Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC): FH Gene Deletion/Duplication

Condition Description

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 FHmutations 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.

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Genes (1)

Indications

This test is indicated for:

  • Confirmation of a clinical diagnosis of HLRCC in individuals who have tested negative for sequence analysis
  • Individuals at-risk for HLRCC due to family history who have tested negative for sequence analysis

Methodology

DNA isolated from peripheral blood is hybridized to a CGH array to detect deletions and duplications. The targeted CGH array has overlapping probes which cover the entire genomic region.

Detection

Detection is limited to duplications and deletions. The CGH array will not detect point or intronic mutations. Results of molecular analysis must be interpreted in the context of the patient's clinical and/or biochemical phenotype.

Specimen Requirements

When sample fails to meet the acceptable criteria, please call 470.378.2200 and ask to speak with a laboratory genetic counselor (eglgc@egl-eurofins.com).
Submit only 1 of the following specimen types
DNA, Isolated
DNA

Requirements
Microtainer
3µg
Isolation using the Perkin Elmer™Chemagen™ Chemagen™ Automated Extraction method or Qiagen™ Puregene kit for DNA extraction is recommended.
Collection and Shipping
Refrigerate until time of shipment in 100 ng/µL in TE buffer. Ship sample at room temperature with overnight delivery.
Whole Blood (EDTA)
WBP

Requirements
EDTA (Purple Top)
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
Collection and Shipping
Ship sample at room temperature for receipt at EGL within 24 hours of collection. Do not refrigerate or freeze.

Special Instructions

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.

  • Sequencing analysis of the FH gene is available (VI) and is required before deletion/duplication analysis.
  • Prenataltesting is available to individuals who are confirmed carriers ofmutations. Please contact the laboratory genetic counselor to discussappropriate testing prior to collecting a prenatal specimen.

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