Hereditary Leiomyomatosis and Renal Cell Cancer: Clinical, Molecular, and Screening Features in a Cohort of 185 Affected Individuals

Claire Forde, Derek H K Lim, Yousef Alwan, George Burghel, Laura Butland, Ruth Cleaver, Abhijit Dixit, D Gareth Evans, Helen Hanson, Fiona Lalloo, Pedro Oliveira, Lindsey Vialard, Yvonne Wallis, Eamonn R Maher, Emma R Woodward

Research output: Contribution to journalArticlepeer-review


BACKGROUND: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumour predisposition syndrome characterised by predisposition to cutaneous and uterine leiomyomata and renal cell carcinoma (RCC).

OBJECTIVE: To define the clinical findings, molecular genetics, and prognosis in a cohort of 69 families with a fumarate hydratase (FH) pathogenic variant and/or clinical features of HLRCC.

DESIGN, SETTING, AND PARTICIPANTS: Clinical and molecular findings were obtained for 185 individuals from 69 families from four UK regional genetics clinics.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Ages at confirmed diagnoses, last dates of follow-up, and molecular results were attained for probands and relatives. To study the effect of potential ascertainment bias, phenotypes of probands and their affected relatives were compared.

RESULTS AND LIMITATIONS: A germline FH variant (19 novel and 21 known, >50% missense variants) was identified in 68/69 probands and 90 relatives. Cutaneous leiomyomata occurred in 90/185 (48.6%) individuals (mean age 45.9 yr) and uterine leiomyomata in 33/107 (30.8%) females (mean age 35.0 yr). Of 185 individuals, 23 (12.4%) had a confirmed renal tumour, and histopathology where known (n = 18) was variable: seven clear cell RCCs, nine papillary RCCs (six of type 2), one collecting duct tumour, and one tumour with oncocytic cystic morphology. Mean age at symptomatic RCC diagnosis was 44.0 yr and median survival was 21.0 mo. Eighty-one individuals underwent 187 renal imaging surveillance scans; three stage 1 RCCs were detected. Mean survival of individuals diagnosed with stage 1/2 RCC was significantly longer than those diagnosed with stage 3/4 RCC (p = 0.0004).

CONCLUSIONS: Management of HLRCC is challenging as RCC occurs in a minority of cases but is highly aggressive. This large multicentre series has identified novel features and evidence that renal screening in HLRCC detects early-stage RCCs.

PATIENT SUMMARY: We show that hereditary leiomyomatosis and renal cell cancer is associated with a 21% lifetime risk of renal cell carcinoma (RCC; 95% confidence interval 8.2-37.1), and renal imaging screening detects early-stage RCC.

Original languageEnglish
Pages (from-to)764-772
Number of pages9
JournalEuropean urology oncology
Issue number6
Early online date9 Dec 2019
Publication statusPublished - Dec 2020


  • Adolescent
  • Adult
  • Aged
  • Carcinoma, Renal Cell/diagnosis
  • DNA Mutational Analysis
  • Early Detection of Cancer/methods
  • Female
  • Follow-Up Studies
  • Fumarate Hydratase/genetics
  • Genetic Testing/statistics & numerical data
  • Humans
  • Kidney/diagnostic imaging
  • Kidney Neoplasms/diagnosis
  • Leiomyomatosis/complications
  • Magnetic Resonance Imaging
  • Male
  • Medical History Taking
  • Middle Aged
  • Molecular Epidemiology
  • Mutation
  • Neoplasm Staging
  • Neoplastic Syndromes, Hereditary/complications
  • Prognosis
  • Skin Neoplasms/complications
  • United Kingdom/epidemiology
  • Uterine Neoplasms/complications
  • Young Adult


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