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Multiple endocrine neoplasia type 1
A rare inherited cancer syndrome, characterized by the development of multiple neuroendocrine tumors of the parathyroids, gastro-entero-pancreatic tract, and anterior pituitary gland, and less commonly the adrenal cortical gland, thymus and bronchi, with other non-endocrine tumors in some patients.
ORPHA:652Classification level: Disorder
Multiple endocrine neoplasia Type 1 (MEN1) is estimated prevalence ranges from 1/10,000 to 1/30,000. The sex ratio in MEN1 is equal.
In individuals with MEN1, tumors can develop at any age. 95% of patients develop clinical symptoms by the 5th decade. Parathyroid tumors are the most common (95% of patients), followed by pancreatic islet tumors (40%) and anterior pituitary tumors (30%). Pancreatic neuroendocrine tumors include gastrinoma (50%), insulinoma (33%), glucagonoma (5%), vasoactive intestinal peptide (VIP)-oma, pancreatic polypeptide (PP)-oma, and non-functioning tumors, and are associated with high levels of morbidity and mortality. Pituitary tumors include prolactinoma (66%), somatotrophinoma (25%), and about 5% each for ACTHomas and non-functioning adenomas. The most common initial manifestation is primary hyperparathyroidism (PHPT) (mean age onset in third decade of life), due to parathyroid hyperplasia and/or adenoma. PHPT can present long period of normal serum level of calcium (normocalcemic PHPT), that is often asymptomatic. When associated with hypercalcemia, and often also hypophosphatemia, PHPT can manifest clinical signs that may include nephrolithiasis, polyuria, polydipsia, constipation, fatigue, depression, confusion, anorexia, osteopenia and osteoporosis. Untreated PHPT can exacerbate over-secretion of gastrina from a concomitant gastrinoma and favor peptic ulcers. Gastrinomas lead to peptic ulcers in > 50% of MEN 1 patients, and it can be associated with the Zollinger-Ellison syndrome.
MEN1 is caused by germinal heterozygote inactivating mutations of the MEN1 gene (11q13) encoding the menin protein, a tumor suppressor. In certain patients (<2%) who present a clinical phenotype very similar to MEN1 (phenocopies), mutations in the cyclin-dependent kinase inhibitor genes have been reported: CDKN1A (6p21.1), CDKN2B, (9p21), and CDKN2C (1p32.3). CDKN2B mutations have been associated to a novel MEN syndrome, named MEN4.
MEN1 is clinically diagnosed in affected patients manifesting at least two of the main endocrine tumors (parathyroid, pituitary, and/or pancreatic) during their life. In these cases, the genetic testing is used to confirm the clinical diagnosis. A genetic diagnosis of the syndrome is made in presence of a germinal mutation of the MEN1 gene.
The differential diagnosis includes other types of MEN, mainly MEN2A and MEN4. Familial primary hyperparathyroidism should also be considered. Differential diagnosis with MEN4 is necessarily made by genetic testing.
Prenatal diagnosis is possible, when one of the parent is carrier of a mutation of the MEN1.
MEN1 displays a high degree of penetrance; mutation carriers show up to 100% of disease penetrance after the age of 55. The inheritance great is autosomal dominant:the heterozygote mutated allele is inherited by the affected parent, independently by sex. Genetic counseling should be provided to affected individuals and their families.
Management and treatment
Annual life-long screening is recommended for all the carriers of a MEN1 mutations and individuals from affected families without an identified MEN1 mutations or who have not undergone the genetic test. 6-monthly screening is recommended for affected patients (CT, MRI, blood biochemistry). Treatment is prevalently by surgery based on approaches for each specific tumor. Unfortunately, surgery can be not completely and/or long-term resolutive because of the multiplicity of tumors PHPT is mainly treated by subtotal or total parathyroidectomy, usually associated with thymectomy to prevent thymic carcinoids. Surgery is indicated for gastro-entero-pancreating tumors. Growth hormone-secreting tumors, ACTH-secreting pituitary tumors, non-secreting pituitary adenomas are treated by transsphenoidal surgery. Surgical removal of adrenocortical tumors that exceed 3.0 cm in diameter can prevent malignancy. Some pharmacological therapies are available for treatment of hormone over-secretion, and related syndromes, of the functioning tumors; calcimimetic can be used to treat PHPT in patients in whom surgery had either failed or was contraindicated. Prior to surgery, bone anti-resorptive agents are used to reduce hypercalcemia and limit bone resorption. Dopamine agonists are used for prolactinoma. somatostatin analogs, octreotide, and lanreotide for GH-secreting tumors and for controlling the secretory hyperfunction associated with carcinoid syndrome. Proton pump inhibitors or H2-receptor blockers reduce gastric acid output caused by gastrinomas.
Malignancy is the main risk in MEN1 patients (accounting for approximately 30% of deaths). Also untreated hormone over-secretion by functioning tumors can account for morbidity and mortality. Early diagnosis and treatment success are the main prognostic factors.