Selective Immunoglobulin M deficiency (SIgMD) has been recently included in the inborn errors of immunity (IEI) classification by the International Union of Immunological Societies Expert Committee. The understanding of SIgMD is still extremely limited, especially so in cases of SIgMD in the pediatric population. The epidemiology of SIgMD in the pediatric population is still unknown. The pathogenesis of SIgMD remains elusive, and thus far no genetic nor molecular basis has been clearly established as a definitive cause of this primary immunodeficiency. Recurrent respiratory infections represent the main clinical manifestations in children, followed by allergic and autoimmune diseases. No conclusive data on the correct therapeutic management of SIgMD are available. Although, for most SIgMD patients, Ig replacement therapy is not required, it may be recommended for patients with significantly associated antibody deficiency and recurrent or severe infections. Prophylactic antibiotics and the prompt treatment of febrile illness are crucial. There is insufficient evidence on the prognosis of this condition. Therefore, further studies are required to define the disease trajectories and to increase our understanding of the molecular mechanisms underlying SIgMD in order to facilitate a better clinical, immunological, and prognostic characterization of the condition and develop tailored therapeutic management strategies.

Background: Primary Atopic Disorders (PAD) represent a recently recognized subset of inborn errors of immunity (IEI), characterized by severe atopy driven by genetic mutations leading to dysregulated type 2 immune responses, excessive mast cell activation, and hyper production of IgE. In PAD patients, severe atopic manifestations, including eczema, asthma, food allergies, and eosinophilic gastrointestinal disorders, are often associated with other signs of immune dysfunction. Methods: Recognizing the need for standardized diagnostic and management guidelines for PAD, a Delphi‐based expert consensus was developed within the Immunology Committee of the Italian Society of Pediatric Allergy and Immunology (SIAIP). After a systematic review of the literature and the development of the clinical statements, 45 specialists from multiple pediatric subspecialties reached an agreement on key aspects of PAD classification, diagnosis, and treatment. Results: The consensus focuses on some red flags that could aid clinicians in suspecting PAD. The document also proposes a diagnostic work‐up to differentiate monogenic PAD from polygenic allergic conditions. It also emphasizes the importance of molecular pathway analysis to direct precision treatments, including biological drugs. Given the complexity of the field and the potential overlap between PAD and other IEI, the consensus recommends a multidisciplinary approach to diagnosis and treatment. The document establishes a framework for early recognition of PAD, integrating emerging genetic insights into clinical practice and promoting personalized therapeutic strategies. Conclusions: The present work is the first structured consensus to standardize PAD diagnosis and management among pediatric subspecialists, aiming to improve patient outcomes through early intervention and tailored therapies.

Background: Inborn errors of immunity (IEI) are mainly genetically driven disorders that affect immune function and present with highly heterogeneous clinical manifestations, ranging from severe combined immunodeficiency (SCID) to adult-onset immune dysregulatory diseases. This clinical heterogeneity, coupled with limited awareness and the absence of a universal diagnostic test, makes early and accurate diagnosis challenging. Although genetic testing methods such as whole-exome and genome sequencing have improved detection, they are often expensive, complex, and require functional validation. Recently, artificial intelligence (AI) tools have emerged as promising for enhancing diagnostic accuracy and clinical decision-making for IEI. Methods: We conducted a systematic review of four major databases (PubMed, Scopus, Web of Science, and Embase) to identify peer-reviewed English-published studies focusing on the application of AI techniques in the diagnosis and treatment of IEI across pediatric and adult populations. Twenty-three retrospective/prospective studies and clinical trials were included. Results: AI methodologies demonstrated high diagnostic accuracy, improved detection of pathogenic mutations, and enhanced prediction of clinical outcomes. AI tools effectively integrated and analyzed electronic health records (EHRs), clinical, immunological, and genetic data, thereby accelerating the diagnostic process and supporting personalized treatment strategies. Conclusions: AI technologies show significant promise in the early detection and management of IEI by reducing diagnostic delays and healthcare costs. While offering substantial benefits, limitations such as data bias and methodological inconsistencies among studies must be addressed to ensure broader clinical applicability.

Since October 2022, alerts have spread from several countries about the increase in invasive group A streptococcal (iGAS) and scarlet fever cases affecting young children. We aim to analyze the epidemiology of GAS infections in the last 12 years in our hospital and identify the clinical features of invasive cases observed in 2023. We conducted a retrospective study enrolling children and adolescents hospitalized at our pediatric clinic from January to December 2023 for a definitive diagnosis of iGAS infection. Clinical, laboratory, and imaging data were collected and analyzed. Comparing 2016 and 2023, we observed a similar number of GAS infections (65 vs. 60 cases). Five children with iGAS infection were hospitalized between March and April 2023. The median age was five years. At admission, all patients showed tachycardia disproportionate to their body temperature. Vomiting was a recurrent symptom (80%). Laboratory tests mostly showed lymphopenia, hyponatremia, and high inflammatory markers. The number of pediatric iGAS cases significantly increased in 2023. Clinical (pre-school-aged children with high fever, unexplained tachycardia, and vomiting) and laboratory parameters (high procalcitonin levels, hyponatremia, and lymphopenia) could help identify and suspect a potential iGAS infection.

Background: A few studies assessed the clinical and immunological features of selective IgM deficiency (SIgMD), especially in the pediatric age. We aimed to characterize the clinical and immunological phenotypes of a cohort of pediatric patients with SIgMD according to the different diagnostic criteria available.Methods: In this multicenter study, we evaluated pediatric SIgMD patients diagnosed at the Pediatric Clinic in Pavia, Italy, or through the Italian Primary Immunodeficiency NETwork (IPINET) and monitored changes in their diagnosis over a time frame that ranges from several months to several years.Results: Forty‐eight patients with SIgMD were included (mean serum IgM: 33 mg/dL). The most common clinical manifestations were recurrent infections (67%) and allergies (48%). Subgroup analysis according to SIgMD definition criteria of the European Society for Immunodeficiencies (ESID) showed no significant difference in clinical manifestations, also considering the group with additional immunological abnormalities. Sixteen patients had long‐term follow‐up, during which 87% preserved their SIgMD diagnosis, while two patients showed a reduction in IgA in addition to low IgM.Conclusions: Our data suggest that the identification of a reduction in serum IgM in children should lead to a complete immunological work‐up to obtain a comprehensive clinical and immunological characterization of the patient. The follow‐up of these patients is fundamental to define the disease evolution and appropriate management.

Inborn errors of immunity with atopic phenotypes (IEIwA) represent a growing and complex subset of monogenic disorders that manifest primarily through severe and multifaceted allergic symptoms. These conditions bridge the fields of immunodeficiency and atopy, posing significant diagnostic and therapeutic challenges. A literature search was performed via the online database PubMed, including all publication years 2021-2024, with the objective of identifying the most recent advancements in the field of IEIwA. This review provides an updated synthesis of the immunogenetic mechanisms underlying IEIwA, categorizing them by pathophysiological pathways, including impaired T cell receptor signaling, cytokine dysregulation, T cell repertoire restrictions, regulatory T cell dysfunction, metabolic abnormalities, and skin barrier defects. Advances in genomic technologies, especially whole exome/genome sequencing, have refined the classification and recognition of these disorders. Moreover, the review highlights red flags that may aid in differentiating monogenic IEIwA from multifactorial allergic conditions. Emerging targeted therapies, such as monoclonal antibodies and small molecules, offer new avenues for precision medicine, though curative treatments like hematopoietic stem cell transplantation remain essential for many conditions. This review underscores the need for heightened awareness, early recognition, and tailored management strategies to improve outcomes in patients with IEIwA.