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L'obésité est une pathologie complexe multifactorielle considérée comme une maladie des centres régulateurs du poids. La contribution de la génétique est constante mais son impact est variable selon les situations allant des obésités génétiques de cause rare (environ 5 % des obésités) aux situations d'obésité dite polygénique (ou obésité commune) plus souvent rencontrées (95 % des cas). D'autres facteurs (déterminants précoces pré- et post-nataux, sociétaux ou psychologiques) interagissent toujours étroitement avec ces facteurs génétiques expliquant la grande variabilité du phénotype et la physiopathologie complexe. Un véritable continuum existe entre toutes ces situations via l'implication de variants génétiques plus ou moins rares situés dans des gènes codant pour des protéines clé de la régulation centrale de la prise alimentaire. Cette meilleure compréhension des mécanismes a permis de mieux préciser les phénotypes associés et d'aboutir depuis quelques années à des innovations thérapeutiques ciblant ces gènes-clé. Cette évolution permet d'envisager à moyen terme le développement d'une véritable médecine personnalisée dans l'obésité précoce associant des traitements médicamenteux ciblés selon l'anomalie génétique identifiée et/ou une prise en charge globale multidisciplinaire ciblée selon le phénotype du patient voire le recours à la chirurgie bariatrique selon les situations cliniques. Obesity is a complex, multifactorial disease due to a dysfunction of the hypothalamic control of weight and food intake. The contribution of genetics is constant, but its impact is variable depending on the situations ranging from rare genetic obesities (around 5% of cases) to more frequently polygenic obesity (or common obesity) (95% of cases). Other factors as pre- and post-natal, societal or psychological determinants always interact closely with these genetic factors explaining the high variability of the phenotype and the complex pathophysiology. A true continuum exists between all these situations through the involvement of more or less rare genetic variants located in genes encoding key proteins in the central regulation of food intake. Rare forms of obesity are characterized by their common phenotype including a very early-onset severe obesity (BMI Z score greater than + 3 SD early before the age of 3 years) with resistance to medical treatment, and major eating disorders characterized by difficulties in voluntary control of food intake. Central endocrine abnormalities such as hypogonadotropic hypogonadism or GH deficiency for example, and metabolic abnormalities due to abnormal adipose tissue distribution are also associated with variable degrees (Alström syndrome for example). Neuropsychological abnormalities are also present such as neurodevelopmental disorders (intellectual disability with variable intensity and/or adaptive development disorders which are part of many syndromes such as in Prader-Wili Syndrome; autism spectrum disorders (in SH2B1 or MYT1L deficiency for example), cognitive disorders with difficulties in emotional regulation (eg: Bardet-Biedl Syndrome or specific rare variants located on genes of the melanocortin pathway), behavioral or psychiatric disorders, sleep disorders and major hypothalamic dysfunctions (eg: Prader-Willi Syndrome, Smith Magenis syndrome). This better understanding of the mechanisms has made it possible to better precise the associated phenotypes and, recently, to lead to therapeutic innovations targeting these key genes. This evolution helps to quickly envisage the development of a real personalized medicine in early onset obesity using the combination of drug treatments targeted according to the identified genetic anomaly and/or a multidisciplinary global approach targeting the patient's phenotype or even the bariatric surgery in specific situations. [ABSTRACT FROM AUTHOR]

La voie leptine-mélanocortines joue un rôle-clé dans l'homéostasie énergétique. Les variants homozygotes sur les gènes de cette voie sont associés à une obésité sévère et précoce avec anomalies endocriniennes. Le rôle des variants hétérozygotes sur ces mêmes gènes n'est pas établi dans l'obésité. Le but de l'étude était de décrire leur fréquence et la relation génotype/phénotype dans une cohorte d'enfants et d'adultes avec obésité sévère. Le séquençage direct sur au moins un gène de la voie (LEP , LEPR , POMC, PCSK1 et MC4R) a été réalisé chez 6347 patients avec obésité sévère et/ou précoce. La fonctionnalité des variants a été déterminée à partir des conséquences protéiques prédites, de 7 outils de prédiction , et des études fonctionnelles décrites. Le phénotype incluait l'âge de début d'obésité et sa sévérité, le comportement alimentaire et les anomalies endocriniennes associées. Le phénotype des sujets porteurs hétérozygotes (n = 60 dont 29 enfants) a été comparé à celui des homozygotes (n = 16 dont 4 enfants) mais aussi selon la fonctionnalité des variants et le nombre de variants hétérozygotes présents chez un même patient (variants combinés) à la recherche d'un effet cumulatif. La fréquence des variants homozygotes était de 0,8 % (n = 26) et des variants hétérozygotes de 3,3 % (n = 110) dont 1,7 % de variants hétérozygotes avec impact fonctionnel (LEP n = 0/22, LEPR n = 23/40, POMC n = 10/21, PCSK1 n = 23/27). Douze sujets (12 %) étaient porteurs de plusieurs variants hétérozygotes (MC4R inclus). Chez les enfants, aucune différence significative n'a été mise en évidence pour l'âge de début d'obésité et sa sévérité entre les porteurs hétérozygotes et homozygotes. L'IMC moyen des adultes était significativement supérieur pour les porteurs homozygotes comparé à celui des porteurs hétérozygotes (IMC 66 vs 53 kg/m2, p = 0,015). De même, l'âge de début d'obésité était plus précoce (0,4 vs 5,4 ans, p < 0,001), l'impulsivité alimentaire plus fréquente (83 % vs 42 %, p = 0,04) ainsi que les anomalies endocriniennes (75 % vs 26 %, p < 0,01). L'IMC des adultes porteurs hétérozygotes était associé à la fonctionnalité des variants (p = 0,015). En cas de variants hétérozygotes combinés, l'IMC était significativement plus élevé par comparaison aux adultes porteurs simples hétérozygotes (65 vs 49 kg/m2, p < 0,01) et comparable à celui des sujets porteurs homozygotes (65 vs 66 kg/m2, NS). La présence d'un ou plusieurs variants hétérozygotes avec impact fonctionnel sur la voie leptine-mélanocortines est associée à une obésité sévère et précoce avec parfois des anomalies endocriniennes et donc un phénotype proche de celui des sujets porteurs homozygotes. Ces données sont donc en faveur de la recherche systématique de variants sur cette voie clé du contrôle de la prise alimentaire en cas d'obésité précoce et sévère avec ou sans anomalie endocrinienne associée afin de discuter l'indication d'un traitement par agoniste MC4R. [ABSTRACT FROM AUTHOR]

Introduction: Pseudohypoparathyroidism, newly classified as inactivating PTH/PTHrP signaling disorder (iPPSD) type 2 or type 3, is a rare disease caused by defects in the GNAS imprinted gene that encodes Gsα. The most common phenotype comprises resistance to hormones binding to G protein-coupled receptors such as PTH, PTHrP, or TSH, subcutaneous ossifications, short stature, brachydactyly, and early onset obesity. Uncommon features have been described including sleep apnea, asthma, and resistance to calcitonin. At the national French reference center for rare calcium and phosphate metabolism diseases, a large cohort of patients with iPPSD type 2 and type 3 is followed. Interestingly, digestive manifestations and in particular intractable constipation were regularly reported by families of children with iPPSD type 2 or type 3., Objective: The aim of our study was therefore to specify the frequency and characteristics of digestive manifestations in children followed up for iPPSD2 or iPPSD3 in our reference center., Material and Methods: Thirty-six patients aged between 2 and 18 years (32 followed up for iPPSD2 and 4 for iPPSD3) were included. Parents completed a specific questionnaire to assess any digestive disorders in their child. The diagnosis of constipation was established using the Bristol visual scale in the event of a score of less than 2 according to stool appearance., Results: Parents reported constipation through the questionnaires in 22/36 (over 60%) of the children. It was the most frequently reported digestive disorder. Among these 22 children, 19 (87%) had a Bristol score for stool shape and texture between 1 and 2 on a scale of 7, confirming constipation. Dedicated treatment had been initiated for 10 (55%) of them, yet only 3 families (16%) considered this treatment effective. Neonatal vomiting and eating disorders, such as lack of satiety or food selectivity, were also noted in 18 (50%) of patients, as was gastroesophageal reflux present in the neonatal period in 14 (40%) of children. There were no significant differences according to the type of iPPSD or patient age., Conclusion: Our work shows for the first time that digestive manifestations, including constipation, occur frequently in children followed for iPPSD, suggesting a potential role of Gsα and G protein receptors in the digestive tract. It is well known that constipation and digestive symptoms alter quality of life. Early management is therefore essential to improve the quality of life of children followed for iPPSD. Our data need to be confirmed on a larger cohort., (© 2024 S. Karger AG, Basel.)

Background: The determinants of early-onset obesity (< 6 years) are not completely elucidated, however eating behavior has a central role. To date no study has explored eating behavior in children with severe, early-onset obesity. Self-administered questionnaire data from these children were examined to evaluate eating behavior and the etiology of early-onset obesity., Methods: Children with severe, early-onset obesity (body mass index [BMI] > International Obesity Task Force [IOTF] 30) of different etiologies (hypothalamic obesity [HO], intellectual disability with obesity [IDO], common polygenic obesity [CO]) were prospectively included. BMI history and responses from the Dykens' Hyperphagia Questionnaire and an in-house Impulsivity Questionnaire at first visit were compared between groups., Results: This cohort of 75 children (39 girls; mean age ± standard deviation [SD] 10.8 ± 4.4 years) had severe, early-onset obesity at an age of 3.8 ± 2.7 years, with a BMI Z-score of 4.9 ± 1.5. BMI history varied between the 3 groups, with earlier severe obesity in the HO group versus 2 other groups (BMI > IOTF40 at 3.4 ± 1.6 vs. 4.6 ± 1.6 and 8.4 ± 4.1 years for the IDO and CO groups, respectively [P < 0.01]). Absence of adiposity rebound was more prevalent in the HO group (87% vs. 63% and 33% for the IDO and CO groups, respectively [P < 0.01]). The Dykens' mean total score for the cohort was 22.1 ± 7.2 with no significant between-group differences. Hyperphagia (Dykens' score > 19) and impulsivity (score > 7) were found in 50 (67%) and 11 children (15%), respectively, with no difference between the HO, IDO and CO groups regarding the number of patients with hyperphagia (10 [67%], 14 [74%], and 26 [63%] children, respectively) or impulsivity (2 [13%], 1 [7%], and 8 [19%] children, respectively). Children with food impulsivity had significantly higher total and severity scores on the Dykens' Questionnaire versus those without impulsivity., Conclusion: The Dykens' and Impulsivity questionnaires can help diagnose severe hyperphagia with/without food impulsivity in children with early-onset obesity, regardless of disease origin. Their systematic use can allow more targeted management of food access control in clinical practice and monitor the evolution of eating behavior in the case of innovative therapeutic targeting hyperphagia., (© 2024. The Author(s).)

Introduction: In France, approximately 100 obese adolescents undergo a bariatric procedure every year. To date, only data from laparoscopic adjustable gastric banding (LAGB) or sleeve gastrectomy (SG) have been published. Our objective was to report the outcomes of a series of French obese adolescents who underwent a Roux-en-Y gastric bypass (RYGB)., Methods: We included all obese adolescents aged 13-19 years who underwent RYGB in our department from 2008 with at least 2 years of follow-up after surgery. We analyzed the course of the anthropometric data, comorbidities, and subsequent adverse events., Results: Starting in September 2008, out of 93 obese adolescents who requested bariatric surgery, 39 (35%) underwent a bariatric procedure. From these adolescents, 2-year follow-up data were available for 26 patients who had a RYGB. At the time of surgery, the mean patient age was 17.4 years (standard deviation [SD]=1.4) and the body mass index (BMI) was 52.0 kg/m² (SD=7.8). One patient was lost to follow-up. At 2 years after surgery,  the mean BMI was 35.7 kg/m² (SD=9.4) with a mean decrease in BMI of 31.9% (SD=11.6). Comorbidities improved for most of the patients: high blood pressure (2/2) and pseudotumor cerebri (1/1) were cured after surgery, and dyslipidemia improved globally. The complications observed were anemia, abdominal pain requiring celioscopy (n = 2), and oxalic nephrolithiasis., Conclusion: Only one third of the obese adolescents requesting bariatric surgery were operated on. Our series including exclusively obese adolescents who underwent an RYGB presents the results of this technique on weight loss and comorbidities; mechanical and nutritional complications remain uncommon. These results are similar to those obtained in studies of adult patients., Competing Interests: Declaration of Competing Interest The authors certify that they have no conflict of interest to declare., (Copyright © 2023 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Obesity derives from impaired central control of body weight, implying interaction between environment and an individual genetic predisposition. Genetic obesities, including monogenic and syndromic obesities, are rare and complex neuro-endocrine pathologies where the genetic contribution is predominant. Severe and early-onset obesity with eating disorders associated with frequent comorbidities make these diseases challenging. Their current estimated prevalence of 5-10% in severely obese children is probably underestimated due to the limited access to genetic diagnosis. A central alteration of hypothalamic regulation of weight implies that the leptin-melanocortin pathway is responsible for the symptoms. The management of genetic obesity has so far been only based, above all, on lifestyle intervention, especially regarding nutrition and physical activity. New therapeutic options have emerged in the last years for these patients, raising great hope to manage their complex situation and improve quality of life. Implementation of genetic diagnosis in clinical practice is thus of paramount importance to allow individualized care. This review describes the current clinical management of genetic obesity and the evidence on which it is based. Some insights will also be provided into new therapies under evaluation., (©Copyright 2023 by Turkish Society for Pediatric Endocrinology and Diabetes | The Journal of Clinical Research in Pediatric Endocrinology published by Galenos Publishing House.)

The better understanding of the molecular causes of rare genetic obesities and its associated phenotype involving the hypothalamus allows today to consider innovative therapeutics focused on hunger control. Several new pharmacological molecules benefit patients with monogenic or syndromic obesity. They are likely to be among the treatment options for these patients in the coming years, helping clinicians and patients prevent rapid weight progression and eventually limit bariatric surgery procedures, which is less effective in these patients. Their positioning in the management of such patients will be needed to be well defined to develop precision medicine in genetic forms of obesity., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dubern reports a relationship with rhythm Pharmaceuticals, Novo Nordisks that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Objectives: Renal and/or urinary manifestations (RUM) have been reported in pediatric patients with inflammatory bowel disease (IBD) but their incidence is unknown. The aims of this study were to assess the prevalence and causes of these manifestations in children with IBD and determine the causal link with 5-aminosalicylic acid (5-ASA) treatment., Methods: A retrospective observational study was performed with children with diagnosis of IBD. All children with RUM during follow-up and/or impaired renal function [estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m 2 ] were identified., Results: Of 228 included patients, 9 (3.9%) had a RUM during follow-up [follow-up: 5 years (1-12 years)] at a median age of 16 years (8-17 years). It concerned 7 of 171 patients with Crohn disease and 2 of 57 with ulcerative colitis. Seven patients were taking 5-ASA at the time of the RUM. Only 1 of them had an iatrogenic renal complication related to this treatment. Patients with RUM had a more severe disease with increased anti-tumor necrosis factor-α use ( P = 0.031), more abscesses ( P = 0.003), and a higher rate of digestive surgery ( P = 0.04). For the whole cohort, a significant decrease in eGFR was found during follow-up (121 vs 107 mL/min/1.73 m 2 , P < 0.001). At the end of follow-up, 38 of 202 (19%) patients had an eGFR < 90 mL/min/1.73 m 2 ., Conclusion: In children with IBD, RUM can occur, independently of treatment with 5-ASA. During follow-up, a significant decrease in eGFR was observed. We suggest monitoring renal function in all patients with IBD., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

In 2019, the French National Authority for Health (Haute Autorité de Santé, HAS) published guidelines on the diagnosis of undernutrition. The present article focuses on the impact of switching from the 2012 guidelines of the Nutrition Committee of the French Paediatric Society (CNSFP) to the HAS guidelines on the frequency of hospital undernutrition in children. We selected for the period 2010-2019 from the ePINUT database: (1) all children aged more than 2 years with (2) clinically confirmed nutritional status in (3) French sites. The frequency of undernutrition was 15.4% vs. 28.8% using the CNSFP and HAS criteria, respectively (p < 0.01; n = 6304). When compared to non-malnourished children regardless of the criteria used, malnourished children: (1) stayed longer in hospital (CNSFP: 9.0 ± 11.8 vs. 6.5 ± 8.7 days, p < 0.01; HAS: 7.8 ± 10.1 vs. 6.4 ± 8.4 days, p < 0.01), (2) gained more weight during hospitalization (% of weight at admission) (CNSFP: +1.4 ± 4.1 vs. -0.3 ± 3.5%, p < 0.01; HAS: +2.3 ± 4.7 vs. -0.1 ± 3.4%, p < 0.01), and (3) received nutritional support more frequently during hospitalization (CNSFP: 20% vs. 5%, p < 0.01; HAS: 13% vs. 4%, p < 0.01). Switching to the HAS guidelines resulted in an almost twofold higher frequency of undernutrition in hospitalized children. Initiation of nutritional care remained low considering the nutritional status. The present study warrants interventional studies to determine which children may benefit more from nutritional therapy to improve their outcome., (Copyright © 2022 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Although central venous catheter (CVC)-related thrombosis (CRT) is a severe complication of home parenteral nutrition (HPN), the amount and quality of data in the diagnosis and management of CRT remain low. We aimed to describe current practices regarding CVC management in French adult and pediatric HPN centers, with a focus on CVC obstruction and CRT. Current practices regarding CVC management in patients on HPN were collected by an online-based cross-sectional survey sent to expert physicians of French HPN centers. We compared these practices to published guidelines and searched for differences between pediatric and adult HPN centers' practices. Finally, we examined the heterogeneity of practices in both pediatric and adult HPN centers. The survey was completed by 34 centers, including 21 pediatric and 13 adult centers. We found a considerable heterogeneity, especially in the responses of pediatric centers. On some points, the centers' responses differed from the current guidelines. We also found significant differences between practices in adult and pediatric centers. We conclude that the management of CVC and CRT in patients on HPN is a serious and complex situation for which there is significant heterogeneity between HPN centers. These findings highlight the need for more well-designed clinical trials in this field.

Rare genetic forms of obesity are linked to impaired energy balance (i.e., eating behaviour and energy expenditure) involving hypothalamic pathways. More than 60 genes coding for proteins located in the hypothalamic leptin/melanocortin pathway contribute to the development of these rare forms of obesity. The ambition of the French National Protocol for the Diagnosis and Care (PNDS) of Obesity of Rare Causes was to establish practical recommendations for assessment and management at all ages. This report is available on the website of the French Health Authority (HAS). In addition to severe obesity, patients often display obesity-related comorbidities and neuropsychological/psychiatric disorders. These complex conditions make clinical management particularly challenging. Early diagnosis is critical for the organization of coordinated specialized multidisciplinary care, with mandatory interaction between caregivers, social partners and families. Strategies to prevent aggravation of obesity consist in limiting access to food, establishing a reassuring daily eating environment, and the practice of sustained adapted supervised daily physical activity. The implementation of genetic diagnosis in clinical practice now enables a personalized medicine approach with access to new drug therapies, and improves the analysis of the risk/benefit ratio of bariatric surgery., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background: In severe obesity, left ventricular (LV) and right ventricular (RV) remodeling and contractile dysfunction have been documented, but less is known regarding left atrial (LA) dysfunction and its association with LV/RV remodeling, especially in children., Purpose: To assess the effects of severe childhood obesity on cardiac function by using multichamber strain analysis with MRI., Study Type: Prospective., Subjects: Forty-five children aged 7-18 years (including 20 with severe obesity, defined as a body mass index values above the 99th percentile)., Field Strength: 5 T., Sequence: Steady-state-free-precession (SSFP) images in short-axis views and longitudinal two- and four-chamber views., Assessment: Cardiac strain measurements were derived from standard SSFP cine images by using a dedicated MR imaging feature tracking software. Inter- and intra-rater reliability were evaluated., Statistical Tests: Independent sample t test, Spearman's correlation coefficient, principal component analysis, Bland-Altman analysis, and intra-class correlation coefficients (ICC). A P value <0.05 was considered statistically significant., Results: As compared to children without obesity, those with obesity showed significantly reduced LA reservoir function (22.2% ± 6.4% vs. 33.8% ± 9.0%) and contractile function (5.4% ± 3.2% vs. 13.3% ± 8.0%) as well as significantly decreased absolute values for LA longitudinal strain in reservoir and contraction phases and LA radial motion fraction in reservoir and contraction phases. Children with severe obesity showed significantly reduced absolute RV radial motion fraction (-10.6% ± 2.9% vs. -18.2% ± 2.9%) and circumferential strain (-10.6% ± 2.9% vs. -16% ± 2.5%) as well as higher LV mass index (28.7% ± 5.1% vs. 21.7 ± 4.6 g/m 2 ) along with significantly reduced LV ejection fraction (56.4% ± 3.9% vs. 60% ± 4.1%), LV radial strain (56% ± 6% vs. 61.8% ± 11.3%), and longitudinal strain (-17.8% ± 1.8% vs. -20.3% ± 3.2%). Reliability was good to excellent, with ICC ranging from 79.1% to 97.7%., Data Conclusion: MR feature-tracking strain analysis revealed multichamber dysfunction in severely obese children with impaired LA reservoir and atrial contraction phases, which suggest an early loss in the compensatory ability of atrial contraction with severe obesity., Level of Evidence: 2 TECHNICAL EFFICACY STAGE: 3., (© 2021 International Society for Magnetic Resonance in Medicine.)

Background and Aims: Home Parenteral Nutrition (HPN) is the cornerstone management for children suffering from chronic intestinal failure (CIF). In France, HPN is organized from a network of 7 certified centers located in University Hospitals spread across the national territory. This study aims to review the data involving children on HPN over a 6-years period in France to outline the global and continuous improvement in care., Patients and Methods: This cross-sectional study included all children enrolled in any of the 7 French HPN certified centers from January 1st, 2014 to December 31st, 2019. Data was recorded from annual databases provided by each center regarding: age at inclusion, indication and duration of HPN, type of intravenous lipid emulsion (ILE), outcome [PN weaning off, transfer to adult center, death, intestinal transplantation (ITx)], rate of catheter-related bloodstream infections (CRSBIs) for 1000 days of HPN, Taurolidine lock procedure (TLP) use and prevalence of cholestasis defined as conjugated bilirubin ≥20 μmol/l., Results: The number of patients increased by 43.6% from 268 in 2014 to 385 in 2019. According to the year of follow up, the indications for HPN were short bowel syndrome (SBS) (42.3-46.6%), congenital enteropathies (CE) (18.5-22.8%), chronic intestinal pseudo-obstruction syndrome (CIPOS) (13.0-16.3%), long segment Hirschsprung's disease (LSHD) (9.7-13.3%), Crohn's disease (CD) (1.6-2.6%) and other non-primary digestive diseases (NPDD) such as immune deficiency, cancer or metabolic disease (4.0-9.2%). The median age at discharge on HPN decreased from 11.7 months in 2014 to 8.3 months in 2019 (p < .001). By December 31st, 2019, 44.8% of children had left the HPN program after a median duration ranging between 39.9 and 66.4 months. Among these patients, 192 (74.2%) were weaned off PN (94.7% SBS), 41 (15.8%) were transferred to adult centers for CIPOS (42%), SBS (31%) or CE (27%), 21 died (8.1%) - mostly in relation to cancer or immune deficiency - and 5 were transplanted (1.9%): 4 underwent combined liver-intestine transplantation for LSHD (n = 2), SBS, CE and one multivisceral Tx for CIPOS. The use of a composite fish-oil based ILE increased from 67.4% in 2014 to 88.3% in 2019 (p < 0.001). CRBSIs dropped from 1.04 CRSBIs per 1000 days HPN in 2014 to 0.61 in 2019 (p < 0.001) while meantime, the percentage of children receiving TLP increased from 29.4% to 63.0% (p < 0.001). The prevalence of cholestasis (conjugated bilirubin ≥ 20 μmol/l) was low and stable between 4.1 and 5.9% of children during the study period., Conclusion: In France, the number of children enrolled in a HPN program continuously increased over a 6 years period. SBS is the leading cause of CIF requiring HPN. The rate of CRBSIs dropped dramatically as the use of TLP increased. Mortality rate was low and mainly in relation to the underlying disease (cancer, immune deficiency). Cholestasis and intestinal Tx remained very rare., Competing Interests: Conflict of interest The authors have no conflict of interest to declare., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Context: Unlike homozygous variants, the implication of heterozygous variants on the leptin-melanocortin pathway in severe obesity has not been established., Objective: To describe the frequency, the phenotype, and the genotype-phenotype relationship for heterozygous variants in LEP, LEPR, POMC, and PCSK1 in severe obesity., Methods: In this retrospective study, genotyping was performed on at least 1 of the LEP, LEPR, POMC, and PCSK1 genes in 1486 probands with severe obesity (600 children, 886 adults). The phenotype was collected in 60 subjects with heterozygous variants and 16 with homozygous variants. We analyzed variant frequency, body mass index (BMI), age of obesity onset, food impulsivity, and endocrine abnormalities., Results: The frequency of subjects with homozygous variants was 1.7% (n = 26), and 6.7% (n = 100) with heterozygous variants. Adults with homozygous variants had a higher BMI (66 vs 53 kg/m2, P = .015), an earlier onset of obesity (0.4 vs 5.4 years, P < .001), more often food impulsivity (83% vs 42%, P = .04), and endocrine abnormalities (75% vs 26%, P < .01). The BMI was higher for subjects with high-impact heterozygous variants (61 vs 50 kg/m², P = .045) and those with a second heterozygous variant on the pathway (65 vs 49 kg/m², P < .01). In children, no significant differences were found for the age of obesity onset and BMI., Conclusion: Heterozygous variants in LEP, LEPR, POMC, and PCSK1 are frequent in severe obesity and sometimes associated with a phenotype close to that of homozygotes. These data suggest a systematic search for variants in severe early-onset obesity, to discuss therapy that targets this key pathway., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)