CASE REPORT. Case report E.ALPSOY, M.A. ÇIFTÇIOĞLU,* _I.KESER, E-M.DE VILLIERS AND C.C.ZOUBOULIS

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1 British Journal of Dermatology 2002; 146: CASE REPORT Epidermodysplasia verruciformis associated with neurofibromatosis type 1: coincidental association or model for understanding the underlying mechanism of the disease? E.ALPSOY, M.A. ÇIFTÇIOĞLU,* _I.KESER, E-M.DE VILLIERS AND C.C.ZOUBOULIS Departments of Dermatology, *Pathology and Medical Genetics, Akdeniz University School of Medicine, Antalya, Turkey Reference Centre for Human Pathogenic Papillomaviruses, Division of Tumour Virus Characterization, Deutsches Krebsforschungszentrum, Heidelberg, Germany Department of Dermatology, University Medical Centre Benjamin Franklin, The Free University of Berlin, Berlin, Germany Accepted for publication 30 August 2001 Summary We describe a 25-year-old man with epidermodysplasia verruciformis (EV) associated with neurofibromatosis type 1 (NF1). The lesions, persisting for more than 15 years, consisted of widespread planar warts on the backs of the hands and wrists, and reddish-brown macules on the trunk, neck and face. During the last 5 years, our patient developed several epithelial tumours, namely solar keratoses, plaques of Bowen s disease and squamous cell carcinomas (SCCs). He also presented with NF1 lesions with neurofibromas, café-au-lait macules, axillary freckling and Lisch nodules. He had left tibial bowing. Polymerase chain reaction analysis of the skin lesions demonstrated the presence of human papillomavirus (HPV) 15 in a flat wart, HPV 20 in a plaque of Bowen s disease, and HPV 15 and HPV 20 in an SCC lesion. Both EV and NF1 show an inherited predisposition to malignancy but the molecular mechanism underlying tumour development is not fully understood. The appearance of both diseases in our patient may be a coincidental association but may also contribute to the identification of loci for susceptibility to NF1 and EV on chromosome 17. Key words: Bowen s disease, epidermodysplasia verruciformis, human papillomavirus, neurofibromatosis type 1, solar keratosis, squamous cell carcinoma Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by flat warts or scaling macules resembling pityriasis versicolor. The condition is associated with widespread and persistent infection by a specific group of related human papillomaviruses (HPVs) and a high risk of development of epithelial tumours such as solar keratosis, Bowen s disease and squamous cell carcinoma (SCC) on sun-exposed skin. The disease is usually considered an autosomal recessive condition. 1 3 Neurofibromatosis type 1 (NF1), a common autosomal dominant disease affecting one in 3500 Correspondence: Erkan Alpsoy. alpsoy@med.akdeniz.edu.tr individuals, is characterized by multiple neurofibromas, café-au-lait macules, axillary freckling, iris hamartomas (Lisch nodules) and a variety of other possible complications, including an increased risk of malignancy. 4,5 We describe a 25-year-old man with EV associated with NF1. Both conditions show an inherited predisposition to malignancy, but the molecular mechanism underlying tumour development in these diseases is not fully understood. Case report A 25-year-old man was referred with persistent, widespread warts and tumoral masses together with Ó 2002 British Association of Dermatologists 503

2 504 E.ALPSOY et al. brown macules, which had been present for more than 15 years. His parents were first cousins. Shortly after birth he was reported to have developed café-au-lait spots and subsequent axillary freckling. He was also noted to have left tibial bowing. He developed several cutaneous or subcutaneous tumours after the age of 10 years. He was unable to walk without support because of tibial bowing that was considered to be an unfavourable type of congenital pseudarthrosis, and his left leg was amputated at the age of 18 years. His parents reported a history of increasing numbers of planar warts on the back of his hands and reddishbrown lesions on his trunk, neck and face since he was aged 7 years. Furthermore, during the last 5 years, he developed several solar keratoses, plaques of Bowen s disease and SCCs arising from reddish-brown lesions on sun-exposed areas of the skin (Fig. 1), which were treated by cryotherapy or surgery. Examination revealed widespread flat-topped, slightly elevated skin-coloured or reddish papules on the backs of the hands and wrists (Fig. 2), and reddish-brown macules similar to those in pityriasis versicolor on the trunk, neck and face (Fig. 3). Our patient also presented several neurofibromas with the typical button-hole sign (Fig. 4). Multiple café-au-lait spots and axillary freckles (Crowe sign) were detected. Ophthalmological Figure 2. Widespread flat-topped, slightly elevated skin-coloured or reddish papules on the backs of the hands and wrists. Figure 3. Reddish-brown macules similar to those in pityriasis versicolor are evident on the trunk and neck. Figure 1. A clinical photograph showing solar keratoses, plaques of Bowen s disease and squamous cell carcinomas arising from reddishbrown lesions. examination revealed bilateral Lisch nodules, confirming the diagnosis of NF1. Biopsy of planar warts from the back of the hand and of a tumour from the arm respectively confirmed the diagnosis of EV and NF. The samples were fixed in 10% buffered formalin and routine histological examination was performed after paraffin embedding and staining with haematoxylin and eosin. In the first biopsy, affected keratinocytes were swollen and irregularly shaped. They showed abundant, slightly basophilic cytoplasm. The nuclei of the affected keratinocytes appeared large, round and empty (Fig. 5). In the second biopsy, a circumscribed non-encapsulated dermal tumour was composed of loosely spaced spindle cells and wavy collagenous strands (Fig. 6). Biopsies of

3 EV ASSOCIATED WITH NF1 505 Figure 6. Histology of a neurofibroma showing a circumscribed, non-encapsulated dermal tumour (haematoxylin and eosin; original magnification 40). Figure 4. Several neurofibromas and reddish-brown macules similar to those in pityriasis versicolor are seen on the back. Figure 7. Histology of a squamous cell carcinoma showing large hyperchromatic pleomorphic nuclei, keratinized cytoplasm and necrosis (haematoxylin and eosin; original magnification 100). Figure 5. Histology of a planar wart on the back of the hand showing abundant, slightly basophilic cytoplasm and large, round empty nuclei (haematoxylin and eosin; original magnification 100). lesions diagnosed as solar keratosis, Bowen s disease and SCC (Fig. 7) were confirmatory. One sample of a flat wart, two samples of an SCC lesion and one of Bowen s disease were subjected to polymerase chain reaction (PCR) analysis. DNA was extracted from paraffin-embedded material and subjected to PCR amplification. Precautions were taken at all stages of handling to avoid contamination. Primers were selected to amplify the majority of mucosal as well as cutaneous HPV types. These included the GP+, 6 CP 7 and FAP 8 primers. All the amplified products were cloned and an average of six clones per product sequenced. The majority of the cloned products resulting from the amplification with the CP primers harboured HPV DNA, whereas the cloned products amplified with the other primers all harboured cellular sequences. HPV 15 DNA was demonstrated in a flat wart, HPV 20 in a sample of Bowen s disease and both HPV 15 and HPV 20 in an SCC lesion. In the latter, many clones harboured HPV 15 DNA, whereas HPV 20 was present in only one of the clones analysed. No obvious sequence differences were observed between clones from a specific HPV type. Full blood count and routine biochemical tests showed normal values. Serum levels of immunoglobulins IgG, IgA, IgM and IgE, IgG subclasses IgG1, IgG2, IgG3 and IgG4, and complement components C3 and

4 506 E.ALPSOY et al. C4 were within normal limits. Percentages and absolute counts of lymphocyte subsets CD3, CD4, CD8, CD19 and CD56 were normal. Our patient had no family history of any similar skin or genetic disorder. GTG-banded chromosome examinations were performed on lymphocyte cultures from our patient to exclude major chromosomal abnormalities. His karyotype was found to be 46,XY according to standard chromosomal analysis. Discussion EV is an extremely rare genodermatosis that is associated with widespread and persistent infection by a distinct group of HPV types present in disseminated flat warts and pityriasis versicolor-like lesions. In about half of the patients with EV, the lesions on sun-exposed sites may progress to carcinoma in situ and invasive SCC during the third and fourth decade of life. 1,2,9 HPV 5 and HPV 8 are the main oncogenic cutaneous HPV types detected in over 90% of EV-associated SCCs. 1 A lesion of SCC from our patient harboured HPV 15 and HPV 20 DNA, both EV-associated HPV types. HPV 20 has occasionally been reported to be associated with SCC. 10,11 The high rate of parental consanguinity in patients with EV, as in our patient, suggests a recessive pattern of inheritance. Besides sex-linked 12 and autosomal dominant inheritance, 13 sporadic cases have also been reported. Ramoz et al. have mapped a susceptibility locus for EV to chromosome 17qter within the 1 cm interval between markers D17S939 and D17S The same authors recently reported a candidate region for a second EV susceptibility locus within the 8 cm interval between markers D2S171 and D2S2347 of the 2p21-p24 region. 15 NF1, a pleiotropic autosomal dominant disorder, is characterized by benign tumour (neurofibroma) growth and increased risk of malignancy. NF1 is caused by mutations in the NF1 gene localized on chromosome 17q11.2. The NF1 gene has a tumoursuppressor function. The product of this gene, neurofibromin, is a major negative regulator of the Ras pathway in cells, which transmits mitogenic signals to the cell nucleus. Therefore, loss of neurofibromin in patients with NF1 leads to accumulation of activated Ras and thus increases downstream mitogenic signalling. 16 Malignancy developing over NF1 lesions, a major cause of morbidity and mortality, appears in approximately 5% of cases; neurofibrosarcoma is the most common tumour. A tendency to develop a Wilm s tumour, a rhabdomyosarcoma or leukaemia has also been reported. 17,18 Although NF1 is known to be a common autosomal disease, the mutation rate in the NF1 gene is one of the highest known for human genes, and approximately half of the cases of NF1 result from new mutations. 19 The parents of our patient showed no evidence of the disease; this suggests a new mutation or occurrence of the disease de novo. On the other hand, the first-degree consanguinity of the parents suggests a recessive pattern of inheritance for EV. Two susceptibility loci for EV have recently been mapped to chromosome regions 2p21-p24 and 17q25 by Ramoz et al. 14,15 The appearance of both diseases in our patient may support the notion that the 17q25 region is the site of the candidate gene for EV. In the frame of Mendelian inheritance, we can speculate that both NF1 and EV may be inherited together on chromosome 17 according to the chromosomal segregation in our patient. We have described a 25-year-old man with EV associated with NF1. This is the first case report, to our knowledge, of EV associated with NF1 and therefore may contribute to the determination of loci for susceptibility to NF1 and EV on chromosome 17. There may be a pleiotrophic effect involving chromosome 17 that induces not only EV but also contributes to the pathogenesis of NF1. This association may also be coincidental. However, further observations are needed to determine the clinical and cytogenetic relevance. References 1 Majewski S, Jablonska S. Human papillomavirus-associated tumors of the skin and mucosa. J Am Acad Dermatol 1997; 36: Orth G. Epidermodysplasia verruciformis: a model for understanding the oncogenicity of human papillomaviruses. Ciba Foundation Symposium 1986; 120: de Villiers E-M. Human papillomavirus infections in skin cancers. Biomed Pharmacother 1998; 52: Riccardi VM. Neurofibromatosis: Phenotype, Natural History and Pathogenesis, 2nd edn. Baltimore: The Johns Hopkins University Press, Wallace MR, Marchuk DA, Anderson LB et al. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three patients. Science 1990; 249: de Roda Husman AM, Walboomers JM, van den Brule AJ et al. The use of general primers GP5 and GP6 elongated at their 3 ends with adjacent highly conserved sequences improves human papillomavirus detection by PCR. J Gen Virol 1995; 76: de Villiers E-M, Lavergne D, McLaren K, Benton EC. Prevailing papillomavirus types in nonmelanoma carcinomas of the skin in renal allograft recipients. Int J Cancer 1997; 73: Forslund O, Antonsson A, Nordin P et al. A broad range of human papillomavirus types detected with a general PCR method suitable

5 EV ASSOCIATED WITH NF1 507 for analysis of cutaneous tumours and normal skin. J Gen Virol 1999; 80: Majewski S, Jablonska S. Epidermodysplasia verruciformis as a model of human papillomavirus-induced genetic cancer of the skin. Arch Dermatol 1995; 131: Berkhout RJ, Bouwes Bavinck JN, ter Schegget J. Persistence of human papillomavirus DNA in benign and (pre)malignant skin lesions from renal transplant recipients. J Clin Microbiol 2000; 38: Harwood CA, Spink PJ, Surentheran T et al. Detection of human papillomavirus DNA in PUVA associated non-melanoma skin cancers. J Invest Dermatol 1998; 111: Androphy EJ, Dvoretzky I, Lowy DR. X-linked inheritance of epidermodysplasia verruciformis. Genetic and virologic studies of a kindred. Arch Dermatol 1985; 121: Jablonska S, Orth G, Obalek S et al. Oncogenic potential of human papillomaviruses epidermodysplasia verruciformis: a counterpart of Shope papilloma carcinoma complex. Arch Geschwulstforsch 1983; 53: Ramoz N, Rueda LA, Bouadjar B et al. A susceptibility locus for epidermodysplasia verruciformis, an abnormal predisposition to infection with the oncogenic human papillomavirus type 5, maps to chromosome 17qter in a region containing a psoriasis locus. J Invest Dermatol 1999; 112: Ramoz N, Taieb A, Rueda LA et al. Evidence for a nonallelic heterogeneity of epidermodysplasia verruciformis with two susceptibility loci mapped to chromosome regions 2p21-p24 and 17q25. J Invest Dermatol 2000; 114: Seizinger B. NF1: a prevalent cause of tumorigenesis in human cancers? Nat Genet 1993; 3: Bader JL. Neurofibromatosis and cancer. Ann NY Acad Sci 1986; 486: Hope DG, Mulvihill JJ. Malignancy in neurofibromatosis. Adv Neurol 1981; 29: Wimmer K, Eckart M, Rehder H, Fonatsch C. Illegitimate splicing of the NF1 gene in healthy individuals mimics mutation-induced splicing alterations in NF1 patients. Hum Genet 2000; 106: