Inborn Errors of Immunity Presenting with Early-Onset Severe Atopy

Abstract

Inborn errors of immunity (IEIs), also known as primary immunodeficiencies, are a group of genetic disorders affecting the development and function of the immune system. While IEIs traditionally present with recurrent infections, an increasing number of cases manifest with early-onset severe atopy, including atopic dermatitis, food allergies, asthma, and allergic rhinitis-features that are often overlooked. This can lead to delayed diagnosis and treatment, which is crucial for IEI patients due to the risk of severe infections. We conducted a literature search and reviewed all IEIs that can present with early-onset severe atopy. The hallmark features of these disorders often include early-onset, persistent, and severe atopic dermatitis, food allergies, and recurrent episodes of asthma, which may be refractory to treatments. Additionally, we discuss the importance of recognizing such severe atopy as a potential indicator of an underlying immune deficiency, particularly when accompanied by unusual infections, growth failure, or autoimmunity. This review aims to raise awareness of this association and emphasize the need for early diagnosis and genetic testing in patients with atypical or treatment-resistant allergic diseases, allowing for more timely diagnosis of underlying immunodeficiencies and appropriate treatments.

Keywords: atopic dermatitis; atopy; inborn errors of immunity; primary immune deficiencies.

Figure 1

The CBM complex controls T cell signaling by the mammalian target of rapamycin (mTOR), nuclear factor kappa B (NF-κB), and c-Jun N-terminal kinase activation (JNK). The T cell receptor leads to the transportation of glutamine, initiating the mTOR pathway.

Figure 2

(a) The JAK/STAT pathways contain various factors, including STAT5, which leads to myeloid activation, or STAT3, which upregulates transcription of the gene ZNF341. (b) TGF-β signaling activates ERBIN/STAT3 complexes, inhibiting SMAD transport into the cell nucleus.

Figure 3

NF-κB signaling pathway, involving either NEMO in the canonical pathway or RelB in the non-canonical pathway, is crucial for cell proliferation and immunity.

Figure 4

The cytoskeletal pathway activated via a T cell receptor contributes to actin assembly, which is necessary for regulatory T cell functioning, intracellular interactions, and NF-κB signaling.

Figure 5

Mast cell degranulation may be triggered easily in PLCγ2 mutations, leading to spontaneous calcium influx that results in degranulation by sub-physiologic temperatures of all hematopoietic cells, except T cells.

Figure 6

Cytokine signaling gets activated by various interleukins, which are critical for immune and inflammation regulation.

Figure 7

The skin barrier is maintained by several components, such as keratinocytes, intercellular adhesion proteins, and protease inhibitors, like SPINK5.

Figure 8

Lymphocyte development involves many significant proteins, such as RAG1&2, which are required for appropriate V(D)J recombination, in which mutations can lead to both B and T cell maturation failure.

Figure 9

Regulatory T cell signaling requires the STAT5 pathway to encode the FOXP3 gene, which is needed for appropriate T cell functioning and regulatory T cell differentiation.

Figure 10

Mutations in the Phosphoacetylglucosamine Mutase 3 can lead to improper glycosylation, resulting in various conditions, such as hyper-IgE syndrome-like findings.