Effectiveness of Recombinant Human Growth Hormone Therapy in Small-for-Gestational-Age Children With Short Stature: A Stratified Analysis Based on Genetic Variant Status.
rhGH therapy can promote growth in children with short stature due to being small for gestational age, but those with pathogenic genetic variants may have a reduced growth response over time.
Where it sits
this study against the rest of the hgh (somatropin) corpusSummary and findings
This study evaluated the impact of pathogenic genetic variants on growth outcomes after 3 years of recombinant human growth hormone (rhGH) therapy in children born small for gestational age with persistent short stature. A total of 179 children were classified into variant-positive (n=30) and variant-negative groups (n=149). Results indicated that rhGH therapy promoted growth, but the variant-positive group showed an attenuated growth response over time.
Abstract
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). A retrospective cohort study. 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). Clinical characteristics and growth outcomes were assessed over 3 years of rhGH therapy. 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). 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.
Background
This study addresses the effectiveness of rhGH therapy in children with short stature due to being small for gestational age (SGA). Prior research has shown that genetic factors can influence growth outcomes, but the specific impact of pathogenic genetic variants in this population was not well understood. Understanding these effects is crucial for developing personalized treatment strategies.
Methods
This was a retrospective cohort study involving 179 children classified into variant-positive (n=30) and variant-negative (n=149) groups. The study assessed clinical characteristics and growth outcomes over 3 years of rhGH therapy. Primary outcomes included height standard deviation scores (SDS) and rates of intellectual disability and congenital anomalies.
Results
At baseline, the variant-positive group had a height SDS of -2.83, while the variant-negative group had -2.28 (p<0.001). After 3 years of therapy, the estimated marginal mean height SDS was -1.30±0.10 for the variant-positive group and -0.93±0.04 for the variant-negative group. There was a significant attenuation in height SDS gain in the variant-positive group over the years, with estimates of -0.18, -0.31, and -0.36 for Years 1, 2, and 3 respectively (all p<0.05).
Interpretation
The findings indicate that while rhGH therapy can promote growth in SGA-SS children, the variant-positive group experienced a lower growth response over time compared to the variant-negative group. This suggests that genetic evaluation may be important for tailoring treatment approaches. However, the clinical significance of the observed differences in height SDS may be limited due to the small sample size in the variant-positive group and the retrospective nature of the study.
Key findings
- -2.83 vs. -2.28 height SDS at baseline in variant-positive vs. variant-negative groups, p<0.001
- 36.7% vs. 7.4% rates of intellectual disability in variant-positive vs. variant-negative groups, p<0.001
- 30.0% vs. 6.7% rates of congenital anomalies in variant-positive vs. variant-negative groups, p<0.001
- After 3 years, EMM of height SDS was -1.30±0.10 in variant-positive and -0.93±0.04 in variant-negative groups
- Estimate of height SDS gain attenuation: Year 1 -0.18, Year 2 -0.31, Year 3 -0.36, all p<0.05
Limitations
- retrospective cohort study
- small n=30 in variant-positive group
- lack of long-term follow-up
- potential confounding factors not controlled