Multiple endocrine neoplasia type 2 (also known as "

Pheochromocytoma Pheochromocytoma (PHEO or PCC) is a rare tumor of the adrenal medulla composed of chromaffin cells, also known as pheochromocytes. When a tumor composed of the same cells as a pheochromocytoma develops outside the adrenal gland, it is referred t ...

and amyloid producing medullary thyroid carcinoma", "PTC syndrome," and "Sipple syndrome") is a group of medical disorders associated with

tumors A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

of the

endocrine system The endocrine system is a messenger system comprising feedback loops of the hormones released by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the neu ...

. The tumors may be

benign Malignancy () is the tendency of a medical condition to become progressively worse. Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous benign tumor, ''benign'' tumor in that a malign ...

or malignant (

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

). They generally occur in endocrine organs (e.g.

thyroid The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...

parathyroid Parathyroid glands are small endocrine glands in the neck of humans and other tetrapods. Humans usually have four parathyroid glands, located on the back of the thyroid gland in variable locations. The parathyroid gland produces and secretes par ...

, and adrenals), but may also occur in endocrine tissues of organs not classically thought of as endocrine. MEN2 is a sub-type of MEN (

multiple endocrine neoplasia Multiple endocrine neoplasia (abbreviated MEN) is a condition which encompasses several distinct syndromes featuring tumors of endocrine glands, each with its own characteristic pattern. In some cases, the tumors are malignant, in others, benign ...

) and itself has sub-types, as discussed below.

Signs and symptoms

MEN2 can present with a sign or symptom related to a tumor or, in the case of multiple endocrine neoplasia type 2b, with characteristic musculoskeletal and/or lip and/or gastrointestinal findings.

Medullary thyroid carcinoma Medullary thyroid cancer is a form of thyroid carcinoma which originates from the parafollicular cells (C cells), which produce the hormone calcitonin.Hu MI, Vassilopoulou-Sellin R, Lustig R, Lamont JP"Thyroid and Parathyroid Cancers"in Pazdur R, ...

(MTC) represents the most frequent initial diagnosis. Occasionally

pheochromocytoma Pheochromocytoma (PHEO or PCC) is a rare tumor of the adrenal medulla composed of chromaffin cells, also known as pheochromocytes. When a tumor composed of the same cells as a pheochromocytoma develops outside the adrenal gland, it is referred t ...

primary hyperparathyroidism Primary hyperparathyroidism (or PHPT) is a medical condition where the parathyroid gland (or a benign tumor within it) produce excess amounts of parathyroid hormone (PTH). The symptoms of the condition relate to the resulting elevated serum calcium ...

may be the initial diagnosis.

occurs in 33-50% of MEN2 cases.Thosani S, Ayala-Ramirez M, Palmer L, Hu MI, Rich T, Gagel RF, Cote G, Waguespack SG, Habra MA, Jimenez C (2013) The characterization of pheochromocytoma and its impact on overall survival in Multiple Endocrine Neoplasia type 2. J Clin Endocrinol Metab In MEN2A, primary hyperparathyroidism occurs in 10–50% of cases and is usually diagnosed after the third decade of life. Rarely, it may present in childhood or be the sole clinical manifestation of this syndrome.MEN2A associates medullary thyroid carcinoma with pheochromocytoma in about 20–50% of cases and with primary hyperparathyroidism in 5–20% of cases. MEN2B associates medullary thyroid carcinoma with pheochromocytoma in 50% of cases, with

marfanoid habitus Marfanoid (or Marfanoid habitus) is a constellation of Symptom, symptoms resembling those of Marfan syndrome, including long limbs, with an arm span that is at least 1.03 of the height of the individual, and a crowded oral maxilla, sometimes with a ...

and with mucosal and digestive

neurofibromatosis Neurofibromatosis (NF) is a group of three conditions in which tumors grow in the nervous system. The three types are neurofibromatosis type I (NF1), neurofibromatosis type II Neurofibromatosis type II (also known as MISME syndrome – multi ...

. In familial isolated medullary thyroid carcinoma the other components of the disease are absent. In a review of 85 patients 70 had MEN2A and 15 had MEN2B. The initial manifestation of MEN2 was medullary thyroid carcinoma in 60% of patients, medullary thyroid carcinoma synchronous with pheochromocytoma in 34% and pheochromocytoma alone in 6%. 72% had bilateral pheochromocytomas.

Causes

The table in the

article lists the genes involved in the various MEN syndromes. Most cases of MEN2 derive from a variation in the ''

RET proto-oncogene The ''RET'' proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor (GDNF) family of extracellular signalling molecules. ''RET'' loss of function mutations are associated with the develop ...

'', and are specific for cells of neural crest origin. A database of MEN-implicated RET mutations is maintained by the University of Utah Department of Physiology. The protein produced by the ''RET gene'' plays an important role in the

TGF-beta Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other sign ...

(transforming growth factor beta) signaling system. Because the TGF-beta system operates in nervous tissues throughout the body, variations in the RET gene can have effects in nervous tissues throughout the body. MEN2 generally results from a gain-of-function variant of a ''RET gene''. Other diseases, such as

Hirschsprung disease Hirschsprung's disease (HD or HSCR) is a birth defect in which nerves are missing from parts of the intestine. The most prominent symptom is constipation. Other symptoms may include vomiting, abdominal pain, diarrhea and slow growth. Symptoms usu ...

, result from loss-of-function variants. OMIM # lists the syndromes associated with the RET gene.

Genetics

When inherited, multiple endocrine neoplasia type 2 is transmitted in an

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

pattern, which means affected people have one affected parent, and possibly affected siblings and children. Some cases, however, result from spontaneous new mutations in the '' RET gene''. These cases occur in people with no family history of the disorder. In MEN2B, for example, about half of all cases arise as spontaneous new mutations.

Diagnosis

Diagnosis is suspected when a patient with family history of two of the three classical tumors (medullary thyroid cancer, pheochromocytoma, parathyroid adenoma) or MEN2 presents with one of the classical tumors. It is confirmed by genetic testing for mutation in RET gene.

Differences in presentation

As noted, all types of MEN2 include

and

medullary thyroid carcinoma Medullary thyroid cancer is a form of thyroid carcinoma which originates from the parafollicular cells (C cells), which produce the hormone calcitonin.Hu MI, Vassilopoulou-Sellin R, Lustig R, Lamont JP"Thyroid and Parathyroid Cancers"in Pazdur R, ...

. MEN2A is additionally characterized by the presence of

parathyroid hyperplasia Parathyroid hormone (PTH), also called parathormone or parathyrin, is a peptide hormone secreted by the parathyroid glands that regulates the serum calcium concentration through its effects on bone, kidney, and intestine. PTH influences bone re ...

. MEN2B is additionally characterized by the presence of

mucocutaneous neuroma A mucocutaneous junction, or mucocutaneous boundary, is a region of the body in which mucosal, mucosa transitions to skin. Mucocutaneous zones occur in animals, at the body orifices. In humans, mucocutaneous junctions are found at the lips, nostril ...

, gastrointestinal symptoms (e.g.

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement ...

and

flatulence Flatulence, in humans, is the expulsion of gas from the intestines via the anus, commonly referred to as farting. "Flatus" is the medical word for gas generated in the stomach or bowels. A proportion of intestinal gas may be swallowed environm ...

), and

muscular hypotonia Skeletal muscles (commonly referred to as muscles) are Organ (biology), organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other ...

. MEN2B can present with a

Marfanoid Marfanoid (or Marfanoid habitus) is a constellation of symptoms resembling those of Marfan syndrome, including long limbs, with an arm span that is at least 1.03 of the height of the individual, and a crowded oral maxilla, sometimes with a high a ...

habitus.

Classification

Before gene testing was available, the type and location of tumors determined which type of MEN2 a person had. Gene testing now allows a diagnosis before tumors or symptoms develop.

A table in the

article compares the various MEN syndromes. MEN2 and MEN1 are distinct conditions, despite their similar names. MEN2 includes

MEN2A Multiple endocrine neoplasia type 2 (also known as "Pheochromocytoma and amyloid producing medullary thyroid carcinoma", "PTC syndrome," and "Sipple syndrome") is a group of medical disorders associated with tumors of the endocrine system. The tu ...

, MEN2B and

familial medullary thyroid cancer Medullary thyroid cancer is a form of thyroid carcinoma which originates from the parafollicular cells (C cells), which produce the hormone calcitonin.Hu MI, Vassilopoulou-Sellin R, Lustig R, Lamont JP"Thyroid and Parathyroid Cancers"in Pazdur R, ...

(FMTC). The common feature among the three sub-types of MEN2 is a high propensity to develop

. A variant of MEAs 2A was described in 1989.Donovan DT, Levy ML, Furst EJ, Alford BR, Wheeler T, Tschen JA, Gagel RF (1989) Familial cutaneous lichen amyloidosis in association with multiple endocrine neoplasia type 2A: a new variant. Henry Ford Hosp Med J 37(3-4):147-150 This variant also has patches of cutaneous amyloidosis in the mid/upper back and is inherited in an autosomal dominant fashion.Jabbour SA, Davidovici BB, Wolf R (2006) Rare syndromes. Clin Dermatol 24(4):299-316

Management

Management of MEN2 patients includes thyroidectomy including cervical central and bilateral lymph nodes dissection for MTC, unilateral adrenalectomy for unilateral pheochromocytoma or bilateral adrenalectomy when both glands are involved and selective resection of pathologic parathyroid glands for primary hyperparathyroidism. Familial genetic screening is recommended to identify at risk subjects who will develop the disease, permitting early management by performing prophylactic thyroidectomy, giving them the best chance of cure.

Prognosis

Prognosis of MEN2 is mainly related to the stage-dependant prognosis of MTC indicating the necessity of a complete thyroid surgery for

index case The index case or patient zero is the first documented patient in a disease epidemic within a population, or the first documented patient included in an epidemiological study. It can also refer to the first case of a condition or syndrome (not n ...

s with MTC and the early thyroidectomy for screened at risk subjects.

References

External links

MEN2 (RET) gene variant database

GeneReview/NIH/UW entry on Multiple Endocrine Neoplasia Type 2
{{DEFAULTSORT:Multiple Endocrine Neoplasia Type 2 Endocrine system Autosomal dominant disorders Endocrine-related cutaneous conditions Syndromes affecting the endocrine system