垂体巨人症是一种罕见的内分泌病，其特征为因生长激素（GH）过度分泌而导致身高增长。此病通常与遗传易感性瘤有关，这些瘤会产生GH或GH释放激素（GHRH）。我们在这里报道了一位日本妇女，从婴儿期开始身材就突出，最终成年身高达到197.4厘米（+7.4标准差）。她的血GH水平明显升高。她没有已知生长控制基因的致病变异体，但在20q11.23有一个至今未报道的752-kb杂合性缺失。微缺失位于GHRH的上游8.9-kb处，横跨放射溶菌酶底物蛋白TTI1的外显子2-9和其他12个基因、假基因和非编码RNA。患者白细胞的转录本分析显示，这种微缺失产生由TTI1外显子1和GHRH所有编码外显子组成的嵌合mRNA。In silico分析检测到TTI1外显子1周围的启动子关联的基因组特征。 携带相同微缺失的基因编辑小鼠从出生几周后加速生长。突变小鼠发展出垂体增生症，并在所有检查的组织中表现出异位的GHRH表达。因此，患者的垂体巨人症极端表型可能反映了由获得性启动子驱动的GHRH过表达。本研究结果显示，生殖细胞亚微小缺失具有导致明显发育异常的潜力，此外，本研究提供了证据表明携带激素编码基因的组成性表达可以导致先天性疾病。©作者2023年。由牛津大学出版社出版。保留所有权利。欲获取权限，请发送电子邮件至journals.permissions@oup.com。

Pituitary gigantism is a rare endocrinopathy characterized by tall stature due to growth hormone (GH) hypersecretion. This condition is generally linked to a genetic predisposition to tumors that produce GH or GH-releasing hormone (GHRH). Here, we report a Japanese woman who exhibited prominent body growth from infancy to reach an adult height of 197.4 cm (+7.4 standard deviation). Her blood GH levels were markedly elevated. She carried no pathogenic variants in known growth-controlling genes but had a hitherto unreported 752-kb heterozygous deletion at 20q11.23. The microdeletion was located 8.9-kb upstream of GHRH and encompassed exons 2-9 of a ubiquitously expressed gene TTI1 together with 12 other genes, pseudogenes, and non-coding RNAs. Transcript analyses of the patient's leukocytes showed that the microdeletion produced chimeric mRNAs consisting of exon 1 of TTI1 and all coding exons of GHRH. In silico analysis detected promoter-associated genomic features around TTI1 exon 1. Genome-edited mice carrying the same microdeletion recapitulated accelerated body growth from a few weeks after birth. The mutant mice developed pituitary hyperplasia and exhibited ectopic Ghrh expression in all tissues examined. Thus, the extreme phenotype of pituitary gigantism in the patient likely reflects GHRH overexpression driven by an acquired promoter. The results of this study indicate that germline submicroscopic deletions have the potential to cause conspicuous developmental abnormalities due to gene overexpression. Furthermore, this study provides evidence that constitutive expression of a hormone-encoding gene can result in congenital disease.© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.