P. Barat

Molecular genetics of hypothalamic–pituitary–adrenal axis activity and function

The hypothalamic–pituitary–adrenocortical (HPA) axis is a major neuroendocrine system involved in the regulation of numerous physiological processes and in adaptation to stress. A wide range of variability can be observed in all the components of the system, and the contribution of genetic factors has been shown in the central regulation of the axis, the production of glucocorticoid hormones by the adrenal cortex, their bioavailability, and the efficiency of their action at the level of receptor and postreceptor mechanisms. Numerous molecular polymorphisms have been described that contribute to physiological variation as well as to HPA axis‐related pathological conditions. Although most studies focus on single gene polymorphisms, future studies should aim to integrate the different sources of variation into a systems genetic model to take into account the strong interdependence of the different components of the axis.

The impact of the control of serum phenylalanine levels on osteopenia in patients with phenylketonuria

Dual-energy X-ray absorptiometry (DEXA) of the spine has shown that phenylketonuric children develop osteopenia [1, 4,5]. While the exact reasons for low bone mineral density remain unclear, many explanations have been proposed: the diet being too restrictive [5], poor dietary compliance [2] or a direct effect of the disease [4]. In order to determine the role of the control of phenylalanine (Phe) blood levels in the pathogenesis of osteopenia, we performed a retrospective study of Phe levels from birth up to the present date in 13 children (5 females, 7 males) with classical phenylketonuria, diagnosed in the neonatal period by the French neonatal screening programme. Amino acid supplementation was started upon diagnosis and regularly adapted, based on the serum Phe levels. We compared the Phe values with the spine bone mineral density (BMD). DEXA was performed at the age of 12 years (range 5–21 years) using a Hologic QDR 4500A instrument. Spine BMD were interpreted according to French references values [3] and expressed as Z-score for gender and age. Patients were divided according to their spine BMD results into two groups: patients with osteopenia (Z-score <)1; n=8) and controls (Z-score ‡)1; n=5). Spine Z-scores were – 2.39±0.88 (range –3.60 to –1.40) and 0.28±0.83 (range –0.70 to 1.40) for osteopenic patients and controls, respectively. All the Phe levels recorded in the patients’ medical notes since the 1st month following birth up to the date the DEXA was done were used for the statistical analysis. The non-parametric MannWhitney test was used to compare continuous data between the two groups. We found that the age when DEXA was performed and the estimators of Phe levels position were similar between osteopenic patients and controls (Table 1). Nevertheless, although the difference was not significant, both the 3rd and 10th percentiles of Phe levels are lower and the percentage of Phe levels <2 mg/dl was higher in osteopenic patients. For the analysis of Phe level variations, we used the mean of cumulative variations which was defined as the sum of the differences between two successive Phe levels divided by the number of the differences studying per patient: i.e. Mean of cumulative variations = (S Phe X – Phe X+1)/(n-1); where Phe X, Phe X+1 are successive Phe levels, n, the number of the successive Phe levels studying per patient. Despite the small size of the population, osteopenic patients had a higher mean of cumulative variations (3.1±0.4 mg/dl) than controls (2.5±0.3 mg/dL, P=0.006). Linear regression analysis revealed a significant negative correlation of BMD spine (Z-score) with mean of cumulative variations (r=)0.61, P=0.025). These results suggest that the variations of serum Phe levels may contribute to osteopenia in phenylketonuric children.

Associations of glucocorticoid receptor and corticosteroid-binding globulin gene polymorphisms on fat mass and fat mass distribution in prepubertal obese children.

Previous studies conducted in adult obese patients have shown that glucocorticoid receptor and corticosteroid-binding globulin gene polymorphisms influence cortisol-driven obesity and metabolic parameters. We investigated the impact of these polymorphisms in prepubertal obese children that were thoroughly examined for hypothalamic–pituitary–adrenal axis activity and for metabolic and obesity parameters. Obese children carrier of the allele G of the BclI polymorphism within glucocorticoid receptor gene tend to present a higher percentage of fat mass as well as a decreased cortisol suppression after low-dose dexamethasone as found in adult studies. Additionally, these allele G carriers show a strong correlation between truncal fat mass distribution and cortisol response to a standardized lunch, whereas this correlation is weak in allele C carriers. No differences were found for obesity or metabolic parameters between genotypes at the corticosteroid-binding globulin locus. However, allele 90 carriers present increased 24-h free urinary cortisol. Overall, this study provides new data showing the influence of glucocorticoid receptor and corticosteroid-binding globulin genes in obesity and/or cortisol action in prepubertal obese children.

Cross reactions elicited by serum 17-OH progesterone and 11-desoxycortisol in cortisol assays

BACKGROUNDnDifferent pathophysiological situations such as congenital adrenal hyperplasia, adrenocortical carcinoma, metyrapone treatment, etc. elicit specificity problems with serum cortisol assay.nnnMETHODSnWe assayed cortisol using 2 kits and performed cross reaction studies as well as multiple regression analysis using 2 other steroids: 11-desoxycortisol and 17-OH progesterone.nnnRESULTSnAnalysis showed the existence of an analytical bias. Importantly, significantly different biases were demonstrated in newborns or patients taking metyrapone. Multiple regression analysis and cross reaction studies showed that 11-desoxycortisol level significantly influenced cortisol determination. Moreover, despite using the normal ranges provided by manufacturers discrepant results occurred such as 17% discordance in the diagnosis of hypocorticism in infants.nnnCONCLUSIONnWe wish to raise awareness about the consequences of the (lack of) specificity of cortisol assays with regard to the evaluation of hypocorticism in infants or when unusual steroids may be increased.

Épidémiologie des diabètes sucrés chez l’enfant

Diabetes mellitus in childhood may correspond to different pathophysiological entities but type 1 diabetes is by far the most common form of diabetes in children. Its incidence has been increasing steadily over the past two decades. This trend is particularly important among younger children, leading to a youngest median age at the discovery of diabetes. Thus, approximately 25% of diagnoses of type 1 diabetes are in children under 5 years. In France, the type 2 diabetes in children is rare despite the rise in obesity. Investigations for the diagnosis are recommended in obese adolescents with a family history of type 2 diabetes. Monogenic diabetes are more common than type 2 diabetes in Europe. Their research depends on the analysis of family history and may lead to a specific therapeutic approach.Resume Le diabete sucre de l’enfant peut correspondre a differentes entites physiopathologiques mais le diabete de type 1 reste de loin la forme de diabete la plus frequente chez l’enfant. Son incidence n’a cesse de progresser au cours des 2 dernieres decennies. Cette progression est particulierement forte chez les plus jeunes enfants, conduisant a un rajeunissement de l’âge de decouverte du diabete et une augmentation du nombre de patients a prendre en charge par les pediatres. Ainsi, environ 25 % des diagnostics de diabete de type 1 se font chez des enfants de moins de 5 ans. En France, le diabete de type 2 reste rare chez l’enfant malgre la progression de l’obesite. Il est a rechercher chez l’adolescent obese aux antecedents familiaux de diabete de type 2. Les diabetes monogeniques sont de diagnostic plus frequent que les diabetes de type 2 de l’enfant. Leur recherche depend de l’analyse de l’anamnese familiale et peut deboucher sur une attitude therapeutique specifi que.

Multidisciplinary care management has a positive effect on paediatric obesity and social and individual factors are associated with better outcomes

The RePPOP Aquitaine network, which was established in south‐west France to prevent and treat paediatric obesity, has developed a multidisciplinary approach based on multicomponent lifestyle interventions and family‐based actions. This study assessed the impact of its care management programme and investigated the factors associated with better outcomes.

Mise au pointImpact neuropsychologique à long terme du diabète de type 1 chez l’enfantLong-term neuropsychological impact of type 1 diabetes in children

Typexa01 diabetes, whose incidence is increasing in the youngest children, could have a long-term neuropsychological impact. Mood disorders are more frequent and some elements of cognitive performance, although within normal ranges, could decrease. In this review, we detail the contribution of animal models to current physiopathological knowledge. We summarize the main clinical studies regarding mood and cognitive performance in diabetic children. Finally, the advantages of imaging in this domain as related to brain development in children are discussed.

Impact neuropsychologique à long terme du diabète de type 1 chez l'enfant

Typexa01 diabetes, whose incidence is increasing in the youngest children, could have a long-term neuropsychological impact. Mood disorders are more frequent and some elements of cognitive performance, although within normal ranges, could decrease. In this review, we detail the contribution of animal models to current physiopathological knowledge. We summarize the main clinical studies regarding mood and cognitive performance in diabetic children. Finally, the advantages of imaging in this domain as related to brain development in children are discussed.

Inflammatory, endocrine and metabolic correlates of fatigue in obese children

Alterations in endocrine functions and low-grade systemic inflammation represent fundamental characteristics of obesity. These biological systems have been repeatedly linked to fatigue symptoms. The aim of the study was to assess the relationship between fatigue dimensions and metabolic/inflammatory markers in a sample of non-diabetic obese children. The possibility that inflammation-induced alterations in tryptophan metabolism relates to specific dimensions of fatigue was also investigated in a subsample of patients. The study was conducted in 41 obese children, median aged 12 [9-15] years, recruited in a pediatric tertiary center. Three dimensions of fatigue (e.g., general fatigue, sleep/rest, cognitive fatigue) were assessed using the Pediatric Quality of Life Inventory Multidimentional Fatigue Scale. In addition, a principal component analysis was performed to identify fatigue dimensions that were specific to the population under study. This analysis extracted five relevant dimensions corresponding respectively to concentration, energy, self-perceived cognitive efficiency, sleep/rest and motivation/anhedonia. Blood samples were collected for the measurement of inflammatory and metabolic markers, including high sensitivity C-reactive protein (hs-CRP), insulin, uricemia and glycaemia. Tryptophan, kynurenine and neopterin levels were also determined in a subsample of 17 patients. In the whole population under study, cognitive fatigue and reduced motivation/anhedonia were associated with BMI, independently of sex and age. The dimension of reduced motivation/anhedonia was associated with insulin resistance and inflammatory biomarkers. The association with insulin resistance persisted when the extent of fat mass (BMI-SDS) was taken into account. No association was found between tryptophan metabolism and specific dimensions of fatigue, but kynurenine and the kynurenine/tryptophan ratio correlated with insulin and HOMA-IR. These data indicate that insulin resistance in non diabetic obese children is associated with both cognitive fatigue and reduced motivation/anhedonia and with alterations in tryptophan metabolism. Further investigations are needed to determine whether inflammation-induced alterations in tryptophan metabolism is directly or indirectly implicated in insulin resistance and related fatigue.

Place de l'axe corticotrope dans le développement de l'obésité abdominale

Obesity is increasing worldwide. Abdominal obesity, which is due to the development of visceral adipose tissue, leads to metabolic disorders. Because abdominal obesity is associated with Cushing syndrome, many studies have been performed to find out how the hypothalamopituitary adrenal axis is involved in this disorder. Here, we propose to review these data before giving our experience on changes in hypothalamopituitary adrenal axis activity regarding fat mass distribution in prepubertal children.