Hereditaryleiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant conditioncharacterized by cutaneous leiomyomata, uterine leiomyomata (fibroids), and/ora single renal tumor. The majority (three-quarters) of individuals with HLRCCpresent with a single or multiple cutaneous leiomyoma. Cutaneous leiomyomataappear as skin-colored to light brown papules or nodules distributed over thetrunk and extremities and occasionally on the face and appear at a mean age of25 years, increasing in size and number with age. Uterine leiomyomata arepresent in almost all females with HLRCC and tend to be numerous and large; ageat diagnosis ranges from 18 to 52 years, with most women experiencing irregularor heavy menstruation and pelvic pain. The presence of cutaneous leiomyomatacorrelates with the presence of uterine fibroids in females. Renal tumorscausing hematuria, lower back pain, and a palpable mass are usually unilateral,solitary, and aggressive and range from type 2 papillary to tubulo-papillary tocollecting-duct carcinomas. They occur in about 10%-16% of individuals withHLRCC; the median age of detection is 44 years. Disease severity showssignificant intra- and interfamilial variation.
HLRCC isdiagnosed by the presence of multiple cutaneous leiomyomas with at least onehistologically confirmed leiomyoma or by a single leiomyoma in the presence ofa positive family history of HLRCC. Diagnosis is confirmed by testing offumarate hydratase enzyme activity in cultured skin fibroblasts orlymphoblastoid cells showing reduced activity (≤60%) or by molecular genetictesting. The FH gene (1q42.1) is the only gene known to be associatedwith HLRCC. Between 80% and 100% of individuals with HLRCC have identifiablesequence variants in FH. No correlation is observed between FH mutations and the occurrence of cutaneous lesions, uterine fibroids, or renalcancer of HLRCC. The proportion of cases caused by de novo mutations isunknown as subtle manifestation in parents has not been evaluated and genetictesting data are insufficient. Early detection of at-risk individuals affectsmedical management. In the absence of an increased risk of developing childhoodmalignancy, however, the American Society of Clinical Oncology (ASCO) recommendsdelaying genetic testing in at-risk individuals during childhood untilindividuals reach 18 years of age and are able to make informed decisionsregarding genetic testing.
Mutationsin the FH gene also occur in theautosomal recessive condition fumerase deficiency (FHD), or fumeric aciduria.FHD results from inherited biallelic mutations in FH, and ischaracterized by rapidly progressive neurologic impairment including hypotonia,seizures, and cerebral atrophy. Homozygous or compound heterozygous germlinemutations in FH are found in individuals with FHD. Leiomyomas and renalcancer have not been reported in FHD. Most individuals with FHD, however,survive only a few months; a very few survive to early adulthood. In onereport, a parent (heterozygous carrier) of an individual with fumarasedeficiency developed cutaneous leiomyomas similar to those observed in HLRCC.
For patients with suspected HLRCC, sequence analysis is recommended as the first step in mutation identification. For patients in whom mutations are not identified by full gene sequencing, deletion/duplication analysis is appropriate.
Click here for the GeneTests summary on this condition.
This test is indicated for:
- Confirmation of a clinical diagnosis of HLRCC
- Individuals at-risk for HLRCC due to family history
Clinical Sensitivity: Between 80% and 100% of individuals with HLRCC have identifiable sequence variants in FH. Mutations in the promoter region, some mutations in the introns and other regulatory element mutations cannot be detected by this analysis. Large deletions will not be detected by this analysis. Results of molecular analysis should be interpreted in the context of the patient's biochemical phenotype.
Analytical Sensitivity: ~99%
Orangene™ Saliva Collection Kit used according to manufacturer instructions. Please contact EGL for a Saliva Collection Kit for patients that cannot provide a blood sample.
Infants and Young Children (<2 years of age): 2-3 ml
Children > 2 years of age to 10 years old: 3-5 ml
Older Children & Adults: 5-10 ml
Autopsy: 2-3 ml unclotted cord or cardiac blood
Isolation using the Perkin Elmer™Chemagen™ Chemagen™ Automated Extraction method or Qiagen™ Puregene kit for DNA extraction is recommended.
Submit copies of diagnostic biochemical test results with the sample, if appropriate. Contact the laboratory if further information is needed.
Sequence analysis is required before deletion/duplication analysis by targeted CGH array. If sequencing is performed outside of EGL Genetics, please submit a copy of the sequencing report with the test requisition.
- Deletion/duplication analysis of the FH gene by CGH array is available for those individuals in whom sequence analysis is negative (VI).
- Custom diagnostic mutation analysis (KM) is available to family members if mutations are identified by targeted mutation testing or sequencing analysis.
- Prenatal testing is available to individuals who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.