Béatrice Dubern

This international Consensus Statement updates 2016 guidelines for diagnosis and management of individuals with Silver–Russell syndrome (SRS), using a Delphi-like process to reach agreement through iterative expert discussions, based on published data and/or expert opinion. Individuals referred with suspected SRS show substantial clinical and genetic heterogeneity. Advances in genomic and epigenomic technology highlight the need for strict, primarily molecular, criteria for diagnosis, which should be made in those with maternal uniparental disomy for chromosome 7 (upd(7)mat) or 11p15 loss of methylation at H19/IGF2:intergenic differentially methylated region (IG-DMR) (due to an imprinting change, copy number variant or upd(11)mat). Molecular stratification enables tailoring of care pathways towards specific genetic and/or epigenetic subgroups. More widely, recommendations are relevant to other growth-related imprinting disorders (including Temple syndrome) and conditions affecting the insulin-like growth factor 2 pathway. An expert, multidisciplinary approach is required, focusing on growth failure, early severe feeding difficulties, later possible rapid weight gain, abnormal body composition, gastrointestinal problems, hypoglycaemia, insulin resistance, accelerated puberty, body asymmetry, neurocognitive issues and psychosocial challenges. Evidence published since the first Consensus Statement highlights the increased risk of metabolic disease from adolescence into adulthood. These updated recommendations have important implications for accurate diagnosis and optimal life-long management of individuals with SRS.

Mutations that enhance type I interferon (IFN-I) activity cause monogenic autoinflammatory disorders termed type I interferonopathies. Along with the typical neurologic and rheumatologic manifestations, severe pulmonary disease is increasingly recognized yet poorly understood. We studied three siblings presenting with early-onset, life-threatening pulmonary alveolar proteinosis (PAP) and autoinflammatory stigmata. Genetic analysis uncovered a novel homozygous variant (R223Q) in STAT2, a key mediator of IFN-I signaling, which also facilitates feedback inhibition via USP18. R223Q STAT2 preserved signal transduction and viral control in vitro. However, cells homozygous for the R223Q variant failed to terminate IFN-I responses, owing to impaired localization of USP18. Unlike in classical forms of PAP, GM-CSF signaling remained intact. Instead, persistent IFN-I signaling antagonized monocyte migration toward chemokines essential for lung trafficking. Informed by these findings, the youngest sibling received JAK inhibitor and anti-IFN-I receptor therapy with marked clinical improvement. Collectively, type I interferonopathy by mutation of STAT2 (TIMS2) compromises monocyte chemotaxis and underlies a novel mechanism of PAP.

Background: Metabolic-bariatric surgery is an efficient therapy in selected adolescents with severe obesity. However, predicting the postoperative weight loss is challenging. A machine learning calculator predicting 5-year weight loss trajectory has been developed in adults, based on seven preoperative features. The aim of the present study was to adapt and test it in adolescents. Methods: Retrospective cohort study in patients aged 12–20 years undergoing Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), or adjustable gastric band (AGB) in France and Sweden between 2001 and 2022. Primary outcome was the accuracy of 5-year BMI prediction, expressed as the median absolute deviation (MAD) between predicted and observed BMI. The model developed in adults, was trained in a subset of 80% of randomly selected adolescents, and secondly tested in the remaining 20%. Results: We enrolled a total of 2255 patients (1705 female [75.6%], 12–20 years [median 19]). Five-year follow-up data were available for 59% of French and 38% of Swedish patients. The median (IQR) 5-year total weight loss was 30.2% (23.9–38.6) for RYGB, 23.4% (13.7–32.8) for SG, and 13.4% (0.0–30.1) for AGB. The adapted model predicted the observed 5-year BMI with a MAD of 3.7 kg/m² (95% CI [3.3–3.9]). The accuracy of the model was maximal for bypass (3.2 kg/m² [3.0–3.7]), good for SG (3.9 kg/m² [3.1–5.0]), and lower for AGB (7.3 kg/m² [5.5–8.4]), and accuracy decreased with time and in adolescents under 19 years. Age, height, weight, and type of intervention influenced 5-year weight loss. Type 2 diabetes influenced weight loss until 2 years after surgery, but not later. Conclusion: The model had an acceptable accuracy for adolescents to predict 5-year postoperative weight loss trajectory. Accuracy decreased over time and was influenced by type of intervention and age. This calculator is available online: https://bariatric-weight-trajectory-prediction.univ-lille.fr/ .

Introduction: Silver-Russell syndrome (SRS) is a rare imprinting disorder characterized by growth retardation, early puberty, and poor pubertal growth, leading to short stature. We aimed to assess the outcome in terms of adult height (AH) and tolerance of combined treatment with recombinant human growth hormone (rhGH) and a gonadotropin-releasing hormone analogue (GnRHa) for children with SRS followed in a reference centre for rare disorders in France. Methods: This was a retrospective observational study that included children with molecularly confirmed SRS, aged 14 years and over, and who received rhGH and GnRHa. We collected data on birth parameters, height and weight at the start of rhGH and at the start and end of GnRHa, bone age, and AH, if reached. Results: Thirty-nine children (17 girls and 22 boys) were analysed. The median age at the start of rhGH was 3.9 years (2.8–5.0) and that at the start of GnRHa was 10.0 years (9.3–11.0). AH was reached for 30 patients (76.9%), with a median AH standard deviation score (SDS) of −1.8 (−2.4 to −1.1). There was no difference in AH between girls −2.1 SDS (−2.4 to −1.5) and boys −1.4 SDS (−1.9 to −1.2). Median pubertal height gain was 26.0 cm (23.0–29.0) for girls and 30.0 cm (28.0–34.0) for boys. Tolerance was good, and there were few drug-related adverse effects. Conclusion: Combined treatment with rhGH and GnRHa for children with SRS resulted in AH within standard references for more than half of our cohort and appears to be safe in this population.

ObsGEN is a free, web-based clinical decision support tool developed to facilitate the identification of rare genetic forms of obesity, including monogenic and syndromic etiologies. Implemented on the REDCap platform, it guides clinicians through a structured 10-15-minute questionnaire covering key phenotypic domains: age of onset, weight trajectory, hyperphagia, neurodevelopmental features, and signs of hypothalamic dysfunction. Based on the inputted data, ObsGEN provides automated, phenotype-driven diagnostic hypotheses, genetic testing recommendations, and direct access to national expert centers. The tool aims to support early recognition of rare obesity syndromes, enabling timely referral, access to targeted therapies, and personalized care strategies. Since its implementation in 2019, ObsGEN has been used by over 1150 clinicians in France, incorporated into national clinical workflows, and contributed to the development of the French National Diagnosis and Care Protocol for rare obesities. By operationalizing a precision medicine approach, ObsGEN enhances diagnostic accuracy and promotes equitable access to expert evaluation in both pediatric and adult obesity care. More info: http://obsgen.nutriomics.org

Objective: Pathogenic variants in five established leptin‐melanocortin pathway genes ( LEP, LEPR, MC4R, PCSK1 , POMC ) are associated with severe early‐onset obesity and are targets for emerging treatments. However, these variants are rare in these patients, suggesting the involvement of additional genes interacting with this pathway. Methods: Next‐generation sequencing (NGS) analysis was performed in 395 patients with severe obesity, including 213 children (mean BMI: 56.3 kg/m ² ; BMI‐ z ‐score: 4.6). The analysis targeted 20 genes, including the 5 established genes. Rare genetic variants were assessed for pathogenicity using prediction algorithms, genetic databases, and literature review. Phenotypic data were retrospectively collected, focusing on obesity severity, age of onset, familial history, eating behavior disorder, neurodevelopmental and endocrine‐associated diseases, and obesity complications. Results: Pathogenic heterozygous variants were identified in 34 patients (8.6%), 18 of them harboring pathogenic variants in the 15 additional genes. In adults, early‐onset obesity was more frequent in potentially pathogenic variants carriers than in non‐carriers (83.3% vs. 55.0%, p = 0.04). No differences were observed in the other phenotypic characteristics. Conclusions: This supports the relevance of expanded genetic testing in severe obesity. Early‐onset obesity remains a key clinical feature to guide genetic investigation and identify patients who may benefit from early personalized care and targeted treatments.

Introduction: Genetic forms of obesity, including monogenic (MO) and syndromic (SO) obesity, are characterised by severe, early-onset weight gain due to disrupted central regulation of body weight, typically involving key pathways such as the leptin-melanocortin axis. These alterations result in marked hyperphagia and complex eating behaviours, yet clinical characterisation remains limited. This review aimed to describe the multidimensional eating behaviour profiles across genetically confirmed obesity, explore their variability, and evaluate existing assessment tools to support early diagnosis, personalised care, and therapeutic monitoring. Methods: We conducted a systematic review following PRISMA guidelines including publications up to 4 September 2025. A total of 162 studies involving individuals with genetically confirmed SO or MO were analysed. Eating behaviours were categorised into nine dimensions: food-centred thinking, food-seeking/stealing, hunger/satiety, ingestive/oral behaviours, nutritional quality, food preferences, food acceptability, loss of control eating, and eating restraint. Assessment tools and methodologies were systematically reviewed. Results: Hyperphagia was consistently reported across genetic aetiologies, though definitions and measures remain heterogeneous. Prader-Willi syndrome (PWS), the most studied condition, was associated with early-onset hyperphagia, increased hunger, pronounced food preoccupation, compulsive food-seeking/stealing and strong preferences for carbohydrate-rich, large quantities and unusual food items. Similar behavioural traits were found in other SO and MO, including Bardet-Biedl syndrome, Alström syndrome, Fragile X syndrome, WAGR syndrome, pseudohypoparathyroidism Ia, 16p11.2 deletion and LEPR, POMC, and MC4R deficiencies. Behavioural traits appeared relatively consistent across sex, age, and genotypes within syndromes. Most studies relied on caregiver reports; existing tools such as the Hyperphagia Questionnaire (HQ) and Food-Related Problem Questionnaire (FRPQ), developed primarily for PWS, did not fully capture the behavioural spectrum or suit all cognitive profiles. Tools applicable to individuals without intellectual developmental disorders, particularly adults living independently, remain scarce. Conclusion: This is the first systematic review to comprehensively map eating behaviours across rare genetic obesity using a multidimensional approach. It highlights the shared feature of disrupted appetite regulation and emphasises the need for standardised, multidimensional tools suitable for both clinical and research contexts. Better behavioural characterisation will support targeted therapies and improve outcome monitoring in these high-need populations.

Context: Silver-Russell syndrome (SRS) is an imprinting disorder characterized by severe intrauterine and postnatal growth retardation, feeding difficulties, and risk of hypoglycemia. Recombinant growth hormone (rGH) therapy has shown its positive effect on adult height in SRS. Objective: We aimed to assess the short-term effects of rGH therapy on the growth and nutritional status of these children. Methods: Retrospective monocentric data of growth and nutritional characteristics of 77 prepubertal children with molecularly proven SRS during the first 2 years of rGH therapy were analyzed. Results: The mean age at the initiation of rGH therapy was 3.7 (1.4-10.3) years. The mean height gain was 0.8 standard deviation score (SDS) after 1 year of treatment and 1.3 SDS after 2 years. The ideal weight for height (WfH), reflecting the nutritional status, increased from a mean of 81% at rGH initiation, to 84% after 1 year of treatment (P < .001) and 86% after 2 years (P < .001). The proportion of SRS children below a WfH of 75% decreased from 22.1% at rGH therapy initiation to 7.8% after 2 years of treatment. Starting rGH therapy before the age of 4 years was associated with a greater increase in height after 2 years, 1.5 vs 1.1 SDS, P = .012. Conclusion: In prepubertal SRS children, the first 2 years of standard-dose rGH therapy significantly enhance both height and nutritional status. Early initiation of treatment, before the age of 4 years, further optimizes height gain.