Sandbox:ajay

• Multiple endocrine neoplasia type-1 occurs due to the mutations in gene MEN-1. This gene encodes for menin protein. Menin prevents the cells from growing and dividing aggressively. Menin is likely involved in cell functions such as copying and repairing DNA and regulating the activity of other genes. Inactivating mutations of both the copies of the MEN1 gene leads to lack of availability of menin to control cell growth and division. This leads to the formation of tumors characteristic of MEN-1 syndrome. Why these tumors preferentially affect endocrine tissues is unclear.

• MEN-1 syndrome is inherited in an autosomal dominant fashion. The altered gene is usually inherited from an affected parent. People with this condition are born with one mutated MEN1 gene copy in each cell. New mutations in MEN-1 without a family history can also occur in some patients.

• In most autosomal dominant conditions, in order to cause the disorder one altered copy of a gene in each cell is usually enough, two copies of the MEN1 gene must be altered to trigger tumor formation in multiple endocrine neoplasia type 1.

• In an individuals lifetime, in a small number of cells a mutation in the second copy of the MEN1 gene occurs. Individuals with one MEN1 mutation acquire a second mutation in few cells leading to form tumors as a result of the unregulated division of cells.

TABL E 408-1 Multiple Endocrine Neoplasia (MEN) Syndromes Type (Chromosomal Location) Tumors (Estimated Penetrance) Gene and Most Frequently Mutated Codons MEN 1 (11q13) Parathyroid adenoma (90%) Enteropancreatic tumor (30–70%) • Gastrinoma (>50%) • Insulinoma (10–30%) • Nonfunctioning and PPoma (20–55%) • Glucagonoma (<3%) • VIPoma (<1%) Pituitary adenoma (15–50%) • Prolactinoma (60%) • Somatotrophinoma (25%) • Corticotropinoma (<5%) • Nonfunctioning (<5%) Associated tumors • Adrenal cortical tumor (20–70%) • Pheochromocytoma (<1%) • Bronchopulmonary NET (2%) • Thymic NET (2%) • Gastric NET (10%) • Lipomas (>33%) • Angiofibromas (85%) • Collagenomas (70%) • Meningiomas (8%) MEN1 83/84, 4-bp del (≈4%) 119, 3-bp del (≈3%) 209-211, 4-bp del (≈8%) 418, 3-bp del (≈4%) 514-516, del or ins (≈7%) Intron 4 ss (≈10%) MEN 2 (10 cen-10q11.2) MEN 2A MTC (90%) RET Pheochromocytoma (>50%) 634, e.g., Cys → Arg (~85%) Parathyroid adenoma (10–25%) MTC only MTC (100%) RET 618, missense (>50%) MEN 2B (also known as MEN 3) MTC (>90%) RET 918, Met → Thr (>95%) Pheochromocytoma (>50%) Associated abnormalities (40–50%) • Mucosal neuromas • Marfanoid habitus • Medullated corneal nerve fibers • Megacolon MEN 4 (12p13) Parathyroid adenomaa Pituitary adenomaa CDKN1B; no common mutations identified to date Reproductive organ tumorsa (e.g., testicular cancer, neuroendocrine cervical carcinoma) ?Adrenal + renal tumorsa