p.R209H GH1 variant challenges short stature assessment

Area of Science:

• Genetics
• Endocrinology
• Pediatrics

Background:

• Short stature is a common pediatric concern with diverse etiologies.
• Growth hormone deficiency (GHD) and growth hormone insensitivity (GHI) are key diagnoses.
• Genetic factors significantly influence growth hormone action and signaling.

Purpose of the Study:

• To investigate the clinical and biochemical variability associated with a specific GH1 gene variant (p.R209H).
• To explore the diagnostic challenges in a large pedigree exhibiting short stature.
• To elucidate the genetic basis of both isolated growth hormone deficiency (IGHD) and growth hormone insensitivity (GHI) phenotypes.

Main Methods:

• Pedigree analysis of a large Argentinean family with short stature.
• Clinical evaluation of affected individuals, including pediatric patients.
• Biochemical assessment of serum IGF-1 and IGFBP-3 levels.
• Growth hormone provocative testing (GHPT).
• Genetic sequencing of the GH1 gene.

Main Results:

• A heterozygous GH1 variant (c.626G>A, p.R209H) was identified in affected individuals.
• The pedigree displayed marked variability, with some patients showing IGHD and others GHI despite normal stimulated GH levels.
• Low serum IGF-1 and IGFBP-3 levels were observed in individuals with short stature and the GH1 variant.

Conclusions:

• The p.R209H GH1 missense variant can present with diverse clinical and biochemical phenotypes, mimicking both GHD and GHI.
• GH1 gene sequencing should be considered in children with short stature, low IGF-1, and IGFBP-3, irrespective of GHPT results.
• This highlights the importance of genetic testing for accurate diagnosis and management of growth disorders.