Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC): Clinical, molecular and surveillance features in a cohort of 185 affected individuals.

Claire Forde1, Derek Lim2, George Burghel1, Laura Butland3, Ruth Cleaver4, Abhijit Dixit3, D. Gareth Evans1,5, Helen Hanson6, Fiona Lalloo1, Pedro Oliveira7, Lindsey Vialard2, Yvonne Wallis2, Eamonn Maher8,9, Emma Woodward1,5

1Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom. 2West Midlands Regional Genetics Service, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, United Kingdom. 3Department of Clinical Genetics, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom. 4Peninsula Clinical Genetics, royal Devon and Exeter Hospital, Exeter, United Kingdom. 5Division of Evolution and Genomic Sciences, School of biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom. 6South West Thames Regional Gentics Serivce, St George’s NHS Foundation Trust, London, United Kingdom. 7Department of Histopathology, The Christie NHS Foundation Trust, Manchester, United Kingdom. 8Department of Clinical Genetics, Cambridge Univerity Hospitals NHS Foundation Trust, Cambridge, United Kingdom. 9Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom



To define the clinical findings, molecular genetics and prognosis in a large cohort of individuals with a FH pathogenic variant and/or clinical features of HLRCC.



Clinical and molecular findings were obtained for 185 individuals from 69 families from 4 UK regional genetics clinics. 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.



A germline FH variant (19 novel and 21 known, >50% missense variants) was identified in 68/68 probands and 90 relatives. Cutaneous leiomyomata occurred in 90/185 (48.6%) individuals (mean age 45.9 years) and uterine leiomyomata in 33/107 (30.8%) females (mean age 35.0 years). 23/185 (12.4%) individuals had a confirmed renal tumour and histopathology where known (n=17) was variable: seven clear cell RCCs, nine papillary RCCs (six type 2), and one tumour with oncocytic cystic morphology. Mean age at symptomatic RCC diagnosis was 44.0 years and median survival 21.0 months. 78 individuals underwent 180 renal imaging surveillance scans, three stage one 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).



The 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 surveillance can prevent RCC-related mortality.