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Pituitary Macroadenoma in a 5-Year-Old: An Early Expression of Multiple Endocrine Neoplasia Type 1¹

Developmental Endocrinology Branch, National Institute of Child Health and Human Development (C.A.S., M.F.K.); Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (D.H.S., S.K.A., M.C.S., S.J.M.); Laboratory of Pathology, National Cancer Institute (S.D.P., I.A.L., Z.Z.); and Surgical Neurology Branch, National Institute of Neurological Diseases and Stroke (R.J.W., E.H.O.), National Institutes of Health, Bethesda, Maryland 20892; and Pediatric Specialty Center (S.M.F.), Joe DiMaggio Children’s Hospital, Hollywood, Florida 33021

Address correspondence and requests for reprints to: Constantine A. Stratakis, M.D., Unit on Genetics and Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N262, MSC1862, 10 Center Drive, Bethesda, Maryland 20892-1862. E-mail: stratakc{at}cc1.nichd.nih.gov

Multiple endocrine neoplasia type 1 (MEN 1) is associated with parathyroid, enteropancreatic, pituitary, and other tumors. The MEN1 gene, a tumor suppressor, 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 become clinically evident in late adolescence or young adulthood, as high levels of PTH, gastrin, or PRL. Because each of these tumors can usually be controlled with medications and/or surgery, MEN 1 has been regarded mainly as a treatable endocrinopathy of adults. Unlike in MEN 2, early testing of children in MEN 1 families is not recommended. We report a 2.3-cm pituitary macroadenoma in a 5-yr-old boy with familial MEN 1. He presented with growth acceleration, acromegaloid features, and hyperprolactinemia. We tested systematically to see whether his pituitary tumor had causes similar to or different from a typical MEN 1 tumor. Germ line DNA of the propositus and his affected relatives revealed a heterozygous point mutation in the MEN1 gene, which leads to a His139Asp (H139D) amino acid substitution. The patient had no other detectable germ-line mutations on either MEN1 allele. DNA sequencing and fluorescent in situ hybridization with a MEN1 genomic DNA sequence probe each demonstrated one copy of the MEN1 gene to be deleted in the pituitary tumor and not in normal DNA, proving MEN1 "second hit" as a tumor cause. Gs 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 patient represents the earliest presentation of any morbid endocrine tumor in MEN 1. A better understanding of early onset MEN 1 disease is needed to formulate recommendations for early MEN 1 genetic testing.

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