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. 2025 Apr 22;110(5):e1303-e1314.
doi: 10.1210/clinem/dgaf010.

Loss-of-Function GHSR Variants Are Associated With Short Stature and Low IGF-I

Lauren D Punt  1 , Sander Kooijman  2   3 , Noa J M Mutsters  4 , Kaiming Yue  2 , Daniëlle C M van der Kaay  5 , Vera van Tellingen  6 , Willie M Bakker-van Waarde  7 , Annemiek M Boot  7 , Erica L T van den Akker  5 , Anneke A van Boekholt  8 , Kirsten de Groote  1 , Anne R Kruijsen  1 , Nancy H G van Nieuwaal-van Maren  9 , M Claire Woltering  10 , Malou Heijligers  11 , Josine C van der Heyden  12 , Ellen M N Bannink  13 , Tuula Rinne  14 , Sabine E Hannema  15   16   17 , Wouter J de Waal  18 , Lucia C Delemarre  19 , Patrick C N Rensen  2   3 , Christiaan de Bruin  1 , Hermine A van Duyvenvoorde  20 , Jenny A Visser  4 , Patric J D Delhanty  4 , Monique Losekoot  20 , Jan M Wit  1 , Sjoerd D Joustra  1
Affiliations

Loss-of-Function GHSR Variants Are Associated With Short Stature and Low IGF-I

Lauren D Punt et al. J Clin Endocrinol Metab. .

Erratum in

Abstract

Context: The growth hormone (GH) secretagogue receptor, encoded by GHSR, is expressed on somatotrophs of the pituitary gland. Stimulation with its ligand ghrelin, as well as its constitutive activity, enhances GH secretion. Studies in knockout mice suggest that heterozygous loss-of-function of GHSR is associated with decreased GH response to fasting, but patient observations in small case reports have been equivocal.

Objective: This work aims to establish the phenotype of GHSR haploinsufficiency and its growth response to GH treatment.

Methods: This case series includes 26 patients with short stature and heterozygous GHSR variants. Pathogenicity was studied in vitro using total protein levels, cell surface expression, and receptor activity in basal, stimulated, and inhibited states.

Results: Ten different variants were identified, of which 6 were novel. Variants showed either partial or complete loss of function, primarily through loss of constitutive activity. Patients (aged 4.0-15.1 years) had proportionate short stature (height -2.8 ± 0.5 SDS), failure to thrive with low appetite (n = 4), a mean serum insulin-like growth factor-I (IGF-I) of -1.6 ± 0.7 SDS, and a normal stimulated GH response. Nine patients received GH treatment, showing a height gain of 0.9 ± 0.4 SDS after 1 year and 1.5 ± 0.4 SDS after 2 years (n = 5).

Conclusion: This study combines phenotypical and functional data in a uniquely large group of children with short stature carrying GHSR variants, and shows their good response to GH treatment. The results strengthen the hypothesis of GHSR's role in GH secretion.

Keywords: GHSR; IGF-I; growth hormone; short stature.

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Figures

Figure 1.
Figure 1.
Snake-plot of variant locations within growth hormone secretagogue receptor (GHSR).
Figure 2.
Figure 2.
Functional assessment of growth hormone secretagogue receptor (GHSR) variants. A, GHSR variant responses to ghrelin dose curves, with baseline level expressed relative to wild-type baseline. B, Basal activity. C, Emax (stimulated activity). D, Cell surface expression. Data are expressed as percentage wild-type ± SEM of 4 to 6 independent experiments. *P less than or equal to .05; **P less than or equal to .0001.
Figure 3.
Figure 3.
Height SDS in patients not on recombinant human growth hormone therapy. The black curve represents the fitted average, and the dotted curves represent the 95% prediction interval.
Figure 4.
Figure 4.
Serum insulin-like growth factor-I (IGF-I) and IGFBP-3 SDS of each patient at presentation, before start of recombinant human growth hormone therapy.
Figure 5.
Figure 5.
Height SDS during the 2 years before and after start of recombinant human growth hormone (rhGH) therapy
See this image and copyright information in PMC

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