ABSTRACT
Introduction: Schaaf-Yang-Syndrome (SYS, OMIM # 615547) is caused by truncating variants of the paternal allele of the maternally imprinted, paternally expressed gene MAGEL2 in the Prader-Willi critical region 15q11–15q13. Prader-Willi syndrome (PWS) and SYS share several phenotypic features, including muscular hypotonia, developmental delay/intellectual disability, and short stature. Evidence exists that similar to PWS, Growth Hormone (GH) deficiency is also a feature of SYS. Since 2000, GH therapy has been approved by the Federal Drug Agency (FDA) for PWS, which poses the question if GH therapy is a suitable treatment for children with SYS. Objective: To assess the prevalence of GH therapy in SYS children, its effect on the clinical endpoints height and body mass index (BMI), possible side effects and parents’ perception of changes during the therapy. Methods: Twenty-eight individuals diagnosed with SYS were recruited through CP Schaaf and the closed Facebook group for SYS. Patients were sent a consent form, a clinical questionnaire, and asked for growth charts of the affected children. Feedback on muscle strength, endurance and satisfaction was measured on a 5-level Likert scale. Height and BMI Z Scores (defined as the standard deviation of average height or BMI compared to children of the same sex and age) were calculated using WHO/CDC data and the PedZ calculator. The effect size of GH therapy was assessed by calculating the change in Height and BMI Z Scoreover the first 6 months of treatment. Data was(figure presented)(figure presented)linearly interpolated if no measurement on exactly 90 and 180 days after treatment start was taken. Results: Of the 28 individuals enrolled, 14 were on GH therapy. Thirteen of the 14 patient families provided feedback for the changes during therapy. Detailed growth charts were available for 8 patients with GH therapy, as well as for 5 patients without GH therapy. GH treatment was initiated at an average age of 2.6 years (range: 5 months up to 8 years). No patient has had to discontinue or interrupt GH therapy. Parental perception of changes after the onset of treatment was unanimously positive: All families noted either an increase (7 patients) or strong increase (6 patients) in muscle strength. For endurance, feedback was exactly the same. Overall, general satisfaction with the treatment was high, with 8 families stating they were very satisfied, 3 families stating they were satisfied and 2 families being neutral. Additional reported benefits were improved cognitive and social skills (6 patients) and improved motor development (5 patients). Negative side effects included worsening of sleep apnea in one individual which did not require further treatment or intervention, and worsening of scoliosis/kyphosis in further two individuals. In both cases of scoliosis, treatment start coincided with local Covid19 restrictions, and physical therapy and new back braces were no longer accessible for both patients.After three months of GH treatment, Height Z Score of the treated group increased on average by +0.70. After six months of treatment, the average increase in Height Z Score was +0.99 (Fig. 1A and 1B). The BMI Z Score of the treated group decreased by −0.48 after three months and by −0.71 after six months of treatment, on average (Fig. 2A and 2B). We calculated Height Z Scores and BMI Z Scores of the treated and nontreated groups, which revealed average Height Z Scores of −1.1 in the treated group, and −3.5 in the non-treated group (Fig. 1C). The average BMI Z Score in the treated group was +0.47, while the average BMI Z Score in the untreated group was +0.93 (Fig. 2C). Conclusion: We present a retrospective, questionnaire-based assessment of GH treatment in individuals with SYS. Our findings suggest that GH therapy should be considered as treatment for SYS. In this cohort, it led to an increase of body height and parental reports suggested an improvement of endurance and muscle strength. Furthermore, several families also noted additional beneficial sideeffects like im roved cognition and motor development. These data pave the way for a prospective clinical trial of GH therapy for individuals with SYS.