Multiple cutaneous and uterine leiomyomas is an autosomal dominant condition that results in benign smooth muscle tumours of the skin and, in females, uterine fibroids. This syndrome overlaps with hereditary leiomyomatosis and renal cell cancer syndrome in which affected individuals may develop the rare type II papillary renal cell cancer, in addition to skin leiomyomas. Recently, heterozygous mutations in the gene encoding fumarate hydratase have been found to underlie both conditions. Fumarate hydratase is an enzyme that catalyses the conversion of fumarate to malate in the Kreb's cycle and may also function as a tumour suppressor gene. We report a family with multiple leiomyomas, uterine fibroids and papillary renal cell cancer. The proband is a 77-year-old Polish woman who developed multiple cutaneous leiomyomas on her right upper arm in her thirties and subsequently underwent a hysterectomy for uterine fibroids in her forties. She has four offspring: her eldest daughter also has skin and uterine leiomyomas with a similar onset; her son has multiple skin leiomyomas and in addition was diagnosed with metastatic papillary renal cell cancer at the age of 50 years; the two youngest daughters are unaffected. DNA sequencing in all the affected individuals disclosed a heterozygous G-->C substitution at nucleotide 173 of the fumarate hydratase gene, that converts an arginine residue (CGA) to proline (CCA). This missense mutation has not been reported previously and is designated R58P. Interestingly, the clinically asymptomatic 20-year-old son of the individual with renal cancer was also found to be heterozygous for R58P. It is likely that he will develop skin leiomyomas in the future but the risk of renal cancer is difficult to predict. Nevertheless, detection of this mutation has important implications for screening and genetic counselling in this and other family members.
"An apparent mutational “hot spot” was observed at Arg190 (Arg190His, Arg190Leu, Arg190Cys) in 18 of 56 unrelated families in a North American cohort24,25 and in 14 of 45 families in a British cohort.39 Founder mutations have been reported among three Dutch HLRCC families,26 four families of Jewish Iranian origin,40 and a German and an English family.41,42 Reduced or loss of fumarate hydratase (FH) enzyme activity was detected in lymphoblastoid and fibroblast cells from HLRCC patients,20,25,35,43 and may serve as a useful diagnostic tool for identifying FH mutation carriers in cases where sequencing and multiplex ligation-dependent probe amplification have not identified any FH variant or gene deletion. "
[Show abstract][Hide abstract] ABSTRACT: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal-dominant hereditary syndrome, which is caused by germline mutations in the FH gene that encodes the tricarboxylic acid cycle enzyme fumarate hydratase (FH). HLRCC patients are predisposed to develop cutaneous leiomyomas, multiple, symptomatic uterine fibroids in young women resulting in early hysterectomies, and early onset renal tumors with a type 2 papillary morphology that can progress and metastasize, even when small. Since HLRCC-associated renal tumors can be more aggressive than renal tumors in other hereditary renal cancer syndromes, caution is warranted, and surgical intervention is recommended rather than active surveillance. At-risk members of an HLRCC family who test positive for the familial germline FH mutation should undergo surveillance by annual magnetic resonance imaging from the age of 8 years. Biochemical studies have shown that FH-deficient kidney cancer is characterized by a metabolic shift to aerobic glycolysis. It is hoped that through ongoing clinical trials evaluating targeted molecular therapies, an effective form of treatment for HLRCC-associated kidney cancer will be developed that will offer an improved prognosis for individuals affected with HLRCC-associated kidney cancer.
International Journal of Nephrology and Renovascular Disease 06/2014; 7:253-60. DOI:10.2147/IJNRD.S42097
"To date, more than 120 FH mutation-positive HLRCC families have been identified worldwide. Benign leiomyomas occur with high penetrance in these families, but malignant RCC tumors are found in about 20% of the families (Tomlinson et al., 2002; Alam et al., 2003, 2005; Toro et al., 2003; Chan et al., 2005; Badeloe et al., 2006; Chuang et al., 2006; Lehtonen et al., 2006, 2007; Wei et al., 2006; Refae et al., 2007). HLRCC renal carcinomas typically occur at young age and are solitary, unilateral, and associated with aggressive disease course (Launonen et al., 2001; Grubb et al., 2007). "
[Show abstract][Hide abstract] ABSTRACT: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumor predisposition syndrome with cutaneous and uterine leiomyomatosis as well as renal cell cancer (RCC) as its clinical manifestations. HLRCC is caused by heterozygous germline mutations in the fumarate hydratase (fumarase) gene. In this study, we used array comparative genomic hybridization to identify the specific copy number changes characterizing the HLRCC-associated RCCs. The study material comprised formalin-fixed paraffin-embedded renal tumors obtained from Finnish patients with HLRCC. All 11 investigated tumors displayed the papillary type 2 histopathology typical for HLRCC renal tumors. The most frequent copy number changes detected in at least 3/11 (27%) of the tumors were gains in chromosomes 2, 7, and 17, and losses in 13q12.3-q21.1, 14, 18, and X. These findings provide genetic evidence for a distinct copy number profile in HLRCC renal tumors compared with sporadic RCC tumors of the same histopathological subtype, and delineate chromosomal regions that associate with this very aggressive form of RCC.
Genes Chromosomes and Cancer 07/2009; 48(7):544-51. DOI:10.1002/gcc.20663 · 4.04 Impact Factor
"Elles surviennent précocement (médiane de 44 ans dans la série de Toro et al. ) et sont souvent découvertes à un stade évolué ou métastatique. De ce fait, une mortalité élevée est associée aux carcinomes rénaux au cours de HLRCC : neuf décès sur 13 patients dans la série de Toro et al., en rapport avec des métastases survenant dans les cinq ans  ; métastases d'emblée dans au moins sept cas sur neuf, pour des observations isolées, avec décès pour huit patients    . L'isoéchogénicité de ces tumeurs rend difficile une surveillance par simple échographie et leur dépistage doit reposer préférentiellement sur l'uro-TDM ou l'IRM. "
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.