Inborn Errors of Immunity in Pediatric Hematology and Oncology: Diagnostic Principles for Clinical Practice

Immune dysregulation is being increasingly recognized as a leading sign of a wide spectrum of inborn errors of immunity (IEIs). Therefore, patients with IEIs are frequently managed in non-immunological settings, including hematology and oncology units, during the diagnostic process or follow-up. The most relevant hematological signs associated with IEIs comprise autoimmune cytopenia (AIC), lymphoproliferative diseases (LPD), malignancies, hemophagocytic lymphohystiocitosis (HLH), bone marrow failure (BMF), myelodysplastic syndromes (MDS), and peripheral or tissue eosinophilia. The prognosis of patients with IEIs can significantly improve when a molecular diagnosis is established, as it can allow the use of targeted treatments, guide appropriate follow-up strategies and, in some cases, support the rationale for hematopoietic stem cell transplantation or gene therapy. Therefore, there is an urgent need to recognize the warning signs suggestive for an underlying IEI among patients presenting with common hematological features and to ensure an appropriate diagnostic approach. As a general rule, clinicians should always provide a clinical alert in the presence of two or more IEI-associated hematological signs, as well as a positive familial history for IEI or hematologic immune dysregulation, a personal history of severe infections, and other signs of immune dysregulation. Concerning AIC, an increased likelihood of IEI is characteristic of patients with treatment refractoriness, autoimmune hemolytic anemia, or multilineage cytopenia. In the case of LPD, the main elements of suspicion are represented by the chronic or recurrent disease course, the persistence of Epstein-Barr Virus (EBV) infection, and the development of lymphoproliferation in atypical localizations. Among patients with malignancy, clinicians should investigate for IEI those with rare neoplasia, virus-associated tumors, and an association with syndromic features, while patients with HLH should always receive an immunological assessment when a clear rheumatologic trigger, underlying malignancy, or well-recognized cause is not evident. The case of MDS and BMF is complex, as new monogenic entities are continuously being described. However, it is pivotal to consider the presence of monocytopenia, warts, vasculitis, and neurological disease, as well as specific cytogenetic abnormalities, such as chromosome 7 monosomy, as warning sings for IEIs. Finally, the main red flags for IEIs in patients with eosinophilia are skeletal/facial abnormalities, recurrent abscesses, refractory eczema, organomegaly, or thrombocytopenia.