Hereditary Leiomyomatosis and Renal Cell Cancer

[HLRCC]

Clinical Diagnosis

The major features of hereditary leiomyomatosis and renal cell cancer (HLRCC):

• 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. The presence of cutaneous leiomyomata correlates with the presence of uterine fibroids in females [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:

• Multiple cutaneous leiomyomas with at least one histologically confirmed leiomyoma

OR

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

Heterozygosity for a fumarate hydratase (fumarase) (FH) mutation 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

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

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

Clinical uses

• Confirmatory diagnostic testing

• Predictive testing

• Prenatal diagnosis

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.

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in HLRCC

Test Method	Mutations Detected	Mutation Detection Frequency  1,  2	Test Availability
Sequence analysis	FH sequence variants	~80%-100%	Clinical

1. Proportion of affected individuals with a mutation(s) as classified by test method
2. Toro et al 2003, Alam et al 2005, Wei et al 2006

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

Testing Strategy

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].

Genetically Related (Allelic) Disorders

Fumarase deficiency (fumaric aciduria, FHD).  FHD, resulting from inherited biallelic mutations in FH, is an autosomal recessive inborn error of metabolism characterized by rapidly progressive neurologic impairment including hypotonia, seizures and cerebral atrophy. Homozygous or compound heterozygous germline mutations in FH are found in individuals with fumarase deficiency [Coughlin et al 1998]. Leiomyomas and renal cancer have not been reported in FHD. However, most individuals with FHD 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 FHD supports the increased risk for HLRCC in the heterozygous relatives of children with FHD [Shih, unpublished].

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 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 presented 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, 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 eleven 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 FH mutation-positive families 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 have been reported with uterine leiomyosarcomas to date. Therefore, the risk of uterine leiomyosarcama in women with HLRCC in general is unknown.

Other.  Four individuals with breast cancer, one case of bladder cancer and a single case of bilateral macronodular adrenocortical disease and Cushing syndrome have been reported; however, it remains to be determined whether these manifestations are truly associated with HLRCC [Alam et al 2005, Matyakhina et al 2005, Lehtonen et al 2006].

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 fumarate hydratase (fumarase) deficiency (FHD) 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.

Anticipation

Anticipation is not known to occur in HLRCC.

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. However, the clear association of cutaneous leiomyomas and kidney cancer was not described until 2001, when Launonen et al 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 100 families with HLRCC have been described from various populations.

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:

• Baseline renal ultrasound examination and abdominal CT scan with contrast or MRI to screen for renal tumors

• 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

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 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, 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 are of a high grade 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.

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.  If both the initial (baseline) and the first annual follow-up abdominal CT scan with contrast or MRI (if CT is not possible) are normal, this evaluation should be repeated every two years.

  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.

Testing of Relatives at Risk

Use of molecular genetic testing for early identification of at-risk family members improves diagnostic certainty and reduces costly screening procedures in at-risk members who have not inherited disease-causing mutations.

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 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 HIF accumulation.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

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 as 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

• The risk to the sibs of the proband depends upon the genetic status of the proband's parents.

• If a parent of a proband is clinically affected or has a disease-causing mutation, each sib of the proband is at a 50% risk of inheriting the mutation.

• If the disease-causing mutation cannot be detected in the DNA of either parent, the risk to sibs is low, but greater than that of the general population because the possibility of germline mosaicism exists.

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.  The risk to other family members depends upon the status of the proband's parents. If a parent is found to be affected or to have a disease-causing mutation, his or her family members are at risk.

Related Genetic Counseling Issues

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 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. Meanwhile, 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 18 years of age 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 is before pregnancy.

DNA banking.  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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

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 15-18 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 available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

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 HIF degradation and overexpression of genes more downstream in the HIF pathway [Isaacs et al 2005].

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 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]. (For more information, see Genomic Databases table above.)

Normal gene product: The FH gene 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].

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Suggested Readings

Revision History

• 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