Endocrine Abstracts

Background: Germline heterozygous mutations in the MEN1 gene located on chromosome 11q13, predisposes to the development of tumors in multiple endocrine tissues. The MEN1 gene encodes a protein of 610 amino acid residues, known as menin which is involved in genome stabilization as well as in several steps of cellular division, conferring tumor suppression activity in MEN1-associated target tissues. The three main endocrine tissues affected by tumors in MEN1 are parathyroid (95%), enteropancreatic neuroendocrine (50%) and pituitary (40%). Primary hyperparathyroidism from parathyroid hormone-secreting adenomas is usually the first clinical manifestation presenting typically between 20 and 25 years of age.

Objective: The present work is aimed at searching for mutations in the MEN1 gene in members of a family with multiple endocrine neoplasias across three generations.

Patients: The index-case, a 46-year-old woman, presented symptomatic hypercalcemia and markedly raised serum PTH. Neck exploration revealed a parathyroid adenoma which was successfully removed. She also reported a history of recurrent peptic ulcers including two duodenal perforations at the age 25 and 30 years suggesting a Zollinger–Ellison syndrome. Gastrin levels were found to be elevated and a hepatic gastrinoma was identified in the Octreoscan. Excision of the tumor led to remission of gastro-intestinal complaints. The father of the index-case presented a long standing symptomatic hyperparathyroidism and had a history of gastric perforation at 40-yr-old due to a carcinoid tumor. The index-case sister, complained of recurrent renal stones since her twenties and suffered of an acute episode of renal failure due to obstructive nephropathy. A parathyroid adenoma was identified and successfully removed. Two of hers three sons presented symptomatic hypercalcemia during their twenties and were submitted to parathyroidectomy. The other son was asymptomatic as well as the two children of the index-case.

Methods: Written informed consent was obtained from each available member of the family. DNA was extracted through conventional methods. Sequencing of the coding exons and splicing regions of the MEN1 gene were carried out after DNA amplification with PCR.

Results: In five members of the family herein reported, it was identified a novel missense germinal mutation involving the exon 2 of the MEN1 gene (c.124G>C) which leads to substitution of glycina by arginina at position 42 (Gly42Arg). The mutation was not found in non-affected members of the family.

Conclusion: Identification of a MEN1 gene mutation is an important tool in the follow-up of asymptomatic carriers avoiding unnecessary tests in noncarriers relatives.