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Clinical Features of Multiple Cutaneous and Uterine Leiomyomatosis
An Underdiagnosed Tumor Syndrome
N. Afrina Alam, MD;
Ella Barclay, MD;
Andrew J. Rowan, BSc;
Jonathan P. Tyrer, PhD;
Eduardo Calonje, MD;
Sanjiv Manek, MD;
David Kelsell, PhD;
Irene Leigh, MD;
Simon Olpin, PhD;
Ian P. M. Tomlinson, MD
Arch Dermatol. 2005;141:199-206.
Objective To investigate the clinical features of the multiple cutaneous and uterine leiomyomatosis (MCUL) syndrome, including the hereditary leiomyomatosis and renal cell cancer syndrome.
Design A case series of patients with multiple skin leiomyomas solicited via a circular letter to dermatologists.
Setting Research institute.
Patients A total of 108 affected individuals, including 46 probands and 62 affected relatives.
Main Outcome Measures The proportion of probands with underlying fumarate hydratase (FH) mutations, the penetrance of FH mutations, and clinicopathologic features of MCUL.
Results Forty-one (89%) of 46 probands with multiple skin leiomyomas had evidence of germline FH mutations, which were highly penetrant. All 26 male mutation carriers had skin leiomyomas. Of 67 women with FH mutations, 46 (69%) had both skin and uterine leiomyomas; 10 (15%) had only skin leiomyomas; 5 (7%) had only uterine leiomyomas; and 6 (9%) were clinically unaffected. Patients presented with skin leiomyomas at a mean age of 24 years and had a mean of 25 lesions. Forty-one individuals (89%) reported painful lesions, particularly in response to cold or trauma. Fibroids were histologically unremarkable, highly symptomatic, and associated with a high risk of early hysterectomy. One individual had a very aggressive collecting duct renal cancer. The G354R FH mutation predisposed patients to uterine fibroids without skin leiomyomas (P = .03). Many patients with skin leiomyomas had not previously presented for medical attention. Fibroids were rarely recognized as cases of MCUL.
Conclusions Highly penetrant FH mutations underlie MCUL. Increased clinical awareness is important because of the associated risk of severe uterine fibroids and, in some cases, aggressive renal cancer.
Author Affiliations: Molecular and Population Genetics Laboratory (Drs Alam, Barclay, and Tomlinson and Mr Rowan), Mathematics, Statistics, and Epidemiology Department (Dr Tyrer), Cancer Research UK, London; Department of Dermatopathology, St John’s Institute of Dermatology, St Thomas’s Hospital, London (Dr Calonje); Department of Histopathology, John Radcliffe Hospital, Oxford (Dr Manek); Centre for Cutaneous Research, St Bartholomew’s and London School of Medicine and Dentistry, Queen Mary and Westfield College, Whitechapel, London (Drs Kelsell and Leigh); and Neonatal Screening and Chemical Pathology, Sheffield Children’s Hospital, Sheffield (Dr Olpin), England.
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