Clinical and Experimental Dermatology

Hereditary leiomyomatosis associated with renal cell carcinoma Z. C. Venables,1 A. Ramaiya,2 S. Holden3 and G. W. M. Millington1 1 Dermatology Department and 2Pathology Department, Norfolk and Norwich University Hospital, Norwich, Norfolk, UK; and 3Department of Medical Genetics, Addenbrooke’s Hospital, Cambridge, UK

doi: 10.1111/ced.12521

A 54-year-old woman presented with several lightbrown painful nodules over her arms and legs, which had become increasingly prevalent since she was a teenager (Fig. 1a). One lesion had been biopsied 11 years previously, and histology had confirmed this to be a benign pilar leiomyoma (Fig. 1b). Her medical history included a hysterectomy for large fibroids at the age of 35 years. Several other family members had similar skin lesions, including the patient’s mother, who had died from renal cell carcinoma (RCC) aged 47 years. The patient reported a recent episode of haematuria, and a urine dipstick test was positive for blood. An urgent opinion was sought from the Urology Department. Computed tomography of the patient’s abdomen and pelvis and results of cystoscopy were normal. The patient was referred to the Medical Genetics Department, who confirmed a germline heterozygous mutation (c.1027C>T, p.Arg343*) of exon 7 of the fumarate hydratase (FH) gene. The patient’s daughter and son also have cutaneous leiomyomata and the same heterozygous mutation in the FH gene. Hereditary leiomyomatosis associated with renal cell carcinoma (HLRCC) is inherited in an autosomal dominant fashion, but the pathogenesis of HLRCC is not fully understood.1,2 A mutation in the FH gene is considered pathogenic.1,2 The FH gene, which has been mapped to the long arm of chromosome 1, encodes the fumarate hydratase enzyme, which catalyses the conversion of fumarate to malate in the Kreb cycle. FH is considered to be a tumour suppressor gene; however, the mechanism resulting in the HLRCC phenotype is unknown.1,2 The main hypothesis is that FH dysfunc-

tion results in pseudohypoxia through stabilization of hypoxia-inducible factor (HIF) 1, a transcription factor responsible for angiogenesis and therefore tumourigenesis.1,2

(a)

(b)

Correspondence: Dr Zoe C. Venables, Dermatology Department, Norfolk and Norwich University Hospital, Colney Lane, Norwich, Norfolk NR4 7UY, UK E-mail: [email protected] Conflict of interest: GWMM is the current editor of Clinical and Experimental Dermatology. Accepted for publication 20 June 2014

ª 2014 British Association of Dermatologists

Figure 1 (a) Papules over the patient’s shin; (b) biopsy showing

immunohistochemical expression of desmin (original magnification 9400).

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Cutaneous leiomyomata affect 76% individuals with HLRCC. They present from the mean age of 25 years as pink to brown papules or nodules over the trunk, extremities or face, and gradually increase in size and number. They can be painful and tender. Rarely, these lesions can transform into leiomyosarcoma.3,4 Uterine leiomyomata affect almost all affected female individuals, and tend to be larger and more symptomatic than those in the normal population. Again rarely, transformation to leiomyosarcoma can occur.3,4 RCCs arise in 10–30% of patients, typically presenting with haematuria and back pain. HLRCC is associated with type II papillary RCC, which is aggressive and often disseminated at presentation. In one study, 9 of 13 subjects died within 5 years of RCC diagnosis.4 There have also been case reports of associations with other malignancies, including bladder cancer, adrenocortical tumours, Leydig-cell tumours of the testis, ovarian cystadenomas and gastrointestinal stromal tumours, the significance of which is yet to be determined.4 Genetic counselling is an important aspect of management. Once a diagnosis is made, family screening and a follow-up arrangement is made with multidisciplinary involvement including the Dermatology, Gynaecology, Urology, Radiology and Medical Genetics Departments. However, there are no guidelines available. Patients must be aware of the warning signs and symptoms suggestive of underlying RCC, and we advise that they should receive an annual magnetic resonance imaging scan of the abdomen and pelvis with contrast in order to encourage early detection of this aggressive form of RCC. Patients should undergo a full dermatological assessment for leimyosarcoma and symptom control, with education on warning signs of transformation to leiomyosarcoma and follow-up as deemed appropriate. Female patients should undergo gynaecological review to assess for the presence and severity of fibroids.4,5 HLRCC is probably underdiagnosed. Most importantly, diagnosis may result in early identification and

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treatment of an aggressive RCC. Leiomyoma is one of a range of benign skin tumours that act as markers of internal malignancy.5,6

Learning points



This case shows the importance of a thorough personal and family history in patients with benign leiomyomata, and the requirement for a multidisciplinary approach in managing patients with HLRCC. • HLRCC is probably underdiagnosed. • Most importantly, diagnosis may result in early identification and treatment of an aggressive RCC.

References 1 Pollard P, Wortham N, Barclay E et al. Evidence of increased microvessel density and activation of the hypoxia pathway in tumours from the hereditary leiomyomatosis and renal cell cancer syndrome. J Pathol 2005; 205: 41–9. 2 Toro JR et al. Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet 2003; 73: 95–106. 3 Wei MH et al. Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer. J Med Genet 2006; 43: 18–27. 4 Lehtonen HJ. Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics. Fam Cancer 2011; 10: 397–411. 5 Al Fares A, Millington GWM, Tischkowitz M. Dermatological features of inherited cancer syndromes in adults. Clin Exp Dermatol 2010; 35: 462–7. 6 Karalis A, Tischkowitz M, Millington GWM. Dermatological manifestations of inherited cancer syndromes in children. Br J Dermatol 2011; 164: 245–56.

ª 2014 British Association of Dermatologists

Hereditary leiomyomatosis associated with renal cell carcinoma.

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