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

Abstract

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.

Keywords: autoimmune cytopenia; autoimmune hemolytic anemia; autoimmune lymphoproliferative immunodeficiencies (ALPID); autoimmune neutropenia; eosinophilia; immune thrombocytopenia; lymphoma; malignancy; myelodysplastic syndromes; polyclonal lymphoproliferation.

Figure 1

Overlaps between inherited bone marrow failure syndromes, inborn errors of immunity, and diseases with germline predisposition to myelodysplastic syndromes and acute myeloid leukemia. Abbreviations: IEIs = inborn errors of immunity; IBMFs = inherited bone marrow failure syndromes; MDS = myelodysplastic syndromes; AML = acute myeloid leukemia.

Figure 2

Clinical overlaps between IEIS presenting with hematological features. Abbreviations: 22q11.2DS = 22q11.2 deletion syndrome; ALPS = autoimmune lymphoproliferative syndrome; APDS = activated PI3K-delta syndrome; CTLA4 = cytotoxic T-lymphocyte antigen 4; CVID = common variable immunodeficiency; DADA2 = deficiency of adenosine deaminase 2; IPEX: Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome; LRBA = lipopolysaccharide-responsive beige-like anchor protein; PKCD = protein kinase C delta; STAT3/STAT1 = signal transducer and activator of transcription 3/1; RALD = RAS-associated autoimmune leukoproliferative disease.

Figure 3

Warning signs for IEIs in patients with hematological diseases. Abbreviations: AIC = autoimmune cytopenia; AHA = autoimmune hemolytic anemia; AIN = autoimmune neutropenia; ALPID = autoimmune lymphoproliferative immunodeficiencies; BM = bone marrow; EBV = Epstein–Barr virus; HLH = hemophagocytic lymphohistiocytosis; IgE = immunoglobulin E; IEIs = inborn errors of immunity ITP = immune thrombocytopenic purpura; LPD = lymphoproliferative disease.

Figure 4

Proposed diagnostic approach for patients with hematological involvement and suspected inborn errors of immunity. (A): Approach for patients with AIC and suspected IEI. (B): Approach for patients with polyclonal lymphoproliferative disease and suspected IEI; (C): Approach for patients with malignancy and suspected IEI; (D): Approach for patients with bone marrow failure syndromes and suspected IEI; (E): Approach for patients with hemophagocytic lymphohistiocytosis and suspected IEI; (F): Approach for patients with eosinophilia and suspected IEI Abbreviations: ADA2: adenosine deaminase 2; AIC = autoimmune cytopenia; ALPS = autoimmune lymphoproliferative syndrome; AML: acute myeloid leukemia; APDS = activated PI3K-delta syndrome; BM = bone marrow; BMFs: Bone marrow failure syndromes; BTK: Bruton tyrosine kinase; CID: combined immunodeficiency; CTLA4 = cytotoxic T-lymphocyte antigen 4; CVID = common variable immunodeficiency; DADA2 = deficiency of adenosine deaminase 2; DEB: Diepoxybutane; DNTs: double-negative T cells; eADA: erythrocyte adenosine deaminase; EBV = Epstein–Barr virus; FA: Fanconi anemia; FASL: FAS ligand; HLH = hemophagocytic lymphohistiocytosis; IgE = immunoglobulin E; IPEX: Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome; LRBA = lipopolysaccharide-responsive beige-like anchor protein; pLPD = polyclonal lymphoproliferative disease; OS: Omenn syndrome; SAP: signaling lymphocyte activation molecule; STAT3/STAT1 = signal transducer and activator of transcription 3/1; Tregs: regulatory T cells; WAS: Wiskott–Aldrich syndrome; XIAP: X-linked inhibitor of apoptosis; XLA: X-linked agammabglobulinemia. The asterisk in panel (E) indicates that serum cytokines and other tests are performed based on clinical suspicion. If functional screening, disease staging, and other tests are negative, extended genetic testing is proceeded.