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Human loss-of-function mutations in IGSF1 cause central hypothyroidism, hypoprolactinemia, and macroorchidism. Additionally, most affected adults exhibit higher than average IGF-1 levels and anecdotal reports describe acromegaloid features in older subjects. However, somatotrope function has not yet been formally evaluated in this condition.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>We aimed to evaluate the role of IGSF1 in human and murine somatotrope function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Patients, Design, and Setting<\/jats:title><jats:p>We evaluated 21 adult males harboring hemizygous IGSF1 loss-of-function mutations for features of GH excess, in an academic clinical setting.<\/jats:p><\/jats:sec><jats:sec><jats:title>Main Outcome Measures<\/jats:title><jats:p>We compared biochemical and tissue markers of GH excess in patients and controls, including 24-hour GH profile studies in 7 patients. Parallel studies were undertaken in male Igsf1-deficient mice and wild-type littermates.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>IGSF1-deficient adult male patients demonstrated acromegaloid facial features with increased head circumference as well as increased finger soft-tissue thickness. Median serum IGF-1 concentrations were elevated, and 24-hour GH profile studies confirmed 2- to 3-fold increased median basal, pulsatile, and total GH secretion. Male Igsf1-deficient mice also demonstrated features of GH excess with increased lean mass, organ size, and skeletal dimensions and elevated mean circulating IGF-1 and pituitary GH levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We demonstrate somatotrope neurosecretory hyperfunction in IGSF1-deficient humans and mice. These observations define a hitherto uncharacterized role for IGSF1 in somatotropes and indicate that patients with IGSF1 mutations should be evaluated for long-term consequences of increased GH exposure.<\/jats:p><\/jats:sec>","DOI":"10.1210\/clinem\/dgz093","type":"journal-article","created":{"date-parts":[[2019,10,25]],"date-time":"2019-10-25T06:26:28Z","timestamp":1571984788000},"page":"e70-e84","source":"Crossref","is-referenced-by-count":31,"title":["IGSF1 Deficiency Results in Human and Murine Somatotrope Neurosecretory Hyperfunction"],"prefix":"10.1210","volume":"105","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4733-9031","authenticated-orcid":false,"given":"Sjoerd D","family":"Joustra","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, Netherlands"},{"name":"Department of Pediatrics, Leiden University Medical Center, Leiden, 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