Dederieke A. M. Festen

High Prevalence of Central Adrenal Insufficiency in Patients with Prader-Willi Syndrome

CONTEXT The annual death rate of Prader-Willi syndrome (PWS) patients is very high (3%). Many of these deaths are sudden and unexplained. OBJECTIVE Because most deaths occur during moderate infections and PWS patients suffer from various hypothalamic insufficiencies, we investigated whether PWS patients suffer from central adrenal insufficiency (CAI) during stressful conditions. DESIGN Overnight single-dose metyrapone tests were performed. Metyrapone (30 mg/kg) was administered at 2330 h. At 0400, 0600, and 0730 h, ACTH, 11-deoxycortisol, cortisol, and glucose levels were measured. Diurnal salivary cortisol profiles were assessed on a different day at wake-up, 30 min after wake-up, at 1400 h, and at 2000 h. SETTING The study was conducted in a pediatric intensive care unit. PATIENTS Patients included 25 randomly selected PWS patients. MAIN OUTCOME MEASURE Patients were considered as having CAI when ACTH levels remained below 33 pmol/liter at 0730 h. RESULTS Median (interquartile range) age was 9.7 (6.8-13.6) yr. Fifteen patients (60%) had an insufficient ACTH response (CAI, P < 0.001). There was no significant difference in age, gender, genotype, and body mass index SD score between patients with CAI and those without. Morning salivary cortisol levels and diurnal profiles were normal in all children, suggesting that CAI becomes apparent only during stressful conditions. CONCLUSIONS Strikingly, 60% of our PWS patients had CAI. The high percentage of CAI in PWS patients might explain the high rate of sudden death in these patients, particularly during infection-related stress. Based on our data, one should consider treatment with hydrocortisone during acute illness in PWS patients unless CAI has recently been ruled out with a metyrapone test.

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.

Randomized controlled GH trial: effects on anthropometry, body composition and body proportions in a large group of children with Prader-Willi syndrome.

Background  Prader–Willi syndrome (PWS) children have impaired growth, and abnormal body composition. Previous 1‐year controlled studies showed improvement of height and body composition during GH‐treatment.

Beneficial Effects of Growth Hormone Treatment on Cognition in Children with Prader-Willi Syndrome: A Randomized Controlled Trial and Longitudinal Study

BACKGROUND Knowledge about the effects of GH treatment on cognitive functioning in children with Prader-Willi syndrome (PWS) is limited. METHODS Fifty prepubertal children aged 3.5 to 14 yr were studied in a randomized controlled GH trial during 2 yr, followed by a longitudinal study during 4 yr of GH treatment. Cognitive functioning was measured biennially by short forms of the WPPSI-R or WISC-R, depending on age. Total IQ (TIQ) score was estimated based on two subtest scores. RESULTS During the randomized controlled trial, mean sd scores of all subtests and mean TIQ score remained similar compared to baseline in GH-treated children with PWS, whereas in untreated controls mean subtest sd scores and mean TIQ score decreased and became lower compared to baseline. This decline was significant for the Similarities (P = 0.04) and Vocabulary (P = 0.03) subtests. After 4 yr of GH treatment, mean sd scores on the Similarities and Block design subtests were significantly higher than at baseline (P = 0.01 and P = 0.03, respectively), and scores on Vocabulary and TIQ remained similar compared to baseline. At baseline, children with a maternal uniparental disomy had a significantly lower score on the Block design subtest (P = 0.01) but a larger increment on this subtest during 4 yr of GH treatment than children with a deletion. Lower baseline scores correlated significantly with higher increases in Similarities (P = 0.04) and Block design (P < 0.0001) sd scores. CONCLUSIONS Our study shows that GH treatment prevents deterioration of certain cognitive skills in children with PWS on the short term and significantly improves abstract reasoning and visuospatial skills during 4 yr of GH treatment. Furthermore, children with a greater deficit had more benefit from GH treatment.

Efficacy and Safety of Long-Term Continuous Growth Hormone Treatment in Children with Prader-Willi Syndrome

BACKGROUND Children with Prader-Willi syndrome (PWS) have abnormal body composition and impaired growth. Short-term GH treatment has beneficial effects. OBJECTIVES The aim of the study was to investigate effects of long-term continuous GH treatment on body composition, growth, bone maturation, and safety parameters. SETTING We conducted a multicenter prospective trial. DESIGN Fifty-five children with a mean +/- sd age of 5.9 +/- 3.2 yr were followed during 4 yr of continuous GH treatment (1 mg/m(2) . d). Data were annually obtained in one center: fat percentage (fat%) and lean body mass (LBM) by dual-energy x-ray absorptiometry, height, weight, head circumference, bone age, blood pressure, and fasting IGF-I, IGF binding protein-3, glucose, insulin, glycosylated hemoglobin, total cholesterol, high-density lipoprotein, and low-density lipoprotein. sd scores (SDS) were calculated according to Dutch and PWS reference values (SDS and SDS(PWS)). RESULTS Fat%SDS was significantly lower after 4 yr of GH treatment (P < 0.0001). LBMSDS significantly increased during the first year (P = 0.02) but returned to baseline values the second year and remained unchanged thereafter. Mean +/- sd height normalized from -2.27 +/- 1.2 SDS to -0.24 +/- 1.2 SDS (P < 0.0001). Head circumference SDS increased from -0.79 +/- 1.0 at start to 0.07 +/- 1.1 SDS after 4 yr. BMISDS(PWS) significantly decreased. Mean +/- sd IGF-I and the IGF-I/IGF binding protein-3 ratio significantly increased to 2.08 +/- 1.1 and 2.32 +/- 0.9 SDS, respectively. GH treatment had no adverse effects on bone maturation, blood pressure, glucose homeostasis, and serum lipids. CONCLUSIONS Our study in children with PWS shows that 4 yr of continuous GH treatment (1 mg/m(2) . d) improves body composition by decreasing fat%SDS and stabilizing LBMSDS and head circumference SDS and normalizes heightSDS without adverse effects. Thus, long-term continuous GH treatment is an effective and safe therapy for children with PWS.

Randomized Controlled Trial to Investigate the Effects of Growth Hormone Treatment on Scoliosis in Children with Prader-Willi Syndrome

CONTEXT The prevalence of scoliosis in children with Prader-Willi syndrome (PWS) is 30-80%, depending on age. Although reports about effects of GH treatment on scoliosis in children with PWS are limited, scoliosis is generally considered a contraindication for GH treatment. OBJECTIVE The aim was to study the effects of GH treatment on the onset of scoliosis and curve progression in children with PWS. DESIGN We conducted a multicenter, randomized, controlled GH study in infants and prepubertal and pubertal children. Infants and prepubertal children were randomized into a GH-treated group (1.0 mg/m(2) . d) and a control group for 1 and 2 yr, respectively. Pubertal children were randomized to receive somatropin 1.0 or 1.5 mg/m(2) . d. Yearly, x-rays of the spine were taken, and height, weight, truncal lean body mass (with dual energy x-ray absorptiometry), and IGF-I were measured. PATIENTS A total of 91 children with PWS (median age, 4.7 yr; interquartile range, 2.1-7.4) participated in the study. MAIN OUTCOME MEASURES We measured the onset of scoliosis (Cobb >10 degrees ) and scoliotic curve progression. RESULTS GH-treated children had similar onset of scoliosis and curve progression as randomized controls (P = 0.27-0.79 and P = 0.18-0.98, respectively). GH treatment, IGF-I sd score (SDS), and catch-up growth had no adverse effect on the onset of scoliosis or curve progression, even after adjustment for confounders. Height SDS, truncal lean body mass, and IGF-I SDS were significantly higher in GH-treated children than in randomized controls. At baseline, a higher IGF-I SDS was associated with a lower severity of scoliosis. CONCLUSIONS Scoliosis should no longer be considered a contraindication for GH treatment in children with PWS.

Eight Years of Growth Hormone Treatment in Children With Prader-Willi Syndrome : Maintaining the Positive Effects

BACKGROUND The most important reason for treating children with Prader-Willi syndrome (PWS) with GH is to optimize their body composition. OBJECTIVES The aim of this ongoing study was to determine whether long-term GH treatment can counteract the clinical course of increasing obesity in PWS by maintaining the improved body composition brought during early treatment. SETTING This was a multicenter prospective cohort study. METHODS We have been following 60 prepubertal children for 8 years of continuous GH treatment (1 mg/m(2)/d ≈ 0.035 mg/kg/d) and used the same dual-energy x-ray absorptiometry machine for annual measurements of lean body mass and percent fat. RESULTS After a significant increase during the first year of GH treatment (P < .0001), lean body mass remained stable for 7 years at a level above baseline (P < .0001). After a significant decrease in the first year, percent fat SD score (SDS) and body mass index SDS remained stable at a level not significantly higher than at baseline (P = .06, P = .14, resp.). However, body mass index SDSPWS was significantly lower after 8 years of GH treatment than at baseline (P < .0001). After 8 years of treatment, height SDS and head circumference SDS had completely normalized. IGF-1 SDS increased to +2.36 SDS during the first year of treatment (P < .0001) and remained stable since then. GH treatment did not adversely affect glucose homeostasis, serum lipids, blood pressure, and bone maturation. CONCLUSION This 8-year study demonstrates that GH treatment is a potent force for counteracting the clinical course of obesity in children with PWS.

Scoliosis in Prader–Willi syndrome: prevalence, effects of age, gender, body mass index, lean body mass and genotype

Background: The reported prevalence of scoliosis in children with Prader–Willi syndrome varies from 15% to 86%. Objective: To study the prevalence of scoliosis and the effects of age, gender, body mass index (BMI), total lean body mass (LBM), LBM of the trunk (trunkLBM) and genotype. Design: Radiographs were taken, length and weight were measured (BMI standard deviation scores (BMI SDS) and body surface area (BSA)), and dual energy x-ray absorptiometry was performed, measuring LBM and trunkLBM. Patients: 96 children, median (interquartile range) age 4.8 years (2.1 to 7.5), were included in a multicentre study. None received growth hormone treatment. Main outcome measures: Two types of scoliosis were identified: (1) long C-curve type scoliosis (LCS) and (2) idiopathic scoliosis (IS). Children were divided into age categories (infants, 0–3 years; juveniles, 3–10 years; adolescents, 10–16 years). Results: The prevalence of scoliosis was 37.5% and increased with age (infants and juveniles, ∼30%; adolescents, 80%); 44% of children with scoliosis had a Cobb angle above 20°. Children with scoliosis were significantly older than those without. Children with LCS were younger and more hypotonic than those with IS: median (interquartile range) age 4.4 years (1.7–5.9) vs 11.1 years (6.5–12.1) (p = 0.002) and trunkLBM/BSA ratio 7080 (6745–7571) vs 7830 (6932–8157) (p = 0.043). Conclusions: The prevalence of scoliosis in children with Prader–Willi syndrome is high (37.5%). Many children with scoliosis (13%) had undergone brace treatment or surgery. The type of scoliosis is affected by age and trunkLBM/BSA ratio.

Thyroid hormone levels in children with Prader-Willi syndrome before and during growth hormone treatment.

Background  Prader–Willi syndrome (PWS) is a neurogenetic disorder characterized by muscular hypotonia, psychomotor delay, obesity and short stature. Several endocrine abnormalities have been described, including GH deficiency and hypogonadotrophic hypogonadism. Published data on thyroid hormone levels in PWS children are very limited.

Psychomotor Development in Infants with Prader-Willi Syndrome and Associations with Sleep-Related Breathing Disorders

Prader-Willi syndrome (PWS) is a neurogenetic disorder with hypotonia, psychomotor delay, obesity, short stature, and sleep-related breathing disorders. The aim of this study was to evaluate the association between psychomotor development and sleep-related breathing disorders in PWS infants. Bayley Scales of Infant Development were performed in 22 PWS infants, with a median (interquartile range, IQR) age of 1.8 (1.1–3.4) y, and a body mass index SD score (BMISDS) of –0.5 (–1.3 to 1.6). We evaluated psychomotor development in relation to results of polysomnography. Median (IQR) mental and motor development was 73.1% (64.3–79.6%) and 55.2% (46.5–63.1%) of normal children, respectively. All infants had sleep-related breathing disorders, mostly of central origin. The apnea hypopnea index was not associated with psychomotor development. Only four infants had obstructive sleep apnea syndrome (OSAS). They had a significantly delayed mental development of 65.5% (60.0–70.3%) of normal. They had a median BMISDS of 1.4 (0.1–1.6), which tended to be higher than in those without OSAS. Our data indicate that psychomotor development in PWS infants is not related to central sleep-related breathing disorders, but infants with OSAS have more severely delayed mental development, suggesting that PWS infants should be screened for OSAS.