Multiple endocrine neoplasia type 1 (ORPHA:652)
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.
Epidemiology
Prevalence of multiple endocrine neoplasia type 1 (MEN1) is estimated to range between 1/10,000-30,000. The sex ratio is equal.
Clinical description
Tumors can develop at any age with 95% of patients developing 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 ACTHomas (5%) and non-functioning adenomas (5%). 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 with long periods 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 more than 50% of MEN 1 patients, and can be associated with Zollinger-Ellison syndrome.
Etiology
MEN1 is caused by germinal heterozygote inactivating mutations of the MEN1 gene (11q13) encoding the menin protein, a tumor suppressor.In many cases the genetic etiology remains unknown.
Diagnostic methods
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 and confirmed by the presence of a germinal mutation of the MEN1 gene.
Differential diagnosis
The differential diagnosis includes other types of MEN, mainly MEN2A and MEN4 (associated to the gene CDKN1B). Familial primary hyperparathyroidism should also be considered. Differential diagnosis with MEN4 is necessarily made by genetic testing.
Antenatal diagnosis
Prenatal diagnosis is possible, when one of the parent is carrier of a mutation of the MEN1.
Genetic counseling
MEN1 displays a high degree of penetrance; mutation carriers show up to 100% of disease penetrance after the age of 55. The inheritance pattern is autosomal dominant and genetic counseling should be provided to affected individuals and their families informing them that the risk of disease transmission is 50% from an individual with a pathogenic variant to their offspring.
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. Six-monthly screening is recommended for affected patients (CT, MRI, blood biochemistry). Treatment is prevalently by surgery based on approaches for each specific tumor. Some pharmacological therapies are available for treatment of hormone over-secretion and related symptoms; 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 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.
Prognosis
Malignancy is the main risk patients (accounting for approximately 30% of deaths); however, untreated hormone over-secretion by functioning tumors can account for morbidity and mortality. Early diagnosis and treatment success are the main prognostic factors.

                            Last update: 
                            April 2020


                            - Expert reviewer(s): 
                            Pr Maria Luisa BRANDI  - Dr Francesca GIUSTI  - Dr Francesca MARINI