M. Tauber

Hyperghrelinemia precedes obesity in Prader-Willi syndrome.

BACKGROUND High plasma ghrelin levels have been reported in Prader-Willi syndrome (PWS). However, little is known about plasma ghrelin in these children during the first years of life characterized by a failure to thrive. OBJECTIVE The objective of the study was to investigate total plasma ghrelin levels in children with PWS and controls from 2 months to 17 years. SUBJECTS AND METHODS Forty children with PWS [24 boys, 16 girls, median age 3.6 yr, median body mass index (BMI) Z-score 0.3] were compared with 84 controls (57 boys, 27 girls, median age 4.2 yr median BMI Z-score 0.1). Children were then divided into two groups according to age and GH treatment. RESULTS Median plasma ghrelin levels were significantly higher in children with PWS, compared with controls at any age (568 vs. 173, P < 0.0001) and decreased with age in both groups (P < 0.0001). In the whole group of PWS, we found an inverse relationship between ghrelin and BMI Z-score, insulin, homeostasis model assessment insulin resistance index, leptin, and lean mass. Plasma ghrelin levels were higher in children with PWS than controls, both in the youngest children below 3 yr who were not receiving GH (771 vs. 233, P < 0.0001) and in the children older than 3 yr, all of whom were treated with GH (428 vs. 159, P < 0.0001). CONCLUSIONS Plasma ghrelin levels in children with PWS are elevated at any age, including during the first years of life, thus preceding the development of obesity.

Endocrine Disorders in Children with Prader-Willi Syndrome – Data from 142 Children of the French Database

Aim: The first results from the French National Prader-Willi pediatric database in a cohort of 142 children aged 0.2–18.8 years are reported. This database gathers information about the endocrine dysfunctions traditionally described in Prader-Willi patients. Methods: Questionnaires were filled in by the patients’ practitioners. The coordination team of the reference center performed the statistical analysis. Results: Median BMI Z-score was +1.3 for a median age of 7.1 years, and 40% of the population were overweight or obese (International Obesity Task Force 2000 criteria). Growth hormone deficiency was present in 80% of patients and 86.7% were treated, with a height gain of +1 SD and a BMI reduction of –0.8 Z-score achieved in the first year of treatment. Hypogonadism was present in 49% of patients, and hypothyroidism in 24.4%. Glucose intolerance was found in 4% of patients, but no diabetes mellitus was detected in the 74 patients explored. Conclusion: Our report gives an overview of endocrine dysfunctions recorded in a large registry database of French children and adolescents with Prader-Willi syndrome. The database, which now encompasses six southern regions of France, will be further extended to the whole country and to adult patients.

GH responsiveness in a large multinational cohort of SGA children with short stature (NESTEGG) is related to the exon 3 GHR polymorphism

Objective  The polymorphic deletion of exon 3 of the GH receptor (d3‐GHR) has recently been linked to the magnitude of growth response to recombinant human GH (rhGH) therapy in short children with or without GH deficiency. We investigated this association in a large multinational cohort from the Network of European Studies of Genes in Growth (NESTEGG), comprising short children born small for gestational age (SGA).

Early Diagnosis and Multidisciplinary Care Reduce the Hospitalization Time and Duration of Tube Feeding and Prevent Early Obesity in PWS Infants

Background/Aims: To describe and evaluate the impact of very early diagnosis and multidisciplinary care on the evolution and care of infants presenting with Prader-Willi syndrome (PWS). Methods: 19 infants diagnosed with PWS before the second month of life were followed by a multidisciplinary team. Median age at the time of analysis was 3.1 years [range 0.4–6.5]. The data were compared with data collected in 1997 from 113 questionnaires filled out by members of the French PWS Association. The patients from this latter data set were 12.0 years [range 4 months to 41 years] at the time of analysis, with a median age of 36 months at diagnosis. Results: The duration of their hospitalization time was significantly reduced from 30.0 [range 0–670] to 21 [range 0–90] days (p = 0.043). The duration of gastric tube feeding was significantly reduced from 30.5 [range 0–427] to 15 [range 0–60] days (p = 0.017). Growth hormone treatment was started at a mean age of 1.9 ± 0.5 years in 10 infants and L-thyroxine in 6 infants. Only 1 infant became obese at 2.5 years. Conclusion: Early diagnosis combined with multidisciplinary care decreases the hospitalization time, duration of gastric tube feeding and prevents early obesity in PWS infants.

Investigation of growth hormone secretion in patients with intrauterine growth retardation.

Rochiccioli, P., Tauher, M., Moisan, V. and Pienkowski C. (Department of Paediatrics, CHU Rangneil, Toulonse Cedex, France). Investigations of growth hormone secretion in patients with intrauterine growth retardation. Acta Paediatr Scand [Suppl] 349: 42, 1989.

Statistical study of 5473 results of nine pharmacological stimulation tests: a proposed weighting index.

A total of 5473 pharmacological stimulation tests were carried out in 3143 children and subjected to statistical analysis. The mean chronological age of the children was 9 years 9 months (range 3 years to 16 years 6 months) and mean bone age was 7 years 6 months (range 2 years to 14 years). Nine pharmacological tests were used: (I)arginine(n = 625); (2) clonidine (n= 339); (3) insulin (n= 198); (4) ornithine (n = 162); (5) insulin and arginine (n= 203); (6) clonidine and betaxolol (n = 2003); (7) L‐dopa (n = 685); (8) glucagon and propranolol (n=443); and (9) glucagon and betaxolol (n = 815). Measurement of plasma growth hormone was always performed using the same method. The distribution of values in each test was of the gausso‐logarithmic type. The results of the mean peak and the 95% confidence limit were as follows: (1) 10.2, 0.45; (2) 11.5,0.7; (3) 11.8,0.8; (4) 14.2,1.2; (5) 14.3, 0.9; (6) 15.7, 1.1; (7) 19.8, 2.1; (8) 20.8, 2.3; (9) 21, 2.5. These results lead to the following conclusions: the specificity of these tests is low, the mean peak may vary two‐fold from one test to another, and the percentage of peaks < 10 ng/ml ranges from 69% for test 1 to 29% for tests 8 and 9. The proportion of growth hormone deficiencies thus varies considerably according to the test used. To avoid these disparities, we propose a weighting index to adjust values according 40 the tests used: weighting index (1) 1.9; (2) 1.48; (3) 1.4; (4) 1.16; (5) 1.06; (6) 1.01; (7) 0.73; (8) 0.69; (9) 0.66.

Elevated Insulin-Like Growth Factor-I Values in Children with Prader-Willi Syndrome Compared with Growth Hormone (GH) Deficiency Children over Two Years of GH Treatment

BACKGROUND Children with Prader-Willi syndrome (PWS) are routinely treated with GH and have a response comparable with that observed in children with GH deficiency (GHD). OBJECTIVE The objective of the study was to compare changes in serum IGF-I, IGF binding protein 3 (IGFBP-3), IGF-I to IGFBP-3 molar ratio, and growth velocity during the first 2 yr of GH therapy in PWS and GHD children. SUBJECTS AND METHODS Thirty-three children with PWS (14 boys, 4.9 ± 3.8 yr) and 591 with GHD (351 boys, 9.6 ± 3.6 yr), all naive to GH treatment, were included in this study. Serum IGF-I and IGFBP-3 were measured at 0, 6, 12, and 24 months of GH therapy. The mean initial dose of GH was 0.9 and 1 mg/m(2) · d in the PWS and GHD groups, respectively. RESULTS Mean ± SD IGF-I sdscore (SDS) and IGFBP-3 SDS were significantly higher in PWS compared with GHD. The IGF-I to IGFBP-3 molar ratio was significantly lower at baseline and subsequently not different. Despite significantly lower GH doses in PWS children at 6, 12, and 24 months (P = 0.021, P = 0.021, P = 0.001), IGF-I reached 2.8 ± 1.2 SDS at 24 months (72% of values > 2 SDS), and remained at 0.7 ± 1.6 SDS in GHD children (17% of values > 2 SDS). IGFBP-3 did not exceed 2 SDS in either group. There was no significant change in the IGF-I to IGFBP-3 molar ratio. CONCLUSIONS IGF-I SDS increases to a greater extent in PWS than GHD. Bioavailable IGF-I is apparently not different, suggesting that any possible safety issues related to elevated IGF-I are similar in both groups.

Nouveaux mécanismes moléculaires impliqués dans l’insensibilité à l’hormone de croissance

Growth hormone (GH), secreted by the anterior pituitary into the circulation, binds to membrane receptors in target tissues to stimulate body growth; most of its effects is mediated by the insulin-like growth factor 1 (IGF-1). In addition to promoting growth, GH has important metabolic actions. The syndrome of GH insensitivity (GHI) was first identified in 1966 by Laron et al. in three children with clinical phenotype characteristic of growth hormone deficiency but associated with elevated serum concentration of GH. Direct evidence of a GH receptor (GHR) abnormality was provided in 1989. More recently, molecular abnormalities in the postreceptor signalling mechanism were found. Mutations of signal transducer and activator of transcription 5b (Stat5b) were reported in patients with growth retardation and primary immunodeficiency. Mutations of the tyrosin phosphatase Shp2 were identified in patients affected by Noonan syndrome characterized by short stature, cardiopathy and increased risk of leukaemia. The unmasking of the molecular bases for these defects will contribute greatly to our future understanding of both normal and aberrant growth. Moreover, this knowledge should bring insight on cancerogenesis or immunodeficiency caused by cytokines resistance.

Modification of 24‐Hour Growth Hormone Secretion after Continuous Subcutaneous Infusion of Growth Hormone‐Releasing Hormone (GHRH (1–29)NH2) in Short Children with Low 24‐Hour Growth Hormone Secretion

Tauber, M.T., Pienkowski, C., Landier, F., Gunnarsson, R. and Rochiccioli, P. (Department of Paediatric Endocrinology, CHU Rangueil, Toulouse Cedex, and Kabi Laboratory, Paris, France and Kabi Peptide Hormones, Stockholm, Sweden). Modification of 24‐hour growth hormone secretion after continuous subcutaneous infusion of growth hormone‐releasing hormone (GHRH (1–29)NH2) in short children with low 24‐hour growth hormone secretion. Acta Paediatr Scand [Suppl] 349: 117, 1989.

Growth hormone (GH) profiles in response to continuous subcutaneous infusion of GH-releasing hormone(1— 29)-NH2 in children with GH deficiency

Six children presenting with partial growth hormone (GH) deficiency (mean GH peak in two different tests, 8.0 k1.3 μg/l) aged 8–10.3 years (mean, 2.7 ± 0.9 years) were treated for 6 months by continuous subcutaneous infusion of GH‐releasing hormone(1–29)‐NH, (GHRH(1–29)‐NH2); 24‐hour GH profiles and height velocity were measured. A biphasic effect of GHRH(1–29)‐NH2 infusion was observed. After an early substantial increase in the 24‐hour integrated concentration of GH, from 1.6 ± 0.1 to 3.5 ± 0.7 μg/l/minute, a subsequent consistent decrease occurred by 3 months, which was more pronounced after 6 months (mean 24‐hour integrated concentration of GH, 1.9± 0.9 μg/l/minute). This effect reflects modification of both pulse amplitude and frequency of GH secretion. At the end of the study, one child had complete suppression of GH secretion and two others showed only one peak above 5 μg/1 during a 24‐hour period. No correlation was found between these changes and height velocity. Three children did not grow significantly; the other three children who had a growth response to GHRH(1–29)‐NH2 were those with the lowest 24‐hour integrated GH concentration at the end of the study. The possible mechanisms involved in this biphasic effect, including GHRH antibodies, changes in somatostatin levels and/or desensitization of pituitary GHRH receptors, have been investigated.