Pathogenic variants (disease-causing) in the FH gene are associated with Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) syndrome. This condition predisposes individuals to cutaneous and uterine leiomyomas (fibroids) and an aggressive form of renal cell carcinoma, often papillary type II. Renal cancers in HLRCC tend to occur at younger ages and can be highly aggressive. Management of FH–related tumor risk includes regular surveillance tailored to guidelines to detect tumors early. FH variants are not known to be more common in the Ashkenazi Jewish population.
Pathogenic variants in FH exhibit autosomal dominant inheritance. This means there is a 50% chance the condition can be passed from generation-to-generation. First degree relatives (parents, siblings, children) have a 50% chance to have the same pathogenic variant whereas second degree relatives (grandparents, aunts/uncles, nieces/nephews, half-siblings) have a 25% chance. More distant relatives have lower chances of having the same pathogenic variant when one is identified in the family.
In addition, when an individual inherits pathogenic variants in both copies of the FH gene, it can cause a rare childhood-onset condition called fumarate deficiency, which presents in infancy or childhood. This condition may result in severe neurological symptoms and developmental delay. Fumarate deficiency exhibits autosomal recessive inheritance. This means that both parents must be have a single pathogenic variant in the FH gene to have a 25% chance to have a child with the condition.
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Written December 2025
