DiagnosisClinical DiagnosisThe major features of hereditary leiomyomatosis and renal cell cancer (HLRCC) are:Cutaneous leiomyomata. The majority (76%) of individuals with HLRCC present with a single or multiple cutaneous leiomyoma.
Clinically, cutaneous leiomyomas appear as skin-colored to light brown papules or nodules distributed over the trunk and extremities, and occasionally on the face. The different presentations include: single, grouped/clustered, segmental, and disseminated. Forty percent of individuals with HLRCC have mild cutaneous manifestations with five or fewer lesions [Wei et al 2006].
Histologically, proliferation of interlacing bundles of smooth muscle fibers with centrally located, long blunt-edged nuclei is observed.Uterine leiomyomata (uterine fibroids). Uterine leiomyomas are present in almost all females with HLRCC [Toro et al 2003, Alam et al 2005, Wei et al 2006]. Fibroids tend to be numerous and large. In females the presence of cutaneous leiomyomata correlates with the presence of uterine fibroids [Toro et al 2003, Alam et al 2005, Wei et al 2006].Renal tumors. Ten percent to 16% of individuals with HLRCC have renal tumors [Toro et al 2003, Alam et al 2005]. Most tumors are classified as 'type 2' papillary renal cancer, which display distinct papillary architecture and characteristic histopathology [Launonen et al 2001, Toro et al 2003]. Other types of renal tumors reported include a spectrum of tumors from tubulo-papillary renal cell carcinomas to collecting-duct renal cell carcinomas [Toro et al 2003, Wei et al 2006].Diagnostic criteria. No consensus diagnostic criteria exist for HLRCC.The clinical dermatologic diagnosis of HLRCC requires one of the following: Multiple cutaneous leiomyomas with at least one histologically confirmed leiomyomaA single leiomyoma in the presence of a positive family history of HLRCCHeterozygosity for a mutation in FH, the gene encoding fumarate hydratase, and either a histologically confirmed HLRCC type of renal cell carcinoma or cutaneous leiomyoma are considered diagnostic.Note: Because the prevalence of uterine leiomyomas in the general population is high, a solitary uterine leiomyoma even in the presence of a heterozygous FH mutation is not sufficient for the diagnosis of HLRCC.TestingFumarate hydratase (fumarase) enzyme activity. Activity of fumarate hydratase enzyme can be measured in cultured skin fibroblasts or lymphoblastoid cells to confirm the diagnosis [Alam et al 2003, Pithukpakorn et al 2006]. Reduced activity (≤60%) of fumarate hydratase enzyme was found in all affected individuals with the diagnosis of HLRCC.Molecular Genetic TestingGene. FH is the only gene known to be associated with hereditary leiomyomatosis and renal cell cancer (HLRCC).Clinical testingSequence analysis. Between 80% and 100% [Toro et al 2003, Alam et al 2005, Wei et al 2006] of individuals with HLRCC have identifiable sequence variants in FH.Deletion/duplication analysis. Multiplex ligation-dependent probe amplification (MLPA) identified a whole-gene deletion in one of 20 index cases from families in which no mutation had been identified on sequence analysis [Smit et al 2011].
Using MLPA, a Finnish study of seven individuals with HLRCC detected in one patient a deletion of FH exon 1, encoding the mitochondrial signal peptide; the patient had numerous painful cutaneous leiomyomas and papillary type renal cell cancer [Ahvenainen et al 2008]. This finding, together with the three patients previously identified with a whole-gene FH deletion, suggests that exonic or whole-gene FH deletions are not a frequent cause of HLRCC syndrome [Tomlinson et al 2002, Smit et al 2011].Table 1. Summary of Molecular Genetic Testing Used in HLRCCView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityFHSequence analysis / mutation scanning 2Sequence variants 3~80%-100% 4ClinicalDeletion / duplication analysis 5Partial- and whole-gene deletions1/20 6-1/7 71. The ability of the test method used to detect a mutation that is present in the indicated gene2. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably between laboratories depending on the specific protocol used.3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. 4. Toro et al [2003], Alam et al [2005], Wei et al [2006]5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.6. Smit et al [2011]7. Ahvenainen et al [2008]Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a probandMolecular genetic testing for a germline FH mutation is indicated in all individuals known to have or suspected of having HLRCC, including individuals with the following:Multiple cutaneous leiomyomas (with at least one histologically confirmed leiomyoma) without a family history of HLRCCA single cutaneous leiomyoma with family history of HLRCCOne or more tubulo-papillary, collecting-duct, or papillary type 2 renal tumors with or without a family history of HLRCCMeasurement of fumarate hydratase enzyme activity can be useful in the diagnosis of HLRCC in cases with atypical presentation and undetectable FH mutations [Alam et al 2003, Pithukpakorn et al 2006].Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersFumarase deficiency (fumaric aciduria). Fumarase deficiency, resulting from inherited biallelic mutations in FH, is an inborn error of metabolism characterized by rapidly progressive neurologic impairment including hypotonia, seizures, and cerebral atrophy. Homozygous or compound heterozygous germline FH mutations are causative [Coughlin et al 1998]. Leiomyomas and renal cancer have not been reported in fumaric aciduria. However, most individuals with fumaric aciduria survive only a few months; a very few survive to early adulthood. A parent (heterozygous carrier) of an individual with fumarase deficiency developed cutaneous leiomyomas similar to those observed in HLRCC [Tomlinson et al 2002]. The death from renal cancer of the mother of a child with fumaric aciduria supports the increased risk for HLRCC in the heterozygous relatives of children with fumaric aciduria [Shih, unpublished]. Inheritance is autosomal recessive.Somatic mutation. Loss of heterozygosity around the FH locus has been identified in two early-onset sporadic uterine leiomyomas and a soft tissue sarcoma of the lower limb without other associated tumors characteristic of the heritable disease [Kiuru et al 2002, Lehtonen et al 2004]. All three tumors displayed biallelic inactivation of FH.}

Natural HistoryThe clinical characteristics of hereditary leiomyomatosis and renal cell cancer (HLRCC) include cutaneous leiomyomas, uterine leiomyomata (fibroids), and/or renal tumors. Affected individuals may have multiple cutaneous leiomyomas, a single skin leiomyoma, or no cutaneous lesion; a single renal tumor or no renal tumors; and/or uterine fibroids. Disease severity shows significant intra- and interfamilial variation [Wei et al 2006].Cutaneous leiomyomas. Clinically, cutaneous leiomyomas present as firm skin-colored to light brown-colored papules and nodules. These cutaneous lesions occur at a mean age of 25 years (range: age 10-47 years) and tend to increase in size and number with age. Affected individuals note that the skin lesions are sensitive to light touch and/or cold temperature and, less commonly, are painful.Uterine fibroids. Women with HLRCC have more uterine fibroids and onset at a younger age than women in the general population. The age at diagnosis ranges from 18 to 52 years (mean: age 30 years). Uterine leiomyomas are usually large and numerous. Most women experience irregular or heavy menstruation and pelvic pain. Women with HLRCC and uterine fibroids undergo hysterectomy or myomectomy for symptomatic uterine fibroids at a younger age (<30 years) than the general population (45 years) [Farquhar & Steiner 2002, Toro et al 2003, Alam et al 2005].Renal cancer. The symptoms of renal cancer may include hematuria, lower back pain, and a palpable mass. However, a large number of individuals with renal cancer are asymptomatic. Furthermore, not all individuals with HLRCC present with or develop renal cancer.Most renal tumors are unilateral and solitary; in a few individuals, they are multifocal. Approximately 10%-16% of individuals with HLRCC who present with multiple cutaneous leiomyomas had renal tumors at the time that renal imaging was performed [Toro et al 2003, Alam et al 2005]. The median age at detection of renal tumors is 44 years. In contrast to other hereditary renal cancer syndromes, renal cancers associated with HLRCC are aggressive, with nine of 13 individuals dying from metastatic disease within five years of diagnosis [Toro et al 2003].The renal tumors associated with HLRCC have unique histologic features, including the presence of cells with abundant amphophilic cytoplasm and large nuclei with large inclusion-like eosinophilic nucleoli. These cytologic features were attributed to type 2 papillary tumors in the original description. However, recent studies have shown that HLRCC is associated with a spectrum of renal tumors ranging from type 2 papillary to tubulo-papillary to collecting-duct carcinoma [Wei et al 2006]. Renal tumors associated with HLRCC may, in the future, constitute a new renal pathologic entity.Uterine leiomyosarcoma. Whether all women with HLRCC have a higher risk of developing uterine leiomyosarcomas is unclear. In the original description of HLRCC, it was reported that two of 11 women with uterine leiomyomas also had uterine leiomyosarcoma, a cancer that may be aggressive if not detected and treated at an early stage [Launonen et al 2001]. To date, six women with a germline mutation in FH have been reported with uterine leiomyosarcoma [Lehtonen et al 2006, Ylisaukko-oja et al 2006]. It seems that individuals/families with a germline FH mutation are, in general, not highly predisposed to uterine cancer; but a few individuals and families seem to be at high risk. In North America, no individuals or families with HLRCC and uterine leiomyosarcomas have been reported to date. Therefore, the risk of uterine leiomyosarcoma in women with HLRCC in general is unknown.Other. Four individuals with breast cancer as well as individuals with bladder cancer, bilateral macronodular adrenocortical disease and atypical Cushing syndrome, adrenal incidentaloma, Leydig-cell tumors of the testis and ovarian cystadenomas, and gastrointestinal stromal tumors (GISTs) have been reported; however, it remains to be determined whether these manifestations are truly associated with HLRCC [Alam et al 2005, Lamba et al 2005, Matyakhina et al 2005, Carvajal-Carmona et al 2006, Lehtonen et al 2006, Smit et al 2011].

Genotype-Phenotype CorrelationsNo genotype-phenotype correlations have been described.No correlation is observed between FH mutations and the occurrence of cutaneous lesions, uterine fibroids, or renal cancer of HLRCC [Wei et al 2006].FH mutations associated with HLRCC are distributed throughout the gene rather than clustering at the amino terminal of FH. The predisposition to HLRCC versus fumarase deficiency likely results from a difference in gene dosage rather than the location of the FH mutation as originally suggested [Tomlinson et al 2002].

Differential DiagnosisCutaneous lesions. Cutaneous leiomyomas are rare and particular to hereditary leiomyomatosis and renal cell cancer (HLRCC). Because leiomyomas are clinically similar to various cutaneous lesions, histologic diagnosis is required.Uterine fibroids. Uterine leiomyoma is the most common benign pelvic tumor in women in the general population. The majority of uterine fibroids are sporadic and nonsyndromic.Renal tumor. Familial renal cancer syndromes are associated with rather specific renal pathology. Familial renal cancer syndromes and their specific renal pathology include:Von Hippel-Lindau (VHL) syndrome. Clear cell renal cell carcinoma. Individuals with VHL syndrome are also at risk for CNS hemangioblastoma, retinal angioma, pheochromocytoma, and endolymphatic sac tumors. Inheritance is autosomal dominant.Hereditary papillary renal cancer (HPRC). Predisposition to type 1 papillary renal cancer. Inheritance is autosomal dominant.Birt-Hogg-Dubé syndrome (BHDS). A spectrum of renal tumors including renal oncocytoma (benign), chromophobe renal cell carcinoma (malignant), and a combination of both cell types, so-called oncocytic hybrid tumor. Individuals with BHDS can present with cutaneous fibrofolliculomas and/or with multiple lung cysts and spontaneous pneumothorax. Inheritance is autosomal dominant.

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with hereditary leiomyomatosis and renal cell cancer (HLRCC), the following evaluations are recommended:Detailed dermatologic examination for evaluation of extent of disease and lesions suspicious for cutaneous leiomyosarcomaBaseline pelvic bimanual examination, pelvic MRI, and/or transvaginal pelvic ultrasound examination to screen for uterine fibroidsBaseline renal ultrasound examination and abdominal CT scan with contrast or MRI to screen for renal tumorsTreatment of ManifestationsCutaneous lesions. Cutaneous leiomyomas should be examined by a dermatologist. Treatment of cutaneous leiomyomas is difficult:Surgical excision may be performed for a solitary painful lesion.Lesions can be treated by cryoablation and/or lasers.Several medications, including calcium channel blockers, alpha blockers, nitroglycerin, antidepressants, and antiepileptic drugs (AEDs), have been reported to reduce pain [Ritzmann et al 2006].Uterine fibroids. Uterine fibroids should be evaluated by a gynecologist. The uterine fibroids of HLRCC are treated in the same manner as sporadic fibroids. However, most women with HLRCC may require medical and/or surgical intervention earlier than the general population. Medical therapy (currently including gonadotropin-releasing hormone agonists (GnRHa), antihormonal medications, and pain relievers) may be used to treat initially for uterine fibroids, to decrease the size of fibroids in preparation for surgical removal, and/or to provide temporary relief from the symptoms of fibroids. When possible, myomectomy to remove fibroids while preserving the uterus is the treatment of choice. Hysterectomy should be performed only when necessary.Renal tumors. Early detection of kidney tumor in HLRCC is important. Surgical excision of these malignancies appears to require earlier and more extensive surgery than other hereditary kidney cancers. Further studies may demonstrate that even small tumors have a high grade of malignancy upon pathologic review. Kidney tumors associated with HLRCC have an aggressive disease course. Therefore, these tumors must be managed with caution until more is known about the natural history. Because of the aggressive nature of renal cancers associated with HLRCC, total nephrectomy should be strongly considered in individuals with a detectable renal mass.SurveillanceThere is no consensus on clinical surveillance; the following recommendations are provisional until a consensus conference is conducted. Individuals with the clinical diagnosis of HLRCC, individuals with heterozygous mutations in FH without clinical manifestations, and at-risk family members who have not undergone molecular genetic testing should have the following regular surveillance by physicians familiar with the clinical manifestations of HLRCC.Skin. Full skin examination is recommended annually to every two years to assess the extent of disease and to evaluate for changes suggestive of leiomyosarcoma.Uterus. Annual gynecologic consultation is recommended to assess severity of uterine fibroids and to evaluate for changes suggestive of leiomyosarcoma.RenalYearly examination with abdominal MRI or CT with and without contrast are recommended for individuals with normal initial baseline or follow-up abdominal MRI or CT. MRI may be preferred because of the potential added radiation exposure associated with CT over lifetime.Any suspicious renal lesion (indeterminate lesion, questionable or complex cysts) at a previous examination should be followed with a CT scan with and without contrast. The use of renal ultrasound examination is helpful in the characterization of cystic lesions. PET-CT may be added to identify metabolically active lesions suggesting possible malignant growth. Caution: Ultrasound examination alone is never sufficient.Renal tumors should be evaluated by a urologic oncology surgeon familiar with the renal cancer of HLRCC.Evaluation of Relatives at RiskWhen the disease-causing mutation in the family is known, molecular genetic testing of asymptomatic at-risk relatives improves diagnostic certainty and allows early surveillance and treatment in those with the family-specific mutation and reduces costly screening procedures in those who have not inherited the disease-causing mutation.Early recognition of clinical manifestations may allow timely intervention and improve outcome. Therefore, clinical surveillance of asymptomatic at-risk relatives for early detection is appropriate.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposesTherapies Under InvestigationRecent studies suggest that hypoxia-inducible factor (HIF) overexpression is involved in HLRCC tumorigenesis [Isaacs et al 2005, Pollard et al 2005]. Therefore, future target therapies for HLRCC-associated tumors may include, for example, anti-HIF therapies such as R59949 that regulate prolyl hydroxylase activity, thus preventing hypoxia-inducible factor accumulation. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Hereditary Leiomyomatosis and Renal Cell Cancer: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDFH1q43Fumarate hydratase, mitochondrialTCA Cycle Gene Mutation Database (FH)FHData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Hereditary Leiomyomatosis and Renal Cell Cancer (View All in OMIM) View in own window 136850FUMARATE HYDRATASE; FH 150800HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER; HLRCCMolecular Genetic PathogenesisGermline mutations in FH, plus somatic mutations and loss of heterozygosity in tumor tissue, suggest that loss of function of the fumarate hydratase protein is the basis of tumor formation in HLRCC [Tomlinson et al 2002]. Intracellular fumarate accumulation as a result of FH inactivation causes decreased hypoxia-inducible factor (HIF) degradation and overexpression of genes further downstream in the HIF pathway [Isaacs et al 2005]. FH-associated neoplasia is characterized by defective mitochondrial function and by upregulation of transcriptional pathways mediated by HIF, although it has been disputed whether and by what means these processes are linked. Upregulation of HIF-1α occurs as a direct consequence of FH inactivation. The upregulation of HIF-1α arises from competitive inhibition of the 2-OG-dependent HIF hydroxylases by fumarate and not from disruption of mitochondrial energy metabolism [O'Flaherty et al 2010].Normal allelic variants. FH consists of ten exons encompassing 22.15 kb of DNA. The gene is highly conserved across species.Pathologic allelic variants. Various FH mutations have been identified in families with HLRCC. Most mutations are missense mutations. Other mutations include nonsense, frameshift, and splice-site mutations [Tomlinson et al 2002, Toro et al 2003, Wei et al 2006]. Evidence for a founder effect has been observed for the 905-1G>A mutation in four families of Jewish Iranian origin, the c.173G>C mutation in a German and English family, and the p.Glu404X mutation in three families in the same province in the Netherlands [Chan et al 2005, Chuang et al 2005, Heinritz et al 2008, Smit et al 2011].Four whole-gene deletions have been identified [Ahvenainen et al 2008, Smit et al 2011]. (For more information, see Table A, locus-specific databases.)Normal gene product. FH encodes the enzyme fumarase (fumarate hydratase) (EC 4.2.1.2.). The active form of the enzyme is a homotetramer. It catalyzes the conversion of fumarate to L-malate in the tricarboxylic acid (Krebs) cycle. The identity between the rat and human amino acid sequences is 96%. In mammals, there are two fumarase isoforms (mitochondrial and cytosolic) that are synthesized from the same mRNA. After initial synthesis, the FH proteins are partially imported and processed at the mitochondrial outer membrane. In yeast, approximately 70%-80% of FH proteins are then released back into the cytosol, while the remaining portion is fully imported into mitochondrial matrix [Knox et al 1998].Abnormal gene product. Reduced activity of the fumarate hydratase enzyme in cutaneous leiomyomas from individuals with HLRCC supports its role in tumor suppression [Tomlinson et al 2002].