Associated disorders

The FH gene is associated with autosomal dominant hereditary leiomyomatosis and renal cell cancer (HLRCC) (MedGen UID: 353771) and autosomal recessive fumarase deficiency (MedGen UID: 87458). Additionally, the FH gene has preliminary evidence supporting a correlation with hereditary paraganglioma-pheochromocytoma (PGL/PCC).

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The FH gene encodes fumarate hydratase, also called fumarase, an enzyme that converts fumarate to malate as part of the Krebs cycle.

FH – hereditary leiomyomatosis and renal cell cancer (HLRCC)
MedGen UID: 353771

Clinical condition
HLRCC is a rare, adult-onset tumor-predisposition syndrome that is characterized by cutaneous leiomyomas, uterine leiomyomas, and renal tumors. Cutaneous leiomyomas appear as skin-colored or light-brown papules that can develop over the trunk, extremities, and occasionally the face. They are often more sensitive than the surrounding skin to cold or light touch, and may be painful. They present in the second to fourth decade of life and tend to increase in size and number over time (PMID: 25012257, 20301430, 12772087).

In addition, uterine leiomyomas (fibroids) are present in almost all females with HLRCC, but they rarely become malignant. Uterine fibroids are very common in the general population, but the fibroids in HLRCC tend to be numerous and have an earlier onset than in the general population. Symptoms include irregular or heavy menstruation and pelvic pain (PMID: 25012257, 20301430).

Approximately 15% of individuals with HLRCC develop renal tumors, including type 2 papillary, tubulo-papillary, collecting-duct carcinoma, and possibly Wilms tumor. Renal tumors in HLRCC are typically unilateral, solitary, and aggressive. Symptoms include hematuria, lower back pain, and a palpable mass, although some have no symptoms until the disease is advanced (PMID: 25012257, 20301430, 25018647).

Invitae considers FH a “preliminary evidence” gene in its association with paragangliomas and pheochromocytomas (PMID: 25004247, 24334767). preliminary evidence genes are selected from an extensive review of the literature and expert recommendations, but the association between the gene and the specific condition has not been completely established. This uncertainty may be resolved as new information becomes available, and therefore clinicians may continue to order these preliminary evidence genes.

Gene information
FH is a tumor suppressor gene, meaning its function is to help control the rate of growth and cell division in the body. The protein encoded by this gene is an enzymatic component of the tricarboxylic acid (TCA) cycle, or Krebs cycle, and catalyzes the formation of L-malate from fumarate ( Gene. Gene ID: 2271. Accessed September 2015). UniProt consortium, UniprotKB – P07954 (FUMH_HUMAN). If there is a pathogenic variant in this gene that prevents it from functioning normally in DNA repair, the risk of developing certain types of cancers is increased.

Variants in the HLRCC gene have autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to their offspring. Once a pathogenic mutation is detected in an individual, it is possible to identify at-risk relatives who can pursue testing for this specific familial variant. Many cases are inherited from a parent, but some cases can occur spontaneously (i.e., an individual with a pathogenic variant has parents who do not have it) (PMID: 20301430).

Individuals with a pathogenic variant in the FH gene are also carriers of a condition called fumarase deficiency (also known as fumarate hydratase deficiency and fumaric aciduria). This is an autosomal recessive condition that results when an individual inherits a pathogenic FH variant from each parent. Fumarase deficiency is an inborn error of metabolism that is characterized by rapidly progressive neurologic impairment, including hypotonia, seizures, and cerebral atrophy. Most survive only for a few months after birth ( NCBI Genetics Home Reference. Fumarase deficiency. http://ghr.nlm.nih.gov/condition/fumarase-deficiency. Accessed September 2015; PMID: 20549362, 21560188). For there to be a risk to offspring of fumarate hydratase, both the patient and their partner would have to have a single pathogenic variant in FH; in such a case, the risk to offspring is 25%.

There are no established surveillance guidelines for HLRCC, though the following has been proposed (PMID: 25012257, 20301430):

  • baseline renal ultrasound examination and abdominal CT scan with contrast or MRI to screen for renal tumors
  • full skin examination every 1–2 years, with cutaneous leiomyomas examined by a dermatologist to evaluate for changes suggestive of leiomyosarcoma

Treatment options for cutaneous leiomyomas include, but are not limited to:
  • surgical excision
  • cryoablation and/or lasers
  • several medications, including calcium channel blockers, alpha blockers, nitroglycerin, antidepressants, and antiepileptic drugs (AEDs), all of which have been reported to reduce pain

Baseline pelvic bimanual examination, pelvic MRI, and/or transvaginal pelvic ultrasound examination to screen for uterine fibroids is suggested, as is an annual gynecologic consultation to assess severity of uterine fibroids and to evaluate for changes suggestive of leiomyosarcoma. HLRCC-related fibroids are treated in the same manner as sporadic fibroids; however, most women with HLRCC require interventions earlier than the general population (PMID: 25012257, 20301430):
  • Initially, medications including gonadotropin-releasing hormone agonists (GnRHa), anti-hormonal medications, and pain relievers may be used to decrease the size of fibroids in preparation for surgical removal and to provide temporary relief from the symptoms of fibroids.
  • When it is possible, the treatment of choice is myomectomy to remove fibroids while preserving the uterus.
  • Hysterectomy should be performed only when necessary.

Baseline renal ultrasound examination and abdominal CT scan with contrast or MRI is suggested to screen for renal tumors. Early detection of kidney tumors in HLRCC is important because these tumors have an aggressive disease course (PMID: 25012257, 20301430).
  • To detect very small tumors, a yearly MRI with 1–3 mm slices through the kidneys is recommended. Renal ultrasound (unless it is the only available imaging modality) is not recommended due to the low sensitivity of ultrasound in detecting small lesions.
  • Nephron-sparing therapy is generally suggested for small renal tumors. This is especially important for patients with hereditary renal cancer that is associated with a predisposition to recurrent, multifocal lesions.
  • Prompt surgical removal with wide surgical margins and consideration of retroperitoneal lymphadenectomy is advised. Total nephrectomy may be recommended if there is doubt that a partial nephrectomy would be curative. Neither radiofrequency ablation (RFA) nor cryotherapy for renal cancer is advised for individuals with HLRCC.

An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors, including personal medical history, family history, and any available genetic information that may result in a personalized plan for cancer prevention and surveillance.

Even though the data regarding FH variants are limited, knowing if a pathogenic variant is present is advantageous. At-risk relatives can be identified, enabling pursuit of a diagnostic evaluation. Further, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant data regarding FH are likely to become available in the near future. Awareness of this cancer predisposition encourages patients and their providers to inform at-risk family members, to consider implementing suggested screening protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.

Review date: September 2015

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
FH NM_000143.3