FH Tumor Predisposition Syndrome

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.