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 a small number of families. Cutaneous leiomyomata appear as skin-colored to light brown papules or nodules distributed over the trunk and extremities, and occasionally on the face, and appear at a mean age of 30 years, increasing in size and number with age. Uterine leiomyomata tend to be numerous and large; age at diagnosis ranges from 18 to 53 years, with most women 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 age 40 years.

Diagnosis/testing.

Diagnosis of FH tumor predisposition syndrome is established by identification of a heterozygous pathogenic variant in FH.

Management.

Treatment of manifestations: Surgical excision, carbon dioxide laser, cryotherapy, or electrodessication to remove painful cutaneous leiomyomas. Medications are used as an adjunct for pain relief, and 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, antihormonal medications, intrauterine devices releasing progesterone, myomectomy, and hysterectomy. Consultation with a urologic oncology surgeon familiar with this syndrome should be sought for kidney tumors. Total or partial nephrectomy with wide margins may be carefully considered in some settings.

Surveillance: Full skin examination every one to two years to assess for extent of disease and evaluate for changes; annual gynecologic consultation to assess severity of uterine fibroids from age 20 years; annual MRI with 1- to 3-mm slices through kidney from age eight years.

Evaluation of relatives at risk: When the FH pathogenic variant in the family is known, molecular genetic testing of asymptomatic at-risk relatives provides diagnostic certainty, allowing for early surveillance and treatment.

Genetic counseling.

FH tumor predisposition syndrome is inherited in an autosomal dominant manner. If a parent of a proband has an FH pathogenic variant, the sibs of the proband have a 50% chance of inheriting the pathogenic variant. Each child of an individual with FH tumor predisposition syndrome has a 50% chance of inheriting the pathogenic variant. The degree of clinical severity is not predictable. Preimplantation genetic testing and prenatal testing are possible if the pathogenic variant in the family is known.

Suggestive Findings

FH tumor predisposition syndrome should be suspected in individuals with the following features.

Cutaneous leiomyomata (~50%) [Smit et al 2011, Muller et al 2017, Bhola et al 2018]

• Skin-colored to light brown/reddish papules or nodules distributed over the trunk, extremities, and occasionally on the face and neck
• May be single, grouped/clustered, segmental, or disseminated
• Histopathology shows bundles of smooth muscle fibers with central, long blunt-edged nuclei [Toro et al 2003].

Uterine leiomyomata (uterine fibroids) (~90% of females) [Wei et al 2006, Smit et al 2011, Muller et al 2017]

• Fibroids tend to be numerous and large.
• Fibroids often demonstrate loss of FH staining and positive cytoplasmic staining for S-(2-succino) cysteine [Martínek et al 2015, Andrici et al 2018, Muller et al 2018].

Renal tumors (~15%) [Muller et al 2017]. Usually solitary, highly aggressive renal cell carcinoma (RCC) that metastasizes early

The spectrum of renal tumors includes type 2 papillary, undefined papillary, unclassified, tubulocystic, and collecting-duct carcinoma [Wei et al 2006].

Establishing the Diagnosis

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

Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

Molecular genetic testing approaches include gene-targeted testing (multigene panel, single-gene testing) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of FH tumor predisposition syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of FH tumor predisposition syndrome has not been considered are more likely to be diagnosed using genomic testing (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. Affected individuals may have a single, multiple, or no cutaneous leiomyomas, typically one or more uterine fibroids, and/or a single or no renal tumors. Rarely, individuals may develop multifocal renal tumors. Disease severity shows significant intra- and interfamilial variation [Wei et al 2006].

Cutaneous leiomyomas. Clinically, cutaneous leiomyomas present as firm skin-colored to light brown-colored papules and nodules. These cutaneous lesions occur at a mean age of 30 years (range: age 10-77 years) [Muller et al 2017] and tend to increase in size and number with age. Affected individuals often note that the skin lesions are painful or sensitive to light touch and/or cold temperature [Lehtonen 2011].

Histologically, proliferation of bundles of smooth muscle fibers with central blunt-edged nuclei is observed [Toro et al 2003].

Cutaneous leiomyosarcoma. In a series of 182 individuals with FH tumor predisposition syndrome from 114 families, three individuals developed skin leiomyosarcoma [Muller et al 2017]. Due to changes in diagnostic criteria and nomenclature, lesions previously called leiomyosarcoma may have been atypical smooth-muscle neoplasms/leiomyomas [Kraft & Fletcher 2011].

Uterine leiomyomas (uterine fibroids). Women with FH tumor predisposition syndrome have more uterine fibroids and onset at a younger age than women in the general population. The age at identification of fibroids ranges from 18 to 53 years (mean: age ~30 years) [Lehtonen 2011]. Uterine fibroids in women with FH tumor predisposition syndrome are usually large and numerous and associated with irregular menses, menorrhagia, or pain [Lehtonen 2011]. Women with FH tumor predisposition syndrome often undergo hysterectomy or myomectomy for symptomatic uterine fibroids at a younger age. In one series, 59 of 114 women (52%) with FH tumor predisposition syndrome had myomectomy or hysterectomy with median age of 35 (range 25-58) [Muller et al 2017].

Among a cohort of 2,060 women with uterine smooth muscle tumors, a prospective screening program identified a tumor with 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 macro-nucleolus surrounded by a halo and eosinophilic globules seen under high magnification [Rabban et al 2019]. Ten women 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].

Uterine leiomyosarcoma. Six women with a germline FH pathogenic variant and uterine leiomyosarcoma have been reported in the Finnish population; including three individuals with an additional pathogenic variant identified in tumor tissue, and one individual with isolated leiomyosarcoma, decreased FH activity, but no pathogenic variant identified on tumor tissue testing [Lehtonen et al 2006, Ylisaukko-oja et al 2006b]. However, uterine leiomyosarcoma has not been reported in other cohorts [Muller et al 2017]. 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. 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.

Of 182 individuals with FH tumor predisposition syndrome from 114 families, 34 (19%) were diagnosed with RCC(s). The median age at diagnosis was 40 years. Of 31 individuals with follow-up data available, 82% developed metastatic disease: 16 (47%) presented with metastatic RCC (de novo metastatic disease) and another 12 (35%) became metastatic within three years. Among individuals with metastatic RCC, median survival was 18 months [Muller et al 2017].

FH tumor predisposition syndrome is associated with a spectrum of renal tumors including type 2 papillary, undefined papillary, unclassified, tubulocystic, and collecting-duct carcinoma [Wei et al 2006].

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 pathogenic variants.

The Cancer Genome Atlas has additionally reported a CpG island methylator phenotype (CIMP) as the signature FH-associated RCC [Cancer Genome Atlas Research Network 2016].

Pheochromocytoma and paraganglioma. In 2014, two studies aimed at identifying new pheochromocytoma and paraganglioma susceptibility genes identified FH germline pathogenic variants in seven of 570 affected individuals [Castro-Vega et al 2014, Clark et al 2014]. Subsequently, two individuals with FH tumor predisposition syndrome from a French cohort (1%) were diagnosed with pheochromocytoma [Muller et al 2017]. The lifetime risks for pheochromocytoma and paraganglioma are unknown.

Other. In a Finnish population-based study of FH tumor predisposition syndrome, four individuals with breast cancer and one individual with bladder cancer were identified. In three of three breast cancers examined, loss of the wild type FH allele was noted [Lehtonen et al 2006].

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 2006a].

Genotype-Phenotype Correlations

No correlation is observed between specific FH pathogenic variants and the occurrence of cutaneous lesions, uterine fibroids, or renal cancer [Wei et al 2006].

FH pathogenic variants reported in families with paraganglioma include the following missense and splice site variants: p.Ala117Pro, c.268-2A>G, p.Thr381Ile, p.Ala194Thr, p.Asn329Ser, p.Cys43Tyr, p.Glu53Lys [Castro-Vega et al 2014, Clark et al 2014].

Pathogenic variant c.700A>G; p.Thr234Ala has been identified in approximately ten families with paraganglioma/pheochromocytoma with and without renal cell carcinoma [Author, personal communication].

Penetrance

Penetrance is currently unknown, as most studies have focused on families with clinical manifestations.

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 emerging understanding.

Prevalence

The prevalence of FH pathogenic variants is not known. FH tumor predisposition syndrome is likely to be under-recognized.

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 3 (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. Treatment of cutaneous leiomyomas may involve the following:

• Surgical excision, especially for a 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 women with FH tumor predisposition syndrome require medical and/or surgical intervention earlier than women without an FH germline pathogenic variant.
• Medical therapies include gonadotropin-releasing hormone agonists (GnRHa) 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 RCC, surgical excision of renal malignancies appears to require earlier and possibly more extensive surgery than other hereditary renal cancers.

• 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. Due to metastatic potential, lymph node dissection may be considered for staging even in the setting of small tumors.
• Given the aggressive nature of these tumors, only total nephrectomy was previously recommended. However, partial nephrectomy with a wide margin may be carefully considered in some settings when small, localized tumors may allow for complete excision (see NCI-PDQ^® Genetics of Renal Cell Carcinoma).
• Consultation by an expert familiar with this syndrome is indicated.
• Non-surgical approaches such as surveillance, cryoablation, and radiofrequency ablation are not appropriate for the management of FH-related renal malignancies [Adams et al 2017].

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 may also be considered for individuals with a suspected diagnosis in whom an FH pathogenic variant has not been identified, as well as for at-risk family members who have not undergone molecular genetic testing. Surveillance guidelines still require prospective validation, preferably in the context of international multicenter collaboration [Menko et al 2014, Schultz et al 2017].

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 and reduce costly screening procedures in those who have not inherited the pathogenic variant.

There have been variable recommendations regarding the most appropriate age at which to perform predictive testing for a familial germline FH pathogenic variant. Consensus recommendations from an American Association for Cancer Research (AACR) workshop on cancer predisposition among children and adolescents supports germline testing from age eight years. Surveillance for RCC in heterozygotes is also suggested to begin at age eight years [Schultz et al 2017]. This age was agreed upon as it precedes the youngest reported cases of FH-related RCC. These include an 8.5-cm papillary RCC discovered on first surveillance ultrasound in a child at age 11 years with a palpable renal mass [Alrashdi et al 2010], and an additional child found to have an RCC at age ten years [Menko et al 2014]. Nevertheless, the overall risk of developing RCC before age 20 years remains low (estimated at 1%-2%) [Menko et al 2014].

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

Therapies Under Investigation

FH-related RCC

• Many individuals with advanced disease have received vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) or mammalian target of rapamycin (mTOR) inhibitors. Several studies of anti-VEGF and novel tyrosine kinase inhibitor treatment in individuals with FH tumor predisposition syndrome and papillary RCC (including papillary type 2 RCC) have been conducted [Linehan & Rouault 2013]. Improvement of progression-free survival in individuals with papillary type 2 RCC with sunitinib was reported [Choueiri et al 2008, Clinical Trials].
• There is also interest in targeting FH-related RCC using a metabolic approach such as metformin in combination with vandetanib to inhibit DNA hypermethylation related to fumarate accumulation [Clinical Trials].
• 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 tumor predisposition syndrome-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 in previously untreated advanced papillary RCC is under way with preliminary results suggesting a 50% (12/20) overall response rate and 100% disease control rate in individuals with FH tumor predisposition syndrome [Srinivasan et al 2014].

Fumarate accumulation in FH-deficient cells may lead to a defect in homologous recombination double-strand break repair. This suggests a vulnerability to PARP (poly ADP-ribose polymerase) inhibition demonstrated in cell lines and in mice with FH-deficient tumors [Sulkowski et al 2018]. Human clinical trials using combination therapy for these tumors are currently in development [Author, personal communication].

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 an 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 cases caused by a de novo pathogenic variant is unknown because subtle manifestations in parents may not have been recognized and genetic testing data are insufficient.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo FH pathogenic variant.
• If the germline FH pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Although no instances of parental germline mosaicism have been reported, it remains a possibility.
• The family history of some individuals diagnosed with FH tumor predisposition syndrome 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. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has confirmed that neither of the parents has the germline FH pathogenic variant identified in the proband.

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, each sib of the proband is at a 50% risk of inheriting the pathogenic variant. 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 sibs who inherit a pathogenic variant.
• If the proband has a known FH pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].

Offspring of a proband. Each child of an individual with FH tumor predisposition syndrome has a 50% chance of inheriting the FH pathogenic variant. The degree of clinical severity in offspring who inherit the FH pathogenic variant is not predictable.

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, his or her 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. 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.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

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 some FH variants may represent hypomorphic alleles and confer risk for fumarate hydratase deficiency in the biallelic state (homozygous or compound heterozygous) even in the absence of manifestations of FH tumor predisposition syndrome in the individual or family.

Prenatal Testing and Preimplantation Genetic Testing

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Introduction. FH encodes the enzyme 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.

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

Within FH-deficient 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)-1α and increased expression of VEGF and GLUT1 [Linehan & Rouault 2013]. These metabolic derangements are the subject of novel efforts to target FH-related tumors (see Therapies Under Investigation).

Recent 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).

FH-specific laboratory considerations. FH encodes two protein isoforms, which are targeted to different subcellular locations: the mitochondria and the cytosol. While the reference sequences in Table 5 are for the longer 510-amino acid mitochondrial isoform, protein variant designations may be based on the shorter 467-amino acid cytosolic. Both designations are found in the literature and in locus-specific databases, as documented by the p.Arg101Pro variant in Table 5. Recently, an alternative transcription initiation mechanism was proposed for the two isoforms [Dik et al 2016], in contrast to previous reports that suggested of 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 Brian M Shuch, MD and Toni Choueiri, MD for their input regarding management of RCC.

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

• 13 August 2020 (jk) Revision: cutaneous lesions (See Differential Diagnosis.)
• 2 April 2020 (sw) Comprehensive update posted live
• 6 August 2015 (me) Comprehensive update posted live
• 2 November 2010 (me) Comprehensive update posted live
• 15 November 2007 (cd) Revision: prenatal diagnosis available on a clinical basis
• 31 July 2006 (me) Review posted live
• 6 March 2006 (jrt) Original submission

Published Guidelines / Consensus Statements

• American Society of Clinical Oncology. Policy statement update: genetic and genomic testing for cancer susceptibility. Available online. 2015. Accessed 9-8-22. [PubMed: 26324357]
• 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. [PMC free article: PMC4574691] [PubMed: 25012257]
• 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. [PubMed: 28620008]

Literature Cited

• Adams A, Sharpe KK, Peters P, Freeman M. Hereditary leiomyomatosis and renal cell cancer (HLRCC): cutaneous and renal manifestations requiring a multidisciplinary team approach. BMJ Case Rep. 2017;2017:bcr2016215115. [PMC free article: PMC5543308] [PubMed: 28400389]
• Alam NA, Barclay E, Rowan AJ, Tyrer JP, Calonje E, Manek S, Kelsell D, Leigh I, Olpin S, Tomlinson IP. Clinical features of multiple cutaneous and uterine leiomyomatosis: an underdiagnosed tumor syndrome. Arch Dermatol. 2005;141:199–206. [PubMed: 15724016]
• Alrashdi I, Levine S, Paterson J, Saxena R, Patel SR, Depani S, Hargrave DR, Pritchard-Jones K, Hodgson SV. Hereditary leiomyomatosis and renal cell carcinoma: very early diagnosis of renal cancer in a paediatric patient. Fam Cancer. 2010;9:239–43. [PubMed: 19967458]
• Andrici J, Gill AJ, Hornick JL. Next generation immunohistochemistry: emerging substitutes to genetic testing? Semin Diagn Pathol. 2018;35:161–9. [PubMed: 28662997]
• Bhola PT, Gilpin C, Smith A, Graham GE. A retrospective review of 48 individuals, including 12 families, molecularly diagnosed with hereditary leiomyomatosis and renal cell cancer (HLRCC). Fam Cancer. 2018;17:615–20. [PubMed: 29423582]
• Cancer Genome Atlas Research Network. Comprehensive molecular characterization of papillary renal-cell carcinoma. N Engl J Med. 2016;374:135–45. [PMC free article: PMC4775252] [PubMed: 26536169]
• Carlo MI, Mukherjee S, Mandelker D, Vijai J, Kemel Y, Zhang L, Knezevic A, Patil S, Ceyhan-Birsoy O, Huang KC, Redzematovic A, Coskey DT, Stewart C, Pradhan N, Arnold AG, Hakimi AA, Chen YB, Coleman JA, Hyman DM, Ladanyi M, Cadoo KA, Walsh MF, Stadler ZK, Lee CH, Feldman DR, Voss MH, Robson M, Motzer RJ, Offit K. Prevalence of germline mutations in cancer susceptibility genes in patients with advanced renal cell carcinoma. JAMA Oncol. 2018;4:1228–35. [PMC free article: PMC6584283] [PubMed: 29978187]
• Castro-Vega LJ, Buffet A, De Cubas AA, Cascón A, Menara M, Khalifa E, Amar L, Azriel S, Bourdeau I, Chabre O, et al. Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Hum Mol Genet. 2014;23:2440–6. [PubMed: 24334767]
• Chan I, Wong T, Martinez-Mir A, Christiano AM, McGrath JA. Familial multiple cutaneous and uterine leiomyomas associated with papillary renal cell cancer. Clin Exp Dermatol. 2005;30:75–8. [PubMed: 15663510]
• Choi Y, Keam B, Kim M, Yoon S, Kim D, Choi JG, Seo JY, Park I, Lee JL. Bevacizumab plus erlotinib combination therapy for advanced hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinoma: a multicenter retrospective analysis in Korean patients. Cancer Res Treat. 2019;51:1549–56. [PMC free article: PMC6790829] [PubMed: 30913859]
• Choueiri TK, Plantade A, Elson P, Negrier S, Ravaud A, Oudard S, Zhou M, Rini BI, Bukowski RM, Escudier B. Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. J Clin Oncol. 2008;26:127–31. [PubMed: 18165647]
• Chuang GS, Martinez-Mir A, Geyer A, Engler DE, Glaser B, Cserhalmi-Friedman PB, Gordon D, Horev L, Lukash B, Herman E, Cid MP, Brenner S, Landau M, Sprecher E, Garcia Muret MP, Christiano AM, Zlotogorski A. Germline fumarate hydratase mutations and evidence for a founder mutation underlying multiple cutaneous and uterine leiomyomata. J Am Acad Dermatol. 2005;52:410–6. [PubMed: 15761418]
• Clark GR, Sciacovelli M, Gaude E, Walsh DM, Kirby G, Simpson MA, Trembath RC, Berg JN, Woodward ER, Kinning E, Morrison PJ, Frezza C, Maher ER. Germline FH mutations presenting with pheochromocytoma. J Clin Endocrinol Metab. 2014;99:E2046–50. [PubMed: 25004247]
• Dik E, Naamati A, Asraf H, Lehming N, Pines O. Human fumarate hydratase is dual localized by an alternative transcription initiation mechanism. Traffic. 2016;17:720–32. [PubMed: 27037871]
• Gardie B, Remenieras A, Kattygnarath D, Bombled J, Lefèvre S, Perrier-Trudova V, Rustin P, Barrois M, Slama A, Avril MF, et al. Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma. J Med Genet. 2011;48:226–34. [PubMed: 21398687]
• Harrison WJ, Andrici J, Maclean F, Madadi-Ghahan R, Farzin M, Sioson L, Toon CW, Clarkson A, Watson N, Pickett J, Field M, Crook A, Tucker K, Goodwin A, Anderson L, Srinivasan B, Grossmann P, Martinek P, Ondič O, Hes O, Trpkov K, Clifton-Bligh RJ, Dwight T, Gill AJ. fumarate hydratase-deficient uterine leiomyomas occur in both the syndromic and sporadic settings. Am J Surg Pathol. 2016;40:599–607. [PMC free article: PMC4830748] [PubMed: 26574848]
• Heinritz W, Paasch U, Sticherling M, Wittekind C, Simon JC, Froster UG, Renner R. Evidence for a founder effect of the germline fumarate hydratase gene mutation R58P causing hereditary leiomyomatosis and renal cell cancer (HLRCC). Ann Hum Genet. 2008;72:35–40. [PubMed: 17908262]
• Kraft S, Fletcher CD. Atypical intradermal smooth muscle neoplasms: clinicopathologic analysis of 84 cases and a reappraisal of cutaneous "leiomyosarcoma.". Am J Surg Pathol. 2011;35:599–607. [PubMed: 21358302]
• Launonen V, Vierimaa O, Kiuru M, Isola J, Roth S, Pukkala E, Sistonen P, Herva R, Aaltonen LA. Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci USA. 2001;98:3387–92. [PMC free article: PMC30663] [PubMed: 11248088]
• Lehtonen HJ. Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics. Fam Cancer. 2011;10:397–411. [PubMed: 21404119]
• Lehtonen HJ, Kiuru M, Ylisaukko-Oja SK, Salovaara R, Herva R, Koivisto PA, Vierimaa O, Aittomaki K, Pukkala E, Launonen V, Aaltonen LA. Increased risk of cancer in patients with fumarate hydratase germline mutation. J Med Genet. 2006;43:523–6. [PMC free article: PMC2564537] [PubMed: 16155190]
• Linehan WM, Rouault TA. Molecular pathways: fumarate hydratase-deficient kidney cancer--targeting the Warburg effect in cancer. Clin Cancer Res. 2013;19:3345–52. [PMC free article: PMC4447120] [PubMed: 23633457]
• Malik K, Patel P, Chen J, Khachemoune A. Leiomyoma cutis: a focused review on presentation, management, and association with malignancy. Am J Clin Dermatol. 2015;16:35–46. [PubMed: 25605645]
• Martínek P, Grossmann P, Hes O, Bouda J, Eret V, Frizzell N, Gill AJ, Ondič O. Genetic testing of leiomyoma tissue in women younger than 30 years old might provide an effective screening approach for the hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC). Virchows Arch. 2015;467:185–91. [PubMed: 25985877]
• 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. [PMC free article: PMC4574691] [PubMed: 25012257]
• Muller M, Ferlicot S, Guillaud-Bataille M, Le Teuff G, Genestie C, Deveaux S, Slama A, Poulalhon N, Escudier B, Albiges L, et al. Reassessing the clinical spectrum associated with hereditary leiomyomatosis and renal cell carcinoma syndrome in French FH mutation carriers. Clin Genet. 2017;92:606–15. [PubMed: 28300276]
• Muller M, Guillaud-Bataille M, Salleron J, Genestie C, Deveaux S, Slama A, de Paillerets BB, Richard S, Benusiglio PR, Ferlicot S. Pattern multiplicity and fumarate hydratase (FH)/S-(2-succino)-cysteine (2SC) staining but not eosinophilic nucleoli with perinucleolar halos differentiate hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinomas from kidney tumors without FH gene alteration. Mod Pathol. 2018;31:974–83. [PubMed: 29410489]
• Naik HB, Steinberg SM, Middelton LA, Hewitt SM, Zuo RC, Linehan WM, Kong HH, Cowen EW. Efficacy of intralesional botulinum toxin a for treatment of painful cutaneous leiomyomas: a randomized clinical trial. JAMA Dermatol. 2015;151:1096–102. [PMC free article: PMC7712636] [PubMed: 26244563]
• Park I, Shim YS, Go H, Hong BS, Lee JL. Long-term response of metastatic hereditary leiomyomatosis and renal cell carcinoma syndrome associated renal cell carcinoma to bevacizumab plus erlotinib after temsirolimus and axitinib treatment failures. BMC Urol. 2019;19:51. [PMC free article: PMC6558845] [PubMed: 31182090]
• Patel VM, Handler MZ, Schwartz RA, Lambert WC. Hereditary leiomyomatosis and renal cell cancer syndrome: n update and review. J Am Acad Dermatol. 2017;77:149–58. [PubMed: 28314682]
• Rabban JT, Chan E, Mak J, Zaloudek C, Garg K. Prospective detection of germline mutation of fumarate hydratase in women with uterine smooth muscle tumors using pathology-based screening to trigger genetic counseling for hereditary leiomyomatosis renal cell carcinoma syndrome: a 5-year single institutional experience. Am J Surg Pathol. 2019;43:639–655. [PubMed: 30741757]
• Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
• Reed WB, Walker R, Horowitz R. Cutaneous leiomyomata with uterine leiomyomata. Acta Derm Venereol. 1973;53:409–16. [PubMed: 4127477]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
• 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. [PubMed: 28620008]
• Smit DL, Mensenkamp AR, Badeloe S, Breuning MH, Simon MEH, van Spaendonck KY, Aalfs CM, Post JG, Shanley S, Krapels IPC, Hoefsloot LH, van Moorselaar RJA, Starink TM, Bayley J-P, Frank J, van Steensel MAM, Menko FH. Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis. Clin Genet. 2011;79:49–59. [PubMed: 20618355]
• Srinivasan R, Su D, Stamatakis L, Siddiqui MM, Singer E, Shuch B, Nix J, Friend J, Hawks G, Shih J, et al. 5 mechanism based targeted therapy for hereditary leiomyomatosis and renal cell cancer (HLRCC) and sporadic papillary renal cell carcinoma: interim results from a phase 2 study of bevacizumab and erlotinib. Eur J Cancer. 2014;50:8.
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197–207. [PMC free article: PMC7497289] [PubMed: 32596782]
• Sulkowski PL, Sundaram RK, Oeck S, Corso CD, Liu Y, Noorbakhsh S, Niger M, Boeke M, Ueno D, Kalathil AN, Bao X, Li J, Shuch B, Bindra RS, Glazer PM. Nat Genet. 2018;50:1086–92. [PMC free article: PMC6072579] [PubMed: 30013182]
• Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, Leigh I, Gorman P, Lamlum H, Rahman S, Roylance RR, Olpin S, Bevan S, Barker K, Hearle N, Houlston RS, Kiuru M, Lehtonen R, Karhu A, Vilkki S, Laiho P, Eklund C, Vierimaa O, Aittomaki K, Hietala M, Sistonen P, Paetau A, Salovaara R, Herva R, Launonen V, Aaltonen LA. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 2002;30:406–10. [PubMed: 11865300]
• Toro JR, Nickerson ML, Wei MH, Warren MB, Glenn GM, Turner ML, Stewart L, Duray P, Tourre O, Sharma N, Choyke P, Stratton P, Merino M, Walther MM, Linehan WM, Schmidt LS, Zbar B. Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet. 2003;73:95–106. [PMC free article: PMC1180594] [PubMed: 12772087]
• Wei MH, Toure O, Glenn GM, Pithukpakorn M, Neckers L, Stolle C, Choyke P, Grubb R, Middelton L, Turner ML, Walther MM, Merino MJ, Zbar B, Linehan WM, Toro JR. Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer. J Med Genet. 2006;43:18–27. [PMC free article: PMC2564499] [PubMed: 15937070]
• Ylisaukko-oja SK, Cybulski C, Lehtonen R, Kiuru M, Matyjasik J, Szymañska A, Szymañska-Pasternak J, Dyrskjot L, Butzow R, Orntoft TF, Launonen V, Lubiñski J, Aaltonen LA. Germline fumarate hydratase mutations in patients with ovarian mucinous cystadenoma. Eur J Hum Genet. 2006a;14:880–3. [PubMed: 16639410]
• Ylisaukko-oja SK, Kiuru M, Lehtonen HJ, Lehtonen R, Pukkala E, Arola J, Launonen V, Aaltonen LA. Analysis of fumarate hydratase mutations in a population-based series of early onset uterine leiomyosarcoma patients. Int J Cancer. 2006b;119:283–7. [PubMed: 16477632]
• Yogev O, Pines O. Dual targeting of mitochondrial proteins: mechanism, regulation and function. Biochim Biophys Acta. 2011;1808:1012–20. [PubMed: 20637721]
• Zhang L, Walsh MF, Jairam S, Mandelker D, Zhong Y, Kemel Y, Chen YB, Musheyev D, Zehir A, Jayakumaran G, Brzostowski E, Birsoy O, Yang C, Li Y, Somar J, DeLair D, Pradhan N, Berger MF, Cadoo K, Carlo MI, Robson ME, Stadler ZK, Iacobuzio-Donahue CA, Joseph V, Offit K. Fumarate hydratase FH c.1431_1433dupAAA (p.Lys477dup) variant is not associated with cancer including renal cell carcinoma. Hum Mutat. 2020;41:103–9. [PMC free article: PMC6930334] [PubMed: 31444830]