Stratakis C A, Schussheim D H, Freedman S M, Keil M F, Pack S D, Agarwal S K, Skarulis M C, Weil R J, Lubensky I A, Zhuang Z, Oldfield E H, Marx S J
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institute of Health, Bethesda, MD 20892-1862, USA.
J Clin Endocrinol Metab. 2000 Dec;85(12):4776-80. doi: 10.1210/jcem.85.12.7064.
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.
1型多发性内分泌腺瘤病（MEN 1）与甲状旁腺、肠胰腺、垂体及其他肿瘤相关。MEN1基因作为一种肿瘤抑制基因，位于11号染色体上。受影响个体遗传了一个突变的MEN1等位基因，特定组织中的肿瘤发生是在剩余的MEN1等位基因失活之后。与MEN 1相关的内分泌肿瘤通常在青春期末期或成年早期出现临床症状，表现为甲状旁腺激素（PTH）、胃泌素或催乳素（PRL）水平升高。由于这些肿瘤通常都可以通过药物和/或手术得到控制，MEN 1一直主要被视为一种可治疗的成人内分泌疾病。与MEN 2不同，不建议对MEN 1家族中的儿童进行早期检测。我们报告了一名5岁患有家族性MEN 1的男孩，其患有一个2.3厘米的垂体大腺瘤。他表现为生长加速、肢端肥大样特征和高催乳素血症。我们进行了系统检测，以确定他的垂体肿瘤是否具有与典型MEN 1肿瘤相似或不同的病因。先证者及其受影响亲属的生殖系DNA显示MEN1基因存在杂合点突变，导致组氨酸139天冬氨酸（H139D）氨基酸替代。患者的两个MEN1等位基因上均未检测到其他可检测到的生殖系突变。DNA测序以及使用MEN1基因组DNA序列探针进行荧光原位杂交均显示垂体肿瘤中有一个MEN1基因拷贝缺失，而正常DNA中没有，证明MEN1“二次打击”是肿瘤的病因。在该肿瘤中未检测到非遗传性生长激素分泌肿瘤中常见的Gsalpha突变。我们得出结论，该垂体大腺瘤表现出典型MEN 1相关肿瘤的分子遗传特征。这名患者代表了MEN 1中任何病态内分泌肿瘤的最早表现。需要更好地了解早发性MEN 1疾病，以便制定关于早期MEN 1基因检测的建议。
