Hyperparathyroidism in MEN1 Syndrome

Multiple Endocrine Neoplasia Type 1 syndrome

Multiple Endocrine Neoplasia Type 1 syndrome is caused by a germline mutation in the multiple endocrine neoplasia type 1 gene encoding the tumor-suppressor protein menin. This syndrome eis presentated with: primary hyperparathyroidism (PHPT) in 95% of patients, pancreatic neuroendocrine tumors (NET) in 40–70% of patients (gastrinomas (40%), insulinomas (10%), glucagonomas (1%), VIPoma (1%), PPomas and nonfunctioning), anterior pituitary tumors in 30–40% of patients (prolactinomas (20%), somatotrophinomas (10%), corticotropinomas (5%), and nonfunctioning adenomas (5%)). In addition: adrenocortical tumors (40%), pheochromocytoma (1%), bronchopulmonary NET (2%), thymic NET (2%), gastric NET (10%), lipomas (30%), angiofibromas (85%), collagenomas (70%), meningiomas (8%), thyroid tumors (adenomas, colloid goiters, carcinomas) (25%) could be seen as well.

The diagnosis is established either clinically: occurrence of 2 or more MEN1-related NET in a single patient or by blood test for the MEN 1 gene mutation.

About 1336 mutations characterized (1133 germline and 203 somatic) in MEN1 gene (> 600 different mutations reported in the Human Gene Mutation Database). Approximately 30 of them - Familial Isolated Hyperparathyroidism (FIHP) syndrome. Penetrance of MEN1 gene is almost complete after the 7th decade of life. No genotype-phenotype correlations have been identified: the same mutation in unrelated families has different phenotypic presentation, unique for the specific family. There is a variation within the family as well.

Primary Hyperparathyroidism in Multiple Endocrine Neoplasia Type 1 syndrome

Presentation of hypercalcemia in MEN Type 1 syndrome is usually mild, parathyroid cancers is very rare (less than 1%). The age of onset of the hypercalcemia is in earlier age (20 to 25 years old). It has been reported, although, that the there is a greater reduction in bone density compare to non-MEN1 primary hyperparathyroidism. The most common findings are hyperplasia of all 4 parathyroid glands, and growth of parathyroid glands is asynchronous and asymmetric, even thought that some glands may appear macroscopically normal; the pathological evaluation still will show hyperplasia. It has been reported that supernumerary glands present in up to 20% of MEN1 patients, which is explains the limitations of preoperative studies. Because of uncontrollable growth pattern and presence of supernumerary (ectopic) glands, the rate of persistent diseases higher and described as less than 20% in expert surgeon and 40–60% in not expert (the definition of an expert parathyroid surgeon is someone who performs more then 50-100 parathyroid surgeries a year)

Initial treatment of primary hyperparathyroidism in MEN1 is recommended to be first as a subtotal parathyroidectomy (3&1/2) with transcervical partial thymectomy. A total parathyroidectomy with autotransplantation may be reserved for those patients with extensive disease either at first or at repeat surgery. Prophylactic transcervical thymectomy should be performed in all patients (consider the presence of supernumerary parathyroid glands and prevents the development of thymic carcinoid). With a subtotal parathyroidectomy (3&1/2 glands), 40 to 60% of patients will have persistence or recurrence of primary hyperparathyroidism within 10 years after surgery; and 10 to 30% of patients will have persistent hypoparathyroidism


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