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FH gene

Associated Syndrome Name: Hereditary Leiomyomatosis and Renal Cell Carcinoma syndrome (HLRCC)

FH Summary Cancer Risk Table

Cancer	Genetic Cancer Risk
Other	High Risk
Renal	High Risk
Skin	Elevated Risk

FH gene Overview

Hereditary Leiomyomatosis and Renal Cell Carcinoma syndrome (HLRCC) 1, 2, 3, 4

Individuals with mutations in the FH gene have Hereditary Leiomyomatosis and Renal Cell Carcinoma syndrome (HLRCC).
Patients with HLRCC have a high risk for type 2 papillary renal cancer, which is highly aggressive. Other types of malignant (cancerous) and non-malignant (benign) renal tumors can also occur.
Most women with HLRCC will develop uterine leiomyomas (fibroids) at relatively young ages. These may be multiple and large in size, requiring surgery. There may be a small risk for these benign uterine tumors to develop into malignant leiomyosarcomas.
Patients with HLRCC often develop non-cancerous smooth muscle tumors of the skin (skin leiomyomas). These may be painful and are most commonly found on the trunk, arms, leg and face. When present, they tend to increase in number and size with age. There may be a small risk for these benign skin tumors to develop into malignant leiomyosarcomas.
Studies have looked at the possibility that patients with HLRCC have an increased risk for other cancers, benign tumors and additional medical problems. In particular, there is some evidence for an increased risk for paragangliomas/pheochromocytomas. However, the data are not conclusive at this time and there are currently no medical management guidelines related to these possible risks.
Although there are high risks for cancer and other medical issues in patients with HLRCC, and there is still uncertainty about all of the associated risks, it may be possible to reduce these risks with appropriate medical management. Guidelines from the National Comprehensive Cancer Network (NCCN), the American Association for Cancer Research (AACR), and the Consensus Meeting of the Second Symposium on HLRCC are provided below. Since HLRCC is a complex condition, patients with FH mutations and a diagnosis of HLRCC should be managed by a multidisciplinary team with experience in the surveillance and treatment of the complications associated with this condition.

FH gene Cancer Risk Table

Cancer Type	Age Range	Cancer Risk	Risk for General Population
Renal	To age 801, 2, 4, 5	16-21%, with a strong tendency towards young ages of diagnosis, median age of diagnosis is estimated to be 44	1.4%
Uterine Leiomyosarcoma	To age 802, 4, 6	Possibly elevated risk	<0.1%
Skin Leiomyosarcoma	To age 802, 4, 6	Possibly elevated risk	<0.1%
Other - Non-malignant features of HLRCC (women only)	All ages2, 4, 6	Most women with HLRCC will develop multiple uterine fibroids at young ages (see Overview)	NA
Other - Non-malignant features of HLRCC	All ages2, 4, 6	Individuals with HLRCC are likely to develop skin leiomyomas (see Overview)	NA

FH Cancer Risk Management Table

The overview of medical management options provided is a summary of professional society guidelines. The most recent version of each guideline should be consulted for more detailed and up-to-date information before developing a treatment plan for a particular patient.

This overview is provided for informational purposes only and does not constitute a recommendation. While the medical society guidelines summarized herein provide important and useful information, medical management decisions for any particular patient should be made in consultation between that patient and his or her healthcare provider and may differ from society guidelines based on a complete understanding of the patient’s personal medical history, surgeries and other treatments.

Cancer Type	Procedure	Age to Begin	Frequency (Unless otherwise indicated by findings)
Renal	Abdominal imaging with MRI (preferred) or CT, with and without contrast6, 7, 8	8 to 10 years	Annually
	Since mutation carriers are at an increased risk for more aggressive kidney cancer, this information may be considered when choosing management options for individuals with any suspicious renal lesion or a diagnosis of renal cancer6, 7	NA	NA
Uterine Leiomyosarcoma	Gynecologic exam, with ultrasound and other imaging as needed to evaluate for severity of uterine fibroids and to monitor for changes suggestive of sarcoma6	Age 20, or younger if symptoms are present	Annually
Skin Leiomyosarcoma	Monitoring of leiomyomas for changes suggestive of sarcoma6	At time of diagnosis of HLRCC	Annually
Other - Non-malignant features of HLRCC	Monitoring and treatment for uterine fibroids6	At time of diagnosis of HLRCC	Annually
	Monitoring and treatment for skin leiomyomas as necessary6	At time of diagnosis of HLRCC	Annually
For Patients With A Cancer Diagnosis	For patients with a gene mutation and a diagnosis of cancer, targeted therapies may be available as a treatment option for certain tumor types (inhibitors of VEGF and EGFR)8	NA	NA

Information for Family Members

The following information for Family Members will appear as part of the MMT for a patient found to have a mutation in the FH gene.

This patient's relatives are at risk for carrying the same mutation(s) and associated cancer risks as this patient. Cancer risks for females and males who have this/these mutation(s) are provided below.

Family members should talk to a healthcare provider about genetic testing. Close relatives such as parents, children, brothers and sisters have the highest chance of having the same mutation(s) as this patient. Other more distant relatives such as cousins, aunts, uncles, and grandparents also have a chance of carrying the same mutation(s). Testing of at-risk relatives can identify those family members with the same mutation(s) who may benefit from surveillance and early intervention.

In rare instances, an individual may inherit mutations in both copies of the FH gene, leading to the condition Fumarase Deficiency, or Fumaric Aciduria. Individuals with this condition have severe neurologic problems during infancy, usually leading to death in childhood. The children of this patient are at risk of inheriting Fumarase Deficiency only if the other parent is also a carrier of an FH mutation. Screening the other biological parent of this patient for FH mutations may be appropriate even if they do not have a diagnosis of HLRCC.4

Since FH mutations have a risk for cancers in children and some screenings may be considered to begin at young ages, mutation testing should be considered in childhood, before beginning MRI screening.3, 6

References

Toro JR, et al. 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. PMID: 12772087.

Forde C, et al. Hereditary Leiomyomatosis and Renal Cell Cancer: Clinical, Molecular, and Screening Features in a Cohort of 185 Affected Individuals. Eur Urol Oncol. 2020 3:764-772. PMID: 31831373.

Grubb RL 3rd, et al. Hereditary leiomyomatosis and renal cell cancer: a syndrome associated with an aggressive form of inherited renal cancer. J Urol. 2007 177:2074-9. PubMed PMID: 17509289.

Kamihara J, et al. FH Tumor Predisposition Syndrome. 2020 Aug 13 In: Adam MP, et al., editors. GeneReviews^® [Internet]. PMID: 20301430.

SEER*Explorer: An interactive website for SEER cancer statistics [Internet]. Surveillance Research Program, National Cancer Institute. [Cited 2020 Sep 14]. Available from https://seer.cancer.gov/explorer/.

Schultz KAP, et al. PTEN, DICER1, FH, and Their Associated Tumor Susceptibility Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood. Clin Cancer Res. 2017 23:e76-e82. PMID: 28620008.

Menko FH, et al. Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment. Fam Cancer. 2014 13:637-44. PMID: 25012257.

Motzer RJ et al. NCCN Clinical Practice Guidelines in Oncology^®: Kidney Cancer. V 1.2022. July 1. Available at https://www.nccn.org.

Last Updated on 20-Jul-2023

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