Ann Christin Lindgren

Mental and motor development before and during growth hormone treatment in infants and toddlers with Prader-Willi syndrome

Background  Prader–Willi syndrome (PWS) is a neurogenetic disorder characterized by muscular hypotonia, psychomotor delay, feeding difficulties and failure to thrive in infancy. GH treatment improves growth velocity and body composition. Research on the effects of GH on psychomotor development in infants with PWS is limited.

Five years of growth hormone treatment in children with Prader-Willi syndrome

The authors have followed 18 prepubertal children (3‐12 years of age) with Prader‐Willi syndrome during 5 years of growth hormone (GH) treatment. Initially, all the children participated in a randomized, controlled GH trial, conducted to assess the effects of GH treatment on growth, body composition and behaviour. GH was administered to group A (n= 9) at a dose of 0.1 IU/kg/day (0.033 mg/kg/day) for 2 years. Group B (n= 9) was untreated for the first year, but the children were given GH at a dose of 0.2 IU/kg/day (0.066 mg/kg/day) during the second year. Thereafter, all children stopped GH treatment for 6 months and were then restarted with GH at a dose of 0.1 IU/kg/day (0.033 mg/kg/day). During the first year of GH treatment, there was a dramatic increase in height SDS in both groups. The attained height percentile was maintained during the continued GH treatment. Five years after the start of GH treatment, mean height SDS is still above average for age. Four children have reached final height, all within ± 2 SD of target height. During the first year GH treatment, body mass index (BMI) SDS decreased significantly from 3.0 to 1.5 SDS in group A and from 2.8 to 1.2 SDS in group B, but it increased again during the 6‐month period without treatment. Following the restart of GH treatment, BMI SDS has stablized at 1.7 SDS for group A and 2.5 SDS for group B. In 16 of 18 patients, fasting insulin, glucose and the A1c fraction of glycosylated haemoglobin remained within normal ranges during 5 years of GH treatment. Following a period of rapid weight gain, two children have developed non‐insulin‐dependent diabetes mellitus. Glucose homeostasis returned to normal when GH treatment was withdrawn. In conclusion, GH treatment has a proven favourable effect on growth and body composition in patients with Prader‐Willi syndrome. Treatment should be individualized, and close surveillance of glucose homeostasis is needed, especially if the patients is severely obese.

Growth Hormone Treatment of Children with Prader-Willi Syndrome: Effects on Glucose and Insulin Homeostasis

Insulin and glucose homeostasis have been studied during growth hormone (GH) treatment in 19 prepubertal children with Prader-Willi syndrome (PWS) and compared with 11 healthy prepubertal obese children. Before treatment, insulin levels in children with PWS were lower (p < 0.01) than in healthy obese children. During GH treatment, fasting insulin levels increased in children with PWS (p < 0.001). Glucose levels were similar for PWS and obese children before treatment. Children with PWS showed a slow glucose disappearance rate (k = 1.7%) which deteriorated (k = 1.3%, p < 0.001) during GH treatment. HbA1c and fasting glucose levels remained normal. Thus, GH treatment of children with PWS resulted in increased insulin blood levels, unchanged fasting glucose and HbA1c but decreased glucose elimination rate after an intravenous glucose test. However, the observed dose-dependent increase in insulin levels during GH treatment, that reached supranormal concentrations in 6/19 patients, and the occurrence of NIDDM in 1 patient during follow-up suggest that close surveillance and low doses of GH should be applied, especially if the PWS patient is very obese.

Increased Leptin Messenger RNA and Serum Leptin Levels in Children with Prader-Willi Syndrome and Nonsyndromal Obesity

To study the potential role of the ob gene pathway in childhood obesity, we have investigated leptin mRNA levels in s.c. adipose tissue obtained from nonobese prepubertal children (n = 20), obese nonsyndromal children (n = 6), and children with Prader-Willi syndrome (n = 6) by in situ hybridization histochemistry. We have also investigated the fasting serum leptin levels in such children. Compared with nonobese children, leptin mRNA expression was higher both in children with Prader-Willi syndrome and in children with nonsyndromal obesity (p < 0.01). Furthermore, the serum leptin levels were also significantly higher in both children with Prader-Willi syndrome and nonsyndromal obesity compared with the nonobese children (p < 0.001). However, no significant differences in adipose tissue leptin mRNA or serum leptin levels were observed between children with Prader-Willi syndrome and nonsyndromal obese children. As expected both fasting serum leptin levels and leptin mRNA expression levels correlated to body mass index (rs = 0.80 and 0.73, respectively, p < 0.005). No difference in leptin expression between Prader-Willi syndrome and nonsyndromal childhood obesity could be revealed in the present study. However, differences in the hypothalamic response to leptin between the two forms of obesity cannot be excluded.

The effect of growth hormone on sleep-related cardio-respiratory control in Prader-Willi syndrome.

Aim:  To evaluate the effects of growth hormone (GH) treatment on control of breathing, heart rate and blood pressure during sleep in Prader–Willi Syndrome (PWS).

Diagnosis of the Prader-Willi syndrome by proving the absence of the unmethylated PW71 DNA fragment

The Prader‐Willi syndrome (PWS) is a genetic disorder which is difficult to diagnose from clinical symptoms in newborns and young children. However, it is known that in PWS a fragment within the q11‐13 region of the paternally derived chromosome 15 is deleted. Recently it has been observed that the D15S63 (PW71) locus in chromosome 15q11‐13 is methylated on the maternally derived chromosome, but unmethylated on the paternally derived chromosome. Based on this observation a rapid diagnostic test (the PW71 methylation test) using methylation‐sensitive restriction enzymes has been developed for patients presumed to have PWS. We have studied 56 patients; 30 patients with classical features of PWS and 26 patients with only psychomotor retardation and obesity, referred to us from different parts of Sweden. Twenty‐nine of the 30 classical PWS patients were found to have an absence of the unmethylated paternally derived PW71(D15S63) locus in chromosome 15q11‐13. None of the patients with only obesity and psychomotor retardation had this “absence” pattern on chromosome 15q11‐13. Using the PW71 methylation test on patients with PWS, a concordance of 96% was found. The PW71 methylation test is presently the method of choice for rapid diagnostic testing of patients suspected of having PWS.

Growth hormone treatment improves vitality and behavioural issues in children with Prader-Willi syndrome.

Prader‐Willi syndrome is a neurogenetic disorder, with characteristics such as obesity, short stature, muscular weakness, intellectual deficiencies and deviant social behaviour. This study evaluated whether growth hormone treatment of children with Prader‐Willi syndrome resulted in possible and lasting effects on their cognition and behaviour.

Growth hormone treatment in aarskog syndrome: analysis of the KIGS (Pharmacia International Growth Database) data.

Aarskog syndrome is an X-linked disorder characterized by faciogenital dysplasia and short stature. The present study set out to determine the effect of growth hormone (GH) therapy in patients with Aarskog syndrome enrolled in KIGS--the Pharmacia International Growth Database. Twenty-one patients (20 males) were evaluated. Median age at start of treatment was 8.3 years (10-90th percentiles, 5.1-14.1 years) and median height SDS was -2.8 (10-90th percentiles, -2.1 to -3.7). The median dose of GH was 0.22 mg/kg/week (10-90th percentiles, 0.15-0.30 mg/kg/week) given at a median frequency of six (4-7) times per week. Prepubertal patients were followed longitudinally for 1 year (n = 13) or 3 years (n = 7). After 1 year, the median height SDS had improved from -2.8 to -2.3 in 13 patients. After 3 years, height SDS had improved significantly (p <0.05) to -1.8 (10-90th percentiles, -2.1 to -1.1) in the seven patients. No adverse events were noted. Although final height data for these patients are still awaited, the present results support the use of GH to promote growth in children with Aarskog syndrome.