Elevated ratio of acylated to unacylated ghrelin in children and young adults with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is characterized by a switch from failure to thrive to excessive weight gain and hyperphagia in early childhood. Hyperghrelinemia may be involved in the underlying mechanisms of the switch. The purpose of this study is to evaluate acylated ghrelin (AG) and unacylated ghrelin (UAG) levels in PWS and investigate their associations with hyperphagia. This is a cross-sectional clinical study conducted in three PWS expert centers in the Netherlands and France. Levels of AG and UAG and the AG/UAG ratio were determined in 138 patients with PWS (0.2-29.4 years) and compared with 50 age-matched obese subjects (4.3-16.9 years) and 39 healthy controls (0.8-28.6 years). AEBSF was used to inhibit deacylation of AG. As a group, PWS patients had higher AG but similar UAG levels as healthy controls (AG 129.1 vs 82.4 pg/ml, p = 0.016; UAG 135.3 vs 157.3 pg/ml, resp.), resulting in a significantly higher AG/UAG ratio (1.00 vs 0.61, p = 0.001, resp.). Obese subjects had significantly lower AG and UAG levels than PWS and controls (40.3 and 35.3 pg/ml, resp.), but also a high AG/UAG ratio (1.16). The reason for the higher AG/UAG ratio in PWS and obese was, however, completely different, as PWS had a high AG and obese a very low UAG. PWS patients without weight gain or hyperphagia had a similar AG/UAG ratio as age-matched controls, in contrast to those with weight gain and/or hyperphagia who had an elevated AG/UAG ratio. The switch to excessive weight gain in PWS seems to coincide with an increase in the AG/UAG ratio, even prior to the start of hyperphagia.

Impairment of adipose tissue in Prader-Willi syndrome rescued by growth hormone treatment.

BACKGROUND: Prader-Willi syndrome (PWS) results from abnormalities in the genomic imprinting process leading to hypothalamic dysfunction with an alteration of growth hormone (GH) secretion. PWS is associated with early morbid obesity and short stature which can be efficiently improved with GH treatment. OBJECTIVES: Our aims were to highlight adipose tissue structural and functional impairments in children with PWS and to study the modifications of those parameters on GH treatment. SUBJECTS AND METHODS: Plasma samples and adipose tissue biopsies were obtained from 23 research centers in France coordinated by the reference center for PWS in Toulouse, France. Lean controls (n=33), non-syndromic obese (n=53), untreated (n=26) and GH-treated PWS (n=43) children were enrolled in the study. Adipose tissue biopsies were obtained during scheduled surgeries from 15 lean control, 7 untreated and 8 GH-treated PWS children. RESULTS: Children with PWS displayed higher insulin sensitivity as shown by reduced glycemia, insulinemia and HOMA-IR compared with non-syndromic obese children. In contrast, plasma inflammatory cytokines such as TNF-α, MCP-1 and IL-8 were increased in PWS. Analysis of biopsies compared with control children revealed decreased progenitor cell content in the stromal vascular fraction of adipose tissue and an impairment of lipolytic response to ß-adrenergic agonist in PWS adipocytes. Interestingly, both of these alterations in PWS seem to be ameliorated on GH treatment. CONCLUSION: Herein, we report adipose tissue dysfunctions in children with PWS which may be partially restored by GH treatment.

Efficacy of modafinil on excessive daytime sleepiness in Prader-Willi syndrome.

Excessive daytime sleepiness is a frequent and a highly disruptive symptom to the daily routine of children with Prader-Willi Syndrome (PWS) and their families. The objective of the study was to evaluate the efficacy of modafinil, a central stimulant, on excessive daytime sleepiness in children and adolescents with PWS. The efficacy of modafinil was evaluated in this open label pilot study comparing the Epworth sleepiness scale before and after treatment. Ten patients with molecularly confirmed PWS and a complaint of excessive daytime sleepiness underwent a night-time sleep recording and multiple sleep latency tests. One patient was excluded because of severe obstructive sleep apnea syndrome. Nine patients (4 males) with median age of 16 years (8-21) received modafinil at a starting dose of 100 mg/day. We found that all patients had excessive daytime sleepiness with an Epworth sleepiness scale at 14 (11-20) and mean sleep latency on multiple sleep latency tests at 5 (3-6) minutes. Moreover, six patients had at least two sleep-onset rapid eye movement periods showing a narcolepsy-like phenotype. Modafinil significantly improved sleepiness in all patients on the Epworth sleepiness scale from 14 (11-20) to 4 (3-12), (P = 0.007). Body mass index of the patients did not change significantly under treatment. No side effects were reported, and the drug was well-tolerated. We posit that this open label case series shows good efficacy of modafinil in nine children and adolescents with PWS.

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.

[Early education for children with Prader-Willi syndrome]. / Préconisations d'education précoce pour les enfants porteurs d'un syndrome de Prader-Willi.

MATERIAL AND METHOD: A cohort of 21 children (under 42 months of age) with Prader-Willi syndrome were followed in a longitudinal way by the referral center team with evaluation of language and cognitive function (every six months). RESULTS: Disorders seen between birth and the second year are primarily related to hypotonia with oropharyngeal dysphagia and impact on the pre-lingual phase of communication. After 2 years the psychomotor delay and the disorders of language acquisition effect development. When compared to patients who had treatment after 4 years and with data published in the literature, those patients with an early diagnosis and early treatment using kinesitherapy and logopedy showed faster linguistic acquisition. However articulation disorders still remain. CONCLUSION AND RECOMMENDATIONS: This work highlights the importance of early readaptation associating kinesitherapy, logopedy and psychomotoricity which can improve the cognitive phenotype of these children.

[Severe delayed apnea in neonates and Prader-Willi syndrome: 2 case studies]. / Apnées sévères différées en période néonatale et syndrome de Prader-Willi: à propos de 2 cas.

We report 2 cases of severe apnea in newborns presenting with Prader-Willi syndrome. They required transient mechanical ventilation and finally returned to spontaneous breathing. Clinical progression was then usual for the syndrome. Respiratory failure appearing after a few days of life could be a new neonatal clinical feature for the diagnosis of Prader-Willi syndrome. It is not related to poor outcome.

Review of 64 cases of death in children with Prader-Willi syndrome (PWS).

Several deaths have been reported in children with Prader-Willi syndrome (PWS) following treatment with growth hormone (GH). We collected all of the reports of deaths in PWS children, both in treatment and non-treatment groups, analyzed the causes of the death and compared the two groups. We conducted an exhaustive search for reports using bibliographic databases, toxicology pharmacovigilance databases, and personal communications. Sixty-four PWS children (42M/22F) aged from a few days to 19 years were identified, 28 received GH treatment. Our results show that respiratory disorders were the most common cause of death (respiratory insufficiency or infections) which were reported in 61% of the children (68% in GH-treated and 55.5% in -untreated patients). We found no significant differences in gender, prevalence of obesity or prevalence of sleep apnea, between the patients treated with GH and the untreated patients. Nevertheless, most of the deaths in GH-treated children (75%) occurred during the first 9 months after the initiation of GH treatment. Our analysis shows the high frequency of respiratory infections in both GH-treated and -untreated PWS children. The first 9 months of GH treatment seems to be a high-risk period emphasizing the need for comprehensive care before and during GH treatment.

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.

[The Prader-Willi syndrome]. / Le syndrome de Prader-Willi.

Prader-Willi syndrome is a rare genetic disorder, affecting 1 out of 25,000 births, in which a critical region of chromosome 15, the 15q11-q13 region, is affected. At birth, PWS infants exhibit severe hypotonia that partially improves, explaining in part suckling and swallowing troubles and the delay in psychomotor development. Characteristic facial features (dysmorphic syndrome) and very small hands and feet are frequently observed at this age. After this initial phase, the most striking signs appear: hyperphagia and absence of satiety often leading to severe obesity in affected children as young as two years. The situation may deteriorate quickly without adequate outside controls and explains in great part the morbidity and mortality of these patients. Other endocrine abnormalities in association with the hypothalamic-pituitary abnormalities contribute to the clinical picture of short stature due to a growth hormone deficiency and incomplete pubertal development. The degree of cognitive dysfunction varies widely from one child to another. It is associated with learning disabilities and impaired speech and language development worsened by psychological and behavioural troubles. The expert consensus is that diagnosis should be based on clinical criteria (Holm's criteria of 1993, revised in 2001) with confirmation by genetic study. Most cases are sporadic and familial cases are rare, those informations should be given as genetic counselling. It is necessary to set up a global and multidisciplinary management. Early diagnosis, early multidisciplinary care and growth hormone treatment have greatly improved the quality of life of these children. We have no long-term data on the effect of GH treatment in adults, on behavioural troubles and autonomy of the persons. In adults, complications particularly linked to obesity and problems of autonomy are still very important.

A case of trisomy 12 mosaicism with pituitary malformation and polycystic ovary syndrome.

We report the case of a patient (followed from birth to 15 years) presenting with trisomy 12 mosaicism, and focus on the endocrine phenotype associating a pituitary malformation and ovarian abnormalities. We describe the dysmorphic features and their evolution, the growth retardation and ovarian symptoms. Complete growth hormone deficiency was confirmed on auxological data, stimulation test and was related to pituitary stalk interruption, diagnosed by magnetic resonance imaging. Effect of growth hormone treatment was satisfactory resulting in a normal adult height. She also presented premature thelarche associated with right ovarian hypertrophy (4 to 5 fold the volume of the left ovary) which remained constant until 15 years of age. Diagnosis of trisomy 12 mosaicism was made on skin and ovarian karyotypes. The possible relation between these endocine findings and some genes located on chromosome 12 involved in pituitary and ovarian development is discussed.

[Use of cloridarol in coronary insufficiency]. / Impiego del cloridarol nell'insufficienza coronarica

The therapeutical activity of a new oral drug with a coronaric and myocardiotrophic action of choice, 2-benzofuryl-p-chlorophenyl-carbinol (Menacor, Menarini) in 20 patients with chronic coronary insufficiency was studied by administering 750 mg/day for at least 20 days. General and gastroenteric tolerance was excellent, while good or fair therapeutic results were obtained in 16 cases (80%). It is felt that the drug can be usefully employed in the management of coronary insufficiency.