Sandbox/01

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Synonyms and keywords: MEN type 4; MEA type 4; Multiple endocrine neoplasms type 4; Multiple endocrine adenomatosis type 4

Overview

Multiple endocrine neoplasia type 4 is a type of tumor that arises from endocrine cells of parathyroid gland and pituitary gland. Multiple endocrine neoplasia type 4 is part of the broad group of diseases called multiple endocrine neoplasia. Heterozygous mutation of Cdkn1b/CDKN1B gene on chromosome 12p13 is suspected to be the cause of multiple endocrine neoplasia type 4. Multiple endocrine neoplasia type 4 must be differentiated from other hereditary tumors such as medullary thyroid carcinoma, C-cell hyperplasia, von Hippel Lindau syndrome, familial hyperparathyroidism, acromegaly, multiple endocrine neoplasia type 1 (MEN 1), multiple endocrine neoplasia type 2a, and multiple endocrine neoplasia type 2b. The most potent risk factor in the development of multiple endocrine neoplasia type 4 is family history. There is insufficient evidence to recommend routine screening for multiple endocrine neoplasia type 4. The most common symptoms of multiple endocrine neoplasia type 4 include lethargy, constipation, and headache. Transsphenoidal surgery is used for treating pituitary adenoma of multiple endocrine neoplasia type 4.

Historical Perspective

• Historical background of multiple endocrine neoplasia type 4 is given in the table below.

MEN IV Historical Background

Years	Scientist	Contribution
2006	Pellegata	Reported a case study of a patient with multiple endocrine neoplasia type 1 like features such as acromegaly, pituitary tumor, and primary hyperparathyroidism
2007	Georgitsi	Reported a case study of a female with small cell neuro endocrine tumor, pituitary adenoma, and hyperparathyroidism
2010	Molatore	Reported a case study of a female with bronchial carcinoid, pituitary adenoma, parathyroid adenoma, and papillary thyroid carcinoma
2012	Malanga	Reported a case study of a female with gastric carcinoid tumor and hyperparathyroidism
2014	Toneli	Reported a case study of a female with hyperparathyroidism and gastrointestinal neuroendocrine tumor

Pathophysiology

Multiple endocrine neoplasia type 4 is a rare genetic disease which is the latest addition to the family of multiple endocrine neoplasia. It is characterized by parathyroid adenoma and pituitary adenoma.

Genetics

• Multiple endocrine neoplasia type 4 is an autosomal dominant disorder caused by genetic mutation of Cdkn1b/CDKN1B gene.
• The chromosome involved in the development of the disease is 12p13.
• A tumor supressor protein called p27Kip1 is encoded by Cdkn1b/CDKN1B gene germline mutation.
• The protein is derived from a cell cycle inhibitor p27.
• The mechanism of action of the gene is to inhibit cyclin/cyclin-dependent kinase complexes.
• Inhibition of cyclin/cyclin-dependent kinase complexes causes cessation of cell cycle progression.

Associated Conditions

• Gastric carcinoid syndrome
• Uterine fibroids
• Adrenal mass
• Zollinger-Ellison syndrome
• Gastrinoma
• Acromegaly
• Cushing's syndrome
• Neuroendocrine tumors of cervix

Causes

• Heterozygous mutation of Cdkn1b/CDKN1B gene on chromosome 12p13 is suspected to be the cause of multiple endocrine neoplasia type 4.

Differentiating Multiple endocrine neoplasia type 4 from other Diseases

Disease	Definition
Multiple endocrine neoplasia type 1 (MEN 1)	An autosomal dominant genetic disorder causing tumors of parathyroid, pancreas, and pituitary gland.
Multiple endocrine neoplasia type 2	An autosomal dominant disorder characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and primary hyperparathyroidism.
von Hippel-Lindau syndrome	An autosomal dominant genetic disorder causing abnormal growth of blood vessels in different parts of the body.
Medullary thyroid carcinoma	Medullary thyroid cancer (MTC) is a form of thyroid carcinoma which originates from the parafollicular cells (C cells), which produce the hormone calcitonin.
C-cell hyperplasia	C-cell hyperplasia is a form of thyroid disease which originates from the parafollicular cells (C cells), which produce the hormone calcitonin.
Familial hyperparathyroidism	A disorder due to excess production of parathyroid hormone characterized by kidney stones, hypercalcemia, constipation, peptic ulcers, and depression.
Acromegaly	A rare syndrome due to excess growth hormone characterized by enlargement of the hands, feet, nose, lips, ears, general thickening of the skin, hypertrichosis, hyperpigmentation, hyperhidrosis, and carpal tunnel syndrome.
Thakker RV. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol Cell Endocrinol. 2014;386(1-2):2-15.

Epidemiology and Demographics

• It is a very rare disease. So far only 12 index cases have been reported and the prevalence of the disease is estimated to be less than 1 in 100,000.

Age

• The age of onset of tumor is variable.
• Pituitary tumors are reported from 3rd decade.
• Parathyroid tumors are reported from 4th decade of life.

Gender

• Females are more affected than males.

Risk Factors

The most potent risk factor in the development of multiple endocrine neoplasia type 4 is family history of pituitary tumors and parathyroid tumors.

Natural History, Complications and Prognosis

There is no established comments on the prognosis of multiple endocrine neoplasia type 4.

Diagnosis

There is no established criteria for the diagnosis of multiple endocrine neoplasia type 4.

Symptoms

• Lethargy
• Depression
• Constipation
• Headache

Treatment

Surgery and Device Based Therapy

• Transsphenoidal surgery is used for treating pituitary adenoma of multiple endocrine neoplasia type 4.