ESPE2023 Free Communications Growth and syndromes (to include Turner syndrome) (6 abstracts)
Pathogenic variants in GHSR cause short stature and growth hormone neurosecretory dysfunction; results from a large case series
Lauren Punt 1 , Sander Kooijman 1 , Danielle van der Kaay 2 , Vera van Tellingen 3 , Willie Bakker - van Waarde 4 , Annemieke Boot 4 , Erica van den Akker 2 , Anneke van Boekholt 5 , Hermine van Duyvenvoorde 1 , Nancy van Nieuwaal - Van Maren 6 , Claire Woltering 7 , Malou Heijligers 8 , Josine van der Heyden 9 , Ellen Bannink 10 , Monique Losekoot 1 , Christiaan de Bruin 1 , Jan Maarten Wit 1 & Sjoerd Joustra 1
1Leiden University Medical Center, Leiden, Netherlands. 2ErasmusMC, Rotterdam, Netherlands. 3Catharina Hospital, Eindhoven, Netherlands. 4Beatrix Children's Hospital, Groningen, Netherlands. 5Viecuri Medical Center, Venlo, Netherlands. 6Gelderse Vallei Hospital, Ede, Netherlands. 7Reinier de Graaf Gasthuis, Delft, Netherlands. 8Maastricht University Medical Center, Maastricht, Netherlands. 9Franciscus Gasthuis & Vlietland, Rotterdam, Netherlands. 10Tergooi MC, Hilversum, Netherlands
Introduction: Ghrelin binds to its receptor GHSR1A, encoded by GHSR, on somatotrophs of the pituitary. Growth hormone (GH) secretion is enhanced by ghrelin binding as well as the receptor’s constitutive activity. Results from in vitro experiments, knock-out mice, and GWAS suggest that heterozygous loss-of-function of GHSR may be associated with short stature, but observations in case studies are equivocal. We aimed to better characterize the phenotype, evaluate in vitro GHSR function, and assess the response to rhGH treatment.
Methods: This case series includes 18 patients with suspected GHSR haploinsufficiency. in vitro variant pathogenicity was studied using transfection of mutated GHSR in HEK293 cells. We assessed cell-surface expression, and used a luciferase assay to measure serum response element-mediated transcriptional activity in the basal state and after stimulation with ghrelin.
Results: Patients (6F, 12M, 2-12 years) had a birthweight of -0.2±1.4 SDS and birth length of -0.7±1.4 SDS. Height at inclusion was -2.7±0.6 SDS, with normal sitting height/height ratio and an average BMI of -0.8±1.0 SDS. Mean serum IGF-I was -1.5±0.5 and IGFBP-3 was -1.2±0.7 SDS. The stimulated GH response was 11.7-32.7 µg/L. In two patients, a low-dose IGF-I generation test (0.025 mg/kg rhGH for seven days, n=2) showed a significant IGF-I increase of 1.2-1.3 SDS. On rhGH treatment (n=4), height gain after 1 and 2 years was +0.6-1.5 SDS and +1.4-1.6 SDS. Ten different rare GHSR variants with ACMG class 3, 4 or 5 were identified (six novel). So far, we have analysed six variants in vitro, showing absence of constitutive activity in five (p.Arg141Pro, p.Ala204Glu, p.Arg107Glyfs*31, p.Trp193*, and p.Ala271Pro) as well as decreased response to ghrelin in two (Ala204Glu, Arg107Glyfs*31), and normal constitutive activity and increased response to ghrelin (Phe279Leu) in one. The latter patient (untreated) had shown the highest stimulated GH response (32.7 µg/L).
Conclusion: This is the first study to combine phenotypical, functional and rhGH response data in a large (n=18) group of short children with suspected GHSR haploinsufficiency. Overall, these children appear to have proportionate short stature, low-normal serum IGF-I and IGFBP-3 levels and a normal stimulated GH response. The 1- and 2-year growth responses to rhGH treatment in four patients appear similar to those in GH-deficient children, supporting the hypothesis that GHSR haploinsufficiency is associated with decreased spontaneous GH secretion. Long-term follow-up of rhGH treatment is needed to establish its efficacy in terms of adult height.
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