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Implications for Disease Management and Tumor Induction

Neil Rajan, MBBS, MRCP; James A. A. Langtry, MBBS, FRCP; Alan Ashworth, PhD, FRS; Catherine Roberts, PhD; Pam Chapman, RN; John Burn, MBBS, MD, FRCP; Alison H. Trainer, MBBS, MRCP, PhD

Arch Dermatol. 2009;145(11):1277-1284.

Objectives  To comprehensively ascertain the extent and severity of clinical features in affected individuals from 2 large families with proven heterozygous mutations in the CYLD locus and to correlate these findings with the 3 appendageal tumor predisposition syndromes (familial cylindromatosis, Brooke-Spiegler syndrome, and multiple familial trichoepitheliomas) known to be associated with such germline mutations.

Design  Interfamilial and intrafamilial observational study.

Setting  Tertiary genetic and dermatology referral center.

Participants  Thirty-four individuals recruited from 2 large multigenerational families with CYLD mutations. Clinical details, history, and tumor maps were obtained from all participants; in 18, the information was corroborated by detailed clinical examination.

Main Outcome Measures  Tumor density, distribution and histologic findings, associated medical conditions, patient symptoms, and impact of disease on quality of life.

Results  The severity of penetrance and phenotype varied within families. Although an approximately equal female to male predisposition was noted, 5 women and 1 man (of 26 patients surveyed [23%]) had undergone total scalp removal. The average age at onset was 16 years (range, 8-30 years). Symptoms reported by affected patients included painful tumors (in 12 of 23 patients [52%] who answered the question), conductive deafness, and sexual dysfunction. Of the 26 surveyed patients, tumors were noted on the scalp in 21 (81%), on the trunk in 18 (69%), and in the pubic area in 11 (42%). Tumor mapping provided clinical evidence that correlated with hormonally stimulated hair follicles being particularly vulnerable to loss of heterozygosity and tumor induction.

Conclusions  The burden of disease at sites other than the head and neck appears to be underreported in the literature and greatly affects quality of life. Differentiation between the clinical diagnoses has little prognostic or clinical utility in genetic counseling, even within individuals from the same family. Thus, we suggest an encompassing diagnosis of "CYLD cutaneous syndrome." Finally, the clinical distribution of tumors suggests that hormonal factors may play an important role in tumor induction in these patients.

Author Affiliations: Institute of Human Genetics, University of Newcastle Upon Tyne (Drs Rajan, Roberts, and Trainer; Prof Burn; and Ms Chapman), and Department of Dermatology, Royal Victoria Infirmary (Dr Langtry), Newcastle Upon Tyne, England; Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, England (Prof Ashworth); and Genetic Health Services Victoria, Murdoch Childrens Research Institute, Parkville, Victoria, Australia (Dr Trainer).

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