Genetic Disorder Reference Sheet: FH Tumor Predisposition Syndrome

May 30, 2023 by Suzanne M. Mahon DNS, RN, AOCN®, AGN-BC, FAAN

Fumarate hydratase (FH) deficiency occurs in individuals who have homozygous (https://www.ons.org/genomics-taxonomy/genome-foundations#heterozygous) pathogenic variants in the tumor suppressor FH gene. The condition results in (https://www.ncbi.nlm.nih.gov/books/NBK1506/) poor feeding, failure to thrive, hypotonia, lethargy, and seizures. Development is severely delayed (https://www.ncbi.nlm.nih.gov/books/NBK1506/), and individuals are often nonverbal, unable to walk, and die in early childhood.

Most individuals with heterozygous (https://www.ons.org/genomics-taxonomy/genome-foundations#heterozygous) pathogenic variants in the FH gene are healthy but have (https://doi.org/10.1136/jclinpath-2021-207830) autosomal-dominant (https://www.ons.org/genomics-taxonomy/mode-inheritance) FH tumor predisposition syndrome. FH is a cancer susceptibility biomarker (https://www.ons.org/genomics-taxonomy/biomarkers) because it predicts an individual’s risk for developing (https://www.ncbi.nlm.nih.gov/books/NBK1252/) cutaneous leiomyomata, uterine leiomyomata (i.e., fibroids), and renal tumors. Some families also have pheochromocytomas and paragangliomas.

Clinical Characteristics

Cutaneous leiomyomata (see images in sidebar) are benign smooth muscle skin tumors that are flesh-colored to light brown papules distributed over the trunk, extremities, and occasionally face. Lesions typically appear around age 30 and continue to increase in size and number with age. They may manifest as single lesions, clusters, or widely disseminated papules.

Uterine leiomyomata tend to be numerous, large, and highly penetrant (https://www.ons.org/genomics-taxonomy/genome-foundations#penetrance) (42%–100% penetrance (https://doi.org/10.1111/aogs.14248)). Most patients are diagnosed at age 18–57 after experiencing irregular or heavy menstruation and pelvic pain, and 53% elect to have a hysterectomy by age 40. Fibroids show loss of FH staining and prominent, inclusion-like eosinophilic nucleoli.

Renal tumors are usually unilateral, solitary, and aggressive, with an estimated risk of 15%–21% (https://doi.org/10.1111/aogs.14248). The variety of pathologies include papillary, tubulocystic, and collecting duct carcinoma. Although the mean age of diagnosis is 40 years, children are also affected. FH-associated renal tumors are linked with poor survival because of their clinical aggressiveness and propensity to metastasize despite a small primary tumor size. Because of that, FH is considered a prognostic biomarker (https://www.ons.org/genomics-taxonomy/biomarkers).

Screening, Early Detection, and Monitoring

Recommendations are continually evolving but currently include (https://www.ncbi.nlm.nih.gov/books/NBK1252/):

Treatment and Management

Recommendations are also continually evolving but currently include (https://www.ncbi.nlm.nih.gov/books/NBK1252/):

Patient Education

Early detection requires patients to self-monitor their health. Oncology nurses can help individuals with FH pathogenic variants understand symptoms to report to their healthcare team immediately:

Nursing Implications

Because renal cancer screening begins at age 8, genetic testing is recommended at that age as well. First-degree relatives have a 50% chance of having a pathogenic variant. Testing partners of individuals with heterozygous variants who are considering conception provides a more accurate risk of the child having FH deficiency. Credentialed genetics professionals can assist families with that process. In addition to education on screening and symptoms to report promptly, patients require psychosocial support and a consistent team of providers to implement detection measures.


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