Allergic diseases and atopy are hallmark features of certain inborn errors of immunity (IEI) and sometimes even constitute the primary manifestation of these conditions (1–4). Although IEI were initially termed “primary immunodeficiencies” [due to their association with increased susceptibility to infection (5)], the term now encompasses a broader spectrum of immune dysregulation disorders, including autoimmunity, autoinflammation, allergy, and malignancy (1, 6). Mechanistic studies of atopy in IEI have identified changes in cytokine signaling, impairments in T-cell receptor signaling, and intrinsic mast cell dysfunction (3). To better classify the monogenic disorders associated with atopy and emphasize the extension of the allergic phenotype beyond susceptibility to infection, Lyons and Milner suggested the term “primary atopic disorder” (7). Similarly, the term “primary immune regulatory disorder” (PIRD) underscores the immune dysregulation that is characteristic of IEI (8). At least 485 distinct IEIs were listed in a classification published in 2022 (6), and that number has now risen to 508 (9). Although each IEI remains rare, the estimated combined prevalence ranges from 1:1,000 to 1:5,000 (10). The phenotypic heterogenicity and rarity of IEI are compounded by limited awareness among clinicians; this often results in delayed diagnosis and treatment and thus high morbidity and mortality rates (11). The same may also be true for primary atopic disorders, which may initially present solely as atopic manifestations and can thus be misdiagnosed as common allergic diseases (2, 12). Recognizing IEI in the context of severe allergic phenotypes is crucial (3) because their progression and management differ significantly from those associated with non-IEI allergic conditions (13).

Atopic disorders include asthma, atopic eczema, allergic rhinitis, and food allergy and constitute a growing public health challenge. Globally, asthma affects more than 300 million individuals (14), while atopic eczema affects 15-20% of children and 1-3% of adults (15, 16). Allergic rhinitis affects up to 25% of the population (17), and the prevalence of food allergy can be as high as 10% (18). These conditions impose substantial social, psychological and financial burdens on patients and their families (17, 19–21) and significantly reduce quality of life (22, 23). Severe allergic reactions (including fatal anaphylaxis) remain a critical concern – particularly with food allergens like peanuts and tree nuts (24). Rising prevalence rates since the 1980s – including an increase in adult-onset allergies (21, 25, 26) – have prompted efforts to understand the etiology of atopic disorders. Factors such as genetic predispositions, microbiome alterations, lifestyle changes, environmental influences, and epithelial barrier dysfunction have all been implicated (27, 28). The dual-exposure hypothesis of food allergy highlights enteral and cutaneous exposures to allergens as drivers (29–31), and emerging evidence suggests that lung exposure via air pollution also has a role (25). Climate change and regional effects may further influence the incidence of allergy (32, 33).

The study of monogenic disorders with allergic phenotypes provides unique insights into the pathogenesis of allergic diseases and offers potential avenues for novel treatments of both syndromic and non-syndromic allergic conditions (7). Although allergy has been explored in specific IEI or subsets of IEI (34–36), comprehensive investigations of allergic manifestations across a broad spectrum of IEI are still required.

In 2021, we analyzed immune dysregulation patterns in IEI by using the GARFIELD mnemonic (“granuloma”, “autoimmunity”, “recurrent fever”, “eczema”, “lymphoproliferation”, and “intestinal disease”) to encompass key features (37, 38). The field has evolved rapidly since then: novel IEI are increasingly identified in patients presenting primarily with severe allergic phenotypes, while allergic manifestations in previously described IEI are also being recognized more readily. To capture this emerging evidence, we have used advanced search strategies to expand our database. This effort has resulted in (i) an updated manuscript on immune dysregulation patterns in IEI (in preparation) and (ii) the present systematic scoping review of literature data on the association between IEI and allergy, with a particular focus on allergic manifestations of previously described IEI and the concomitant occurrence of allergic diseases and other features of immune dysregulation.

This scoping review was conducted in alignment with the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines (39). No formal protocol was registered for this scoping review.

Our systematic scoping review of literature data on IEI patients with immune dysregulation included 738 studies and 3050 patients, 226 (7.4%) of whom had an allergy. The highest prevalence of allergy was found in patients suffering from genetic disorders caused by variants in DOCK8, CARD11 (AD DN), ARPC1B, and PLCG2, while there were no occurrences of allergy in patients with defects in the LRBA and RAG1 genes. Food allergies were the most common kind of allergy. Allergy patients were less frequently affected by other forms of immune dysregulation, although there were exceptions to this rule. Our data provide insights into the prevalence and relevance of allergy in the setting of IEI and reveal associations with other diseases.

The proportion of IEI patients with allergy in the present review (7.4%) was higher than in our previous review on immune dysregulation in IEI (4%) (37). Overall, our findings concerning allergy as a typical feature of IEI were in line with the literature data. For instance, allergy is known to be frequent in people with a CARD11 (AD DN) deficiency (45, 46), a DOCK8 deficiency (4, 46) or a PGM3 deficiency (7, 47). While the IUIS 2022 classification report (6) states that allergy or atopy is characteristic for these conditions, it does not do so for ARPC1B, PLCG2, and IL6ST deficiencies – all of which had a high prevalence of allergy in our study. However, other researchers have suggested that allergic conditions are a common presentation of these IEI (13, 46, 48, 49).

Many IEI stood out because of a lack of reported allergy among affected patients. For RAG SCID, this lack can be explained by the absence of IgE or type 2 T helper (Th2) cells (3). However, people with a hypomorphic loss of function variant can present with Omenn syndrome and concomitant eczema and elevated IgE levels but with no known allergen specificity (48). To our surprise, there were two reports of allergy in patients with BTK deficiency (also known as X-linked agammaglobulinemia); this disease is characterized by B cell deficiency, the absence of plasma cells, and very low serum levels of all immunoglobulin isotypes (50). In a report on the prevalence of food allergy in IEI patients within the United States Immunodeficiency Network (USIDNET), there was also one case of food allergy among the 332 patients with X-linked agammaglobulinemia (51). For familial Mediterranean fever, Celiksoy et al. found the prevalences of allergic rhinitis, food allergy and atopic dermatitis in their cohort of patients with MEFV variants to be 75%, 7.5% and 22%, respectively (52). However, none of our 21 patients reportedly exhibited any manifestation of atopy. It must be borne in mind that our sample was much smaller than that of Celiksoy et al.’s study (n=454). In contrast, our population of patients with X-linked Wiskott-Aldrich syndrome (WAS XL) was larger (n=252), although the prevalences of allergy and food allergy were only 4.4% and 2.8%, respectively. Our finding contradicts (i) statements about food allergy being a common feature of WAS (53, 54), and (ii) the results published by Lexmond et al. (36) in a notably smaller study of 15 patients, three (20%) of whom suffered from a clinically relevant food allergy.

There are various definitions of allergy in the literature, and many researchers refer to food allergy, allergic rhinitis, asthma, and atopic dermatitis. In the present review, the prevalence of any atopic condition would be 10.8% if one considered only eczematous dermatitis specified as atopic and 26.9% if one also considered unspecified “eczema”. In general, data on the frequency of atopic conditions in IEI are scarce, with estimates ranging from 10% to 28.8% (48). In an international study of atopic manifestations in IEI, El-Sayed et al. compared data from their own cohort with data from the USIDNET; the prevalence of atopy was 16.3% and 68.8%, respectively (55). The prevalence of food allergy in our review (5.6%) was higher than in El-Sayed et al.’s report (1.3%) and in the USIDNET data (0.1%), whereas the estimated prevalence in the general population ranges from 5% to 10% (18, 56). In contrast, the prevalence of allergic rhinitis in our review (1.8%) was lower than in El-Sayed et al.’s report (3%) and in the USIDNET data (8.2%) and well below the values of up to 25% reported for the general population (17); this might be due (at least partly) to under-reporting. The prevalence of asthma in our review (3.7%) was similar to that reported by El-Sayed et al. (3.6%) but the value in the USIDNET data was 46.9%. The prevalence of atopic dermatitis was 3.6% in El-Sayed et al.’s cohort and 23.7% in the USIDNET data. The prevalence of atopic dermatitis in our review depended on whether or not general mentions of “eczema” were considered, giving values of 24.6% and 4.2%, respectively. The interstudy differences in prevalence might be related to disparities in the methodology and in the proportions of IUIS groups.

In the general population, allergic rhinitis is more common than food allergy (17, 18). In our systematic review, however, the reported prevalence of allergic rhinitis was relatively low. This may reflect under-reporting in the literature and the predominance of pediatric cases, as severe IEI usually manifest early in life and are reported first. In accordance with the concept of the atopic march, children would be expected to develop food allergies first, while manifesting allergic rhinitis later. In the general population, atopic dermatitis is more prevalent than food allergy in children but less so in adults (15, 16). In our analysis, food allergy prevalence exceeded that of explicitly reported atopic dermatitis, which may be explained by inconsistent reporting of eczema subtypes in IEI, as authors often did not specify whether the eczema was “atopic”. Conversely, when combining atopic dermatitis with unspecified eczema, the prevalence (24.6%) clearly exceeded that of food allergy (5.6%), though this value may be exaggerated by inclusion of non-atopic eczema.

Beyond these methodological aspects, immunological factors may contribute to the predominance of food allergy in IEI. Defects in epithelial barrier function, impaired induction of oral tolerance, regulatory T cell deficiency, and mucosal microbiota dysbiosis are likely to favor allergic sensitization via the gastrointestinal tract (3, 48). Hyper-IgE states (e.g., in DOCK8 or CARD11 deficiency) are also recognized to accentuate food allergy as a clinical manifestation. Additionally, atypical mechanisms may mimic such states: in our own recent work, we described neutralizing anti-IL-6 autoantibodies in a patient with immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome (57), which likely induced a hyper-IgE-like phenotype with prominent food allergy, despite the absence of overt Th2 skewing. Taken together, these observations suggest that in IEI, food allergy may result not only from classical Th2 skewing but also from disease-specific immune dysregulation, including autoantibody-mediated modulation of the cytokine network.

Besides IgE-dependent allergy, several forms of IgE-independent allergy have been identified. An example of a food allergen-triggered disease is eosinophilic esophagitis, which appears to be a Th2-driven inflammation rather than an IgE-mediated disease and is frequently associated with other atopic conditions (58). On the other hand, the pathophysiology of food-protein induced enterocolitis syndrome (FPIES), a non-IgE, cell-mediated food allergy characterized by delayed onset vomiting and diarrhea and in severe cases, clinically relevant hypotension and marked dehydration (59–61), is suspected to involve antigen-specific T-cell responses and activation of innate immune cells (62). Furthermore, non-IgE-mediated hypersensitivity reactions to drugs, such as complement activation-related pseudo-allergy (CARPA), can present with symptoms resembling classical allergies, including anaphylactoid reactions (63, 64).

In the present study, we systematically reviewed the literature on the overlap between allergy and IEI. By using (i) a web application developed specifically for the creation of our database and (ii) HPO phenotype codes for data extraction, we recorded and extracted data in a standardized manner and produced an individual profile for each patient. This method will facilitate further expansion of the database and thus updating of the results. During the publication selection process, we sought to avoid the multiple inclusion of patients described in several different publications. By considering only the original publication, we eliminated a source of bias towards patients described in several reports.

Nonetheless, our review had some limitations. Firstly, we were unable to draw firm conclusions about the overall prevalence of allergy in IEI because cases of IEI presenting without immune dysregulation were not included. Secondly, the review’s design meant that publication bias is inherent: whether or not a case report is published depends on many factors, with rare and atypical case presentations being favored. Similarly, the presence of allergy may not have been reported or investigated at all if it was of no relevance to a study’s principal objective. As with genetic testing for IEI, allergy testing may prove more difficult in regions in which diagnostic resources are limited. Under-reporting of allergy can therefore be suspected, and our quantitative results should be interpreted with caution. In this regard, the apparent absence of allergic manifestations in LRBA deficiency – a disorder characterized by impaired regulatory T cell function and immune dysregulation – may at least in part reflect under-reporting. Furthermore, the spectrum and prevalence of observed allergies may depend on the age group and geographic region (24, 65), neither of which were considered in our analysis, as information on age at symptom onset, country of origin as well as sex was missing for many patients. Lastly, the severity and clinical presentation of allergies were not addressed in our review.

Our literature review highlighted IEI (spread over several IUIS tables and IEI subgroups) associated with a high prevalence of allergy and thus emphasized the utility of viewing atopy-associated IEI as a distinct group. The term “primary atopic disorder” suggested by Lyons and Milner (7) appears to be appropriate, with the possibility of further grouping IEI according to the underlying atopic mechanism. Furthermore, our results may serve as a template upon which future studies of the prevalence, distribution, and nature of atopic manifestations in monogenic disorders can be conducted. This approach might reveal new areas of interest and provide a better understanding of immune system function and dysfunction.

Our evidence-based overview of allergy in IEI highlighted disorders with particularly high or low prevalences of allergy. The results may raise clinicians’ awareness of these IEI, which might not be diagnosed and treated rapidly if allergic conditions constitute the predominant initial signs and symptoms (66). Furthermore, our findings should remind clinicians treating patients with IEI to determine whether clinical allergy is present; if other manifestations (such as infection or autoimmunity) are the primary focus, allergies might be left untreated. Our present work also shows why it is important to provide detailed clinical reports on patients with IEI. Atopic conditions may be the initial manifestation of an IEI. Conversely, when infectious or immune dysregulation symptoms are prominent, allergies need to be diagnosed and treated. Lastly, we hope that this review will foster future research on the mechanisms behind these disorders and, ultimately, on new approaches for treating allergic disease.