The typical features of hereditary leiomyomatosis and renal cell cancer (HLRCC) (MIM 605839) [http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?605839] are benign leiomyomas of the skin and the uterus (fibroids, myomas). The condition is also referred to as multiple cutaneous and uterine leiomyomatosis (MCUL) (MIM 150800). [http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?150800]
Predisposition to early-onset renal cell carcinoma and uterine leiomyosarcoma is present in a subset of families. Renal cancer is typically of papillary type 2 histology, although collecting duct carcinomas have also been detected.
The predisposing gene is FH (MIM 136850). [http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?136850] Germline mutations in FH have been found in 85% of the HLRCC families.
Homozygous or compound heterozygous mutations of FH cause a recessive disorder, FH deficiency (MIM 606812). [http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?606812] The syndrome is characterized by neurologic impairment, growth and developmental delay, fumaric aciduria, and absent or reduced enzyme activity in all tissues.
There seem not to be clear-cut genotype-phenotype correlations between the detected mutations and their clinical outcomes. Therefore, predisposition to malignancy may be due to currently unknown modifying factors, as some families appear to have high risk of cancer at early age, and others little or no risk.
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant tumor susceptibility syndrome caused by heterozygous germline mutations in the FH gene. It is characterized by predisposition to benign leiomyomas of the skin and the uterus (fibroids, myomas). Predisposition to papillary type 2 and collecting duct renal cell carcinoma and uterine leiomyosarcoma at a young age is present in a subset of families.
From 2001 to 2003, 105 families with clinical features of HLRCC have been identified (Table 41.2-1). In all, 89 families with leiomyomatosis have been found to harbour a germline FH mutation: 7 of 7 studied in Finland (Kiuru et al, 10; Launonen et al, 10) (unpublished data), 35 of 47 in the UK (Alam et al, 1; Alam et al, 2), 31 of 35 in North America (Toro et al, 17), and 16 of 16 from other countries including Tunisia, Ethiopia, Greece, Puerto Rico, Iran, and Australia (Chuang et al, 14; Martinez-Mir et al, 2). At present, there are no population-based prevalence estimates of the disease. Among 299 Finnish patients with tumors not associated with the HLRCC phenotype, no germline mutations were detected (Lehtonen et al, 13). By contrast, among selected patient material of 200 Finnish patients with a tumor associated with HLRCC phenotype, 2 patients with a germline mutation were identified (2 of 200; 1%) (Kiuru et al, 9).
Table 41.2-1Numbers of All Reported HLRCC Families and those with Renal Cell Carcinoma and Uterine Leiomyosarcoma |Favorite Table|Download (.pdf) Table 41.2-1 Numbers of All Reported HLRCC Families and those with Renal Cell Carcinoma and Uterine Leiomyosarcoma
| Reference || Country of Origin || Families || Mutation-Positive Families || Families with ...|