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

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 knock-out 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: To establish the phenotype of GHSR haploinsufficiency and their 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 six were novel. Variants showed either partial or complete loss-of-function, primarily through loss of constitutive activity. Patients (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 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.