Effectiveness of Recombinant Human Growth Hormone Therapy in Small-for-Gestational-Age Children With Short Stature: A Stratified Analysis Based on Genetic Variant Status.

OBJECTIVE

This study aimed to evaluate the impact of pathogenic genetic variants on growth outcomes following 3 years of recombinant human growth hormone (rhGH) therapy in children born small for gestational age with persistent short stature (SGA-SS).

DESIGN

A retrospective cohort study.

PATIENTS: One hundred and seventy-nine SGA-SS children who underwent clinical and genetic evaluation were classified into variant-positive (n = 30) and variant-negative groups (n = 149).

MEASUREMENTS: Clinical characteristics and growth outcomes were assessed over 3 years of rhGH therapy.

RESULTS

At baseline, the variant-positive group had significantly lower height standard deviation score (SDS) (-2.83 vs. -2.28, p < 0.001) and higher rates of intellectual disability (36.7% vs. 7.4%, p < 0.001) and congenital anomalies (30.0% vs. 6.7%, p < 0.001). rhGH therapy promoted longitudinal growth in both groups (evaluated n = 142); after 3 years, the estimated marginal mean (EMM) of height SDS reached -1.30 ± 0.10 in the variant-positive group and -0.93 ± 0.04 in the variant-negative group. However, linear mixed model analysis revealed a progressive attenuation of incremental height SDS gain in the variant-positive group as the treatment progressed, with significant interaction estimates observed at Year 1 (Estimate -0.18), Year 2 (Estimate -0.31) and Year 3 (Estimate -0.36; all p < 0.05).

CONCLUSION

As one of the first longitudinal analyses utilizing repeated-measures modelling in a genetically characterized patient population, this study demonstrates that while rhGH therapy effectively promoted linear growth in SGA-SS children, patients with a molecular diagnosis presented with lower baseline stature and an attenuated incremental growth response over time, highlighting the importance of genetic evaluation for personalized treatment strategies.