Abstract

Idiopathic short stature (ISS) is a term used to describe a selection of short children for whom no precise aetiology has been identified. Molecular investigations have made notable discoveries in children with ISS, thus removing them from this category. However, many, if not the majority of children referred with short stature, are designated ISS. Our interest in defects of GH action, i.e. GH resistance, has led to a study of children with mild GH resistance, who we believe can be mis-categorised as ISS leading to potential inappropriate management. Approval of ISS by the FDA for hGH therapy has resulted in many short children receiving this treatment. The results are extremely variable. It is therefore important to correctly assess and investigate all ISS subjects in order to identify those with mild but unequivocal GH resistance, as in cases of PAPP-A2 deficiency. The correct identification of GH resistance defects will direct therapy towards rhIGF-I rather than rhGH. This example illustrates the importance of recognition of GH resistance among the very large number patients referred with short stature who are labelled as ‘ISS’.

Highlights

  • Frontiers in EndocrinologyReceived: 22 September 2021 Accepted: November 2021 Published: December 2021. Citation: Savage MO and Storr HL (2021) GH Resistance Is a Component of Idiopathic Short Stature: Implications for recombinant hGH (rhGH) Therapy

  • The term idiopathic short stature (ISS) was first applied to short children without a known aetiology over 35 years ago, long before the era of molecular investigation

  • In the context of child with short stature, it is the milder forms of GH resistance, which tend to be confused with ISS

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Summary

Frontiers in Endocrinology

Received: 22 September 2021 Accepted: November 2021 Published: December 2021. Citation: Savage MO and Storr HL (2021) GH Resistance Is a Component of Idiopathic Short Stature: Implications for rhGH Therapy. Many, if not the majority of children referred with short stature, are designated ISS. Approval of ISS by the FDA for hGH therapy has resulted in many short children receiving this treatment. It is important to correctly assess and investigate all ISS subjects in order to identify those with mild but unequivocal GH resistance, as in cases of PAPP-A2 deficiency. The correct identification of GH resistance defects will direct therapy towards rhIGF-I rather than rhGH. This example illustrates the importance of recognition of GH resistance among the very large number patients referred with short stature who are labelled as ‘ISS’

INTRODUCTION
GH RESISTANCE
THE ORIGIN OF THE ISS DESIGNATION
ENDOCRINE ABNORMALITIES IN PATIENTS INITIALLY CONSIDERED TO HAVE ISS
GH RESISTANCE AS A COMPONENT OF ISS
VARIANTS IN GENES REGULATING GH ACTION WITH PHENOTYPES CONSISTENT WITH ISS
GHR MUTATIONS ASSOCIATED WITH MILD PHENOTYPES
Dominant Negative GHR Mutations
The Intronic GHR Pseudoexon Mutation
Small chin
Heterozygous Mutations Causing Short Stature
ISS AS AN INDICATION FOR RHGH THERAPY
INFLUENCE OF GH RESISTANCE ON GROWTH RESPONSE TO RHGH
Findings
CONCLUSIONS
Full Text
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