Clinical Information

Tumors occurring within the endocrine and neuroendocrine systems, including thyroid/parathyroid tumors, pituitary tumors, pheochromocytomas (PCC), and paragangliomas (PGL), may occasionally be caused by an underlying hereditary predisposition. Suspicion may be raised for a hereditary cause in families with a strong history of endocrine cancers, patients diagnosed with an endocrine cancer at an early age, patients with multiple primary endocrine cancer diagnoses, and patients with specific histological subtypes, such as medullary thyroid cancer.

The most common endocrine-related malignancy is thyroid cancer, with a lifetime risk of approximately 1.2%.(1,2) Papillary thyroid cancers are typically sporadic but can be seen in individuals or families with familial adenomatous polyposis (FAP) syndrome, caused by variants within the APC gene (cribriform-morular variant). Additionally, about 5% of cases of isolated papillary thyroid cancer cluster in a familial pattern; however, in most cases, no underlying genetic predisposition has yet been identified.(3-6)

Follicular and/or papillary thyroid cancers may be seen in families with PTEN hamartoma tumor syndrome (PHTS). Individuals with disease-causing PTEN variants have a 70-fold increased incidence of thyroid cancer compared to the general population.(7) Thyroid cancers with follicular or papillary features can also be seen in individuals with disease-causing DICER1 variants, as well as individuals with Carney complex, which is caused by disease-causing variants within the PRKAR1A gene.(8,9)

Approximately 25% of cases of medullary thyroid cancer (MTC) are caused by an inherited RET variant.(10) Some disease-causing RET variants are associated with only familial MTC, while others cause a syndrome called multiple endocrine neoplasia type 2 (MEN2). Individuals with MEN2 have a high risk for MTC and may also have other tumors of the endocrine/neuroendocrine system, including PGL, PCC, and parathyroid tumors.(11)

Parathyroid and pituitary tumors may be caused by disease-causing variants within MEN1, CDKN1B, and CDC73. The AIP gene is associated with hereditary predisposition for isolated pituitary adenomas.

PCC and PGL are rare neuroendocrine tumors, 30% of which may have an underlying hereditary predisposition.(12) The genes most frequently associated with increased risk for PGL/PCC are the succinate dehydrogenase-associated genes: SDHA, SDHAF2, SDHB, SDHC, and SDHD.

Germline alterations in the MAX gene are typically associated with increased risk for PCC, although some individuals have been identified with PGL. MAX variants occur in approximately 1% of patients with hereditary PGL/PCC syndromes.(13)

TMEM127 variants are most commonly associated with PCC and rarely PGL.(12) Alterations of TMEM127 account for approximately 2% of individuals with hereditary PGL/PCC (13).

Recent evidence suggests that disease-causing variants in FH increase risk for PGL/PCC.(14,15) Individuals with disease-causing FH variants also have a significantly increased risk for cutaneous or uterine leiomyomata and renal tumors.(16)

Alterations in VHL, NF1, and RET also increase risk for PGL/PCC in addition to other features and tumor types.(17)

The National Comprehensive Cancer Network and the American Cancer Society provide recommendations regarding the medical management of individuals with hereditary endocrine tumor syndromes.(17,18)