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Purpose <p>Isolated growth hormone deficiency (IGHD) is one of the treatable causes of short stature. We aimed to describe the clinical, biochemical, and molecular characteristics of IGHD and identify clinical predictors of mutation positivity and first-year height response to recombinant human growth hormone (rhGH).</p> Methods <p>Sixty-three children with IGHD who were on a minimum of one year of rhGH therapy were included. Detailed auxology, growth hormone provocative testing, and pituitary MRI were performed. Genetic variants were identified by whole-exome sequencing and correlated with auxological and biochemical parameters. The first-year height response was assessed as ΔHeight SDS, and predictors of response were analysed using regression models.</p> Results <p>The mean age at presentation was 8.9 ± 2.9 years; 57% were born to consanguineous parents. Severe auxological impairment was observed, with a mean height SDS of − 4.29 ± 1.09, and a mean genetic height deficit of − 2.42 ± 1.12 SDS. Genetic variants were identified in 49% of the cohort, predominantly in <i>GHRHR</i> (39.7%), with the p.Glu72Ter being the most frequent, while G<i>H1</i> variants were less prevalent (4.8%). Genetic variant-positive children presented at a younger age, with more severe growth failure, and a better response to rhGH therapy. Regression analysis identified genetic variant-positive status as an independent predictor of favourable first-year growth response (ΔHeight-SDS:1.24 ± 0.50).</p> Conclusion <p>The South Indian IGHD cohort exhibits a distinct genetic profile, with <i>GHRHR</i> 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.</p>

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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

  • 期刊论文

  • 发表日期：

    2025年12月22日

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  • Shanmugam Dhivya,
  • Subbiah Sridhar,
  • M. Kathirvel,
  • Palaniappan Sreenivasan,
  • Nandini Kuppusamy,
  • Rahila Chellapillai,
  • Jayachandran SenthilKumar

摘要

Purpose

Isolated growth hormone deficiency (IGHD) is one of the treatable causes of short stature. We aimed to describe the clinical, biochemical, and molecular characteristics of IGHD and identify clinical predictors of mutation positivity and first-year height response to recombinant human growth hormone (rhGH).

Methods

Sixty-three children with IGHD who were on a minimum of one year of rhGH therapy were included. Detailed auxology, growth hormone provocative testing, and pituitary MRI were performed. Genetic variants were identified by whole-exome sequencing and correlated with auxological and biochemical parameters. 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 8.9 ± 2.9 years; 57% were born to consanguineous parents. Severe auxological impairment was observed, with a mean height SDS of − 4.29 ± 1.09, and a mean genetic height deficit of − 2.42 ± 1.12 SDS. Genetic variants were identified in 49% of the cohort, predominantly in GHRHR (39.7%), with the p.Glu72Ter being the most frequent, while GH1 variants were less prevalent (4.8%). Genetic variant-positive children presented at a younger age, with more severe growth failure, and a better response to rhGH therapy. Regression analysis identified 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.