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Hereditary Leiomyomatosis and Renal Cell Cancer

Synonym: HLRCC

, MD and , MD.

Author Information
, MD
Division of Medical Genetics
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: August 6, 2015.

Summary

Clinical 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.

The diagnosis of HLRCC is established with the identification of a heterozygous pathogenic variant in FH in combination with multiple cutaneous leiomyomas, with at least one histologically confirmed leiomyoma, a single leiomyoma in the presence of a positive family history of HLRCC, and/or one or more tubulo-papillary, collecting-duct, or papillary type 2 renal tumors with or without a family history of HLRCC. Testing of fumarate hydratase enzyme activity is an alternative in those with atypical presentation and an undetectable FH pathogenic variant.

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; yearly examination with abdominal MRI for individuals with normal initial baseline or follow-up scans; 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 FH pathogenic variant in the family is known, molecular genetic testing of asymptomatic at-risk relatives improves diagnostic certainty and allows early surveillance and treatment. If the pathogenic variant in the family is not known, fumarate hydratase enzyme assay can be used to clarify the disease status of at-risk relatives.

Genetic counseling.

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

Diagnosis

Suggestive Findings

Hereditary leiomyomatosis and renal cell cancer (HLRCC) should be suspected in individuals with one or more of the following major features:

Cutaneous leiomyomata. The majority (76%) of individuals with HLRCC present with a single or multiple cutaneous leiomyomata.

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. 40% 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. 10%-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, displaying a 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].

Establishing the Diagnosis

For individuals or families with suspected clinical phenotypes, clinical diagnosis of HLRCC should be considered as follows:

Major criterion. Histopathologically confirmed multiple cutaneous leiomyomas

Minor criteria

  • Surgery required; symptomatic and/or multiple uterine leiomyomas before age 40 years
  • Type 2 papillary renal cell carcinoma before age 40 years
  • A first-degree relative who meets one of the above criteria

The diagnosis is likely when an individual meets the major criterion; HLRCC may be suspected when an individual meets at least two minor criteria [Smit et al 2011].

The diagnosis of HLRCC is established in a proband with identification of a heterozygous pathogenic variant in FH on molecular genetic testing (see Table 1) in combination with the following clinical findings:

  • Multiple cutaneous leiomyomas (with ≥1 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

Note: (1) Because the prevalence of uterine leiomyomas in the general population is high, a solitary uterine leiomyoma even in the presence of a heterozygous FH pathogenic variant is not sufficient for the diagnosis of HLRCC. (2) Measurement of fumarate hydratase enzyme activity can be useful in the diagnosis of HLRCC in cases with atypical presentation and undetectable FH pathogenic variants [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 testing approaches can include single-gene testing and use of a multi-gene panel.

  • Single-gene testing. Sequence analysis of FH is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
  • A multi-gene panel that includes FH and other genes of interest (see Differential Diagnosis) may also be considered. Note: The genes included and sensitivity of multi-gene panels vary by laboratory and over time.

Table 1.

Molecular Genetic Testing Used in HLRCC

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
FHSequence analysis 370%-90% 4
Gene-targeted deletion/duplication analysis 51/20 6-1/7 7
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.
7.

Clinical Characteristics

Clinical Description

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 leiomyomata. 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.

Histologically, proliferation of interlacing bundles of smooth muscle fibers with centrally located, long blunt-edged nuclei is observed.

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 are at 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]. Six women with a germline FH pathogenic variant and uterine leiomyosarcoma have been reported [Lehtonen et al 2006, Ylisaukko-oja et al 2006]. However, studies from other cohorts showed no reported leiomyosarcoma among women with germline FH pathogenic variants and no germline FH pathogenic variants in three women with uterine leiomyosarcomas and/or family history of uterine leiomyosarcomas [Gardie et al 2011, Smit et al 2011]. It appears that individuals/families with a germline FH pathogenic variant are, in general, not highly predisposed to uterine cancer; but a few individuals and families appear to be at high risk. In North America, no individuals or families with HLRCC and uterine leiomyosarcomas have been reported. Therefore, the risk to women with HLRCC of developing uterine leiomyosarcoma 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; 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 specific FH pathogenic variants and the occurrence of cutaneous lesions, uterine fibroids, or renal cancer of HLRCC [Wei et al 2006].

FH pathogenic variants 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 pathogenic variant as originally suggested [Tomlinson et al 2002].

Penetrance

Based on three major clinical manifestations, penetrance of HLRCC is considered to be very high. However, an asymptomatic individual who was an obligate heterozygote for a FH pathogenic variant in one family has been reported [Gardie et al 2011].

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 has been refered to 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 among individuals with cutaneous leiomyomas it is impossible to distinguish between those at and those not at increased risk for renal cancer.

Prevalence

More than 300 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 (see Table 2 for comparison) 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.
  • 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.
  • Hereditary papillary renal cancer (HPRC) (OMIM 605074). Predisposition to type 1 papillary renal cancer. Inheritance is autosomal dominant.

Table 2.

Familial Renal Cancer Syndrome Comparisons

ConditionRenal TumorCutaneous LesionsUterine FibroidsOther Common Findings
HLRCCPapillary type 2 RCCCutaneous leiomyomaEarly onset; multiple lesionsNone
VHL syndromeClear cell RCCNoneNoneCNS hemangioblastoma, retinal angioma, renal cysts, pancreatic cysts, pancreatic tumor, pheochromocytoma
BHDSVarious: oncocytoma, chromophobe RCC, hybrid chromophobe/oncocytic tumorCutaneous fibrofolliculoma, trichodiscoma, acrochordonNoneMultiple lung cysts
HPRCPapillary type 1 RCCNoneNoneNone

RCC = renal cell carninoma

CNS = central nervous system

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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 to include biopsy for histologic confirmation
  • Baseline pelvic bimanual examination, pelvic MRI, and/or transvaginal pelvic ultrasound examination to screen for uterine fibroids
  • Baseline renal ultrasound examination and MRI to screen for renal tumors; abdominal CT scan with contrast should be reserved for when MRI is contraindicated
  • Consultation with a medical geneticist and/or genetic counselor

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 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 initially to treat 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 pathogenic variants 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 is recommended for individuals with normal initial baseline or follow-up abdominal MRI. MRI is preferred because of the potential added radiation exposure associated with CT over lifetime. Abdominal CT scan with contrast should be reserved for when MRI is contraindicated.
  • Any suspicious renal lesion (indeterminate lesion, questionable or complex cysts) deteced 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

It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.

  • If the pathogenic variant in the family is known, molecular genetic testing of asymptomatic at-risk relatives improves diagnostic certainty, allows early surveillance and treatment in those with the family-specific pathogenic variant, and reduces costly screening procedures in those who have not inherited the pathogenic variant.
  • If the pathogenic variant in the family is not known, fumarate hydratase enzyme assay can be used to clarify the disease status of at-risk relatives. 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

Several studies of anti-VEGF and novel tyrosine kinase inhibitor treatment in HLRCC and papillary RCC (including papillary type 2 RCC) have been conducted [Linehan et al 2013]. Early report demonstrated improvement of progression-free survival in patients with papillary type 2 RCC with Sunitinib [Choueiri et al 2008, Clinical Trials].

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 FH pathogenic variant.
  • The proportion of cases caused by a de novo pathogenic variant is unknown because subtle manifestation in parents has not been evaluated and genetic testing data are insufficient.
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • Recommendations for evaluation of parents of a proband with an apparent de novo pathogenic variant include molecular genetic testing if the FH pathogenic variant in the proband has been identified.
  • The family history of some individuals diagnosed with HLRCC 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. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations (e.g., molecular genetic testing) have been performed on the parents of the proband.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of a proband is clinically affected or has an FH pathogenic variant, each sib of the proband is at a 50% risk of inheriting the pathogenic variant.
  • If the FH pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

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

Other family members of a proband.

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected or has a pathogenic variant, his or her family members are at risk.

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 pathogenic variant. 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 pathogenic variant.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with HLRCC has the pathogenic variant or clinical evidence of the disorder, the FH variant is likely de novo. 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 clinical surveillance. Interpretation of the result is most accurate when a pathogenic variant has been identified in an affected family member. Those who have a pathogenic variant require regular lifelong surveillance. Family members who have not inherited the pathogenic variant 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 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

If the FH pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the FH pathogenic variant 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.

  • HLRCC Family Alliance
    2001 Beacon Street
    Suite 208
    Boston MA 02135-7787
    Phone: 617-277-5667 ext. 709; 800-767-4845 ext. 709 (toll-free)
    Fax: 858-712-8712; 866-209-0288 (toll-free)
    Email: hlrcc@vhl.org
  • My46 Trait Profile
  • 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

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein 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 pathogenic variants in FH, plus somatic variants 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.

Pathogenic allelic variants. Various FH pathogenic variants have been identified in families with HLRCC. Most are missense variants; others are nonsense, frameshift, and splice-site variants [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 pathogenic variant in four families of Jewish Iranian origin, the c.302G>C pathogenic variant in a German and English family, and the p.Glu404Ter pathogenic variant 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.

Table 3.

FH Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias) 1
Protein Amino Acid Change
(Alias) 1
Reference Sequences
c.905-1G>ANM_000143​.3
NP_000134​.2
c.302G>C 2
(173G>C)
p.Arg101Gln 2
(Gly58Ala)
c.1210G>Tp.Glu404Ter

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

2.

For nomenclature change see TCA Cycle Gene Mutation Database (FH).

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

Published Guidelines/ Consensus Statements

  1. American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. Available online. 2003. Accessed 8-4-15.
  2. American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available online; registration or institutional access required. 2010. Accessed 8-4-15.

Literature Cited

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Suggested Reading

  1. Menko FH, Maher ER, Schmidt LS, Middelton LA, Aittomäki K, Tomlinson I, Richard S, Linehan WM. Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment. Fam Cancer. 2014;13:637–44. [PMC free article: PMC4574691] [PubMed: 25012257]

Chapter Notes

Revision History

  • 6 August 2015 (me) Comprehensive update posted live
  • 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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