ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: J Clin Endocrinol Metab 2018 pii: jc.2018-00687.

Prader-Willi syndrome (PWS) is a rare genetic disorder secondary to absent expression of the paternal active genes in the PWS critical region of chromosome 15. 70% of patients have a microdeletion, 28% a uniparental disomy (UPD) and 1% an imprinting defect. PWS has an estimated incidence rate of 1 in 25,000 live births and represents the most common form of genetic obesity. The clinical phenotype of PWS patients includes neonatal hypotonia, endocrine defects, scoliosis, developmental delay, cognitive impairment, and characteristic facial appearance, besides severe obesity [1,2]. GH therapy in PWS patients contributes to improve growth, body composition, resting energy expenditure, motor development, muscle strength, exercise tolerance, bone health and lipid profiles [3]. It has recently been reported that short-term GH therapy may improve neurological and motor skills in children with PWS [4].

This study, a large prospective patient cohort, for the first time reports the long-term effectiveness of GH therapy in improving motor and mental development in children affected by genetically confirmed PWS. 63 children and toddlers with PWS (median age 1 year) were evaluated by Bayley Scales of Infant Development II (BSIDII) tests over the 3 years of GH treatment.

The results showed a significant improvement of mental and motor skills during treatment, reducing the performance gap between PWS children and healthy control children. In particular baseline mental and motor development were 58.1% and 41.9% vs. healthy reference subjects (P<0.001) and increased to 79.6 and 78.2%, respectively, after three years of treatment. A younger age at start of GH treatment was associated with a greater improvement in both mental and motor development. The head circumference increased from −1.0 SDS at baseline to 0.1 SDS after 3 years (P<0.01) but this change was not associated with the course of mental and motor development. At least part of the observed improvement of mental and motor development may be explained by spontaneous improvement of hypotonia with age and early start of physical therapy. Since IGF-I is involved in brain development and myelinization, the observed effect of GH treatment is probably mediated by the neurotrophic actions of IGF-I [5].

The lack of an untreated group is the major weakness of this study, however, a prospective randomized control trial is unethical since GH therapy is started in all patients with genetic confirmation of PWS. On the basis of these results showing a better psychomotor development when GH treatment is started at a younger age, the initiation of GH treatment in young infants with PWS should be encouraged.

References: 1. Cassidy SB, Schwartz S, Miller JL, Driscoll DJ. Prader-Willi syndrome. Genet Med 2012; 14: 10–26.

2. Grugni G, Crinò A, Bosio L et al. The Italian National Survey for Prader-Willi syndrome. An epidemiologic study. Am J Med Genet A 2008; 146: 861–872.

3. Deal CL et al. Growth Hormone Research Society Workshop Summary. Consensus Guidelines for Recombinant Human Growth Hormone Therapy in Prader-Willi Syndrome. J Clin Endocrinol Metab 2013;98:E1072–87.

4. Siemensma EP, Tummers-de Lind van Wijngaarden RF, Festen DA, Troeman ZC, van Alfen-van der Velden AA, Otten BJ, Rotteveel J, Odink RJ, Bindels-de Heus GC, van Leeuwen M, Haring DA, Oostdijk W, Bocca G, Mieke Houdijk EC, van Trotsenburg AS, Hoorweg Nijman JJ, van Wieringen H, Vreuls RC, Jira PE, Schroor EJ, van Pinxteren-Nagler E, Willem Pilon J, Lunshof LB, Hokken-Koelega AC. Beneficial effects of growth hormone treatment on cognition in children with Prader-Willi syndrome: a randomized controlled trial and longitudinal study. J Clin Endocrinol Metab. 2012;97:2307–2314.

5. Nyberg F, Hallberg M. Growth hormone and cognitive function. Nat Rev Endocrinol. 2013;9:357–365.