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Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC)
FH (fumarate hydratase; fumarase)
This rare cancer predisposition syndrome is characterized by susceptibility to three distinct tumor types: cutaneous leiomyomas (smooth muscle tumors of the skin), uterine leiomyomas (smooth muscle tumors of the uterus or "uterine fibroids"), and renal cell cancer. The differential diagnosis for HLRCC includes Von Hippel-Lindau syndrome (VHL) and Birt-Hogg-Dubé syndrome (BHD), as these disorders all share renal involvement, and HLRCC and BHD have similar skin features. Genetic testing for all three syndromes is available at GeneDx.
HLRCC is an autosomal dominant disorder with incomplete penetrance caused by heterozygous mutations in the FH gene. In HLRCC, FH most likely acts as a tumor suppressor. In the homozygous or compound heterozygous form (in which two mutations are present, one on each FH allele), germline mutations in the FH (fumarate hydratase) gene are associated with autosomal recessive fumarate hydratase deficiency (FHD). Parents (heterozygous carriers) of children with FHD have been reported to develop cutaneous leiomyomas (similar to individuals affected with HLRCC).
FH mutations have been identified in 76%-100% of clinically diagnosed individuals, the majority being missense and frameshift mutations. Although mutations are distributed throughout the gene, emerging hotspot mutations include R58X in exon 2 and R190H in exon 4. Two large deletions of 2.5 Mb and 1.9 Mb in size have been described, which both encompass the entire FH gene and several flanking genes in chromosomal region 1q43.
Using genomic DNA obtained from buccal (cheek) swabs or blood (1-5 mL in EDTA), bi-directional sequence analysis of the FH gene is offered in two tiers. Tier 1 includes analysis of exon 4 only, as >34% of patients with identifiable FH mutations have their mutation in exon 4. Tier 2 analysis includes sequencing of the remaining exons of the FH gene (exons 1-3 and 5-10). This approach is expected to identify >99% of existing small, intrageneic mutations. In rare cases when sequencing results cannot excluded a partial or whole gene deletion, CopyDxTM quantitative PCR analysis is available for detecting an abnormal gene copy number. Mutation-specific testing in family members and prenatal diagnosis in at-risk pregnancies is available once a mutation in an affected person has been defined.
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Hereditary Leiomyomatosis Renal Cell Cancer; HLRCC; cancer; predisposition syndrome; tumor; leiomyomas; cutaneous; smooth muscle; skin; uterus; uterine; fibroids; renal cell; Von Hippel-Lindau; VHL; Birt-Hogg-Dubé; BHD; autosomal dominant; incomplete penetrance; FH gene; fumarate hydratase
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