularis) is the most important disorder to be distinguished from acrokeratosis. Darier disease, acrokeratosis verruciformis, epidermodysplasia verruciformis, plane warts, and seborrheic keratoses can be differentiated by histologic examination of biopsy samples from individual lesions. The hard nevus of Unna can be differentiated clinically by its late onset.

Pathophysiology

The close similarity of Hopf disease to the acral warty lesion of keratosis follicularis has been noted by Hopf and Darier themselves. The similarities led later observers to postulate a relationship between the two diseases. The exact relationship between acrokeratosis verruciformis and Darier disease has not yet been satisfactorily resolved. A classic case of Darier disease poses no diagnostic problem. However, deciding whether a forme fruste of Darier disease (with atypical acral papules) is identical to acrokeratosis verruciformis remains difficult.

Frequency

International

Unknown

Race

Acrokeratosis verruciformis has been described in individuals of many races.

Age

Acrokeratosis verruciformis is usually present at birth or in early childhood. Onset may be delayed until the fifth decade of life.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Acrokeratosis verruciformis is usually present at birth or in early childhood, but onset may be delayed until the fifth decade of life.
• Data from kinships published in the literature suggest an autosomal dominant mode of transmission.

Physical

• Skin-colored or reddish-brown, flat, warty papules resembling flat warts are observed on the dorsum of the hands and, at times, on the dorsum of the feet.
• Papules predominantly occur on the dorsum of the hands and/or feet, but they also may be found on the knees, elbows, or forearms.
• Small groups or isolated papules may develop on other parts of the body.
• Papules sometimes are more easily felt than seen.
• Palmar skin may be thickened and may show punctate keratosis or punctiform breaks in dermatoglyphics identical to those observed in persons with Darier and Grover diseases.

Causes

• Acrokeratosis verruciformis and Darier disease are allelic disorders.
• • Acrokeratosis verruciformis of Hopf is a localized disorder of keratinization that affects the distal extremities. Onset is early in life, and the disease is inherited in an autosomal dominant fashion. Although the histology of acrokeratosis verruciformis lesions shows no evidence of dyskeratosis, a possible relationship with Darier disease has long been postulated on the basis of clinical similarity. ATP2A2 encoding the sarco(endo)plasmic reticulum Ca2⁺ ATPase2 pump has been identified as the defective gene in Darier disease.
  • In this report, a family affected with acrokeratosis verruciformis in 6 generations was studied, and a heterozygous P602L mutation in ATP2A2 was identified. This mutation predicts a nonconservative amino acid substitution in the ATP binding domain of the molecule. The mutation segregates with the disease phenotype in the family and was not found in 50 controls. Moreover, functional analysis of the P602L mutant showed that it has lost its ability to transport Ca2⁺. This result demonstrates loss of function of the sarco(endo)plasmic reticulum Ca2⁺ ATPase2 mutant in acrokeratosis verruciformis, thus providing evidence that acrokeratosis verruciformis and Darier disease are allelic disorders.
  • Acrokeratosis verruciformis of Hopf is caused by mutation in ATP2A2—evidence that it is allelic to Darier disease (Dhitavat, 2003).
• An autosomal dominant mode of transmission has been suggested. In 1947, Niedleman published the largest series. In 1962, the follow-up series by Niedleman and McKusick described 24 cases in 4 generations in the same family.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Procedures

• Skin biopsy is needed to establish the diagnosis.

Histologic Findings

Sections reveal hyperkeratosis, regular acanthosis, and papillomatosis, which impart a regular, undulating appearance to the surface. These changes have been likened to church spires. No parakeratosis, no epidermal vacuolation, and little dermal inflammatory infiltrate are found.

Darier disease is the most important differential diagnosis, and patients may show identical findings upon clinical examination. Dyskeratotic cells are characteristic of Darier disease but are not present upon histologic examination of acrokeratosis verruciformis.

Epidermodysplasia verruciformis, plane warts, and seborrheic keratoses, which may also clinically simulate lesions of acrokeratosis verruciformis, can be distinguished by histologic features.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The only effective treatment is superficial ablation. Treatment is not generally recommended, but medical and surgical treatments have been tried. Applications of retinoic acid have been helpful in some individuals. Destruction of the lesions with cryotherapy or laser, especially destructive lasers such as a carbon dioxide or Nd:YAG laser, may be used. Untreated lesions persist and become more noticeable after prolonged sun exposure because of darkening.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drug Category: Retinoids

Tretinoin has been reported to be successful in some individuals with these lesions.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Complications

• Squamous cell carcinoma of the skin has been reported in 2 cases.

Prognosis

• Lesions tend to persist throughout life and become more prominent following prolonged sun exposure.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• A forme fruste of Darier disease may be impossible to differentiate from acrokeratosis verruciformis of Hopf based on clinical findings. Looking for dyskeratosis histologically, which favors a diagnosis of Darier disease, is important. Following up with patients and performing a biopsy on the lesion is recommended if the diagnosis is in doubt.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Dhitavat J, Macfarlane S, Dode L, et al. Acrokeratosis verruciformis of Hopf is caused by mutation in ATP2A2: evidence that it is allelic to Darier''s disease. J Invest Dermatol. Feb 2003;120(2):229-32. [Medline].
• Dogliotti M, Schmaman A. Acrokeratosis verruciformis: malignant transformation. Dermatologica. 1971;143(2):95-9. [Medline].
• Humbert P, Laurent R, Faivre B, Agache P. Nevoid basal cell carcinoma syndrome and acrokeratosis verruciformis. Occurrence of two rare inherited autosomal dominant conditions in the same patient. Dermatologica. 1990;180(3):169-70. [Medline].
• Niedleman ML, McKusick VA. Acrokeratosis verruciformis (Hopf). A follow-up study. Arch Dermatol. Dec 1962;86:779-82. [Medline].
• Panja RK. Acrokeratosis verruciformis: (Hopf)--A clinical entity?. Br J Dermatol. Jun 1977;96(6):643-52. [Medline].
• Raff M, Szilvassy J. Specific dermatoglyphic patterns: a characteristic manifestation of acantholytic dyskeratotic dermatoses. J Am Acad Dermatol. Nov 1989;21(5 Pt 1):958-60. [Medline].
• Schueller WA. Acrokeratosis verruciformis of Hopf. Arch Dermatol. Jul 1972;106(1):81-3. [Medline].
• Su WP. Histopathologic varieties of epidermal nevus. A study of 160 cases. Am J Dermatopathol. Apr 1982;4(2):161-70. [Medline].
• Verbov J. Acrokeratosis verruciformis of Hopf with steatocystoma multiplex and hypertrophic lichen planus. Br J Dermatol. Jan 1972;86(1):91-4. [Medline].

Article Last Updated: Apr 7, 2006