Characterization of lymphocyte profiles in children with syndromic obesity.

BACKGROUND: Little is known about blood lymphocyte subpopulations in children with common (CO) or syndromic (SO) obesity. We aimed to describe the blood lymphocyte profiles of obese children and to search for associations with clinical phenotypes. METHODS: Main blood lymphocyte subpopulations were analyzed in 159 children with CO and 34 with SO in a retrospective cohort. Phenotypes included obesity history, body mass index (BMI) Z score, percentage fat mass, and inflammatory parameters. Correlations were performed between phenotypes and circulating lymphocyte profiles. RESULTS: Children with SO had a higher BMI Z score (5.5 ± 1.7 SD) than children with CO (4.7 ± 0.9 SD; p = 0.01). Significant differences were found for lymphocyte counts, including a higher percentage of CD19+ B cells (SO = 20.1 ± 6.7 vs. CO = 17.1 ± 6.1%, p = 0.03), despite lower absolute numbers (SO = 0.57 ± 0.20 vs. CO = 0.63 ± 1.9 g/L, p < 0.01). However, no difference in the lymphocyte profile was found between children with SO and those with the most severe CO (BMI Z score ≥ 4.7 SD). CONCLUSION: Children with SO have altered blood lymphocyte profiles with increased prevalence of CD19+ B cells, which is closely linked to the degree of obesity severity and inflammatory markers.

[Obesity in childhood: What are the respiratory risks?] / Prise de poids chez l'enfant : quels risques respiratoires ?

In childhood and adolescence overweight is defined as a body mass index (BMI) above the 97th percentile for age and sex, according to the curves established by the International Obesity Task Force (IOTF). In France, it is estimated that 25 % of children under 18 years old are overweight. Overweight and obesity in this population are multifactorial, with an important influence of genetic factors, modulated by pre and post-natal (maternal smoking), societal and psychological determinants. The impact of obesity on respiratory function in children is mostly characterized by a decreased FEV1/FCV. Moreover, several studies have shown an association between asthma and overweight/obesity, with a pejorative impact of BMI on asthma control. However, asthma is still poorly characterized in this population, and the determinants of bronchial obstruction seem to differ from non-obese children, with less eosinophilic inflammation. Obstructive sleep apnea syndrome (OSAS) is a frequent complication of obesity, affecting up to 80% of obese children and adolescents. It has a specific polysomnographic definition in children. Symptoms are similar to adult OSAS, but with cognitive and neurobehavioral alterations often more important in adolescents. The treatment consists in ENT surgery when indicated (with systematic post-operative polysomnography), and nocturnal continuous positive airway pressure (CPAP). The obesity-hypoventilation syndrome (OHS) has the same definition in children as in adults and affects up to 20% of obese patients. Treatment consists in nocturnal ventilation using bilevel positive airway pressure (BiPAP). Finally, in some extreme cases, bariatric surgery can be performed. The indication should be discussed in a specialised paediatric reference centre.

Impact of transitional care on endocrine and anthropometric parameters in Prader-Willi syndrome.

CONTEXT: The transition of patients with Prader-Willi syndrome (PWS) to adult life for medical care is challenging because of multiple comorbidities, including hormone deficiencies, obesity and cognitive and behavioral disabilities. OBJECTIVE: To assess endocrine management, and metabolic and anthropometric parameters of PWS adults who received (n = 31) or not (n = 64) transitional care, defined as specialized pediatric care followed by a structured care pathway to a multidisciplinary adult team. PATIENTS AND STUDY DESIGN: Hormonal and metabolic parameters were retrospectively recorded in 95 adults with PWS (mean ± s.d. age 24.7 ± 8.2 years, BMI: 39.8 ± 12.1 kg/m²) referred to our Reference Center and compared according to transition. RESULTS: Among the entire cohort, 35.8% received growth hormone (GH) during childhood and 16.8% had a GH stimulation test after completion of growth. In adulthood, 14.7% were treated with GH, 56.8% received sex-hormone therapy, whereas 91.1% were hypogonadic and 37.9% had undergone valid screening of the corticotropic axis. The main reason for suboptimal endocrine management was marked behavioral disorders. Patients receiving transitional care were more likely to have had a GH stimulation test and hormonal substitutions in childhood. They also had a lower BMI, percentage of fat mass, improved metabolic parameters and fewer antidepressant treatments. Transitional care remained significantly associated with these parameters in multivariate analysis when adjusted on GH treatment. CONCLUSION: A coordinated care pathway with specialized pediatric care and transition to a multidisciplinary adult team accustomed to managing complex disability including psychiatric troubles are associated with a better health status in adults with PWS.

Chronic intestinal pseudo-obstruction in a child with Treacher Collins syndrome.

BACKGROUND: Treacher Collins syndrome (TCS) mainly presents with severe craniofacial developmental abnormalities characterized by a combination of bilateral downward-slanting palpebral fissures, colobomas of the lower eyelids, hypoplasia of the facial bones, cleft palate, malformation of the external ears, atresia of the external auditory canals, and bilateral conductive hearing loss. It is due to mutations in Treacher Collins syndrome 1 (TCOF1) (5q32-q33.1) and Polymerase RNA 1 polypeptides D and C (POLR1D [13q12.2], and POLR1C [6p21.1]) genes, which are responsible for increased neuroepithelial apoptosis during embryogenesis resulting in the lack of neural crest cells involved in facial bone and cartilage formation. Altered function of the upper digestive tract has been reported, whereas severe dysmotility disorders have never been reported. We describe here the first case of TCS associated with histologically proven chronic intestinal pseudo-obstruction (CIPO) in humans. Case presentatios A 12-year-old boy with TCS due to TCOF1 gene deletion experienced nutritional difficulties and digestive intolerance from birth. CIPO was suspected during childhood because of severe intestinal dysmotility leading to enteral-jejunal nutrition intolerance and dependence on total parenteral nutrition. Diagnosis of CIPO with nervous abnormalities was histologically confirmed on a surgical rectal biopsy that showed enlarged ganglionic myenteric plexus. At the age of 9 years, an isolated colonic stenosis without dilatation responsible for severe abdominal pain and altered quality of life led to digestive derivation contributing to rapid disappearance of chronic abdominal pain. At the age of 12 years, the patient was still dependent on total home parenteral nutrition 7 days a week to maintain regular growth velocity. CONCLUSION: Recently, mice studies have pointed out the role played by TCOF1 in ganglionic cell migration in the foregut, suggesting that the synergistic haploinsufficiency of Tcof1 and Pax3, a transcription factor regulating the RET gene involved in disorders of neural crest cell development, probably results in colonic aganglionosis and may explain the association described here between TCS and CIPO. This case may correspond to this possible mechanism in humans. These findings and our clinical report suggest that CIPO may be assessed as unusual digestive manifestations in TCS with TCOF1 deletion.

[Duodenal duplication revealed by acute pancreatitis]. / Duplication duodénale révélée par une pancréatite aiguë.

INTRODUCTION: Duodenal duplications are rare congenital malformations whose revealing signs are highly variable and nonspecific. OBSERVATION: We report the case of a female infant who presented with neonatal acute pancreatitis complicated by recurrent ascites, profound hypoalbuminemia responsible for pleural and pericardial effusions, revealing a duodenal duplication cyst. The unusual and original clinical presentation as well as the difficulty detecting the duplication radiologically delayed the diagnosis. A prolonged medical treatment with octreotide, albumin infusions, and exclusive parenteral nutrition led to an almost total disappearance of the ascites before surgery. The outcome was favorable after surgical removal of the duplication with 1 year of follow-up. CONCLUSION: The diagnosis of duodenal duplication can be difficult and it may be necessary to repeat the ultrasound examinations. Surgical resection is delicate, especially when there is an abundant pancreatic ascites. Therefore, an adequate prolonged medical treatment to reduce this ascites is recommended before the surgery.

[Narcolepsy in sleepy obese children. Two case reports]. / Narcolepsie chez l'enfant obèse. À propos de 2 cas.

Narcolepsy is a disabling disorder, characterized by excessive daytime sleepiness, irresistible sleep attacks, and partial or complete cataplexy. Many cases of obesity and precocious puberty have been reported in narcoleptic children, suggesting that the deficiency of hypocretin in narcolepsy could also be implicated in appetite stimulation. We report the observations of two young girls, who were referred for obesity and who developed narcolepsy accompanied by an abrupt weight gain. In both cases, specific drugs promoted wakefulness and overweight stabilization. Narcolepsy has to be suspected in sleepy obese children and not misdiagnosed as obstructive apnea. A nocturnal polysomnography with multiple sleep latency tests should be performed to confirm the diagnosis and begin specific treatment that is effective for sleep disorders and weight gain.

[Bariatric surgery in obese adolescents: When and how should the transition from pediatric to adult medical management be made?]. / Prise en charge médico-chirurgicale de l'obésité de l'adolescent : quand et comment réaliser la transition vers la prise en charge adulte ?

INTRODUCTION: In young obese patients, the transition from adolescence to adulthood, i.e., the transition from the pediatric to the adult medical team, is a new issue. In particular, it is important to define when and how this transition should be made in the setting of bariatric surgery. MATERIALS AND METHODS: Fourteen young obese patients (under the age of 20), who underwent bariatric surgery, were included in the study (nine cases of Roux-en-Y gastric by-pass, three sleeve gastrectomy, one gastric banding). After surgery, the patients were followed in both the pediatric and adult departments (protocol 1) or only in the pediatric department during the 1st year and then in the adult department afterwards (protocol 2). Anthropometric and metabolic data, before and after surgery, and compliance monitoring were analyzed using a retrospective design. Twelve patients completed a questionnaire assessing how they experienced the transition. RESULTS: Before surgery, mean age±SD was 16.3±1.8 years old and mean body mass index (BMI) 55.0±8.6kg/m(2). At 1 year after surgery, mean weight loss was -32.1±8.2% of initial body weight. Adherence to vitamin supplementation was judged to be adequate (vitamins were not taken less than once a week) for only 57.5% patients. Mean follow-up was 34.8±25.1 months [95% CI, 9.5-78.4]. None of the patients was lost to follow-up. Compliance was significantly better for patients following protocol 2. Adolescents reported being satisfied with meetings and newsletters about surgery, specific to this age group (91.7%). They also reported that information on the adult department was sufficient and 91.7% of them expressed satisfaction on the first outpatient visit in the adult department. However, all patients spontaneously reported having difficulties identifying members of the different teams: nutritionist pediatrician, nutritionist, and adult surgeon. DISCUSSION: These preliminary data suggest that, in obese adolescents, it is important to differentiate the transition period and the time and preparation for bariatric surgery. A prospective follow-up with a larger number of subjects and recommendations are needed to better define and improve the specific clinical management of obese adolescents transitioning to adulthood.

Eating behaviour in obese patients with melanocortin-4 receptor mutations: a literature review.

Melanocortin-4 receptor (MC4R) mutations are the most common known cause of monogenic obesity and an important contributor to polygenic obesity. MC4R mutations with partial or total loss of function, as well as the variant rs17782313 mapped near MC4R, are positively associated with obesity. MC4R is involved in the leptin-melanocortin signalling system, located in hypothalamic nuclei, that controls food intake via both anorexigenic or orexigenic signals. Impairment in this receptor might affect eating behaviours. Thus, in the case of MC4R mutation carriers, obesity could be related, at least partly, to inadequate control over eating behaviours. Many published studies address eating behaviours in MC4R mutation carriers. Most studies focus on binge eating disorder, whereas others examine various aspects of intake and motivation. Up to now, no evaluation of this literature has been performed. In this review, we examine the available literature on eating behaviours in carriers of MC4R mutations and variant rs17782313 near MC4R gene. We address binge eating disorder, bulimia nervosa, mealtime hyperphagia, snacking, psychological factors, satiety responsiveness and intake of energy and macro/micronutrient. In a small number of studies, MC4R mutations seem to impair eating behaviours or motivation, but no clear causal effects can be found in the balance of the evidence presented. Improvements in methodologies will be necessary to clarify the behavioural effects of MC4R mutations.

Relevance of increased serum cystatin C to vascular alterations in obese children.

OBJECTIVE: Epidemiological studies report a positive relationship between serum cystatin C and cardiovascular outcomes in adults. Here, we tested the relevance of cystatin C as a biomarker for early vascular alterations in severely obese children. METHODS: Two hundred nineteen obese (140 girls; age = 11.7 ± 2.7 years, BMI Z-score = 4.7 ± 1.2 SD) and 262 non-obese children (129 girls; age = 11.6 ± 0.6 years, body mass index [BMI] Z-score = 0.1 ± 1.0 SD). Serum cystatin C was measured by immunonephelometry. Intima media thickness (IMT), incremental elastic modulus, and flow-mediated and glyceryl-trinitrate-mediated dilations were determined at the common carotid artery and the brachial artery in obese children. RESULTS: Obese children had significantly higher serum cystatin C than normal weight controls (0.86 ± 0.01 vs. 0.80 ± 0.01, P < 0.0001). In obese children, serum cystatin C correlates positively with BMI and the homeostasis model assessment index and negatively with the quantitative insulin sensitivity check index and adiponectin. A positive relationship was found between serum cystatin C and carotid IMT (r = 0.23, P = 0.0005), which remained significant in multivariate models adjusted for BMI (P = 0.01) and adiponectin with a trend towards significance (P = 0.05). CONCLUSION: This study positions cystatin C and adiponectin as covariables associated with arterial wall thickness in obese children. Although the underlying pathophysiology linking cystatin C to early vascular disease remains to be deciphered, cystatin C may represent a novel adipose tissue-derived biomarker implicated in obesity-related comorbidities early in life.

[Childhood obesity and sleep breathing disorders]. / Obésité et troubles respiratoires nocturnes chez l'enfant.

Obstructive sleep apnea (OSA) is common in childhood obesity and is mainly due to adenoid and tonsillar hypertrophy. Surgical management with adenotonsillectomy will be the first line of treatment for obese children with OSA in addition to weight loss. In addition, recent data suggested that sleep deprivation in infancy may be associated with obesity later in life, probably due to hypothalamic dysregulation with modifications in hormones involved in food intake regulation. It confirms that it is crucial to evaluate sleep for all obese children with questionnaire in order to improve their management and their quality of life.

Cathepsin S genotypes are associated with Apo-A1 and HDL-cholesterol in lean and obese French populations.

Cathepsin S (CTSS) is a cysteine protease that has a central role in remodeling the extracellular matrix and, as such, has been implicated in the etiology of cardiovascular disease. This study used five tag single nucleotide polymorphisms (tSNPs) to screen the CTSS gene in healthy lean (n = 1891) and obese French populations (n = 477) for their association with various phenotypes: body mass index, waist-to-hip ratio, glycemia, total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (Apo-A1) and apolipoprotein B. Significant associations were identified between rs11576175 tSNP (A/G) and Apo-A1 and HDL-C plasma levels in a sex-specific manner. Lean female subjects homozygous for the minor A-allele had higher levels of circulating Apo-A1 (p = 0.0003), while lean male A/A carriers had higher levels of HDL-C (p = 0.007) compared with the other genotypes. In the obese cohort, associations were found between three tSNPs and Apo-A1 levels in adult female subjects: rs10888390 (G/A), p = 0.01; rs10888394 (T/C), p = 0.03; and rs1136774 (C/T), p = 0.02; however, only rs10888390 remained significant in a combined model (p = 0.03). These results provide the first evidence that CTSS sequence variations are associated with two human metabolic risk factors for cardiovascular diseases: plasma Apo-A1 and HDL-C concentrations.

Presence of increased stiffness of the common carotid artery and endothelial dysfunction in severely obese children: a prospective study.

BACKGROUND: Epidemiological studies suggest that obesity-induced atherosclerosis may start in childhood, but this process has never been demonstrated. We looked for arterial changes and investigated their relation to cardiovascular risk factors in obese children. METHODS: Non-invasive ultrasonographic measurements were made in 48 severely obese children and 27 controls to investigate arterial mechanics and endothelial function. Plasma lipid concentrations, indices of insulin resistance, and body composition were assessed in the obese children. FINDINGS: The obese children had significantly lower arterial compliance than the healthy controls (median 0.132 [0.022-0.273] vs 0.143 [0.112-0.237] mm(2).mm Hg; p=0.02) and lower distensibility (0.60 [0.10-1.00] vs 0.70 [0.50-1.10] mm Hg(-1).10(-2); p=0.0001). Conversely, the obese children had higher values than the controls for wall stress (3.36 [2.00-5.01] vs 2.65 [2.13-3.54] mm Hg.10(2); p=0.0001) and incremental elastic modulus (1.68 [0.72-10.8] vs 0.96 [0.64-1.47]; p=0.0001). Endothelium-dependent and independent function were also lower in the obese than in the control children. An android fat distribution was positively correlated with indices of insulin resistance and plasma triglyceride concentrations and was negatively correlated with plasma HDL-cholesterol concentration and arterial compliance. Endothelial dysfunction was correlated with low plasma apolipoprotein A-I and with insulin resistance indices. INTERPRETATION: Severe obesity in children is associated with arterial wall stiffness and endothelial dysfunction. Low plasma apolipoprotein A-I, insulin resistance, and android fat distribution may be the main risk factors for these arterial changes, which are of considerable concern as possible early events in the genesis of atheroma.

Mutational analysis of melanocortin-4 receptor, agouti-related protein, and alpha-melanocyte-stimulating hormone genes in severely obese children.

OBJECTIVE: To search for mutations in melanocortin pathway elements, that is, the melanocortin-4 receptor (MC4R ), agouti-related protein (AGRP ), and (alpha-melanocyte-stimulating hormone (alpha MSH ) genes in children with severe obesity. STUDY DESIGN: Direct sequencing of the MC4R encoding sequence and single-strand polymorphism conformation analysis of AGRP and alpha MSH genes were performed in 63 severely obese children. Polymerase chain reaction (PCR) assays of restriction fragment length polymorphism were used to assess the frequency of each newly discovered mutation in 283 non-obese control subjects. RESULTS: Four dominantly inherited, heterozygous, missense MC4R mutations (Val50Met, Ser58Cys, Ile102Ser, and Ile170Val) were identified in 4 unrelated children and none of the control subjects. Expression of the obese phenotype was variable in mutation-positive family members. Clinical and laboratory features were similar in the obese children with and without an MC4R mutation. Two polymorphisms were detected in the AGRP -encoding sequence (a silent mutation in exon 1 and Ala67Thr in exon 2), with similar frequencies in the obese and control groups. No mutations were found in the alpha MSH gene. CONCLUSIONS: MC4R mutations may be a non-negligible cause of severe obesity in children with variable expression and penetrance. Mutations in AGRP and alpha MSH genes were not among the causes of obesity in our population.

Orthotopic liver transplantation for mitochondrial respiratory chain disorders: a study of 5 children.

BACKGROUND: Liver involvement in mitochondrial respiratory chain disorders (MRCD) frequently ends in liver failure and death. Because of the high risk of extrahepatic, particularly neuromuscular, manifestations of the disease, the indication of orthotopic liver transplantation (OLT) in these patients remains controversial. We report on 5 such children in whom OLT was carried out, in an attempt to help clarify the matter. PATIENTS: Patients 1 and 2 presented with fulminant liver failure at ages 7 and 6 months respectively. Emergency liver transplantation was performed before etiological investigations were completed. Retrospective examination of the explanted livers showed defects in complexes I, III and IV. In patient 1, severe neurological deterioration occurred 2 months after OLT with fatal outcome 9 months later. Patient 2 is alive 22 months after OLT with moderate motor impairment. Patients 3, 4 and 5 presented with progressive liver failure before 6 months of age. Surgical liver biopsies displayed a 50% defect in complex IV (patient 3), a defect in complexes I, IV (patient 4) and in complexes I, III, IV (patient 5). Because there was no clinical extrahepatic involvement on investigations, OLT was carried out in these patients. Patient 3 died of multiple organ failure soon after OLT, patients 4 and 5 are alive respectively 21 months and 12 months after OLT with normal neurological examination. CONCLUSION: OLT may be a valid therapeutic option in infants with delayed liver cell failure due to MRCD, only after performing in emergency a thorough inves tigation to exclude clinically significant extrahepatic, especially neuromuscular, involvement.