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GH therapy improves height in children with rare genetic mutation
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A small group of children with aggrecan deficiency, a rare genetic mutation that causes inherited short stature and early-onset joint disease, experienced a “robust” rate of growth after 6 months of recombinant human growth hormone treatment, according to study data presented at the Pediatric Endocrine Society annual meeting.
“With our increased use of novel genetic technologies, we are starting to learn more about the genetic causes of short stature and that many patients who were previously classified as having idiopathic short stature are now being found to have various genetic causes,” Andrew Dauber, MD, MMSc, chief of endocrinology at Children’s National Health System in Washington, D.C., told Endocrine Today. “Mutations in this specific gene, the aggrecan gene, are now estimated to potentially cause up to 2% of cases that we see in clinic of patients with idiopathic short statue.”
In an open-label, prospective pilot study, Dauber and colleagues analyzed data from six children aged 4 to 8 years with aggrecan deficiency and a normal insulin-like growth factor I concentration who were treatment-naive (three boys; mean height standard deviation score [SDS], –2.6; mean BMI SDS, 1.6). Children received GH treatment (50 mcg/kg per day) for 6 months as part of an ongoing, 12-month study that aims to enroll 10 children, Dauber said. Primary outcomes are change in height SDS and height velocity from baseline to 12 months.
After 6 months of treatment, mean annualized height velocity for the cohort was 9.5 cm per year. Mean change in height SDS was 0.46, he said.
In 12-month data available for four children, mean annualized height velocity was 8.7 cm per year and mean change in height SDS was 0.67.
“This is a robust rate of growth, almost 4 inches per year,” Dauber said. “This is an impressive growth rate for someone we know has a genetic condition affecting their growth plates.”
All children remained prepubertal, and there were no unexpected adverse events, according to researchers. Three children experienced a change in IGF-I of at least 2 SDS at 6 months, prompting a 10% to 20% protocol-driven dose reduction.
Researchers also sought to identify early signs of joint disease in the children, who underwent MRI of the knee. Researchers found that two children had osteochondritis dissecans that had not yet presented with clinical symptoms.
Dauber said the study, initially planned for 1 year, will likely be extended for multiple years to better assess the efficacy of GH therapy in children with aggrecan deficiency and learn more about early indicators of joint disease.
“We’re going to have to work together with genetic testing companies to develop a more rational panel for specific subclasses of short statue so we can make these diagnoses more rapidly,” Dauber said. “For aggrecan gene mutations, these children stop growing at an earlier age because the growth plates fuse. If one is going to intervene with growth hormone, earlier intervention is necessary.”
Dauber said future genetic research will likely reveal dozens or potentially hundreds of causes behind what has been termed idiopathic short stature.
“It behooves us to look at individual therapy, such as growth hormone, in each of those subclasses of short stature and decide, is this beneficial or not?” Dauber said.
Reference:
Alexandrou E, et al. Clinical characterization and trial of growth hormone in patients with aggrecan deficiency: 6 month data. Presented at: Pediatric Endocrine Society Annual Meeting; April 27-30, 2019; Baltimore.
Disclosure: Novo Nordisk funded this study. Dauber reports he has received consultant fees from Novo Nordisk.