Sequencing of candidate genes for obesity in Labrador retriever dogs identified a 14 bp deletion in pro-opiomelanocortin (POMC) with an allele frequency of 12%. The deletion disrupts the β-MSH and β-endorphin coding sequences and is associated with body weight (per allele effect of 0.33 SD), adiposity, and greater food motivation. Among other dog breeds, the deletion was only found in the closely related flat-coat retriever (FCR), where it is similarly associated with body weight and food motivation. The mutation is significantly more common in Labrador retrievers selected to become assistance dogs than pets. In conclusion, the deletion in POMC is a significant modifier of weight and appetite in Labrador retrievers and FCRs and may influence other behavioral traits.

Key Points: Trisomy 12 CLL cells exhibit upregulated integrin signaling and enhanced VLA-4-directed adhesion and motility. The increased expression of β2-integrins on trisomy 12 CLL cells is modulated by intercurrent NOTCH1 mutations.

Chronic granulomatous disease (CGD) is a group of rare primary inborn errors of immunity characterised by a defect in the phagocyte respiratory burst, which leads to severe and life-threatening infective and inflammatory complications. Despite recent advances in our understanding of the genetic and molecular pathophysiology of X-linked and autosomal recessive CGD, and growth in the availability of functional and genetic testing, there remain significant barriers to early and accurate diagnosis. In the current review, we provide an up-to-date summary of CGD pathophysiology, underpinning current methods of diagnostic testing for CGD and closely related disorders. We present an overview of the benefits of early diagnosis and when to suspect and test for CGD. We discuss current and historical methods for functional testing of NADPH oxidase activity, as well as assays for measuring protein expression of NADPH oxidase subunits. Lastly, we focus on genetic and genomic methods employed to diagnose CGD, including gene-targeted panels, comprehensive genomic testing and ancillary methods. Throughout, we highlight general limitations of testing, and caveats specific to interpretation of results in the context of CGD and related disorders, and provide an outlook for newborn screening and the future.

Chronic granulomatous disease (CGD) is a group of rare primary inborn errors of immunity characterised by a defect in the phagocyte respiratory burst, which leads to severe and life-threatening infective and inflammatory complications. Despite recent advances in our understanding of the genetic and molecular pathophysiology of X-linked and autosomal recessive CGD, and growth in the availability of functional and genetic testing, there remain significant barriers to early and accurate diagnosis. In the current review, we provide an up-to-date summary of CGD pathophysiology, which underpins methods of diagnostic testing for CGD and closely related disorders. We present an overview of the benefits of early diagnosis and when to suspect and test for CGD. We discuss current and historical methods for functional testing of NADPH oxidase activity, as well as assays for measuring protein expression of NADPH oxidase subunits. Lastly, we focus on genetic and genomic methods employed to diagnose CGD, including gene-targeted panels, comprehensive genomic testing and ancillary methods. Throughout, we highlight general limitations of testing, and caveats specific to interpretation of results in the context of CGD and related disorders, and provide an outlook for newborn screening and the future.

Host inflammatory responses contribute substantially to infection-related morbidity, and in severe cases such as sepsis, acute respiratory distress syndrome (ARDS) and haemophagocytic lymphohistiocytosis, immune-mediated tissue injury may exceed the direct effects of pathogens themselves. Although traditional wisdom has considered immunosuppression risky when antimicrobial therapy is required, modern insights into immune biology reveal a more nuanced landscape in which targeted immunomodulators can attenuate harmful inflammation without broadly compromising host defence. This evolution is particularly relevant in paediatrics, influenced by developmental stage, distinct exposure history and patterns of host response. The COVID-19 pandemic catalysed wider acceptance of immunomodulation in infection management, including corticosteroids in children and highlighted safe use of agents such as baricitinib. Platform trials of the hyperinflammatory syndrome (paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2) also identified benefits of methylprednisolone and tocilizumab in select groups. For other paediatric infections, including dengue, influenza and Epstein-Barr virus, the evidence remains sparse, with emerging mechanistic and early-phase clinical studies exploring interleukin (IL)-1 blockade, corticosteroids, immunoglobulin and anticytokine biologics. In paediatric sepsis, immunophenotype-guided trials represent a major conceptual advance. Adaptive studies, such as TRIPS and GRACE-2, aim to tailor immunomodulation to hyperinflammation or immunoparalysis, though definitive efficacy data are awaited. Parallel efforts in ARDS explore statins, IL-6 blockade and cell-based therapies, but robust paediatric evidence is still lacking. Collectively, evolving insights and trial designs offer renewed opportunities to use targeted immunomodulation in the management of paediatric infection. Large-scale, collaborative paediatric research networks will be essential to translate these advances and better integrate infection research into everyday paediatric practice.