FH tumour predisposition syndrome / hereditary leiomyomatosis and renal cell cancer (HLRCC)

FH tumour predisposition syndrome is a multisystem condition involving the skin, the uterus, and the kidney, with a smaller subset of families showing pheochromocytoma or paraganglioma associated with specific FH germline pathogenic variants. Cutaneous leiomyomas typically arise in the second to fourth decades, while uterine leiomyomata (fibroids) are identified at a mean age of around 30 years and frequently lead to early gynaecological intervention. Renal cell carcinoma occurs in a minority of affected individuals but is typically solitary, highly aggressive, and prone to early metastasis; paediatric cases are also described. Clinical expression is highly variable within and between families.

The estimated prevalence is 1/901 to 1/1,252, reflecting the carrier frequency of FH pathogenic variants in the general population.

FH tumour predisposition syndrome is caused by germline heterozygous pathogenic variants in FH (1q43), which encodes fumarate hydratase, the enzyme catalysing the conversion of fumarate to L-malate within the tricarboxylic acid (Krebs) cycle. Tumourigenesis follows a two-hit mechanism, with loss of the wild-type allele in tumour tissue producing fumarate accumulation, pseudohypoxic stabilisation of HIF-1α, a Warburg-like metabolic shift, and impaired homologous-recombination repair of DNA double-strand breaks. Biallelic germline loss-of-function variants in FH cause the distinct, recessively inherited fumarate hydratase deficiency, a severe neurometabolic disorder.

FH tumour predisposition syndrome is inherited in an autosomal dominant manner. Each first-degree relative of an affected individual has a 50% a priori risk of having inherited the familial pathogenic variant.

A clinical diagnosis of FH tumour predisposition syndrome is suggested by the combination of cutaneous leiomyomas, early-onset multiple uterine leiomyomata, and/or characteristic renal tumours. No internationally established consensus criteria currently define the syndrome, and there is no specific biochemical or imaging marker. The diagnosis is established primarily by identification of a germline heterozygous pathogenic variant in FH on molecular genetic testing.

• : renal tumours (hybrid oncocytoma/chromophobe tumour, clear cell carcinoma, oncocytoma) with characteristic cutaneous fibrofolliculomas/trichodiscomas, pulmonary cysts, and spontaneous pneumothorax rather than cutaneous and uterine leiomyomata; FLCN
• : clear cell renal cell carcinoma with BAP1-inactivated melanocytic tumours, cutaneous melanoma, basal cell carcinoma, uveal melanoma, and malignant mesothelioma rather than HLRCC-spectrum papillary RCC and smooth-muscle tumours; BAP1
• : multiple bilateral type 1 papillary renal cell carcinoma without cutaneous, uterine, or paraganglioma manifestations, in contrast to the type 2 / unclassified / collecting-duct spectrum of FH-related RCC; MET

• Establishing the molecular genetic diagnosis confirms the clinical suspicion and provides the basis for individualised medical care.
• Identification of the underlying pathogenic variant enables specific, individualised surveillance—in this condition with a particular emphasis on early detection of renal cell carcinoma—and is a prerequisite for targeted medical care directed by the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variant has been identified, predictive testing of at-risk relatives becomes possible, clarifying their individual risk and guiding clinical follow-up.

• Kamihara J, Schultz KA, Rana HQ. FH tumor predisposition syndrome. 2006 Jul 31 [updated 2025 May 8]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: PMID:20301430.
• Forde C, Lim DHK, Alwan Y, Burghel G, Butland L, Cleaver R, et al. Hereditary leiomyomatosis and renal cell cancer: clinical, molecular, and screening features in a cohort of 185 affected individuals. Eur Urol Oncol. 2020;3(6):764-72. doi:10.1016/j.euo.2019.11.002. PMID:.
• Shuch B, Li S, Risch H, Bindra RS, McGillivray PD, Gerstein M. Estimation of the carrier frequency of fumarate hydratase alterations and implications for kidney cancer risk in hereditary leiomyomatosis and renal cancer. Cancer. 2020;126(16):3657-66. doi:10.1002/cncr.32914. PMID:; PMCID: PMC10316675.
• Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 2002;30(4):406-10. doi:10.1038/ng849. PMID:.