Heightened awareness for a possible genetic predisposition should be considered in all patients with medullary thyroid carcinoma, pheochromocytomas or paragangliomas, younger (< 30-40 years) patients with hyperparathyroidism or functional pituitary tumors, and patients with more than one endocrine tumor either personally or within their family.

A small proportion of endocrine tumors, both benign and malignant, are inherited and can be part of endocrine tumor syndromes. Such patients will be referred to our specialized genetics team for further testing, risk assessment counseling and screening. The most common endocrine neoplasia syndromes include:

MEN1

MEN1

MEN1 is an inherited genetic syndrome generally caused by a mutation in the menin gene. All patients develop primary hyperparathyroidism with 4-gland hyperplasia (Some can also have a CDKN1b mutation instead of a menin mutation) , and many patients develop pituitary tumors and/or pancreatic neuroendocrine tumors, all of which secrete hormones and therefore cause a variety of other symptoms. Other tumors that can be associated with the syndrome include adrenal or small bowel tumors. Diagnosis is made through germline genetic testing as well as a detailed family history. Affected patients require lifelong screening and surveillance for associated neuroendocrine tumors as well as surgical intervention when tumors are diagnosed.

MEN2

MEN2

MEN2 is an inherited endocrine disorder caused by a defect in the RET gene that results in clinically important syndromes of hormone excess that require effective strategies for early diagnosis and optimal surgical management. Almost all patients develop medullary thyroid cancer, about 50% of patients develop an adrenal pheochromocytoma, and some patients will develop primary hyperparathyroidism, either single or multigland disease or mucousal neuromas and gangliofibromas. Diagnosis is made through germline genetic testing  – different mutational variants (codons) carry age-associated risks of medullary thyroid cancer development and aggressiveness. Affected patients require lifelong screening and surveillance for associated neuroendocrine tumors as well as surgical intervention when tumors are diagnosed. All patients with medullary thyroid cancer should be evaluated for a RET mutation.

There are three main subtypes:

MEN 2A – multiple codons have been identified with varying ages of onset for medullary thyroid cancer and varying rates of penetrance of hyperparthyroidism and pheochromocytoma.
MEN 2B – most aggressive and earliest onset medullary thyroid cancer, pheochromocytoma, a marfanoid habitus, and mucousal neuromas.
FMTC (Familial Medullary Thyroid Cancer) – FMTC is the only tumor that patients develop.

Syndroms

Hereditary Pheochromocytoma / Paraganglioma Syndrome (including Succinate Dehydrogenase deficiencies SDH-A,B,C,D), Von Hippel Landau, Neurofibromatosis 1, 2

Close to 50% of patients with a pheochromocytoma or paraganglioma have a germline genetic mutation. Some of these are syndromes associated with other cancers or endocrine tumors. Therefore, all patients should be referred for genetics screening

Associated Syndromes

Papillary Thyroid Cancer Associated Syndromes

Certain genetic mutations/syndromes increase the risk for papillary thyroid cancer. These include familial adenomatous polyposis (APC), Li-Fraumeni syndrome (TP53), Cowden syndrome (PTEN), Carney complex (PRKAR1A) and DICER1syndrome (DICER1).