IGSF1 deficiency results in human and murine somatotrope neurosecretory hyperfunction

Joustra, S.D.; Roelfsema, F.; Trotsenburg, A.S.P. van; Schneider, H.J.; Kosilek, R.P.; Kroon, H.M.; Logan, J.G.; Butterfield, N.C.; Zhou, X.; Toufaily, C.; Bak, B.; Turgeon, M.O.; Brule, E.; Steyn, F.J.; Gurnell, M.; Koulouri, O.; Tissier, P. le; Fontanaud, P.; Bassett, J.H.D.; Williams, G.R.; Oostdijk, W.; Wit, J.M.; Pereira, A.M.; Biermasz, N.R.; Bernard, D.J.; Schoenmakers, N.

doi:doi:10.1210/clinem/dgz093

Context: The X-linked immunoglobulin superfamily, member 1 (IGSF1), gene is highly expressed in the hypothalamus and in pituitary cells of the POU1F1 lineage. 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.Objective: We aimed to evaluate the role of IGSF1 in human and murine somatotrope function.Patients, Design, and Setting: We evaluated 21 adult males harboring hemizygous IGSF1 loss-of-function mutations for features of GH excess, in an academic clinical setting.Main Outcome Measures: 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...Show moreContext: The X-linked immunoglobulin superfamily, member 1 (IGSF1), gene is highly expressed in the hypothalamus and in pituitary cells of the POU1F1 lineage. 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.Objective: We aimed to evaluate the role of IGSF1 in human and murine somatotrope function.Patients, Design, and Setting: We evaluated 21 adult males harboring hemizygous IGSF1 loss-of-function mutations for features of GH excess, in an academic clinical setting.Main Outcome Measures: 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.Results: 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.Conclusions: 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.Show less

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IGSF1 deficiency results in human and murine somatotrope neurosecretory hyperfunction