Tumor mapping in 2 large multigenerational families with CYLD mutations: implications for disease management and tumor induction.
OBJECTIVE
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.


METHODS
Interfamilial and intrafamilial observational study.


METHODS
Tertiary genetic and dermatology referral center.


METHODS
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.


METHODS
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.
Rajan
Neil
N
MRCP, Institute of Human Genetics, University of Newcastle Upon Tyne, Newcastle Upon Tyne NE13BZ, England. drneilrajan@googlemail.com
Langtry
James A A
JA
Ashworth
Alan
A
Roberts
Catherine
C
Chapman
Pam
P
Burn
John
J
Trainer
Alison H
AH
D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D017668:Age of Onset; D001707:Biopsy, Needle; D003528:Carcinoma, Adenoid Cystic / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics / Q000473:pathology / Q000601:surgery; D002648:Child; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D003638:Deafness / Q000175:diagnosis; D000074749:Deubiquitinating Enzyme CYLD; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D005820:Genetic Testing / Q000379:methods; D018095:Germ-Line Mutation; D006258:Head and Neck Neoplasms / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics* / Q000601:surgery; D006801:Humans; D007150:Immunohistochemistry; D015994:Incidence; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D012307:Risk Factors; D012535:Scalp / Q000601:surgery; D012680:Sensitivity and Specificity; D017678:Sex Distribution; D012735:Sexual Dysfunction, Physiological / Q000175:diagnosis; D012878:Skin Neoplasms / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics* / Q000601:surgery; D013577:Syndrome; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult
D025521:Tumor Suppressor Proteins; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD