Clinical and Molecular Genetic Analysis of Children with Severe Short Stature due to Isolated Growth Hormone Deficiency: Insights from a South Indian Cohort and Predictors of Growth Response.

Purpose: Isolated growth hormone deficiency (IGHD) is one among the treatable causes of short stature. We aimed to describe the clinical, biochemical, and molecular characteristics of IGHD as well as to identify clinical predictors of mutation positivity and first-year height response to recombinant human growth hormone (rhGH). Methods: Sixty-three children with IGHD who had received minimum of one year of rhGH therapy were included. Detailed auxology, growth hormone provocative testing, pituitary MRI were performed and genetic analysis was done by using whole-exome sequencing. The mutation positivity was correlated with auxological and biochemical diagnosis of IGHD. The first-year height response was assessed as ΔHeight SDS and predictors of response were analysed using regression models. Results: The mean age at presentation was 9 years; 57% were born to consanguineous parents. Severe auxological impairment (mean height SDS − 4.29, and mean genetic height deficit − 2.42 SDS) was observed. Genetic variants were identified in 49% of the study cohort, predominantly in GHRHR (39.7%), with p.Glu72Ter being the most frequent, whereas G H1 variants were less prevalent (4.8%). Genetic-variant positive children had a younger age at onset, more severe growth failure, and a better response to rhGH treatment. Regression analysis revealed genetic-variant positive status as an independent predictor of favourable first-year growth response (ΔHeight-SDS:1.24 ± 0.50). Conclusion The South Indian IGHD cohort exhibits a distinct genetic profile, with GHRHR p.Glu72Ter being the most frequent variant, consistent with a founder effect. Severe short stature, low peak stimulated growth hormone levels, and superior first-year growth response indirectly predicted mutation positivity.