Gwenaelle Diene

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.

Oxytocin may be useful to increase trust in others and decrease disruptive behaviours in patients with Prader-Willi syndrome: a randomised placebo-controlled trial in 24 patients

BackgroundPrader-Willi syndrome (PWS) is a complex neurodevelopmental genetic disorder with hypothalamic dysfunction, early morbid obesity with hyperphagia, and specific psychiatric phenotypes including cognitive and behavioural problems, particularly disruptive behaviours and frequent temper outbursts that preclude socialization. A deficit in oxytocin (OT)-producing neurons of the hypothalamic paraventricular nucleus has been reported in these patients.MethodsIn a double-blind, randomised, placebo-controlled study, 24 adult patients with PWS received a single intranasal administration of 24 IU of OT or placebo and were tested 45 min later on social skills. Behaviours were carefully monitored and scored using an in-house grid as follows: over the two days before drug administration, on the half-day following administration, and over the subsequent two days. All patients were in a dedicated PWS centre with more than ten years of experience. Patients are regularly admitted to this controlled environment.ResultsPatients with PWS who received a single intranasal administration of OT displayed significantly increased trust in others (P = 0.02) and decreased sadness tendencies (P = 0.02) with less disruptive behaviour (P = 0.03) in the two days following administration than did patients who received placebo. In the half-day following administration, we observed a trend towards less conflict with others (p = 0.07) in the OT group compared with the placebo group. Scores in tests assessing social skills were not significantly different between the two groups.ConclusionsThis study needs to be reproduced and adapted. It nevertheless opens new perspectives for patients with PWS and perhaps other syndromes with behavioural disturbances and obesity.Trial registration numberClinicalTrials.gov: NCT01038570

Scoliosis in Patients With Prader-Willi Syndrome

OBJECTIVE. Our goals were to determine the prevalence and estimate the evolution of spinal deformities in patients suffering from Prader-Willi syndrome; find out which kind of spine deformity predominates regarding genotype and clinical patterns; and evaluate the affect of growth-hormone treatment on the onset and progression of spinal deformities. PATIENTS AND METHODS. This was a retrospective longitudinal, clinical, and radiologic study. One hundred forty-five children followed between 1980 and 2006 were studied in 2 referral centers for Prader-Willi syndrome. Genetic testing confirmed the diagnosis in 133 patients. Ninety-three patients (64%) received growth-hormone therapy. For statistical analysis, age-adjusted comparison between groups was performed by using multivariate logistic regression. RESULTS. Mean age of the patients was 10.2 ± 6.2 years. Sixty-three (43.4%) patients were afflicted with scoliosis. Scoliosis frequency steadily rose with age, and a large majority of patients were affected at skeletal maturity (66.7%). Scoliosis prevalence was not affected by the genotype or by growth-hormone treatment. Patients with higher BMI values had an increased risk of developing a kyphotic deformity in association with scoliosis. We found a statistical association between kyphotic deformity and the need for surgical treatment. CONCLUSIONS. Scoliosis is a major concern for patients with Prader-Willi syndrome, and a regular (annual) systematic back examination is mandated. The role of growth-hormone treatment on the natural history of scoliosis could not be determined, and careful monitoring during treatment is recommended.

Long-term evolution of endocrine disorders and effect of GH therapy in 35 patients with pituitary stalk interruption syndrome

We report long-term evolution of endocrine functions and the results of GH treatment in 35 patients (26 male and 9 female) with pituitary stalk interruption. At diagnosis, mean chronological age was 4.8 ± 2.7 years, mean SDS for height –3.1 ± 0.8 with a bone age retardation of 2.3 ± 1.3 years and a mean SDS for growth velocity of –0.5 ± 1.1; 80% presented complete GH deficiency (GHD) and 20% partial GHD; thyroid deficiency was present in 47.1% of children with complete GHD but absent in all partial GHD. Diagnosis was made during the first months of life in only 2 patients while 23% presented with severe neonatal distress; neonatal signs were only observed in the group with pituitary height below 2 mm (45.7% of patients). GHD was isolated in 40.6% of patients below 10 years while multiple hormone deficiencies was consistent at completion of growth in all patients. Height gain was significantly higher in patients who started GH treatment before 4 years (p = 0.002). GH treatment is very effective: in 13 patients, final height was –0.4 ± 1.0, total height gain 3.2 ± 1.2 and distance to target height –0.3 ± 1.6 SDS.

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.

New candidate loci identified by array‐CGH in a cohort of 100 children presenting with syndromic obesity

Syndromic obesity is defined by the association of obesity with one or more feature(s) including developmental delay, dysmorphic traits, and/or congenital malformations. Over 25 syndromic forms of obesity have been identified. However, most cases remain of unknown etiology. The aim of this study was to identify new candidate loci associated with syndromic obesity to find new candidate genes and to better understand molecular mechanisms involved in this pathology. We performed oligonucleotide microarray‐based comparative genomic hybridization in a cohort of 100 children presenting with syndromic obesity of unknown etiology, after exhaustive clinical, biological, and molecular studies. Chromosomal copy number variations were detected in 42% of the children in our cohort, with 23% of patients with potentially pathogenic copy number variants. Our results support that chromosomal rearrangements are frequently associated with syndromic obesity with a variety of contributory genes having relevance to either obesity or developmental delay. A list of inherited or apparently de novo duplications and deletions including their enclosed genes and not previously linked to syndromic obesity was established. Proteins encoded by several of these genes are involved in lipid metabolism (ACOXL, MSMO1, MVD, and PDZK1) linked with nervous system function (BDH1 and LINGO2), neutral lipid storage (PLIN2), energy homeostasis and metabolic processes (CDH13, CNTNAP2, CPPED1, NDUFA4, PTGS2, and SOCS6).

PET scan perfusion imaging in the Prader–Willi syndrome: new insights into the psychiatric and social disturbances

The Prader–Willi syndrome (PWS), a rare multisystem genetic disease, leads to severe disabilities, such as morbid obesity, endocrine dysfunctions, psychiatric disorders, and social disturbances. We explored the whole brain of patients with PWS to detect abnormalities that might explain the behavioral and social disturbances, as well as the psychiatric disorders of these patients. Nine patients with PWS (six males, three females; mean age 16.4 years) underwent a positron emission tomography (PET) scan with H215O as a tracer to measure regional cerebral blood flow (rCBF). The images were compared with those acquired from nine controls (six males, three females; mean age 21.2 years). A morphologic magnetic resonance imaging (MRI) was also performed in PWS patients, and their cognitive and behavioral skills were assessed with Wechsler Intelligence Scale for Children III and the Child Behavior Check List (CBCL). The MRI images showed no evident anatomic abnormalities, whereas PET scans revealed hypoperfused brain regions in PWS patients compared with controls, particularly in the anterior cingulum and superior temporal regions. We observed a significant relationship (P<0.05) between rCBF in the hypoperfused regions and CBCL scores. The functional consequences of these perfusion abnormalities in specific brain regions might explain the behavioral and social problems observed in these individuals.

French database of children and adolescents with Prader-Willi syndrome.

BackgroundPrader-Willi syndrome (PWS) is a rare multisystem genetic disease leading to severe complications mainly related to obesity. We strongly lack information on the natural history of this complex disease and on what factors are involved in its evolution and its outcome. One of the objectives of the French reference centre for Prader-Willi syndrome set-up in 2004 was to set-up a database in order to make the inventory of Prader-Willi syndrome cases and initiate a national cohort study in the area covered by the centre.Descriptionthe database includes medical data of children and adolescents with Prader-Willi syndrome, details about their management, socio-demographic data on their families, psychological data and quality of life of the parents. The tools and organisation used to ensure data collection and data quality in respect of good clinical practice procedures are discussed, and main characteristics of our Prader-Willi population at inclusion are presented.Conclusionthis database covering all the aspects of PWS clinical, psychological and social profiles, including familial psychological and quality of life will be a powerful tool for retrospective studies concerning this complex and multi factorial disease and could be a basis for the design of future prospective multicentric studies. The complete database and the Stata.do files are available to any researcher wishing to use them for non-commercial purposes and can be provided upon request to the corresponding author.

Pituitary Stalk Interruption Syndrome from Infancy to Adulthood: Clinical, Hormonal, and Radiological Assessment According to the Initial Presentation.

Background Patients with pituitary stalk interruption syndrome (PSIS) are initially referred for hypoglycemia during the neonatal period or growth retardation during childhood. PSIS is either isolated (nonsyndromic) or associated with extra-pituitary malformations (syndromic). Objective To compare baseline characteristics and long-term evolution in patients with PSIS according to the initial presentation. Study Design Sixty-seven patients with PSIS were included. Data from subgroups were compared: neonates (n = 10) versus growth retardation patients (n = 47), and syndromic (n = 32) versus nonsyndromic patients (n = 35). Results Neonates displayed a more severe hormonal and radiological phenotype than children referred for growth retardation, with a higher incidence of multiple hormonal deficiencies (100% versus 34%; P = 0.0005) and a nonvisible anterior pituitary lobe (33% versus 2%; P = 0.0017). Regular follow-up of growth might have allowed earlier diagnosis in the children with growth retardation, as decreased growth velocity and growth retardation were present respectively 3 and 2 years before referral. We documented a progressive worsening of endocrine impairment throughout childhood in these patients. Presence of extra-pituitary malformations (found in 48%) was not associated with more severe hormonal and radiological characteristics. Growth under GH treatment was similar in the patient groups and did not vary according to the pituitary MRI findings. Conclusions PSIS diagnosed in the neonatal period has a particularly severe hormonal and radiological phenotype. The progressive worsening of endocrine impairment throughout childhood justifies periodic follow-up to check for additional hormonal deficiencies.

Is scoliosis an issue for giving growth hormone to children with Prader–Willi syndrome?

Prader–Willi syndrome (PWS) is a rare genetic disorder with a large range of severe co-morbidities including severe neonatal hypotonia with failure to thrive and dysmorphic features during the first months of life followed by the development of morbid obesity and endocrine disorders related to hypothalamic dysfunction (growth hormone (GH) deficiency, hypogonadism, oxytocin deficiency) associated with learning disabilities and behavioural and psychiatric problems.1 2 Early diagnosis combined with multidisciplinary care, parental guidance and GH treatment prevent precocious and morbid obesity in most cases.3 Since optimisation of the management of obesity and other endocrine disorders in these children, experts now have to deal with other pathological conditions that were less often reported when morbid obesity was the biggest challenge. Indeed, management of psychiatric disorders and other co-morbidities of this highly complex disease, such as scoliosis, requires specific attention. These “new” issues appear as a result of improved knowledge of the natural history of the disease and the use of drugs. GH treatment is now commonly used in children with PWS and has greatly changed the clinical presentation of these children as a result of its efficacy on growth, body composition and muscle strength.4 Sudden and unexplained deaths have been reported in children with or without GH treatment, and the effects of GH are not yet clearly elucidated, but its involvement cannot be ruled out.5 Potential complications of GH …