Multiple endocrine neoplasia type 1: new clinical and basic findings.

Multiple endocrine neoplasia type 1 (MEN1) provides a prime example of how a rare disease can advance our understanding of basic cell biology, neoplasia and common endocrine tumors. MEN1 is expressed mainly as parathyroid, enteropancreatic neuroendocrine, anterior pituitary and foregut carcinoid tumors. It is an autosomal dominant disease caused by mutation of the MEN1 gene. Since its identification, the MEN1 gene has been implicated in many common endocrine and non-endocrine tumors. This is a brief overview of recent scientific advances relating to MEN1, including newly recognized clinical features that are now better characterized by genetic analysis, insights into the function of the MEN1-encoded protein menin, and refined recommendations for mutation testing and tumor screening, which highlight our increasing understanding of this complex syndrome.

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 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. Gsalpha 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.

Osteoporosis and low bone mass in premenopausal and perimenopausal women.

OBJECTIVE: To characterize the historical, clinical, and biochemical features of 111 young women (age, <55 years) referred for evaluation of osteoporosis or low bone mass. METHODS: Women with a bone mineral density T score < or = -2.0 (N = 111) at one or more anatomic sites (by dual-energy x-ray absorptiometry) were assessed relative to anthropomorphic and biochemical characteristics and risk factors for osteoporosis. RESULTS: Of 111 women with low bone mass or osteoporosis, 73 (66%) had identifiable causes of bone loss, of which estrogen deficiency (menopause, premenopausal estrogen deficiency) and conditions associated with estrogen deficiency (anorexia nervosa, cancer chemotherapy) were the most common. Prolonged use of glucocorticoids was the most common secondary cause of osteoporosis. Of 38 women with no identifiable cause of bone loss, 21 were premenopausal (mean age, 38 +/- 10 years [standard deviation]) and 17 were perimenopausal (mean age, 50 +/- 3 years). The mean lumbar spine T score was -2.18 +/- 1.0 in the premenopausal and -2.51 +/- 0.6 in the perimenopausal women. Nontraumatic fractures were reported by 42% of the premenopausal women and 18% of the perimenopausal women. A family history of osteoporosis was reported by 71% of the premenopausal and 47% of the perimenopausal women. CONCLUSION: Most young women with osteoporosis or low bone mass had estrogen deficiency or another secondary cause of premature bone loss (or both). A subset of premenopausal and perimenopausal women, however, had no identifiable cause of bone loss. The strong family history of osteoporosis, especially in the premenopausal women, provides further support for current theories of a genetic predisposition to osteoporosis.