[PRIMARY CARE INTERVENTIONS FOR PEDIATRIC OVERWEIGHT OR OBESITY]. / Prise en charge de l'enfant en surpoids ou obèse.

Obesity is a slow progressive chronic disease, for the complications as well as efficacy of the care. A long-term success requires a comprehensive educational diagno- sis that explores the various dimensions of the child and his family, thus allowing to define the care project. Both the motivational Interviewing that is based on the technics of therapeutic patient education and the parents' implication are the key factors for the success of the care. They allow, from the assessment of competencies of parents and child to propose, according to child's situation, the best targeted management. The follow up will be step by step, in long-term concerted interdisciplinarity, with in each visit the possibility of choosing a new objective or reinforcing some objectives suitable for the child, in combination with strategies that frequently involve the parents. Negotiation between caregiver(s), the child and his family are suitable. The greatest flexibility on both sides will allow to go forward together to reach the chosen aim.

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).

Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes.

We identified a locus on chromosome 6q16.3-q24.2 (ref. 1) associated with childhood obesity that includes 2.4 Mb common to eight genome scans for type 2 diabetes (T2D) or obesity. Analysis of the gene ENPP1 (also called PC-1), a candidate for insulin resistance, in 6,147 subjects showed association between a three-allele risk haplotype (K121Q, IVS20delT-11 and A-->G+1044TGA; QdelTG) and childhood obesity (odds ratio (OR) = 1.69, P = 0.0006), morbid or moderate obesity in adults (OR = 1.50, P = 0.006 or OR = 1.37, P = 0.02, respectively) and T2D (OR = 1.56, P = 0.00002). The Genotype IBD Sharing Test suggested that this obesity-associated ENPP1 risk haplotype contributes to the observed chromosome 6q linkage with childhood obesity. The haplotype confers a higher risk of glucose intolerance and T2D to obese children and their parents and associates with increased serum levels of soluble ENPP1 protein in children. Expression of a long ENPP1 mRNA isoform, which includes the obesity-associated A-->G+1044TGA SNP, was specific for pancreatic islet beta cells, adipocytes and liver. These findings suggest that several variants of ENPP1 have a primary role in mediating insulin resistance and in the development of both obesity and T2D, suggesting that an underlying molecular mechanism is common to both conditions.

Weight changes in overweight children enrolled in a therapeutic education program.

BACKGROUND: Between 2016 and 2018, overweight children in the Midi-Pyrénées region of France were invited to participate in the Tout sur l'EQuilibre Alimentaire et l'Activité Physique (TEQAAP; All About Balanced Eating and Physical Activity) education program offered by the Structure d'Expertise Régionale Obésité Occitanie (SEROO; Regional Expert Center for Obesity in Occitanie). OBJECTIVES: To describe the patient population and evaluate the program efficacy. The primary criterion was the body mass index (BMI) Z-score of the patients at the end of the program compared to the beginning. METHODS: This retrospective, descriptive, and analytical study included 262 children (mean age: 10 years+10 months; 64% female) between 1 January 2016 and 31 December 2018. Data from 138 patients (52.7%) were accessible and analyzed. The mean study duration was 9 months. RESULTS: The mean BMI at inclusion was 23.3 kg/m² with a mean Z-score of 2.8 ± 0.6; 82% were overweight, 11.1% were obese, and 6.1% were normal weight. Socioeconomic categories were well-balanced (35% high, 28% intermediate, 37% low). At the end of the study, 87% of the children had improved or stabilized their BMI, and Z-scores were lower by 9%±2 (p<0.001). CONCLUSION: The TEQAAP program led to an improvement in the BMI of overweight children.

Obesity, Overweight, and Pituitary Stalk Interruption Syndrome in Children and Young Adults.

CONTEXT: Pituitary stalk interruption syndrome (PSIS) is rare in the pediatric population. It combines ectopic posterior pituitary stalk interruption and anterior pituitary hypoplasia with hormonal deficiencies. The phenotype is highly heterogeneous and obesity/overweight seems to be underreported in the literature. OBJECTIVE: To identify patients with PSIS and obesity or overweight, describe their phenotype, and compare them with patients with PSIS without overweight/obesity. METHODS: Sixty-nine children and young adults with PSIS in a Toulouse cohort from 1984 to 2019 were studied. We identified 25 obese or overweight patients (OB-OW group), and 44 were nonobese/overweight (NO group). Then the groups were compared. RESULTS: All cases were sporadic. The sex ratio was 1.6. The main reason for consultation in both groups was growth retardation (61% in OB-OW group, 77% in NO group). History of neonatal hypoglycemia was more common in the OB-OW than in the NO group (57% vs 14%, P = .0008), along with extrapituitary malformations (64% vs 20%, P < 0001). The incidence of caesarean section was higher in the OB-OW group (52%) than in the NO group (23%), although not significant (P = .07). CONCLUSION: Patients with PSIS who are obese/overweight display interesting phenotypic differences that suggest hypothalamic defects. Studies are needed that include additional information on hormonal levels, particularly regarding oxytocin and ghrelin.

Low bone mass in Noonan syndrome children correlates with decreased muscle mass and low IGF-1 levels.

Although musculoskeletal abnormalities have long been described in patients with Noonan syndrome (NS), only a few studies have investigated the bone status of these patients. The aim of this retrospective observational study was to describe the bone health of children with NS. Thirty-five patients with a genetically confirmed diagnosis of NS were enrolled. We analyzed the axial skeleton (lumbar spine) using dual energy X-ray absorptiometry and the appendicular skeleton (hand) with the BoneXpert system. Bone metabolism markers, including mineral homeostasis parameters, serum 25-hydroxy vitamin D (25-OHD) levels and markers of bone formation and resorption were also reported. Compared to the general population, axial and appendicular bone mass was significantly decreased in children with NS (p < 0.0001). Serum 25-OHD levels were low in about half of the patients and were negatively correlated with age (r = -0.52; p < 0.0001). Patients with NS exhibited reduced bone formation marker levels and increased bone resorption marker levels (p < 0.0001). No gender difference or genotype-phenotype correlations were found for the different bone parameters. Muscle mass and, to a lesser extent, serum insulin-like growth factor 1 (IGF-1) levels were independent predictors of whole-body bone mineral content (p < 0.0001 for both parameters; adjusted R2 = 0.97). In conclusion, bone mass is reduced in children with NS and correlates with decreased muscle mass and low serum IGF-1 levels. These data justify addressing all potential threats to bone health including sufficient calcium and vitamin D intake, regular physical exercise, and hormone replacement therapy.

Factors associated with early menarche: results from the French Health Behaviour in School-aged Children (HBSC) study.

BACKGROUND: Puberty is a transition period making physiological development a challenge adolescents have to face. Early pubertal development could be associated with higher risks of poor health. Our objective was to examine risk behaviours, physical and psychological determinants associated with early menarche (<11 years). METHODS: Early menarche was assessed in the Health Behaviour in School-aged Children French cross-sectional survey. Data were collected in 2006 by anonymous self-reported standardized questionnaire from a nationally representative sample of 1072 15 years old girls in school classrooms. Family environment, school experience, physical and psychological factors, risk behaviours (substance use and sexual initiation) were recorded. Logistic regression models were applied (analysing for crude and adjusted relationships between early menarche and risk behaviours controlled for family context). RESULTS: Median age at menarche was 13.0 years; 57 girls (5.3%) were early-matured. Controlled for familial environment, early menarche was associated with having had more than two life-drunkenness episodes (adjusted OR = 2.5 [1.3-4.6]), early sexual initiation (adjusted OR = 2.8 [1.3-6.0]) and overweight (adjusted OR = 7.3 [3.6-14.9]). CONCLUSION: Early-maturing girls may affiliate with older adolescents, hence engage in risk behaviours linked to their appearance rather than their maturity level. Factors associated with early menarche highlight the need to focus attention on early-matured girls to prevent further health problems linked to risk behaviours.

Short-term and long-term positive outcomes of the multidisciplinary care implemented by the French health networks for the prevention and care of paediatric overweight and obesity.

BACKGROUND: The nine French regional health networks for the prevention and care of paediatric obesity offer a 2-year program of multidisciplinary primary care (medical, dietetical, psychological, adapted physical activity) based on multicomponent lifestyle interventions. OBJECTIVES: To assess the short-term and long-term impact of care management. METHODS: The impact of the multidisciplinary care was assessed by changes in the body mass index (BMI) Z score during the period of the care, and at least 2 years after the end. Anthropometric data were collected at baseline and at the end of the care either through a digital medical file or through direct phone contacts with the referring. Long-term outcomes were assessed through studies relative to post follow-up evaluation. RESULTS: At the end of the period of the care in a network, 72.9% of 6947 children had decreased their BMI Z score from 3.6 ± 1.0 DS at baseline to 3.3 ± 1.1 DS at the end. The four studies relative to long-term evaluation showed a pursuit of the decrease of BMI Z score during the 5.1 years after the beginning of the care. CONCLUSIONS: The care provided by regional French networks for prevention and care of paediatric obesity induce a reduction of BMI that continues afterwards.

Noonan syndrome males display Sertoli cell-specific primary testicular insufficiency.

Context Abnormalities in the hypothalamo-pituitary-gonadal axis have long been reported in Noonan syndrome (NS) males with only few data available in prepubertal children. Objective The aim of this study was to describe the gonadal function of NS males from childhood to adulthood. Design It is a retrospective chart review. Patients and methods A total of 37 males with a genetically confirmed diagnosis of NS were included. Clinical and genetic features, as well as serum hormone levels (LH, FSH, testosterone, anti-Müllerian hormone (AMH), and inhibin B) were analysed. Results Of the 37 patients, 16 (43%) children had entered puberty at a median age of 13.5 years (range: 11.4-15.0 years); age at pubertal onset was negatively correlated with BMI SDS (r = -0.541; P = 0.022). In pubertal boys, testosterone levels were normal suggesting a normal Leydig cell function. In contrast, NS patients had significant lower levels of AMH (mean SDS: -0.6 ± 1.1; P = 0.003) and inhibin B (mean SDS: -1.1 ± 1.2; P < 0.001) compared with the general population, suggesting a Sertoli cell dysfunction. Lower AMH and inhibin B levels were found in NS-PTPN11 patients, whereas these markers did not differ from healthy children in SOS1 patients. No difference was found between cryptorchid and non-cryptorchid patients for AMH and inhibin B levels (P = 0.43 and 0.62 respectively). Four NS-PTPN11 patients had a severe primary hypogonadism with azoospermia/cryptozoospermia. Conclusions NS males display Sertoli cell-specific primary testicular insufficiency, whereas Leydig cell function seems to be unaffected.

Bardet-Biedl syndrome gene variants are associated with both childhood and adult common obesity in French Caucasians.

Bardet-Biedl syndrome (BBS) is a rare developmental disorder with the cardinal features of abdominal obesity, retinopathy, polydactyly, cognitive impairment, renal and cardiac anomalies, hypertension, and diabetes. BBS is genetically heterogeneous, with nine genes identified to date and evidence for additional loci. In this study, we performed mutation analysis of the coding and conserved regions of BBS1, BBS2, BBS4, and BBS6 in 48 French Caucasian individuals. Among the 36 variants identified, 12 were selected and genotyped in 1,943 French-Caucasian case subjects and 1,299 French-Caucasian nonobese nondiabetic control subjects. Variants in BBS2, BBS4, and BBS6 showed evidence of association with common obesity in an age-dependent manner, the BBS2 single nucleotide polymorphism (SNP) being associated with common adult obesity (P = 0.0005) and the BBS4 and BBS6 SNPs being associated with common early-onset childhood obesity (P = 0.0003) and common adult morbid obesity (0.0003 < P < 0.007). The association of the BBS4 rs7178130 variant was found to be supported by transmission disequilibrium testing (P = 0.006). The BBS6 variants also showed nominal evidence of association with quantitative components of the metabolic syndrome (e.g., dyslipidemia, hyperglycemia), a complication previously described in BBS patients. In summary, our preliminary data suggest that variations at BBS genes are associated with risk of common obesity.

ACDC/adiponectin polymorphisms are associated with severe childhood and adult obesity.

Common single nucleotide polymorphisms (SNPs) in the ACDC adiponectin encoding gene have been associated with insulin resistance and type 2 diabetes in several populations. Here, we investigate the role of SNPs -11,377C > G, -11,391G > A, +45T > G, and +276G > T in 2,579 French Caucasians (1,229 morbidly obese and 1,350 control subjects). We found an association between severe forms of obesity and -11,377C (odds ratio 1.23, P = 0.001) and +276T (1.19, P = 0.006). Surprisingly, alternative alleles -11,377G and +276G have been previously reported as risk factors for type 2 diabetes. Transmission disequilibrium tests showed a trend in overtransmission (56.7%) of a risk haplotype 1((C))-1((G))-1((T))-2((T)) including -11,377C and +276T in 634 obesity trios (P = 0.097). Family-based analysis in 400 trios from the general population indicated association between obesity haplotype and higher adiponectin levels, suggesting a role of hyperadiponectinemia in weight gain. However, experiments studying the putative roles of SNPs -11,377C > G and +276G > T on ACDC functionality were not conclusive. In contrast, promoter SNP -11,391G > A was associated with higher adiponectin levels in obese children (P = 0.005) and in children from the general population (0.00007). In vitro transcriptional assays showed that -11,391A may increase ACDC activity. In summary, our study suggests that variations at the ACDC/adiponectin gene are associated with risk of severe forms of obesity. However, the mechanisms underlying these possible associations are not fully understood.

Factors associated with overweight in preschool-age children in southwestern France.

BACKGROUND: Pediatric overweight and obesity are becoming an epidemic worldwide, which indicates the need for formulating preventive programs and policies during a child's early years. OBJECTIVE: We identified factors associated with overweight in young children in southwestern France. DESIGN: Children [n = 1780; x (+/-SD) age: 3.9 +/- 0.4 y] were recruited in kindergarten. Medical information on the parents, grandparents, and child as well as the child's 3-d dietary intake, participation in organized sports, and television-viewing habits were ascertained, and anthropometric measurements of the child were taken. RESULTS: The prevalence of overweight was 9.1% when using body mass index >or= 90th percentile of French reference curves as a cutoff. In a multivariate logistic regression, overweight at 4 y was associated with female sex, having an overweight mother, and having >or=1 diabetic grandparent; odds ratios (ORs; 95% CIs) for these variables were 1.9 (1.2, 3.0), 2.2 (1.0, 4.7), and 2.6 (1.6, 4.1), respectively. Being small or large for gestational age was not associated with the risk of overweight at 4 y, whereas this risk was increased for children who were overweight at 9 or 24 mo: ORs (95% CIs) were 4.0 (2.4, 6.9) and 11.7 (6.1, 22.2), respectively. Nutrient intakes did not differ significantly with weight status in girls; however, overweight boys had significantly greater energy and lipid intakes than did their nonoverweight counterparts. Overweight was positively associated with television viewing (>1 h/d) in both sexes and with participation in organized sports in girls only. CONCLUSIONS: A family history of overweight or diabetes, overweight in the first 2 y of life, and television viewing are associated with overweight at 4 y. These factors should be considered in developing programs for the prevention of overweight in early childhood.

Secretory granule neuroendocrine protein 1 (SGNE1) genetic variation and glucose intolerance in severe childhood and adult obesity.

BACKGROUND: 7B2 is a regulator/activator of the prohormone convertase 2 which is involved in the processing of numerous neuropeptides, including insulin, glucagon and pro-opiomelanocortin. We have previously described a suggestive genetic linkage peak with childhood obesity on chr15q12-q14, where the 7B2 encoding gene, SGNE1 is located. The aim of this study is to analyze associations of SGNE1 genetic variation with obesity and metabolism related quantitative traits. METHODS: We screened SGNE1 for genetic variants in obese children and genotyped 12 frequent single nucleotide polymorphisms (SNPs). Case control analyses were performed in 1,229 obese (534 children and 695 adults), 1,535 individuals with type 2 diabetes and 1,363 controls, all French Caucasians. We also studied 4,922 participants from the D.E.S.I.R prospective population-based cohort. RESULTS: We did not find any association between SGNE1 SNPs and childhood or adult obesity. However, the 5' region SNP -1,701A>G associated with higher area under glucose curve after oral glucose tolerance test (p = 0.0005), higher HOMA-IR (p = 0.005) and lower insulinogenic index (p = 0.0003) in obese children. Similar trends were found in obese adults. SNP -1,701A>G did not associate with risk of T2D but tends to associate with incidence of type 2 diabetes (HR = 0.75 95%CI [0.55-1.01]; p = 0.06) in the prospective cohort. CONCLUSION: SGNE1 genetic variation does not contribute to obesity and common forms of T2D but may worsen glucose intolerance and insulin resistance, especially in the background of severe and early onset obesity. Further molecular studies are required to understand the molecular bases involved in this process.

Truncal distribution of fat mass, metabolic profile and hypothalamic-pituitary adrenal axis activity in prepubertal obese children.

OBJECTIVE: To investigate whether truncal distribution of fat mass (TDFM) is associated with variations of the hypothalamic-pituitary-adrenocortical (HPA) axis activity in prepubertal obese children. STUDY DESIGN: TDFM, assessed with dual energy X-ray absorptiometry and a comprehensive set of measures of HPA axis activity and reactivity have been studied in 45 prepubertal obese children aged 6 to 11 years (girls) and 6 to 13 years (boys). RESULTS: After adjustment for whole body fat mass (%) (WBFM), TDFM correlated positively with insulin (r = 0.50, 95% CI [0.23; 0.70]) and homeostasis model assessment of insulin resistance (r = 0.52, 95% CI [0.25; 0.71]). When adjusted for WBFM, TDFM correlated positively with morning plasma cortisol (r = 0.38, 95% CI [0.15; 0.64]) in the total population. TDFM correlated negatively with the rise of salivary cortisol after a standard meal (r = -0.43, 95% CI [-0.71; -0.02]), obviously in girls. When adjusted for WBFM and TDFM, morning plasma cortisol correlated positively with total cholesterol (r = 0.41, 95% CI [0.11; 0.65]) and triglyceride (r = 0.44, 95% CI [0.14; 0.67]). The rise of salivary cortisol after a standard meal was negatively (r = -0.56, 95% CI [-0.85; -0.01]) and positively (r = 0.74, 95% CI [0.16; 0.94]) correlated with homeostasis model assessment of insulin resistance in boys and girls, respectively. CONCLUSIONS: Association exists in prepubertal obese children between TDFM and markers of HPA axis activity. These data suggest that HPA axis could be involved early in life in obesity associated with pejorative metabolic profile.

Association of melanin-concentrating hormone receptor 1 5' polymorphism with early-onset extreme obesity.

Murine models have been highly effective in identifying the monogenic forms of human obesity discovered to date. Melanin-concentrating hormone receptor 1 (MCHR1) has been shown to be significant in the downstream orexigenic activity of the leptin-melanocortin pathway by such models. In this study, the human MCHR1 gene was extensively characterized by sequencing 3.5 kb of coding, untranslated and intronic regions plus 1 kb of putative promoter region in 180 morbidly obese adults and 87 morbidly obese children, a total of >2.4 Mb of sequencing. Thirty-nine single nucleotide polymorphisms (SNPs) were found, seven of which encode an amino acid change. One mutation, R248Q, appeared to cosegregate with the obesity trait in one pedigree but was also found to be a rare polymorphism in control samples. To investigate the possible polygenic role of MCHR1, the six common SNPs (minor allele frequency >5%) found in the sequenced regions were then screened in 557 morbidly obese adults, 552 obese children, and 1,195 nonobese nondiabetic control subjects. The plausible promoter SNP, rs133068, was found to be associated with protection against obesity in obese children only (allele frequency P = 0.006 and genotype frequency P = 0.004). Most significant results were found when using a dominant model (P = 0.001, odds ratio 0.695 [95% CI 0.560-0.863]). However, similar associations were found when both adults and children were analyzed together (P = 0.006, 0.783 [0.658-0.930]), suggesting that severe forms of obesity with early onset may be associated with SNPs in MCHR1.

Is glutamate decarboxylase 2 (GAD2) a genetic link between low birth weight and subsequent development of obesity in children?

Low birth weight is a risk factor for obesity and type 2 diabetes. The fetal insulin hypothesis proposes that low birth weight might be mediated partly by genetic factors that impair insulin secretion/sensitivity during the fetal stage, as shown for glucokinase, the ATP-sensitive K+ channel subunit Kir6.2, and the small heterodimer partner genes. Glutamic acid decarboxylase 2 gene (GAD2) overexpression impairs insulin secretion in animals. Recently, polymorphisms in the GAD2 gene were associated with adult morbid obesity. In the present study, we investigated potential effects of the functional -243 A-->G polymorphism in the 5' promoter region of the GAD2 gene on fetal growth, insulin secretion, food intake, and risk of obesity in 635 French Caucasian severely obese children from three different medical centers. The case/control study confirmed the association between the GAD2 single-nucleotide polymorphism (SNP) -243 A-->G and obesity (odds ratio, 1.25; P = 0.04). In addition, SNP -243 GG children carriers showed a 270 g lower birth weight and a 1.5 cm lower birth height compared with AA carriers (P = 0.009 and P = 0.013, respectively). The relation between birth weight and Z score of BMI was linear in AA carrier children (P = 0.00001) and quadratic (U-shaped curve) in AG/GG carrier children (P = 0.0009). G allele children carriers presented a trend toward lower insulinogenic index with 25% reduction of insulin secretion in response to glucose load compared with A carriers (P = 0.09). Eighteen percent of GG obese carriers vs. 5.7% of AA carriers reported binge eating phenotype (P = 0.04). These results confirm the association between GAD2-243 promoter SNP and the risk for obesity and suggest that GAD2 may be a polygenic component of the complex mechanisms linking birth weight to further risk for metabolic diseases, possibly involving the pleiotropic effect of insulin on fetal growth and later on feeding behavior.

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.