Prader-Willi syndrome : diagnosis and effects of growth hormone treatment

Sammanfattning: Prader-Willi syndrome (PWS) is a rare neurogenetic disorder characterised by hypotonia (especially pronounced in the perinatal period) with "failure to thrive", hypogonadism, hypoventilation, dysmorphic features, final short stature and mental retardation. From the age of 2 years hyperphagia develops leading to obesity if the caloric intake is not limited. The genetic background in PWS is the absence of functioning genes on the paternally derived chromosome 15q11-13. PWS is one of the first described human disorders due to genomic imprinting. Thus, the maternally derived genes of this region on chromosome 15 are inactivated. An early diagnosis of PWS is important in order to prevent obesity and its complications. The diagnosis is clinical but an easy and reliable molecular genetic method is needed as a complement. We have validated the molecular genetic DNA methylation test (PW71), based on a difference in methylation pattern, on a well clinically and molecular-genetically defined population with PWS and found a good concordance. Subjects with PWS have a poor linear growth velocity during childhood and a final short stature, in spite of the present hypogonadism. They also have a body composition similar to that in subjects with growth hormone (GH) deficiency; increased fat mass and decreased lean body mass. Twenty-nine children with PWS participated in a controlled randomised GH trial, where one group was treated with GH during two years, while the other group served as controls during the first year and then was treated with GH in a larger dose. The aim with the study was to investigate linear growth, body composition, bone mineral content, lipolysis, and the effects of GH on glucose and insulin homeostasis and breathing in prepubertal children. Before start of GH treatment, the children had very low levels of serum GH and IGF-I During the treatment, linear growth increased markedly and body composition changed with increased lean body mass and decreased fat mass compared to the group of controls with PWS. During GH treatment, the bone mineral content increased. Both in vitro and in vivo lipolysis increased during GH treatment and decreased slowly when treatment was withdrawn. Fasting insulin levels increased during treatment, but none of the children developed glucose intolerance or type 11 diabetes mellitus. GH treatment increased ventilation drive and chemoreceptor sensitivity to CO2 in children with PWS. In summary, an early diagnosis through DNA methylation testing, makes it possible to institute PWS specific treatment before obesity and its complications have occured. GH treatment of children with PWS improved linear growth, body composition, bone mineral content and respiratory functions. This supports the conclusion that most children with PWS have a functional GH deficiency. This improvement has been reported by the participating parents to contribute to an increased quality of life.