Hereditary Leiomyomatosis and Renal Cell Cancer or Fumarase Deficiency via the FH Gene

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is characterized by cutaneous leiomyomata, which is a benign tumor of smooth muscle origin, uterine leiomyomata (fibroids), and/or renal tumors (Badeloe et al. Eur J Dermatol 19(6): 545-551, 2009). The cutaneous leiomyomata occur in the majority of individuals and are located on the trunk, extremities, and sometimes on the face. These skin colored/brown nodules or papules appear at an average age of 25 years and increase in size and number with age. Females are affected with uterine leiomyomata and tend to have irregular or heavy menstruation and pelvic pain. A single aggressive kidney tumor occurs in up to one-third of families, at a median age of 44 years, and can cause hematuria and lower back pain (Pithukpakorn and Toro. GeneReviews. 2010; Sudarshan et al. Nat Clin Pract Urol 4(2):104-110, 2007). Approximately 50% of these renal tumors result in metastasis. Most renal tumors are papillary, but other kidney tumor types include tubulo-papillary renal cell carcinomas to collecting-duct renal cell carcinomas (Badeloe et al., 2009).

Fumurase Hydratase Deficiency, also known as fumaric aciduria and fumarase deficiency, is an inborn error of metabolism that causes rapid progressive neurologic impairment including hypotonia, seizures, and cerebral atrophy (Deschauer et al. Mol Genet Metab. 88(2): 146–152, 2006). The disease is heterogeneous as patients can show different clinical and biochemical features (Ottolenghi et al. Hum Mutat 32(9): 1046–1052, 2011). Most individuals survive only a few months and during this time no leiomyomata or renal tumors have been observed. A parent who is a carrier of a FH mutation for fumurase hydratase deficiency is at an increased risk of HLRCC (Pithukpakorn and Toro., 2010).

HLRCC is inherited in an autosomal dominant manner with high penetrance and is caused by mutations in the FH gene. The FH gene is thought to be a tumor suppressor encoding fumurate hydratase, which is involved in the conversion of fumurate to L-malate in the tricarboxylic acid (Krebs) cycle (Maher. Nephron Exp Nephrol 118(1):e21–e26, 2011; Sudarshan et al. (2007)). It is thought that mutations result in a loss of function leading to increases in cellular fumurate. This increase causes decreased hypoxia-inducible factor (HIF) degradation and overexpression of genes further downstream in the HIF pathway leading to tumor formation (Pithukpakorn and Toro., 2010; Badeloe et al., 2009). No clear genotype-phenotype observations have been observed and HLRCC can occur sporadically or can be inherited. Mutations are located throughout the FH gene with the majority represented by missense, nonsense and small deletions, however small insertions, splicing mutations, and large deletions and insertions have also been reported (Human Gene Mutation Database; Bayley et al. BMC Medical Genetics 9:20, 2008). The second hit within the tumor is thought to occur through loss of the wild-type allele through a mechanism of loss of heterozygosity. There is no strong evidence that somatic mutations of FH have a significant role in sporadic kidney cancer (Sudarshan et al., 2007).

Fumurase Hydratase Deficiency is inherited in an autosomal recessive manner and is caused by a homozygous FH mutation or compound heterozygous mutations in the FH gene. HLRCC vs. fumurase deficiency are likely distinguished as the result of FH gene dosage (Pithukpakorn and Toro., 2010). Mutations are located throughout the FH gene with the majority represented by missense mutations, however nonsense, small deletions and insertions, splicing mutations, and large deletions have also been reported (Human Gene Mutation Database; Bayley et al., 2008).

Pathogenic variants in the FH gene will be detected by sequencing in 80-100% of individuals suspected of having hereditary leiomyomatosis and renal cell cancer or fumarase deficiency (Pithukpakorn and Toro. GeneReviews, 2010; Ewbank et al. GeneReviews, 2013).

Gross deletions and duplications will be detected in up to 14% of individuals affected with HLRCC (Pithukpakorn and Toro. GeneReviews, 2010; Campione et al. J Invest Dermatol 127(9): 2271-2273, 2007). A gross deletion has been reported for fumarase deficiency (Mroch et al. Am J Med Genet A 158A(1): 155-158, 2011).

This test provides full coverage of all coding exons of the FH gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.