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Hereditary Leiomyomatosis and Renal Cell Cancer

Synonym: HLRCC

, MD and , MD.

Author Information
, MD
Department of Medicine
Faculty of Medicine
Siriraj Hospital
Mahidol University
Bangkok, Thailand
, MD
Genetic Epidemiology Branch
Division of Cancer Epidemiology and Genetics
National Cancer Institute
National Institutes of Health
Dermatology Section
DCVA Medical Center
Washington, DC

Initial Posting: ; Last Update: November 2, 2010.

Summary

Disease characteristics. Hereditary leiomyomatosis and renal cell cancer (HLRCC) is characterized by cutaneous leiomyomata (multiple or single in 76% of affected individuals), uterine leiomyomata (fibroids), and/or a single renal tumor. Cutaneous leiomyomata appear as skin-colored to light brown papules or nodules distributed over the trunk and extremities, and occasionally on the face, and appear at a mean age of 25 years, increasing in size and number with age. Uterine leiomyomata are present in almost all females with HLRCC and tend to be numerous and large; age at diagnosis ranges from 18 to 52 years, with most women experiencing irregular or heavy menstruation and pelvic pain. Renal tumors causing hematuria, lower back pain, and a palpable mass are usually unilateral, solitary, and aggressive and range from type 2 papillary to tubulo-papillary to collecting-duct carcinomas. They occur in about 10%-16% of individuals with HLRCC; the median age of detection is 44 years.

Diagnosis/testing. HLRCC is diagnosed by the presence of multiple cutaneous leiomyomas, with at least one histologically confirmed leiomyoma, or by a single leiomyoma in the presence of a positive family history of HLRCC. Diagnosis is confirmed by testing of fumarate hydratase enzyme activity in cultured skin fibroblasts or lymphoblastoid cells showing reduced activity (≤60%) or by molecular genetic testing. FH is the only gene known to be associated with HLRCC.

Management. Treatment of manifestations: Surgical excision, cryoablation, and/or laser excision to remove painful cutaneous leiomyomas; pain medication includes calcium channel blockers, alpha blockers, nitroglycerin, antidepressants, or antiepileptic drugs. Treatment of uterine fibroids can include gonadotropin-releasing hormone agonists, antihormonal medications, pain relievers, myomectomy, and hysterectomy. Total nephrectomy should be considered in individuals with kidney tumors.

Surveillance: For FH heterozygotes and at-risk family members who have not undergone molecular genetic testing: every one to two years full skin examination to evaluate for changes suggestive of leiomyosarcoma; annual gynecologic consultation to assess severity of uterine fibroids and to evaluate for changes suggestive of leiomyosarcoma; every two years abdominal/pelvic CT scan with contrast or MRI to evaluate for renal lesions if previous scans are normal; once a renal lesion is identified, CT scan with and without contrast and renal ultrasound examination, PET-CT scan to identify metabolically active lesions, and evaluation by a urologic oncology surgeon familiar with the renal cancer of HLRCC.

Evaluation of relatives at risk: When 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.

Genetic counseling. HLRCC is inherited in an autosomal dominant manner. If a parent of a proband is clinically affected or has a disease-causing mutation, the sibs of the proband have a 50% chance of inheriting the mutation. Each child of an individual with HLRCC has a 50% chance of inheriting the mutation. The degree of clinical severity is not predictable. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation in a family is known.

Diagnosis

Clinical Diagnosis

The 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 leiomyoma
  • A single leiomyoma in the presence of a positive family history of HLRCC

Heterozygosity 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.

Testing

Fumarate 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 Testing

Gene. FH is the only gene known to be associated with hereditary leiomyomatosis and renal cell cancer (HLRCC).

Clinical testing

  • Sequence 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 HLRCC

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
FHSequence analysis 4 / mutation scanning 5Sequence variants~80%-100% 6
Deletion/duplication analysis 7Partial- and whole-gene deletions1/20 8-1/7 9

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. 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. For issues to consider in interpretation of sequence analysis results, click here.

5. 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.

6. Toro et al [2003], Alam et al [2005], Wei et al [2006]

7. Testing that identifies exonic or whole-gene 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.

8. Smit et al [2011]

9. Ahvenainen et al [2008]

Testing Strategy

To confirm/establish the diagnosis in a proband

  • Molecular 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 HLRCC
    • A single cutaneous leiomyoma with family history of HLRCC
    • One or more tubulo-papillary, collecting-duct, or papillary type 2 renal tumors with or without a family history of HLRCC
  • Measurement 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.

Clinical Description

Natural History

The 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 Correlations

No 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].

Penetrance

Based on three major clinical manifestations, penetrance of HLRCC is considered to be very high.

Nomenclature

Historically, the predisposition to the development of cutaneous leiomyomas was referred to as multiple cutaneous leiomyomatosis (MCL).

Reed et al [1973] described two kindreds in which multiple members over three generations exhibited cutaneous leiomyomas and uterine leiomyomas and/or leiomyosarcomas inherited in an autosomal dominant pattern. In this report, they also described a 20-year old woman with uterine leiomyosarcoma and metastatic renal cancer. Since then, the association of cutaneous and uterine leiomyomas became known as Reed's syndrome.

The clear association of cutaneous leiomyomas and kidney cancer was not described until Launonen et al [2001] reported two Finnish families in which cutaneous and uterine leiomyomas and papillary type 2 renal cell carcinoma co-segregated. The name hereditary leiomyomatosis and renal cell cancer (HLRCC) was designated, and the disorder was assigned OMIM number 605839. The term hereditary leiomyomatosis and renal cell cancer is preferred because it is impossible to distinguish between individuals with cutaneous leiomyomas who do and do not have an increased risk of renal cancer.

Prevalence

More than 200 families with HLRCC from various populations have been described.

Differential Diagnosis

Cutaneous 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.

Management

Evaluations Following Initial Diagnosis

To 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 leiomyosarcoma
  • Baseline pelvic bimanual examination, pelvic MRI, and/or transvaginal pelvic ultrasound examination to screen for uterine fibroids
  • Baseline renal ultrasound examination and abdominal CT scan with contrast or MRI to screen for renal tumors

Treatment of Manifestations

Cutaneous 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 on 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.

Surveillance

There 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.

Renal

  • Yearly 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 Risk

When 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 purposes

Therapies Under Investigation

Recent 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

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Some individuals diagnosed with HLRCC have an affected parent, and some have HLRCC as the result of a de novo gene mutation.
  • The proportion of cases caused by de novo mutations is unknown because subtle manifestation in parents has not been evaluated and genetic testing data are insufficient.
  • Recommendations for evaluation of parents of a proband with a suspected de novo mutation include molecular genetic testing if the FH disease-causing mutation in the proband has been identified.

Note: Although some individuals diagnosed with HLRCC have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

Offspring of a proband. Each child of an individual with HLRCC has a 50% chance of inheriting the mutation. The degree of clinical severity is not predictable.

Other family members of a proband

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment

Predicting the phenotype in individuals who have inherited a disease-causing mutation. It is not possible to predict whether symptoms will occur, or if they do, what the age of onset, severity and type of symptoms, or rate of disease progression will be in individuals who have a disease-causing mutation.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Testing at-risk asymptomatic family members. Molecular genetic testing of at-risk family members is appropriate in order to identify the need for continued, lifelong, clinical surveillance. Interpretation of the result is most accurate when a disease-causing mutation has been identified in an affected family member. Those who have a disease-causing mutation require lifelong, regular surveillance. Family members who have not inherited the mutation and their offspring have risks similar to the general population.

Early detection of at-risk individuals affects medical management. However, in the absence of an increased risk of developing childhood malignancy, the American Society of Clinical Oncology (ASCO) recommends delaying genetic testing in at-risk individuals during childhood until individuals reach age 18 years and are able to make informed decisions regarding genetic testing [American Society of Clinical Oncology 2003].

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Kidney Cancer Association
    PO Box 96503
    Washington DC 20090
    Phone: 800-850-9132 (toll-free); 312-436-1455
    Fax: 847-332-2978
    Email: kidney.cancer@hotmail.com
  • National Uterine Fibroids Foundation (NUFF)
    PO Box 9688
    Colorado Springs CO 80932-0688
    Phone: 800-874-7247 (toll-free); 719-633-3454
    Email: info@NUFF.org

Molecular Genetics

Information 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 Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
FH1q43Fumarate hydratase, mitochondrialTCA Cycle Gene Mutation Database (FH)FH

Data 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)

136850FUMARATE HYDRATASE; FH
150800HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER; HLRCC

Molecular Genetic Pathogenesis

Germline 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].

Gene structure. FH consists of ten exons encompassing 22.15 kb of DNA. The gene is highly conserved across species. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic 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.Glu404Ter 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.

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].

References

Literature Cited

  1. Ahvenainen T, Lehtonen HJ, Lehtonen R, Vahteristo P, Aittomäki K, Baynam G, Dommering C, Eng C, Gruber SB, Grönberg H, Harvima R, Herva R, Hietala M, Kujala M, Kääriäinen H, Sunde L, Vierimaa O, Pollard PJ, Tomlinson IP, Björck E, Aaltonen LA, Launonen V. Mutation screening of fumarate hydratase by multiplex ligation-dependent probe amplification: detection of exonic deletion in a patient with leiomyomatosis and renal cell cancer. Cancer Genet Cytogenet. 2008;183:83–8. [PubMed: 18503824]
  2. Alam NA, Barclay E, Rowan AJ, Tyrer JP, Calonje E, Manek S, Kelsell D, Leigh I, Olpin S, Tomlinson IP. Clinical features of multiple cutaneous and uterine leiomyomatosis: an underdiagnosed tumor syndrome. Arch Dermatol. 2005;141:199–206. [PubMed: 15724016]
  3. Alam NA, Rowan AJ, Wortham NC, Pollard PJ, Mitchell M, Tyrer JP, Barclay E, Calonje E, Manek S, Adams SJ, Bowers PW, Burrows NP, Charles-Holmes R, Cook LJ, Daly BM, Ford GP, Fuller LC, Hadfield-Jones SE, Hardwick N, Highet AS, Keefe M, MacDonald-Hull SP, Potts ED, Crone M, Wilkinson S, Camacho-Martinez F, Jablonska S, Ratnavel R, MacDonald A, Mann RJ, Grice K, Guillet G, Lewis-Jones MS, McGrath H, Seukeran DC, Morrison PJ, Fleming S, Rahman S, Kelsell D, Leigh I, Olpin S, Tomlinson IP. Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Hum Mol Genet. 2003;12:1241–52. [PubMed: 12761039]
  4. American Society of Clinical Oncology. Statement on genetic testing for cancer susceptibility. Available online. 2003. Accessed 9-2-14.
  5. Carvajal-Carmona LG, Alam NA, Pollard PJ, Jones AM, Barclay E, Wortham N, Pignatelli M, Freeman A, Pomplun S, Ellis I, Poulsom R, El-Bahrawy MA, Berney DM, Tomlinson IP. Adult leydig cell tumors of the testis caused by germline fumarate hydratase mutations. J Clin Endocrinol Metab. 2006;91:3071–5. [PubMed: 16757530]
  6. Chan I, Wong T, Martinez-Mir A, Christiano AM, McGrath JA. Familial multiple cutaneous and uterine leiomyomas associated with papillary renal cell cancer. Clin Exp Dermatol. 2005;30:75–8. [PubMed: 15663510]
  7. Chuang GS, Martinez-Mir A, Geyer A, Engler DE, Glaser B, Cserhalmi-Friedman PB, Gordon D, Horev L, Lukash B, Herman E, Cid MP, Brenner S, Landau M, Sprecher E, Garcia Muret MP, Christiano AM, Zlotogorski A. Germline fumarate hydratase mutations and evidence for a founder mutation underlying multiple cutaneous and uterine leiomyomata. J Am Acad Dermatol. 2005;52:410–6. [PubMed: 15761418]
  8. Coughlin EM, Christensen E, Kunz PL, Krishnamoorthy KS, Walker V, Dennis NR, Chalmers RA, Elpeleg ON, Whelan D, Pollitt RJ, Ramesh V, Mandell R, Shih VE. Molecular analysis and prenatal diagnosis of human fumarase deficiency. Mol Genet Metab. 1998;63:254–62. [PubMed: 9635293]
  9. Farquhar CM, Steiner CA. Hysterectomy rates in the United States 1990-1997. Obstet Gynecol. 2002;99:229–34. [PubMed: 11814502]
  10. Heinritz W, Paasch U, Sticherling M, Wittekind C, Simon JC, Froster UG, Renner R. Evidence for a founder effect of the germline fumarate hydratase gene mutation R58P causing hereditary leiomyomatosis and renal cell cancer (HLRCC). Ann Hum Genet. 2008;72:35–40. [PubMed: 17908262]
  11. Isaacs JS, Jung YJ, Mole DR, Lee S, Torres-Cabala C, Chung YL, Merino M, Trepel J, Zbar B, Toro J, Ratcliffe PJ, Linehan WM, Neckers L. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell. 2005;8:143–53. [PubMed: 16098467]
  12. Kiuru M, Lehtonen R, Arola J, Salovaara R, Jarvinen H, Aittomaki K, Sjoberg J, Visakorpi T, Knuutila S, Isola J, Delahunt B, Herva R, Launonen V, Karhu A, Aaltonen LA. Few FH mutations in sporadic counterparts of tumor types observed in hereditary leiomyomatosis and renal cell cancer families. Cancer Res. 2002;62:4554–7. [PubMed: 12183404]
  13. Knox C, Sass E, Neupert W, Pines O. Import into mitochondria, folding and retrograde movement of fumarase in yeast. J Biol Chem. 1998;273:25587–93. [PubMed: 9748223]
  14. Lamba M, Verma S, Prokopetz R, Pierscianowski TA, Jabi M, Moyana T. Multiple cutaneous and uterine leiomyomas associated with gastric GIST. J Cutan Med Surg. 2005;9:332–5. [PubMed: 16699905]
  15. Launonen V, Vierimaa O, Kiuru M, Isola J, Roth S, Pukkala E, Sistonen P, Herva R, Aaltonen LA. Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci USA. 2001;98:3387–92. [PMC free article: PMC30663] [PubMed: 11248088]
  16. Lehtonen HJ, Kiuru M, Ylisaukko-Oja SK, Salovaara R, Herva R, Koivisto PA, Vierimaa O, Aittomaki K, Pukkala E, Launonen V, Aaltonen LA. Increased risk of cancer in patients with fumarate hydratase germline mutation. J Med Genet. 2006;43:523–6. [PMC free article: PMC2564537] [PubMed: 16155190]
  17. Lehtonen R, Kiuru M, Vanharanta S, Sjoberg J, Aaltonen LM, Aittomaki K, Arola J, Butzow R, Eng C, Husgafvel-Pursiainen K, Isola J, Jarvinen H, Koivisto P, Mecklin JP, Peltomaki P, Salovaara R, Wasenius VM, Karhu A, Launonen V, Nupponen NN, Aaltonen LA. Biallelic inactivation of fumarate hydratase (FH) occurs in nonsyndromic uterine leiomyomas but is rare in other tumors. Am J Pathol. 2004;164:17–22. [PMC free article: PMC1602244] [PubMed: 14695314]
  18. Matyakhina L, Freedman RJ, Bourdeau I, Wei MH, Stergiopoulos SG, Chidakel A, Walther M, Abu-Asab M, Tsokos M, Keil M, Toro J, Linehan WM, Stratakis CA. Hereditary leiomyomatosis associated with bilateral, massive, macronodular adrenocortical disease and atypical cushing syndrome: a clinical and molecular genetic investigation. J Clin Endocrinol Metab. 2005;90:3773–9. [PubMed: 15741255]
  19. O'Flaherty L, Adam J, Heather LC, Zhdanov AV, Chung YL, Miranda MX, Croft J, Olpin S, Clarke K, Pugh CW, Griffiths J, Papkovsky D, Ashrafian H, Ratcliffe PJ, Pollard PJ. Dysregulation of hypoxia pathways in fumarate hydratase-deficient cells is independent of defective mitochondrial metabolism. Hum Mol Genet. 2010;19:3844–51. [PMC free article: PMC2935862] [PubMed: 20660115]
  20. Pithukpakorn M, Wei MH, Toure O, Steinbach PJ, Glenn GM, Zbar B, Linehan WM, Toro JR. Fumarate hydratase enzyme activity in lymphoblastoid cells and fibroblasts of individuals in families with hereditary leiomyomatosis and renal cell cancer. J Med Genet. 2006;43:755–62. [PMC free article: PMC2564577] [PubMed: 16597677]
  21. Pollard PJ, Briere JJ, Alam NA, Barwell J, Barclay E, Wortham NC, Hunt T, Mitchell M, Olpin S, Moat SJ, Hargreaves IP, Heales SJ, Chung YL, Griffiths JR, Dalgleish A, McGrath JA, Gleeson MJ, Hodgson SV, Poulsom R, Rustin P, Tomlinson IP. Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet. 2005;14:2231–9. [PubMed: 15987702]
  22. Reed WB, Walker R, Horowitz R. Cutaneous leiomyomata with uterine leiomyomata. Acta Derm Venereol. 1973;53:409–16. [PubMed: 4127477]
  23. Ritzmann S, Hanneken S, Neumann NJ, Ruzicka T, Kruse R. Type 2 segmental manifestation of cutaneous leiomyomatosis in four unrelated women with additional uterine leiomyomas (Reed's Syndrome). Dermatology. 2006;212:84–7. [PubMed: 16319483]
  24. Smit DL, Mensenkamp AR, Badeloe S, Breuning MH, Simon MEH, van Spaendonck KY, Aalfs CM, Post JG, Shanley S, Krapels IPC, Hoefsloot LH, van Moorselaar RJA, Starink TM, Bayley J-P, Frank J, van Steensel MAM, Menko FH. Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis. Clin Genet. 2011;79:49–59. [PubMed: 20618355]
  25. Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, Leigh I, Gorman P, Lamlum H, Rahman S, Roylance RR, Olpin S, Bevan S, Barker K, Hearle N, Houlston RS, Kiuru M, Lehtonen R, Karhu A, Vilkki S, Laiho P, Eklund C, Vierimaa O, Aittomaki K, Hietala M, Sistonen P, Paetau A, Salovaara R, Herva R, Launonen V, Aaltonen LA. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 2002;30:406–10. [PubMed: 11865300]
  26. Toro JR, Nickerson ML, Wei MH, Warren MB, Glenn GM, Turner ML, Stewart L, Duray P, Tourre O, Sharma N, Choyke P, Stratton P, Merino M, Walther MM, Linehan WM, Schmidt LS, Zbar B. Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet. 2003;73:95–106. [PMC free article: PMC1180594] [PubMed: 12772087]
  27. Wei MH, Toure O, Glenn GM, Pithukpakorn M, Neckers L, Stolle C, Choyke P, Grubb R, Middelton L, Turner ML, Walther MM, Merino MJ, Zbar B, Linehan WM, Toro JR. Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer. J Med Genet. 2006;43:18–27. [PMC free article: PMC2564499] [PubMed: 15937070]
  28. Ylisaukko-Oja SK, Kiuru M, Lehtonen HJ, Lehtonen R, Pukkala E, Arola J, Launonen V, Aaltonen LA. Analysis of fumarate hydratase mutations in a population-based series of early onset uterine leiomyosarcoma patients. Int J Cancer. 2006;119:283–7. [PubMed: 16477632]

Suggested Reading

  1. Kiuru M, Launonen V. Hereditary leiomyomatosis and renal cell cancer (HLRCC). Curr Mol Med. 2004;4:869–75. [PubMed: 15579034]

Chapter Notes

Revision History

  • 2 November 2010 (me) Comprehensive update posted live
  • 15 November 2007 (cd) Revision: prenatal diagnosis available on a clinical basis
  • 31 July 2006 (me) Review posted to live Web site
  • 6 March 2006 (jrt) Original submission

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