A proof-of-concept study of growth hormone in children with Phelan-McDermid syndrome.

BACKGROUND: Phelan-McDermid syndrome (PMS) is caused by 22q13 deletions including SHANK3 or pathogenic sequence variants in SHANK3 and is among the more common rare genetic findings in autism spectrum disorder (ASD). SHANK3 is critical for synaptic function, and preclinical and clinical studies suggest that insulin-like growth factor-1 (IGF-1) can reverse a range of deficits in PMS. IGF-1 release is stimulated by growth hormone secretion from the anterior pituitary gland, and this study sought to assess the feasibility of increasing IGF-1 levels through recombinant human growth hormone (rhGH) treatment, in addition to establishing safety and exploring efficacy of rhGH in children with PMS. METHODS: rhGH was administered once daily for 12 weeks to six children with PMS using an open-label design. IGF-1 levels, safety, and efficacy assessments were measured every 4 weeks throughout the study. RESULTS: rhGH administration increased levels of IGF-1 by at least 2 standard deviations and was well tolerated without serious adverse events. rhGH treatment was also associated with clinical improvement in social withdrawal, hyperactivity, and sensory symptoms. LIMITATIONS: Results should be interpreted with caution given the small sample size and lack of a placebo control. CONCLUSIONS: Overall, findings are promising and indicate the need for larger studies with rhGH in PMS. Trial registration NCT04003207. Registered July 1, 2019, https://clinicaltrials.gov/ct2/show/NCT04003207 .

A randomized controlled trial of intranasal oxytocin in Phelan-McDermid syndrome.

BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene and characterized by global developmental delays, deficits in speech and motor function, and autism spectrum disorder (ASD). Monogenic causes of ASD such as PMS are well suited to investigations with novel therapeutics, as interventions can be targeted based on established genetic etiology. While preclinical studies have demonstrated that the neuropeptide oxytocin can reverse electrophysiological, attentional, and social recognition memory deficits in Shank3-deficient rats, there have been no trials in individuals with PMS. The purpose of this study is to assess the efficacy and safety of intranasal oxytocin as a treatment for the core symptoms of ASD in a cohort of children with PMS. METHODS: Eighteen children aged 5-17 with PMS were enrolled. Participants were randomized to receive intranasal oxytocin or placebo (intranasal saline) and underwent treatment during a 12-week double-blind, parallel group phase, followed by a 12-week open-label extension phase during which all participants received oxytocin. Efficacy was assessed using the primary outcome of the Aberrant Behavior Checklist-Social Withdrawal (ABC-SW) subscale as well as a number of secondary outcome measures related to the core symptoms of ASD. Safety was monitored throughout the study period. RESULTS: There was no statistically significant improvement with oxytocin as compared to placebo on the ABC-SW (Mann-Whitney U = 50, p = 0.055), or on any secondary outcome measures, during either the double-blind or open-label phases. Oxytocin was generally well tolerated, and there were no serious adverse events. LIMITATIONS: The small sample size, potential challenges with drug administration, and expectancy bias due to relying on parent reported outcome measures may all contribute to limitations in interpreting results. CONCLUSION: Our results suggest that intranasal oxytocin is not efficacious in improving the core symptoms of ASD in children with PMS. Trial registration NCT02710084.