ESPE Abstracts

Introduction: Homozygous loss-of-function mutations of the growth hormone receptor (GHR) gene result in GH insensitivity due to a dysfunctional receptor protein. Heterozygous mutations may result in a variable clinical spectrum ranging from normal height to severe short stature. Gain-of-function variants have been reported rarely.

Case Report: We hereby report the case of a Russian boy who was referred to our endocrine outpatient clinic for faltering growth at the age of 7.25 years. Since he was adopted, neither mid-parental height nor birth weight and length were available. Upon the time of consultation, his height was -3.17 SDS – WHO growth charts. The combination of a remarkably delayed bone age (2.7 years), baseline IGF-I levels equal to -1.57 SDS, a pathological response to two GH-stimulation tests (GH peaks: 4.7 and 3.4 ng/ml, respectively) and the findings of severe pituitary hypoplasia with intrasellar arachnoid diverticulum prompted the diagnosis of GH deficiency. As a consequence, treatment with recombinant human GH (rhGH) was undertaken at a daily starting dose of 0.029 mg/Kg. The patient showed an excellent auxological response, with an overall height gain of 1.57 SDS in 24 months. However, after the first year of treatment, IGF-I levels showed a persistent increase above +2 SDS (maximum value recorded + 10.64 SDS), irrespectively of a stepwise down-titration to a daily dose of 0.018 mg/kg. Treatment was therefore discontinued resulting in a timely normalization of IGF-I levels (-1.24 SDS). Given this unexplained responsiveness to rhGH, the patient underwent a genetical assessment: a novel heterozygous c.535C>T (p.Arg179Cys) variant involving the GHR gene was demonstrated in the proband. The mutation involved a functional domain and it was therefore predicted to be likely disease-causing by bioinformatic pathogenicity prediction tools.

Discussion: The overall response to rhGH treatment in GH-deficient patients is the result of both genetic and non-genetic factors. Increased responsiveness to rhGH associated to polymorphisms of the GHR gene has already been described in patients with idiopathic short stature. The novel variant hereby described may positively affect the sensitivity to treatment.

Conclusions: Growth hormone-deficient patients presenting with an excellent auxological response and persistent IGF-I levels above +2 SDS despite low rhGH doses may be carriers of GHR gene polymorphisms. GHR genotype influences sensitivity to GH; therefore, GH doses should be customized on the basis of IGF-I levels and clinical response. Further studies should be performed to define the optimal GHR genotype-based dose.