FH – Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC)

Hereditary leiomyomatosis and renal cell cancer (HLRCC; MONDO:0007888) is an autosomal dominant cancer predisposition syndrome caused by germline mutations in the fumarate hydratase gene (FH) that encodes a key Krebs cycle enzyme. Affected individuals develop multiple cutaneous piloleiomyomas (HP:0007620), early-onset uterine leiomyomas (HP:0000131), and aggressive papillary type II renal cell carcinoma (HP:0005584). Early recognition enables targeted genetic counseling and surveillance.

Initial genetic studies in 35 North American families identified FH mutations in 31 families (89%), including 20 novel alleles spanning missense, small deletions, insertions, and splice-site changes (PMID:12772087) with a recurrent R190H founder variant in 11 unrelated kindreds. Subsequent screening of 89 probands with cutaneous leiomyomas detected FH mutations in 76% of cases, confirming autosomal dominant inheritance with high penetrance of cutaneous and uterine manifestations (PMID:16029320).

Segregation analysis across diverse cohorts demonstrated variant co-segregation in 46 probands and 62 affected relatives, supporting pathogenicity for heterozygous FH loss-of-function alleles (PMID:15724016). The variant spectrum includes 58% missense, 27% frameshift, 9% nonsense, and 7% whole-gene deletions, with several hypomorphic and deep-intronic alleles reported. Founder effects have been documented for R58P and Asn373Ser in European and Spanish populations, respectively.

Functional studies of missense and truncating FH variants uniformly show reduced enzyme activity, impaired tetramer assembly, and fumarate accumulation with oncometabolite-driven HIF stabilization (PMID:12761039). Structural analyses of C-terminal domains (SCR19-20) pinpoint disrupted C3b/C3d and glycosaminoglycan binding sites underlying tumor suppressor loss. Chemical chaperones partially rescue secretion of R127H-mutant FH in patient fibroblasts, highlighting potential therapeutic avenues (PMID:22904312).

FH mutation carriers exhibit early RCC onset (median age ~40 years), often with metastatic disease at presentation; renal imaging surveillance beginning in adolescence is justified given documented cases of pediatric RCC at age 7 (PMID:19967458). Male infertility and leiomyoma-only phenotypes further expand the clinical spectrum, informing tailored counseling and reproductive planning.

No credible studies have refuted FH’s role in HLRCC. Disputed alleles are rare and often correlate with somatic mosaicism or incomplete penetrance. Knockout murine models recapitulate metabolic and tumorigenic features, reinforcing causal inference.

Key Take-home: FH germline mutations are definitively associated with HLRCC, warranting early molecular testing in patients with multiple leiomyomas or familial RCC to guide surveillance and prevent advanced renal cancer.

References

• American Journal of Human Genetics • 2003 • Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. PMID:12772087
• Archives of Dermatology • 2005 • Clinical features of multiple cutaneous and uterine leiomyomatosis: an underdiagnosed tumor syndrome. PMID:15724016
• Human molecular genetics • 2003 • Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. PMID:12761039
• Human molecular genetics • 2014 • Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. PMID:24334767

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