Pituitary macroadenoma in a 5-year-old: An early expression of multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1 (MEN 1) is associated with parathyroid, enteropancreatic, pituitary, and other tumors. The MEN1 gene, a tumor supp ressor, is located on chromosome 11. Affected individuals inherit a mutated MEN1 allele, and tumorigenesis in specific tissues follows inactivation of the remaining MEN1 allele. MEN 1-associated endocrine tumors usually becom e clinically evident in late adolescence or young adulthood, as high levels of PTH, gastrin, or PRL. Because each of these tumors can usually be contr olled with medications and/or surgery, MEN 1 has been regarded mainly as a treatable endocrinopathy of adults. Unlike in MEN 2, early testing of child ren in MEN 1 families is not recommended. We report a 2.3-cm pituitary macr oadenoma in a 5-yr-old boy with familial MEN 1. He presented with growth ac celeration, acromegaloid features, and hyperprolactinemia. We tested system atically to see whether his pituitary tumor had causes similar to or differ ent from a typical MEN 1 turner. Germ line DNA of the propositus and his af fected relatives revealed a heterozygous point mutation in the MEN1 gene, w hich leads to a His139Asp (H139D) amino acid substitution. The patient had no other detectable germ-line mutations on either MEN1 allele. DNA sequenci ng and fluorescent in situ hybridization with a MEN1 genomic DNA sequence p robe each demonstrated one copy of the MEN1 gene to be deleted in the pitui tary tumor and not in normal DNA, proving MEN1 "second hit" as a tumor caus e. Gs alpha mutation, common in nonhereditary GH-producing tumors, was not detected in this tumor. We conclude that this pituitary macroadenoma showed molecular genetic features of a typical MEN 1-associated tumor. This patie nt represents the earliest presentation of any morbid endocrine tumor in ME N 1. A better understanding of early onset MEN 1 disease is needed to formu late recommendations for early MEN 1 genetic testing.