Loss-of-function <em>GHSR</em> variants are associated with short stature and low IGF-I

Lauren D Punt; Sander Kooijman; Noa J. M Mutsters; Kaiming Yue; der Kaay Danielle C. M van; Tellingen Vera van; Waarde Willie M Bakker-van; Annemiek M Boot; den Akker Erica L. T van; Boekholt Anneke A van; Groote Kirsten de; Anne R Kruijsen; G Nancy H.; van Nieuwaal-van Maren; Woltering M Claire; C. van der Heyden Malou Heijligers, Josine; Ellen M. N Bannink; Tuula Rinne; Sabine E Hannema; Waal Wouter J de; Lucia C Delemarre; Patrick C. N Rensen; Bruin Christiaan de; Duyvenvoorde Hermine A van; Jenny A Visser; Patric J. D Delhanty; Monique Losekoot; Jan M Wit; Sjoerd D Joustra

doi:10.1530/ey.22.4.2

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ESPE Yearbook of Paediatric Endocrinology (2025) 22 4.2 | DOI: 10.1530/ey.22.4.2

ESPEYB25 4. Growth and Growth Factors Novel Genetic Insights (3 abstracts)

4.2. Loss-of-function GHSR variants are associated with short stature and low IGF-I

Lauren D Punt , Sander Kooijman , Noa J. M Mutsters , Kaiming Yue , Daniëlle C. M van der Kaay , Vera van Tellingen , Willie M Bakker-van Waarde , Annemiek M Boot , Erica L. T van den Akker , Anneke A van Boekholt , Kirsten de Groote , Anne R Kruijsen , Nancy H. G , van Nieuwaal-van Maren , M Claire Woltering , Malou Heijligers , Josine C. van der Heyden , Ellen M. N Bannink , Tuula Rinne , Sabine E Hannema , Wouter J de Waal , Lucia C Delemarre , Patrick C. N Rensen , Christiaan de Bruin , Hermine A van Duyvenvoorde , Jenny A Visser , Patric J. D Delhanty , Monique Losekoot , Jan M Wit & Sjoerd D Joustra

J Clin Endocrinol Metab, 2025, 110, e1303–e1314. doi: 10.1210/clinem/dgaf010 PMID: 39785833

Brief summary: The growth hormone secretagogue receptor (GHSR), encoded by GHSR, is expressed on pituitary somatotrophs and enhances growth hormone (GH) secretion through both constitutive activity and stimulation by ghrelin. Although knockout mouse models suggested that heterozygous GHSR loss-of-function reduces GH response to fasting, data from small human case series have remained inconclusive.

This study aimed to define the clinical phenotype of GHSR haploinsufficiency and evaluate the growth response to GH therapy in affected patients. The authors investigated 26 children (aged 4.0–15.1 years) with short stature carrying heterozygous GHSR variants. Ten distinct variants were identified, including 6 novel ones. Functional in vitro studies demonstrated that these variants led to partial or complete loss of receptor function, primarily by abolishing its constitutive activity. Clinically, affected patients presented with proportionate short stature (mean height −2.8 SDS), reduced IGF-I levels (mean −1.6 SDS), normal stimulated GH peaks, and, in some cases, failure to thrive associated with low appetite. Nine patients were treated with recombinant human GH (rhGH), achieving significant height improvements: an average gain of +0.9 SDS after 1 year and +1.5 SDS after 2 years. Two patients reached near-adult height, showing gains of +1.7 to +1.9 SDS from baseline. The study concludes that GHSR variants cause short stature through GH neurosecretory dysfunction, as receptor loss-of-function impairs spontaneous GH release despite normal responses in GH stimulation tests. These findings underscore the critical physiological role of GHSR in GH regulation and support rhGH therapy as an effective intervention. Notably, the study also observed incomplete penetrance, with some carriers of pathogenic GHSR variants exhibiting normal stature—suggesting the influence of additional genetic or environmental modifiers.

Overall, this work strengthens the concept that pathogenic GHSR variants decrease linear growth by impairing both ghrelin-induced and constitutive GH secretion. The authors propose that, beyond rhGH therapy, GH secretagogue receptor agonists might represent a promising therapeutic option in the future. This study thus broadens the molecular spectrum of treatable short stature and highlights the value of genetic testing in children with unexplained growth failure.

References: 1. Howard AD, Feighner SD, Cully DF, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 1996;273(5277):974-977.2. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656-660.3. Devesa J. The Complex world of regulation of pituitary growth hormone secretion: the role of ghrelin, klotho, and nesfatins in it. Front Endocrinol (Lausanne). 2021;12:636403.4. Labarthe A, Zizzari P, Fiquet O, et al. Effect of growth hormone secretagogue receptor deletion on growth, pulsatile growth hormone secretion, and meal pattern in male and female mice. Neuroendocrinology. 2022;112(3):215-234.