medwireNews: A study of Brazilian children with isolated SHOX haploinsufficency who were followed up until adult height has demonstrated a long-term benefit of recombinant human growth hormone (rhGH) therapy with or without puberty modulator treatment.
“This longitudinal retrospective long-term study emphasizes the real-world effectiveness of rhGH treatment in children with SHOX haploinsufficiency”, say Alexander Jorge, from Faculdade de Medicina da Universidade de Sao Paulo in Brazil, and co-authors.
As reported in Hormone Research in Paediatrics, the team identified 47 patients with a SHOX loss of function defect (n=37), deletion within the regulatory region (n=6) or missense mutation (n=4), and no evidence of other causes of growth impairment.
The 29 patients who received rhGH at a median dose of 49 µg/kg per day were more likely to have short stature than the 18 patients who did not (height standard deviation score [SDS] below –2.0; 69 vs 28%) but had similar adult height predictions, which the researchers say reflects the younger bone age in the rhGH-treated versus -untreated patients (median 12.0 vs 10.3 years).
Among the children given rhGH therapy, nine girls and two boys had puberty postponed using a gonadotropin-releasing hormone agonist (GnRHa) and two boys also received aromatase inhibitors to “slow bone age advancement and allow the progression of secondary sex characteristics”, the investigators observe.
Adult height was attained by 18 patients in the rhGH group, including 10 also given GnRHa, and 13 patients in the no rhGH therapy group, report Jorge et al.
Patients who were not given rhGH therapy showed a decrease in their median height SDS of –0.8 between baseline and adulthood and the prevalence of short stature increased from 31% to 77%.
By contrast, among patients given rhGH therapy, there was a significant improvement in adult height SDS of 0.6 versus predicted adult height at baseline, translating to a 4.2 cm gain, and there was a significant decrease in the prevalence of short stature, which fell from 61% to 28%.
Noting that this total height SDS change is lower than previously reported for rhGH therapy, however, the authors suggest “it might be explained by the fact that several of our children started treatment just after pubertal onset and by the high prevalence of [loss of function] and missense mutation in SHOX gene in our cohort”, which are associated with a poorer response to rhGH therapy than the regulatory region deletion.
Overall, the differences between the treated and untreated groups translated to a 1 SD greater adult height – approximately 6.3 cm – with rhGH use and there was no difference in adult body proportion, BMI or Madelung deformity between the groups, report Jorge and co-authors.
The team also found that there was a similar adult height attainment in patients given rhGH alone or together with GnRHa despite the majority of children given puberty modulators being pubertal at time of rhGH initiation.
There was a “slightly better” height SDS change relative to adult height prediction with GnRHa/aromatase inhibitors versus without puberty modulators (0.8 vs 0.2), say the researchers. Puberty modulator use was also associated with “attenuation of body disproportion” compared with rhGH therapy alone, with a significant difference in the median change from baseline to adulthood in sitting height to height SDS median, at –0.6 versus 0.9.
“In patients who do not have the opportunity to start treatment in the [prepubertal] age or who have a worse adult height prediction, the use of combination therapy can be a strategy to improve adult height”, they suggest.
The investigators add that adult height was available for three of the four girls who had SHOX haploinsufficiency and central precocious puberty after a median 4.9 years of rhGH therapy and a median 3.9 years of GnRHa treatment; all three achieved an adult height within the reference range.
“Although [limited] by its retrospective design and by relatively small number of patients [who] reached adult height, our study has provided a deeper insight into the natural growth patterns of children with SHOX defects and into the benefits of rhGH treatment with or without puberty modulators to improve adult height”, summarise Jorge and team.
Noting that the “recommendation to treat children with SHOX haploinsufficiency that have height within the lower normal range has not yet been established”, the researchers emphasize that “children with heights within the reference range need careful monitoring as they often show a negative change in height SDS during puberty and treatment with rhGH can prevent this loss in height potential.”
By Lynda Williams
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