Mutations in fumarate hydratase cause hereditary leiomyomatosis and renal cell carcinoma in families in North America1

Hereditary leiomyomatosis and renal cell cancer (HLRCC) (OMIM 605839) is an autosomal dominant disorder characterized by smooth muscle tumors of the skin and uterus and/or renal cancer. Although the identification of germline mutations in fumarate hydratase (FH) in European families supports FH as the susceptibility gene for HLRCC, its role in North American families has not been studied. We screened for germline mutations in FH in 35 North American families with cutaneous leiomyomas. Sequence analysis revealed mutations in FH in 31 families (88%). Twenty different mutations in FH gene were identidied, of which 18 were novel. Of these 20 mutations, 2 were insertions and 5 were deletions that caused frameshifts leading to premature truncation of the protein, and 13 were missense mutations. Eleven unrelated families shared a common mutation: R190H. Eighty-one individuals (47 women and 34 men) had cutaneous leiomyomas. Ninety-eight percent (46/47) of women with cutaneous leiomyomas also had uterine fibroids. Eighty-nine percent (41/46) of women with leiomyomas and uterine fibroids had a total hysterectomy, 44% by the age of 30 years. We identified 13 individuals in 5 families with unilateral and solitary renal tumors. Six individuals from 4 families had papillary type II renal cell carcinoma and one individual from one family had collecting duct renal cell carcinoma. Our study shows that mutations in FH are associated with HLRCC in North American families. HLRCC is associated with clinically significant uterine fibroids and aggressive renal tumors. Our study expands the histologic spectrum of renal tumors and mutations in FH associated with HLRCC.