Clinical characteristics.

FH tumor predisposition syndrome is characterized by cutaneous leiomyomata, uterine leiomyomata (fibroids), and/or renal tumors. Pheochromocytoma and paraganglioma have also been described in affected individuals from a small number of families with specific FH pathogenic variants. Cutaneous leiomyomata appear as skin-colored to light brown papules or nodules distributed across the trunk and extremities and occasionally on the face, and are usually noted in the second to fourth decades of life, increasing in size and number with age. Uterine leiomyomata tend to be numerous and large; mean age at diagnosis is ~30 years, with most females experiencing irregular or heavy menstruation and pelvic pain. Renal tumors are usually unilateral, solitary, and aggressive. They are associated with poor survival due to clinical aggressiveness and propensity to metastasize despite small primary tumor size. The median age of detection is approximately 40 years.

Diagnosis/testing.

Diagnosis of FH tumor predisposition syndrome is established in a proband with a heterozygous pathogenic variant in FH identified by molecular genetic testing.

Management.

Treatment of manifestations: Treatment of cutaneous leiomyomas can include surgical excision, carbon dioxide laser, cryotherapy, or electrodessication. Medications for pain relief may include drugs that lead to vasodilation (e.g., nitroglycerin, nifedipine, phenoxybenzamine, doxazosin) and/or drugs for neuropathic pain (e.g., gabapentin, pregabalin, duloxetine). Treatment of uterine fibroids can include gonadotropin-releasing hormone agonists, intrauterine devices releasing progesterone, myomectomy, and hysterectomy; histologic examination to differentiate between atypical smooth muscle neoplasm and leiomyosarcoma should be performed in those undergoing surgery. Consultation with a urologic oncology surgeon familiar with this syndrome should be sought for renal tumors. Total or partial nephrectomy with wide margins may be carefully considered in some settings. In addition, treatment with erlotinib plus bevacizumab or cabozantinib plus nivolumab may be beneficial for kidney tumors.

Surveillance: Full skin examination every one to two years to assess extent of disease and evaluate for changes; gynecologic consult as needed for symptomatic lesions and reproductive counseling; annual MRI with 1- to 3-mm slices through the kidneys from age eight years; prompt follow up for suspicious renal lesions. For individuals with specific FH pathogenic variants associated with increased risk of pheochromocytoma and/or paraganglioma, blood pressure with every medical visit, annual plasma or urine fractionated metanephrines, and limited whole-body MRI (neck, chest, abdomen, and pelvis) every two years beginning at age ten years.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual by molecular genetic testing for the familial FH pathogenic variant in order to identify as early as possible those who would benefit from early surveillance and treatment and to reduce costly screening procedures in those who have not inherited the pathogenic variant.

Genetic counseling.

FH tumor predisposition syndrome is inherited in an autosomal dominant manner. Some individuals diagnosed with FH tumor predisposition syndrome inherited a germline pathogenic variant from a heterozygous parent who may or may not have manifestations of FH tumor predisposition syndrome. Each child of an individual with FH tumor predisposition syndrome has a 50% chance of inheriting the FH pathogenic variant. It is not possible to precisely predict the likelihood of manifestations, age of onset, severity and type of features, or rate of disease progression in offspring who inherit the FH pathogenic variant. Once the FH pathogenic variant has been identified in a family member, predictive testing for at-risk family members and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

FH tumor predisposition syndrome should be suspected in individuals with any combination of the following clinical features in the individual's personal or family history. FH tumor predisposition syndrome should also be investigated in any individuals with tumors that have characteristic histologic features.

Cutaneous leiomyomata

• Skin-colored to light brown/reddish papules or nodules distributed across the trunk, extremities, and occasionally on the face and neck
• Most often multiple; may be grouped/clustered, segmental, or disseminated
• Histopathology shows bundles of smooth muscle fibers with central, long, blunt-edged nuclei [Toro et al 2003, Schmidt & Linehan 2014].

Uterine leiomyomata (uterine fibroids)

• Tend to be numerous and large
• Often demonstrate loss of fumarate hydratase (FH) staining and positive cytoplasmic staining for S-(2-succino) cysteine [Martínek et al 2015, Andrici et al 2018, Muller et al 2018]
• Usually classified as atypical histology, with staghorn blood vessels, bizarre nuclei, and alveolar pattern edema [Nathanson 2025]

Renal tumors

• Usually solitary, highly aggressive renal cell carcinoma (RCC) that metastasizes early
• Spectrum includes type 2 papillary, undefined papillary, unclassified, tubulocystic, and collecting-duct carcinoma [Wei et al 2006, Muller et al 2017]

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis due to possibility of a de novo pathogenic variant, variable expressivity, or decreased penetrance.

Establishing the Diagnosis

The diagnosis of FH tumor predisposition syndrome is established in a proband with a heterozygous pathogenic (or likely pathogenic) variant in FH identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous FH variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

FH tumor predisposition syndrome is characterized by cutaneous leiomyomas, uterine leiomyomata (fibroids), and/or renal tumors. Pheochromocytoma and paraganglioma have also been described in a small number of families with specific FH pathogenic variants. Affected individuals usually present with multiple cutaneous leiomyomas, one or more uterine fibroids, and/or a single or no renal tumors. Rarely, individuals may develop multifocal or bilateral renal tumors. Current estimates based on public databases suggest that the frequency of pathogenic variants in the general population may be higher than initially anticipated, suggesting that many individuals may go unrecognized [Shuch et al 2020]. As further population-based testing occurs, a wider phenotypic variability among individuals with FH tumor predisposition is expected to emerge.

Cutaneous leiomyomas. Clinically, cutaneous leiomyomas present as firm skin-colored or light brown papules and nodules. These cutaneous lesions are usually noted in the second to fourth decades of life [Scharnitz et al 2023]. Some are noted to occur in childhood and tend to increase in size and number with age. Skin lesions may be symptomatic, and affected individuals often note that the lesions are painful or sensitive to cold temperature or touch [Scharnitz et al 2023].

Cutaneous leiomyosarcoma. While instances of leiomyosarcoma have been described among individuals with an FH pathogenic variant, due to changes in diagnostic criteria and nomenclature, lesions previously called leiomyosarcoma may have been atypical smooth muscle neoplasms/leiomyomas [Kraft & Fletcher 2011, Muller et al 2017, O'Connor et al 2024].

Uterine leiomyomas (uterine fibroids). Females with FH tumor predisposition syndrome have more uterine fibroids and onset at a younger age than females in the general population. The mean age at identification of fibroids is about 30 years [Scharnitz et al 2023]. Multiple uterine fibroids are often found in females with FH tumor predisposition syndrome and are associated with abdominal pain, irregular menses, and/or menorrhagia [Lehtonen 2011]. Females with FH tumor predisposition syndrome often undergo surgical procedures including hysterectomy or myomectomy for symptomatic uterine fibroids at a younger age [Nathanson 2025]. In one series, 59 of 114 females (52%) with FH tumor predisposition syndrome had myomectomy or hysterectomy at a median age of 35 (range: 25-58) [Muller et al 2017]. Thus, early referral to reproductive specialists may be appropriate for counseling and family planning.

Among a cohort of 2,060 females with uterine smooth muscle tumors, a prospective screening program identified a tumor with fumarate hydratase (FH)-deficient morphology in 30 individuals (1.4%). Histologic criteria for FH-deficient morphology included alveolar pattern edema and staghorn-shaped blood vessels under low magnification, and smooth muscle cells with a macronucleolus surrounded by a halo and eosinophilic globules seen under high magnification [Rabban et al 2019]. Ten females with a tumor with this morphology elected to proceed with germline FH molecular testing; of these, five were found to have a germline FH pathogenic variant, suggesting that uterine tumor histology could be used to identify individuals with FH tumor predisposition syndrome [Rabban et al 2019].

Atypical uterine leiomyoma may also be an indication for germline testing. In one large center, a retrospective review identified that 12 of 144 individuals with uterine leiomyoma (8.3%) were found to have a germline pathogenic variant in FH. However, only 34% of all individuals had undergone germline genetic testing, suggesting the need for further testing guided by tumor histology [Kipnis et al 2024]. An additional study supports consideration of germline testing for individuals with FH-deficient uterine leiomyoma. As in the previous study, less than 40% of individuals underwent germline testing [McHenry et al 2025].

Uterine leiomyosarcoma. Although rare instances of uterine leiomyosarcoma have been previously reported, due to changes in diagnostic criteria and nomenclature, lesions previously called leiomyosarcoma may in fact be atypical smooth muscle neoplasms/leiomyomas [Muller et al 2017].

Renal cancer. Most renal tumors are unilateral and solitary; in a few individuals, they are multifocal or bilateral. 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 FH tumor predisposition syndrome present with or develop renal cancer. Current estimates are lower than initially reported, suggesting ascertainment bias in previous studies as well as a much higher prevalence of FH pathogenic variant heterozygotes in the general population than previously recognized [Shuch et al 2020].

In one review of published reports, of 672 individuals diagnosed with HLRCC-related renal cell cancer (RCC) (FH pathogenic variant status not specified), the mean age at diagnosis when available for 51 individuals was 36.1 years (range: 11-79) [Chayed et al 2021]. In a recent series of 185 individuals from 69 families in the United Kingdom, 23 (12.4%) were reported to have a renal tumor. The mean age at symptomatic presentation of RCC was age 44 years and median survival was 21 months. Mean survival was significantly shorter for individuals with stage III or IV RCC (15.8 months) compared to mean survival of individuals with stage I or II RCC (80.7 months), supporting a role for screening for early detection [Forde et al 2020].

FH-related RCC is a molecularly defined subtype that may have a range of histologic phenotypes [Degenhardt et al 2025]. FH-related RCC often shows loss of FH staining and positive staining for S-(2-succino) cysteine. Immunohistochemistry cannot distinguish between tumors due to FH tumor predisposition syndrome and those due to biallelic somatic FH pathogenic variants.

A distinct CpG island methylator phenotype (CIMP) has been described for FH-associated RCC [Sun et al 2021, Ricketts et al 2022]. FH-deficient RCC has also been shown to have increased T cell infiltration in tumors with high expression of PD-L1 [Sun et al 2021].

Pheochromocytoma and paraganglioma. Germline FH pathogenic variants have also been described among individuals with paraganglioma/pheochromocytoma (see Genotype-Phenotype Correlations).

Other tumors. While other tumors have been described in individuals with germline FH pathogenic variants, further data will be needed to determine whether these are FH-related tumors [Lehtonen et al 2006, Ylisaukko-oja et al 2006].

Genotype-Phenotype Correlations

Pheochromocytoma/paraganglioma. Emerging data suggests that specific FH pathogenic variants are associated with an increased risk of pheochromocytoma/paraganglioma, including the following predominantly missense variants c.157G>A (p.Glu53Lys), c.220A>T (p.Arg74Ser), c.268-2A>G, c.349G>C (p.Ala117Pro), c.580G>A (p.Ala194Thr), c.700A>G (p.Thr234Ala), c.816_836del21 (p.Ala273_Val279del), c.908T>C (p.Leu303Ser), c.986A>G (p.Asn329Ser), c.1142C>T (p.Thr381Ile), and c.1301G>A (p.Cys434Tyr) (see Table 6) [Fuchs et al 2023, Zavoshi et al 2023]. Individuals with these variants are less likely to have HLRCC or FH deficiency [Zavoshi et al 2023], although some overlap has been reported, including an individual with paraganglioma and a maternally inherited FH pathogenic variant whose mother had a uterine leiomyoma at age 30 years (immunohistochemistry not available) [Fuchs et al 2023], and an individual with a family history of RCC (unknown if FH deficient) [Richter et al 2019]. An individual with FH deficiency had biallelic FH pathogenic variants including p.Leu303Ser [Richter et al 2019].

Fumarate hydratase (FH) deficiency. Emerging data suggests that specific FH pathogenic variants in the biallelic state (homozygous or compound heterozygous), including c.521C>G (p.Pro174Arg), c.923C>G (p.Ala308Gly), c.1127A>C (p.Gln376Pro), and c.1431_1433dupAAA (p.Lys477dup) (see Table 6), may lead to FH deficiency without an increased risk of tumors associated with HLRCC [Shuch et al 2020, Kamihara et al 2021].

Penetrance

Penetrance is currently unknown. Most studies have focused on families with clinical manifestations; therefore, penetrance estimates will continue to be refined as more population-based testing occurs.

Nomenclature

Historically, the predisposition to the development of cutaneous leiomyomas was referred to as multiple cutaneous leiomyomatosis (MCL/MCUL).

Reed et al [1973] described two kindreds in which multiple members exhibited cutaneous leiomyomas and uterine leiomyomas inherited in an autosomal dominant manner. Subsequently, the association of cutaneous and uterine leiomyomas was referred to as Reed's syndrome.

The association of cutaneous and uterine leiomyomas with renal cancer was described in two Finnish families [Launonen et al 2001]. The name hereditary leiomyomatosis and renal cell cancer (HLRCC) was designated.

Germline FH pathogenic variants are now known to be associated with a predisposition to a variety of tumors; the term "FH tumor predisposition syndrome" acknowledges this association.

Prevalence

The prevalence of FH pathogenic variants in the general population is estimated to range from 1:2,563 to 1:3,247 using data from the BRAVO and gnomAD population databases [Popp et al 2020]. The prevalence ranges from 1:901 to 1:1,252 using data from the Exome Aggregation Consortium (ExAC) and 1000 Genomes Project [Shuch et al 2020]. FH tumor predisposition syndrome is likely to be underrecognized.

Founder variants have been reported in a few populations (see Table 6).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with FH tumor predisposition syndrome, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Cutaneous lesions. Cutaneous leiomyomas should be examined by a dermatologist.

• Surgical excision, especially for solitary or a few symptomatic lesions, is considered standard therapy [Malik et al 2015, Patel et al 2017].
• Lesions may also be treated by carbon dioxide laser, cryotherapy, or electrodessication [Malik et al 2015, Adams et al 2017, Patel et al 2017].
• Lesions have a high rate of recurrence [Malik et al 2015].
• Medications are used as an adjunct for pain relief and may include drugs that lead to vasodilation (such as nitroglycerin, nifedipine, phenoxybenzamine, or doxazosin) and/or drugs for neuropathic pain (such as gabapentin, pregabalin, and duloxetine) [Patel et al 2017].
• In one small randomized controlled trial, intralesional botulinum toxin improved quality of life [Naik et al 2015].

Uterine fibroids should be evaluated by a gynecologist. Most females with FH tumor predisposition syndrome require medical and/or surgical intervention earlier than females without an FH germline pathogenic variant.

• Medical therapies include gonadotropin-releasing hormone agonists and intrauterine devices releasing progesterone [Patel et al 2017].
• Surgical options include myomectomy and hysterectomy. If surgery is performed, careful histologic examination is recommended to differentiate between atypical smooth muscle neoplasm and leiomyosarcoma.

Renal tumors. Given the aggressiveness and poor prognosis associated with FH-related renal cell carcinoma (RCC), early detection and surgical excision are critical at the first sign of FH-related RCC.

• Expert opinion should be sought with a urologic oncology surgeon familiar with FH tumor predisposition syndrome. Prompt surgical resection (regardless of size) with wide margins is recommended; total radical nephrectomy should be considered (see NCCN Guidelines, Kidney Cancer Version 3.2025). Small, localized tumors may allow for complete excision. Due to metastatic potential, lymph node dissection may be considered for staging even in the setting of small tumors.
• Nonsurgical approaches such as surveillance, cryoablation, and radiofrequency ablation are not appropriate for the management of FH-related renal malignancies [Adams et al 2017].
• Treatment with erlotinib plus bevacizumab demonstrated benefit in individuals with HLRCC-related metastatic RCC [Srinivasan et al 2020] (see NCCN Guidelines, Kidney Cancer Version 3.2025).
• Cabozantinib plus nivolumab may be useful.

Surveillance

Regular surveillance with an emphasis on early detection of RCC by clinicians familiar with the clinical manifestations of FH tumor predisposition syndrome is recommended. Surveillance guidelines still require prospective validation, preferably in the context of international multicenter collaboration [Michaeli et al 2025; NCCN Guidelines, Kidney Cancer Version 3.2025].

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual by molecular genetic testing for the FH pathogenic variant in the family in order to:

• Identify as early as possible those who would benefit from early surveillance and treatment;
• Reduce costly screening procedures in those who have not inherited the pathogenic variant.

Although surveillance may also be considered for at-risk family members who have not undergone molecular genetic testing or while testing is pending, definitive predictive testing is recommended as soon as possible.

Recommendations vary regarding the most appropriate age at which to perform predictive testing for a familial germline FH pathogenic variant. Predictive testing can be performed around the time that surveillance would begin. Consensus recommendations from an American Association for Cancer Research (AACR) workshop on cancer predisposition among children and adolescents supports renal tumor surveillance from age ten years [Michaeli et al 2025].

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

FH-related RCC

• Targeting of tumor vasculature and glucose transport has been attempted using bevacizumab and erlotinib. Park et al [2019] reported long-term response to bevacizumab plus erlotinib after failure of temsirolimus followed by axitinib in an adult with FH-related RCC [Park et al 2019]. A retrospective analysis of this combination in ten individuals, including untreated and previously treated individuals, showed an overall response rate of 50% [Choi et al 2019]. A prospective trial of this combination (erlotinib and bevacizumab; NCT01130519) in 42 individuals with advanced HLRCC showed an objective response rate in 64% (27/42 individuals) (95% CI: 49-77) and longer median progression-free survival in individuals with FH-related HLRCC compared with sporadic HLRCC (21.1 months vs 8.7 months) [Srinivasan et al 2014, Srinivasan et al 2020].
• A single-center, single-arm trial currently open in China includes individuals with locally advanced or metastatic FH-deficient RCC and treatment with a tyrosine kinase inhibitor (lenvatinib) and an anti-PD-1 inhibitor (tislelizumab) as first-line therapy (NCT05877820).
• An open Phase II clinical trial focuses on the combination of bevacizumab, erlotinib, and atelzolizumab in HLRCC-related advanced/metastatic RCC (NCT04981509) [Kong et al 2025].

Fumarate accumulation in fumarate hydratase (FH)-deficient cells may lead to a defect in homologous recombination double-strand break repair. This suggests a vulnerability to poly ADP-ribose polymerase (PARP) inhibition, demonstrated in cell lines and in mice with FH-deficient tumors [Sulkowski et al 2018]. Preclinical efficacy of a low-dose chemotherapy with PARP inhibitor combination has been reported [Ueno et al 2022]. A trial of pamiparib and temozolomide treatment in HLRCC was halted due to low enrollment (NCT04603365).

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

FH tumor predisposition syndrome is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Some individuals diagnosed with FH tumor predisposition syndrome inherited a germline FH pathogenic variant from a heterozygous parent. A heterozygous parent may or may not have manifestations of FH tumor predisposition syndrome.
• Some individuals diagnosed with FH tumor predisposition syndrome have the disorder as the result of a de novo FH pathogenic variant. The proportion of individuals who have FH tumor predisposition syndrome as the result of a de novo FH pathogenic variant is unknown.
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance (penetrance is currently unknown), early death of a parent before the onset of symptoms, or late onset of the disease in an affected parent. Therefore, de novo occurrence of an FH pathogenic variant cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the FH pathogenic variant.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.

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 has an FH pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. Given variable penetrance of manifestations, it is not possible to precisely predict the likelihood of manifestations, age of onset, severity and type of features, or rate of disease progression in sibs who inherit a germline FH pathogenic variant.
• If the FH pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [Rahbari et al 2016].
• If the parents are clinically unaffected but their genetic status is unknown, sibs of a proband are presumed to be at increased risk for FH tumor predisposition syndrome because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism.

Offspring of a proband

• Each child of an individual with FH tumor predisposition syndrome has a 50% chance of inheriting the FH pathogenic variant.
• It is not possible to precisely predict the likelihood of manifestations, age of onset, severity and type of features, or rate of disease progression in offspring who inherit the FH pathogenic variant.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has an FH pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of surveillance, early diagnosis, and treatment.

Testing of at-risk asymptomatic family members

• Predictive testing for at-risk family members is possible once the FH pathogenic variant has been identified in an affected family member.
• Molecular genetic testing of at-risk family members is appropriate to identify the need for clinical surveillance. Those who have a pathogenic variant should be offered regular lifelong surveillance. Family members who have not inherited the pathogenic variant and their subsequent offspring have risks similar to the general population.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.
• Genetic counseling for individuals known to be heterozygous for an FH pathogenic variant and reproductive partner testing is recommended. This is particularly important as emerging data suggest that specific FH pathogenic variants (see Genotype-Phenotype Correlations) may confer risk for fumarate hydratase deficiency in the biallelic state (homozygous or compound heterozygous) even in the absence of clinical manifestations of FH tumor predisposition syndrome in the heterozygous individual.

Prenatal Testing and Preimplantation Genetic Testing

Once the FH pathogenic variant has been identified in a family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

FH encodes the enzyme fumarate hydratase (FH) (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.

Germline pathogenic variants in FH, plus somatic variants and loss of heterozygosity in tumor tissue, suggest that loss of function of FH is the basis of tumor formation in FH tumor predisposition syndrome [Tomlinson et al 2002].

Within FH-deficient renal cell cancer (RCC), there is impaired oxidative phosphorylation and a shift to aerobic glycolysis, known as the Warburg effect. AMP-activated protein kinase levels are decreased, with a variety of downstream effects including decreased p53 levels, lower cellular iron levels, and stabilization of hypoxia-inducible factor (HIF) 1-alpha and increased expression of VEGF and GLUT1 [Linehan & Rouault 2013].

Other work also suggests that fumarate accumulation in FH-deficient cells leads to defective homologous recombination double-strand break repair, which may provide an additional approach for therapeutic investigation (see Therapies Under Investigation).

Mechanism of disease causation. Loss of function

FH-specific laboratory technical considerations. FH encodes two protein isoforms, which are targeted to different subcellular locations: the mitochondria and the cytosol. While the reference sequences in Table 6 are for the longer 510-amino-acid mitochondrial isoform, protein variant designations may be based on the shorter 467-amino-acid cytosolic isoform. Both designations are found in the literature and in locus-specific databases, as documented by the p.Arg101Pro alias in Table 6. An alternative transcription initiation mechanism has been proposed for the two isoforms [Dik et al 2016], in contrast to previous reports that suggested alternative translation initiation. For a detailed discussion of the data supporting these mechanisms, see Dik et al [2016].

Acknowledgments

First and foremost, the authors would like to express our gratitude to all the individuals and families with FH tumor predisposition syndrome who continue to teach us. The authors would also like to thank the previous authors of this GeneReview, Manop Pithukpakorn, MD, and Jorge R Toro, MD, as well as Jason Hornick, MD, and Toni Choueiri, MD, for their input regarding histopathology of atypical leiomyomas and management of renal cell carcinoma, respectively.

Author History

Junne Kamihara, MD, PhD (2020-present)
Manop Pithukpakorn, MD; Mahidol University, Bangkok (2006-2020)
Huma Q Rana, MD (2020-present)
Kris Ann Schultz, MD (2020-present)
Jorge R Toro, MD; National Cancer Institute (2006-2020)

Revision History

• 8 May 2025 (sw) Comprehensive update posted live
• 2 April 2020 (sw) Comprehensive update posted live
• 6 August 2015 (me) Comprehensive update posted live
• 2 November 2010 (me) Comprehensive update posted live
• 31 July 2006 (me) Review posted live
• 6 March 2006 (jrt) Original submission

Published Guidelines / Consensus Statements

• 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.
• Schultz KAP, Rednam SP, Kamihara J, Doros L, Achatz MI, Wasserman JD, Diller LR, Brugières L, Druker H, Schneider KA, McGee RB, Foulkes WD. PTEN, DICER1, FH, and their associated tumor susceptibility syndromes: clinical features, genetics, and surveillance recommendations in childhood. Clin Cancer Res. 2017;23:e76-e82.

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