Scholarly article on topic 'A distinct variant of Epidermodysplasia verruciformis in a Turkish family lacking EVER1 and EVER2 mutations'

A distinct variant of Epidermodysplasia verruciformis in a Turkish family lacking EVER1 and EVER2 mutations Academic research paper on "Biological sciences"

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Academic research paper on topic "A distinct variant of Epidermodysplasia verruciformis in a Turkish family lacking EVER1 and EVER2 mutations"

Journal of Dermatological Science (2007) 46, 214—216

_ Journal Of I . I

Dermatoloqical

SCIENCE

www.intl.elsevierhealth.com/journals/jods

LETTER TO THE EDITOR

A distinct variant of Epidermodysplasia verruciformis in a Turkish family lacking EVER1 and EVER2 mutations

Epidermodysplasia verruciformis (EV) is a rare gen-odermatosis associated with a high risk of skin

cancer. This condition is characterized by an abnormal susceptibility to human papillomavirus genotypes from the genus beta. The cutaneous lesions of EV first appear in childhood and are highly polymorphic. Multiple squamous cell carcinomas (SCC) of the skin develop subsequently on sun-exposed

Fig. 1 (a) Hyperpigmented SK-like lesions on the boy's face and forehead. (b) Brown, scaly PV-like macules on the neck and trunk. (c) Successful treatment of SK-like lesions by cryosurgery. (d) Multiple brownish plaques and SK-like lesions on face, neck and trunk of the female. (e) PV-like lesions on the hands.

0923-1811 /$30.00 © 2007 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jdermsci.2007.01.002

sites in about half of the patients. Benign cutaneous lesions are associated with polymorphic lesions such as pityriasis versicolor-like (PV-like) macules, flat warts and red macules. EV is believed to be an autosomal recessive disease (reviewed in ref. [1]). Two susceptibility loci, EV1 and EV2, have been mapped with EV1 containing the characterized EVER1 and EVER2 genes [2].

In this report, we present a 22-year-old Turkish male and his 45-year-old mother with extensive seborrheic keratosis-like (SK-like) viral warts with no family history of EV. Initial facial lesions developed aged 8 years and disseminated with time. PV-like brown scaly macules resembling pityriasis versicolor were observed on the trunk and neck (Fig. 1b and d). The patients showed SK-like viral warts characterized by dark brown or black pig-mented proliferative lesions with hyperkeratotic surfaces. Facial SK-like lesions were dark and plaque-like (Fig. 1a and d). All lesions disappeared following liquid nitrogen cryosurgery (Fig. 1c). Blood profile (son) including full blood count, erythrocyte sedimentation rate, C-reactive protein, liver and renal function tests, serum lipid and cholesterol level, levels of immunoglobulins, complement components and circulating immune complexes were normal. The patient showed no decrease in the number of CD8+ T-cells as described previously for EV [10]. The patient was HIV-negative.

Skin biopsies were taken from a SK-like wart and histopathologic evaluation of a warty lesion revealed hyperkeratosis and hypergranulosis with vacuolation and koiliocytes consistent with HPV infection. The lesion showed mild to moderate dysplasia in the

epidermis (Fig. 2). The dermatopathological findings were pathognomic for EV.

HPV DNA analysis was performed on a formalin-fixed, paraffin-embedded hyperkeratotic lesion from the face. The sample was tested positive for oncogenic HPV type 8 using a multiple nested degenerated PCR method with the capacity to detect a broad spectrum of cutaneous, alpha-and beta-HPV types [3]. No other HPV types were detected.

Genetic analysis of the genes EVER1 and EVER2, two known genes to be associated with this disease, did not detect any loss of function mutations by sequencing the coding exons from genomic DNA with previously described primers [2]. We found only a non-synonymous single nucleotide polymorphism in the intron between exon 10 and exon 11 (cacctgccc[c/g]ctggggaggcag) of EVER1.

This phenotype of EV, dominated by SK-like lesions, has previously been reported in a subset of African EV patients [4-6]. This is the first report of this EV phenotype in a Caucasian family. The diagnosis of EV is supported by the characteristic histology and the presence of the EV-associated HPV8. Both patients showed PV-like scaly macules in addition to the clinically dominant SK-like warts. To our knowledge, EVER mutations have previously been described in few reports [2,7-9], with only one publication reporting the lack of EVER mutation [10]. Our analysis shows also lack of EVER1 and EVER2 mutations and represents a distinct clinical and genetic variant of EV underlining the probable involvement of other genetic loci in the development of this disease.

Fig. 2 Histology of SK-like viral wart from the boy (a and b) and his mother (c and d) showing typical EV changes. (a and c) 50-fold magnification; (b and d) 200-fold magnification.

Acknowledgments

We thank Dr. G. Orth and Dr. M. Favre, Institut Pasteur, Paris, France, for their contribution to EVER1 and EVER2 gene sequencing and Dr. Catherine Harwood for helpful discussion. This study was supported by grants from the Dr. Mildred Scheel Stiftung fur Krebsforschung/Deutsche Krebshilfe and Cancer Research UK.

References

[1] Akgul B, Cooke JC, Storey A. HPV-associated skin disease. J Pathol 2006;208:165-75.

[2] Ramoz N, Rueda LA, Bouadjar B, Montoya LS, Orth G, Favre M. Mutations in two adjacent novel genes are associated with Epidermodysplasia verruciformis. Nat Genet 2002;32: 579-81.

[3] Harwood CA, Spink PJ, Surentheran T, Surentheran T, Leigh IM, de Villiers EM, et al. Degenerate and nested PCR: a highly sensitive and specific method for detection of human papil-lomavirus infection in cutaneous warts. J Clin Microbiol 1999;37:3545-55.

[4] Roncalli de Oliveira W, Neto CF, Rady PL, Tyring SK. Seborrheic keratosis-like lesions in patients with Epidermodysplasia verruciformis. J Dermatol 2003;30:48-53.

[5] Jacyk WK, Dreyer L, de Villiers EM. Seborrheic keratoses of black patients with Epidermodysplasia verruciformis contain human papillomavirus DNA. Am J Dermatopathol 1993;15:1 — 6.

[6] JacykWK, De Villiers EM. Epidermodysplasia verruciformis in Africans. Int J Dermatol 1993;32:806-10.

[7] Zuo YG, Ma D, Zhang Y, Qiao J, Wang B. Identification of a novel mutation and a genetic polymorphism of EVER1 gene in two families with Epidermodysplasia verruciformis. J Der-matol Sci 2006;26.

[8] Sun XK, Chen JF, Xu AE. A homozygous nonsense mutation in the EVER2 gene leads to Epidermodysplasia verruciformis. Clin Exp Dermatol 2005;30:573-4.

[9] Tate G, Suzuki T, Kishimoto K, Mitsuya T. Novel mutations of EVER1/TMC6 gene in a Japanese patient with Epidermodysplasia verruciformis. J Hum Genet 2004;49:223-5.

[10] Azzimonti B, Mondini M, De Andrea M, et al. CD8+ T-cell lymphocytopenia and lack of EVER mutations in a patient with clinically and virologically typical Epidermodysplasia verruciformis. Arch Dermatol 2005;141:1323-5.

BakiAkgul*

Skin Tumour Laboratory, Cancer Research UK, Centre for Cutaneous Research, Institute for Cell and Molecular Science, London E1 2AT, UK

Osman Kose Gulhane Military Medical Academy, Department of Dermatology, 06018 Ankara, Turkey

Mukerrem Safali Gulhane Military Medical Academy, Department of Pathology, 06018 Ankara, Turkey

Karin Purdie

Skin Tumour Laboratory, Cancer Research UK, Centre for Cutaneous Research, Institute for Cell and Molecular Science, London E1 2AT, UK

Rino Cerio Institute of Pathology, Bart's and the London Queen Mary's School of Medicine and Dentistry, University of London,

London E1 2AT, UK

Charlotte Proby Alan Storey

Skin Tumour Laboratory, Cancer Research UK, Centre for Cutaneous Research, Institute for Cell and Molecular Science, London E1 2AT, UK

Corresponding author. Tel.: +44 207882 2348;

fax: +44 207882 7172 E-mail address: baki.akguel@web.de

(B. Akgül)

1 November 2006

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