4221

MEN1

MEAI|MENIN|SCG2;multiple endocrine neoplasia I;MEN1;multiple endocrine neoplasia I

endocrine adenomatosis, multiple|menin

11q13

protein-coding

Prolactinomas are rare tumors in prepubertal children. A prolactinoma in a youngchild may be due to sequence variants in genes that are known to cause these tumors ( MEN1, PRKAR1A, AIP). An 11-year-old boy with a macroprolactinoma was treated with cabergoline and the tumor receded. We studied the patient and his family for genetic causes of this tumor. No mutations were present in the codingsequence of PRKAR1A and AIP. A novel heterozygous substitution (IVS3-7 c>a) was identified in intron 3 of MEN1. We also found an additional PCR amplicon that incorporated the entire intron 3 of the gene (210 bp) in the patient's cDNA. Thesame amplicon was present with lower intensity in some of the control individuals who were not mutation carriers. Intron 3 harbors an in-frame stop codon and its incorporation is predicted to result in a prematurely terminated protein. We conclude that a novel MEN1 variation was identified in a young boy with prolactinoma and six of his relatives who did not present with prolactinoma or other MEN1 related symptoms. This novel MEN1 variation may be associated with low penetrance of the disease. The IVS3-7 c>a defect is suggested to be pathogenic because it is associated with lower menin levels in the cells of these patients,but its consequences may be mitigated by a variety of factors including changes in transcription and translation of the MEN1 gene.#CI- Copyright Georg Thieme Verlag KG Stuttgart. New York.

CONTEXT: Multiple endocrine neoplasia type 1 (MEN1) is caused by mutations in the menin (MEN1) gene. The mechanism(s) by which MEN1 mutations lead to pituitary tumor formation remain(s) unknown. OBJECTIVE: The aim of the study was to identify the pediatric MEN1-associated pituitary tumor transcriptome. PATIENTS AND METHODS: A patient harboring a MEN1 mutation (c.525C>G; p.H139D) who presented with an early-onset mammosomatotroph pituitary adenoma was studied. Microarray analysis was performed in the tumor sample and compared with the profile observed in normal pituitaries and in a sporadic mammosomatotropinoma. Validation of the microarray results was performed using quantitative real-time PCR and immunohistochemical analysis for selected genes. RESULTS: In the MEN1-associated pituitary adenoma, 59 and 24 genes were found to be significantly up- and down-regulated, respectively. The up-regulated genes included those involved in cell growth and maintenance, apoptosis, growth arrest, and tumorigenesis. Moreover, we observed decreased expression in genes neuroendocrine in nature and related to growth or apoptosis. Only 21 of the 59 genes differentially expressed in the MEN1-associated adenoma showed a similar expression profile to that seen in the sporadic mammosomatotropinoma; for some genes an opposite expression profile was observed. CONCLUSIONS: We identified changes in the transcriptome that occur in pituitary GH- and PRL-producing cellsafter the loss of menin expression; some of the gene changes are necessary for tumor evolution, and others may be tertiary. Nevertheless, the rare overlap between the expression profiles of the MEN1 tumor vs. that of its sporadic counterpart suggests that these tumors evolve along different molecular pathways.