{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T07:57:29Z","timestamp":1776326249551,"version":"3.50.1"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"14","license":[{"start":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T00:00:00Z","timestamp":1681776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["17H06428"],"award-info":[{"award-number":["17H06428"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007786","name":"National Center for Child Health and Development","doi-asserted-by":"publisher","award":["2022A-1"],"award-info":[{"award-number":["2022A-1"]}],"id":[{"id":"10.13039\/100007786","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,7,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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\u00a0cm (+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\u20139 of a ubiquitously expressed gene TTI1 together with 12 other genes, pseudogenes and non-coding RNAs. Transcript analyses of the patient\u2019s 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.<\/jats:p>","DOI":"10.1093\/hmg\/ddad053","type":"journal-article","created":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T11:59:37Z","timestamp":1681819177000},"page":"2318-2325","source":"Crossref","is-referenced-by-count":4,"title":["Chromosomal microdeletion leading to pituitary gigantism through hormone-gene overexpression"],"prefix":"10.1093","volume":"32","author":[{"given":"Yuko","family":"Katoh-Fukui","sequence":"first","affiliation":[{"name":"Department of Molecular Endocrinology, National Research Institute for Child Health and Development (Kokuritsu Kenkyu Kaihatsu Hojin Kokuritsu Seiiku Iryo Kenkyu Center Kenkyujo) , Tokyo 157-8535 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsushi","family":"Hattori","sequence":"additional","affiliation":[{"name":"Department of Molecular Endocrinology, National Research Institute for Child Health and Development (Kokuritsu Kenkyu Kaihatsu Hojin Kokuritsu Seiiku Iryo Kenkyu Center Kenkyujo) , Tokyo 157-8535 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruogu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Molecular Endocrinology, National Research Institute for Child Health and Development (Kokuritsu Kenkyu Kaihatsu Hojin Kokuritsu Seiiku Iryo Kenkyu Center Kenkyujo) , Tokyo 157-8535 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miho","family":"Terao","sequence":"additional","affiliation":[{"name":"Department of Systems BioMedicine, National Research Institute for Child Health and Development (Kokuritsu Kenkyu Kaihatsu Hojin Kokuritsu Seiiku Iryo Kenkyu Center Kenkyujo) , Tokyo 157-8535 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuji","family":"Takada","sequence":"additional","affiliation":[{"name":"Department of Systems BioMedicine, National Research Institute for Child Health and Development (Kokuritsu Kenkyu Kaihatsu Hojin Kokuritsu Seiiku Iryo Kenkyu Center Kenkyujo) , Tokyo 157-8535 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuhiko","family":"Nakabayashi","sequence":"additional","affiliation":[{"name":"Department of Maternal\u2013Fetal Biology, National Research Institute for Child Health and Development (Kokuritsu Kenkyu Kaihatsu Hojin Kokuritsu Seiiku Iryo Kenkyu Center Kenkyujo) , Tokyo 157-8535 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenichiro","family":"Hata","sequence":"additional","affiliation":[{"name":"Department of Maternal\u2013Fetal Biology, National Research Institute for Child Health and Development (Kokuritsu Kenkyu Kaihatsu Hojin Kokuritsu Seiiku Iryo Kenkyu Center Kenkyujo) , Tokyo 157-8535 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yutaka","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Hakodate Central General Hospital , Hakodate 040-8585 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nobuo","family":"Matsuura","sequence":"additional","affiliation":[{"name":"Department of Reproductive and Developmental Medicine , Graduate School of Medicine, , Sapporo 060-0808 , Japan"},{"name":"Hokkaido University School of Medicine , Graduate School of Medicine, , Sapporo 060-0808 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maki","family":"Fukami","sequence":"additional","affiliation":[{"name":"Department of Molecular Endocrinology, National Research Institute for Child Health and Development (Kokuritsu Kenkyu Kaihatsu Hojin Kokuritsu Seiiku Iryo Kenkyu Center Kenkyujo) , Tokyo 157-8535 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,4,18]]},"reference":[{"key":"2023070515074291300_ref1","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1038\/s41574-018-0114-1","article-title":"The causes and consequences of pituitary gigantism","volume":"14","author":"Beckers","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"2023070515074291300_ref2","doi-asserted-by":"crossref","first-page":"4379","DOI":"10.1210\/jcem.84.12.6222","article-title":"Gigantism","volume":"84","author":"Eugster","year":"1999","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2023070515074291300_ref3","volume-title":"GeneReviews","author":"Iacovazzo","year":"2018"},{"key":"2023070515074291300_ref4","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1530\/ERC-15-0320","article-title":"Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients","volume":"22","author":"Rostomyan","year":"2015","journal-title":"Endocr. Relat. Cancer"},{"key":"2023070515074291300_ref5","doi-asserted-by":"crossref","first-page":"2363","DOI":"10.1056\/NEJMoa1408028","article-title":"Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation","volume":"371","author":"Trivellin","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"2023070515074291300_ref6","first-page":"941","article-title":"A case of pituitary giantism: therapeutic effect of CB-154 (in Japanese)","volume":"25","author":"Yamada","year":"1977","journal-title":"Horumon To Rinsho [Clinical Endocrinology (Tokyo)]"},{"key":"2023070515074291300_ref7","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1530\/ERC-15-0038","article-title":"X-Linked acrogigantism syndrome: clinical profile and therapeutic responses","volume":"22","author":"Beckers","year":"2015","journal-title":"Endocr. Relat. Cancer"},{"key":"2023070515074291300_ref8","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.ajhg.2023.01.006","article-title":"Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly","volume":"110","author":"Serey-Gaut","year":"2023","journal-title":"Am. J. Hum. Genet."},{"key":"2023070515074291300_ref9","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/314279a0","article-title":"Independent effects of growth hormone releasing factor on growth hormone release and gene transcription","volume":"314","author":"Barinaga","year":"1985","journal-title":"Nature"},{"key":"2023070515074291300_ref10","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1038\/314281a0","article-title":"Growth induced by pulsatile infusion of an amidated fragment of human growth hormone releasing factor in normal and GHRF-deficient rats","volume":"314","author":"Clark","year":"1985","journal-title":"Nature"},{"key":"2023070515074291300_ref11","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1210\/jc.2011-2930","article-title":"Clinical characteristics and outcome of acromegaly induced by ectopic secretion of growth hormone-releasing hormone (GHRH), a French nationwide series of 21 cases","volume":"97","author":"Garby","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2023070515074291300_ref12","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/j.ando.2012.09.004","article-title":"Acromegaly induced by ectopic secretion of GHRH: a review 30 years after GHRH discovery","volume":"73","author":"Borson-Chazot","year":"2012","journal-title":"Ann. Endocrinol. (Paris)"},{"key":"2023070515074291300_ref13","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1159\/000507837","article-title":"Established and novel mechanisms leading to de novo genomic rearrangements in the human germline","volume":"160","author":"Hattori","year":"2020","journal-title":"Cytogenet. Genome Res."},{"key":"2023070515074291300_ref14","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1210\/mend-2-7-606","article-title":"Dramatic pituitary hyperplasia in transgenic mice expressing a human growth hormone-releasing factor gene","volume":"2","author":"Mayo","year":"1988","journal-title":"Mol. Endocrinol."},{"key":"2023070515074291300_ref15","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/315413a0","article-title":"Expression of human growth hormone-releasing factor in transgenic mice results in increased somatic growth","volume":"315","author":"Hammer","year":"1985","journal-title":"Nature"},{"key":"2023070515074291300_ref16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.33029\/9704-4951-6-PEND-1-848","volume-title":"Williams Textbook of Endocrinology","author":"Melmed","year":"2020"},{"key":"2023070515074291300_ref17","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/s40142-017-0129-2","article-title":"Copy number variation disorders","volume":"5","author":"Shaikh","year":"2017","journal-title":"Curr. Genet. Med. Rep."},{"key":"2023070515074291300_ref18","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/nrg.2016.167","article-title":"Limb development, a paradigm of gene regulation","volume":"18","author":"Petit","year":"2017","journal-title":"Nat. Rev. Genet."},{"key":"2023070515074291300_ref19","doi-asserted-by":"crossref","first-page":"2429","DOI":"10.1093\/hmg\/ddab206","article-title":"WNT2 activation through proximal germline deletion predisposes to small intestinal neuroendocrine tumors and intestinal adenocarcinomas","volume":"30","author":"Aavikko","year":"2021","journal-title":"Hum. Mol. Genet."},{"key":"2023070515074291300_ref20","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.ecl.2011.01.012","article-title":"Glucocorticoid-remediable aldosteronism","volume":"40","author":"Halperin","year":"2011","journal-title":"Endocrinol. Metab. Clin. N. Am."},{"key":"2023070515074291300_ref21","doi-asserted-by":"crossref","first-page":"E1035","DOI":"10.1210\/jc.2011-0145","article-title":"Aromatase excess syndrome, identification of cryptic duplications and deletions leading to gain of function of CYP19A1 and assessment of phenotypic determinants","volume":"96","author":"Fukami","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2023070515074291300_ref22","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.ajhg.2021.02.012","article-title":"De novo structural mutation rates and gamete-of-origin biases revealed through genome sequencing of 2,396 families","volume":"108","author":"Belyeu","year":"2021","journal-title":"Am. J. Hum. Genet."},{"key":"2023070515074291300_ref23","first-page":"825","volume-title":"Williams Textbook of Endocrinology","author":"Katugampola","year":"2020"},{"key":"2023070515074291300_ref24","doi-asserted-by":"crossref","first-page":"236","DOI":"10.33029\/9704-4951-6-PEND-1-848","volume-title":"Williams Textbook of Endocrinology","author":"Melmed","year":"2020"},{"key":"2023070515074291300_ref25","doi-asserted-by":"crossref","first-page":"79","DOI":"10.4158\/EP10165.CR","article-title":"Ectopic acromegaly due to a pancreatic neuroendocrine tumor producing growth hormone-releasing hormone","volume":"17","author":"Weiss","year":"2011","journal-title":"Endocr. Pract."},{"key":"2023070515074291300_ref26","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.clineuro.2014.08.012","article-title":"Growth hormone secreting pituitary microadenomas and empty sella - an under-recognized association?","volume":"126","author":"Liu","year":"2014","journal-title":"Clin. Neurol. Neurosurg."},{"key":"2023070515074291300_ref27","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1530\/eje.1.01824","article-title":"Gross total resection or debulking of pituitary adenomas improves hormonal control of acromegaly by somatostatin analogs","volume":"152","author":"Petrossians","year":"2005","journal-title":"Eur. J. Endocrinol."},{"key":"2023070515074291300_ref28","doi-asserted-by":"crossref","first-page":"2953","DOI":"10.1210\/jc.2007-2283","article-title":"Treatment of pituitary gigantism with the growth hormone receptor antagonist pegvisomant","volume":"93","author":"Goldenberg","year":"2008","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2023070515074291300_ref29","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.3390\/jcm10071377","article-title":"Genetics of acromegaly and gigantism","volume":"10","author":"Bogus\u0142awska","year":"2021","journal-title":"J. Clin. Med."},{"key":"2023070515074291300_ref30","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1507\/endocrj.EJ17-0150","article-title":"Next generation sequencing-based mutation screening of 86 patients with idiopathic short stature","volume":"64","author":"Hattori","year":"2017","journal-title":"Endocr. J."},{"key":"2023070515074291300_ref31","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1038\/nrendo.2015.165","article-title":"Short and tall stature, a new paradigm emerges","volume":"11","author":"Baron","year":"2015","journal-title":"Nat. Rev. Endocrinol."},{"key":"2023070515074291300_ref32","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/s13148-020-00865-x","article-title":"Contribution of gene mutations to Silver-Russell syndrome phenotype, multigene sequencing analysis in 92 etiology-unknown patients","volume":"12","author":"Inoue","year":"2020","journal-title":"Clin. Epigenetics"},{"key":"2023070515074291300_ref33","doi-asserted-by":"crossref","first-page":"R145","DOI":"10.1530\/EJE-15-0937","article-title":"Mechanisms in endocrinology. Novel genetic causes of short stature","volume":"174","author":"Wit","year":"2016","journal-title":"Eur. J. Endocrinol."},{"key":"2023070515074291300_ref34","doi-asserted-by":"crossref","first-page":"bqab217","DOI":"10.1210\/endocr\/bqab217","article-title":"Human SRY expression at the sex-determining period is insufficient to drive testis development in mice","volume":"163","author":"Tsuji-Hosokawa","year":"2022","journal-title":"Endocrinology"},{"key":"2023070515074291300_ref35","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1093\/hmg\/ddab071","article-title":"Humanization of a tandem repeat in IG-DMR causes stochastic restoration of paternal imprinting at mouse Dlk1-Dio3 domain","volume":"30","author":"Hara","year":"2021","journal-title":"Hum. Mol. Genet."}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddad053\/50287296\/ddad053.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/32\/14\/2318\/50823317\/ddad053.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/32\/14\/2318\/50823317\/ddad053.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,5]],"date-time":"2023-07-05T19:28:10Z","timestamp":1688585290000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/32\/14\/2318\/7127668"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,18]]},"references-count":35,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2023,4,18]]},"published-print":{"date-parts":[[2023,7,4]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddad053","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,7,15]]},"published":{"date-parts":[[2023,4,18]]}}}