Abstract
Simple SummaryHereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is a very rare hereditary disorder characterized by cutaneous leiomyomas (CLMs), uterine leiomyomas (ULMs), renal cysts (RCys) and renal cell cancer (RCC), with no data on its prevalence worldwide. No genotype-phenotype associations have been described. The aim of our study was to describe the genotypic and phenotypic features of the largest series of patients with HLRCC from Spain reported to date. Of 27 FH germline pathogenic variants, 12 were not previously reported in databases. Patients with missense pathogenic variants showed higher frequencies of CLMs, ULMs and RCys, than those with loss-of-function variants. The frequency of RCCs (10.9%) was lower than those reported in the previously published series.Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) is a very rare hereditary disorder characterized by cutaneous leiomyomas (CLMs), uterine leiomyomas (ULMs), renal cysts (RCys) and renal cell cancers (RCCs). We aimed to describe the genetics, clinical features and potential genotype-phenotype associations in the largest cohort of fumarate hydratase enzyme mutation carriers known from Spain using a multicentre, retrospective study of individuals with a genetic or clinical diagnosis of HLRCC. We collected clinical information from medical records, analysed genetic variants and looked for genotype-phenotype associations. Analyses were performed using R 3.6.0. software. We included 197 individuals: 74 index cases and 123 relatives. CLMs were diagnosed in 65% of patients, ULMs in 90% of women, RCys in 37% and RCC in 10.9%. Twenty-seven different pathogenic variants were detected, 12 (44%) of them not reported previously. Patients with missense pathogenic variants showed higher frequencies of CLMs, ULMs and RCys, than those with loss-of-function variants (p = 0.0380, p = 0.0015 and p = 0.024, respectively). This is the first report of patients with HLRCC from Spain. The frequency of RCCs was lower than those reported in the previously published series. Individuals with missense pathogenic variants had higher frequencies of CLMs, ULMs and RCys.
Highlights
More than 200 hereditary cancer susceptibility syndromes associated with specific gene mutations are known: some of these are very rare
We identified 197 heterozygous carriers of 27 germline variants in fumarate hydratase (FH): 74 index cases and 123 relatives belonging to 74 different families
Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) is a very rare form of genodermatosis characterized by the presence of cutaneous leiomyomas (CLMs), uterine leiomyomas (ULMs) and renal tumours
Summary
More than 200 hereditary cancer susceptibility syndromes associated with specific gene mutations are known: some of these are very rare. The study of hereditary tumours has improved understanding of the molecular basis of tumorigenesis and in developing therapeutic target agents, especially for renal cancers. 20-year-old patient with renal cell cancer (RCC). It was named multiple cutaneous and uterine leiomyomatosis or Reed syndrome. In 2001, Launonen et al [2] proposed the term hereditary leiomyomatosis and renal cell cancer (HLRCC; OMIM #150800). In 2002, Tomlinson et al [3] proved that germline heterozygous pathogenic variants in the gene encoding fumarate hydratase (FH) cause this syndrome, adding to the group of known hereditary renal cancer genes such as VHL, MET, TSC1, TSC2, FLCN and SDH
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