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The National Academies Press

Prader-Willi syndrome

Ghrelin is a peptide predominantly produced by the stomach. Ghrelin displays strong GH-releasing activity. This activity is mediated by the activation of the so-called GH secretagogue receptor type 1a. This receptor had been shown to be specific for a family of synthetic, peptidyl and nonpeptidyl GH secretagogues. Apart from a potent GH-releasing action, ghrelin has other activities including stimulation of lactotroph and corticotroph function, influence on the pituitary gonadal axis, stimulation of appetite, control of energy balance, influence on sleep and behavior, control of gastric motility and acid secretion, and influence on pancreatic exocrine and endocrine function as well as on glucose metabolism. Cardiovascular actions and modulation of proliferation of neoplastic cells, as well as of the immune system, are other actions of ghrelin. Therefore, we consider ghrelin a gastrointestinal peptide contributing to the regulation of diverse functions of the gut-brain axis. So, there is indeed a possibility that ghrelin analogs, acting as either agonists or antagonists, might have clinical impact.

/pdf/biological-physiological-pathophysiological-and-k7otyeslc1.pdf

Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin.

/pdf/elevated-plasma-ghrelin-levels-in-prader-willi-syndrome-oytwiabgmp.pdf

Elevated plasma ghrelin levels in Prader Willi syndrome.

Introduction
Prader-Willi syndrome (PWS) is a multisystemic complex genetic disorder caused by lack of expression of genes on the paternally inherited chromosome 15q11.2-q13 region. There are three main genetic subtypes in PWS: paternal 15q11-q13 deletion (65–75 % of cases), maternal uniparental disomy 15 (20–30 % of cases), and imprinting defect (1–3 %). DNA methylation analysis is the only technique that will diagnose PWS in all three molecular genetic classes and differentiate PWS from Angelman syndrome. Clinical manifestations change with age with hypotonia and a poor suck resulting in failure to thrive during infancy. As the individual ages, other features such as short stature, food seeking with excessive weight gain, developmental delay, cognitive disability and behavioral problems become evident. The phenotype is likely due to hypothalamic dysfunction, which is responsible for hyperphagia, temperature instability, high pain threshold, hypersomnia and multiple endocrine abnormalities including growth hormone and thyroid-stimulating hormone deficiencies, hypogonadism and central adrenal insufficiency. Obesity and its complications are the major causes of morbidity and mortality in PWS.

/pdf/prader-willi-syndrome-a-review-of-clinical-genetic-and-21f77l45y3.pdf

Prader-Willi syndrome: a review of clinical, genetic, and endocrine findings

Prader-Willi syndrome is a genetic disorder occurring in 1 in 10,000-16,000 live-born infants. In the general population, approximately 60 people in every 1,000,000 are affected. The condition is characterized by short stature, low lean body mass, muscular hypotonia, mental retardation, behavioral abnormalities, dysmorphic features, and excessive appetite with progressive obesity. Furthermore, morbidity and mortality are high, probably as a result of gross obesity. Most patients have reduced GH secretory capacity and hypogonadotropic hypogonadism, suggesting hypothalamic-pituitary dysfunction. Replacement of GH and/or sex hormones may therefore be beneficial in Prader-Willi syndrome, and several clinical trials have now evaluated GH replacement therapy in affected children. Results of GH treatment have been encouraging: improved growth, increased lean body mass, and reduced fat mass. There was also some evidence of improvements in respiratory function and physical activity. The long-term benefits of GH treatment are, however, still to be established. Similarly, the role of sex hormone replacement therapy needs to be clarified as few data exist on its efficacy and potential benefits. In summary, Prader-Willi syndrome is a disabling condition associated with GH deficiency and hypogonadism. More active treatment of these endocrine disorders is likely to benefit affected individuals.

Endocrine dysfunction in Prader-Willi syndrome: a review with special reference to GH.

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 of 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 stabilized 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 patient is severely obese.

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

A controlled, randomized study was conducted to assess the effect of growth hormone (GH) treatment on growth, body composition and behaviour in prepubertal children (3–12 years of age) with Prader—Willi syndrome. GH treatment was given to one group of 15 patients (group A) at a dose of 0.1 IU/kg/day for 2 years. The second group (group B; n = 12) was not treated for the first year and was then given GH at a dose of 0.2 IU/kg/day for the second year. All patients had low 24-hour levels of GH and insulin-like growth factor I before GH treatment. Height velocity SDS increased from −1.9 ± 2.0 to 6.0 ± 3.2 during the first year of GH treatment in group A, and from −1.4 ± 1.2 to 10.1 ± 3.9 in the second year of the study in group B. When GH treatment was stopped, height velocity declined dramatically. Height SDS followed a similar pattern. GH treatment reduced the percentage body fat and increased the muscle area of the thigh. Isometric muscle strength was also increased. In addition, GH treatment appeared to have psychological and behavioural benefits, which were reversed after cessation of treatment. It was concluded that GH treatment improves growth, body composition and behaviour in children with Prader—Willi syndrome. □ Prader—Willi syndrome, growth hormone treatment, growth, body composition, behaviour

Effects of growth hormone treatment on growth and body composition in Prader—Willi syndrome: a preliminary report

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.

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

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).



Study design:  in a prospective clinical case series study, sixteen consecutive PWS patients (median age 16 months at enrolment) were followed-up 6 months (2–32 months) after commencing GH treatment. We compared heart rate (HR), Pulse Transit Time (PTT; an index of blood pressure, BP) and ventilatory responses to standard chemostimuli (4% CO2 and 100% O2) during quiet sleep prior to and after commencing GH treatment.



Results:  Growth hormone treatment increased arterial oxygenation during sleep but did not significantly improve breathing stability (apnoea-hypopnoea index remained unchanged). GH treatment did not alter ventilatory, HR and PTT chemoreceptor-mediated responsiveness (p = 0.23–0.97) but did significantly improve the coupling between and HR and PTT, indicating that HR and BP rose (or fell) in parallel after but not before GH therapy (p = 0.01).



Conclusion:  Growth hormone treatment improves arterial oxygenation and cardiovascular function during sleep; these changes are not owing to improved (stronger) chemoreflex-mediated autonomic drive.

The effect of growth hormone on sleep‐related cardio‐respiratory control in Prader–Willi syndrome

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