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Very Elevated IgE, Atopy, and Severe Infection: A Genomics-Based Diagnostic Approach to a Spectrum of Diseases

Very Elevated IgE, Atopy, and Severe Infection: A Genomics-Based Diagnostic Approach to a... Hindawi Case Reports in Immunology Volume 2021, Article ID 2767012, 5 pages https://doi.org/10.1155/2021/2767012 Case Report Very Elevated IgE, Atopy, and Severe Infection: A Genomics-Based Diagnostic Approach to a Spectrum of Diseases 1 1 2 A. Chin, S. Balasubramanyam, and C. M. Davis Baylor College of Medicine, Department of Internal Medicine Houston, Houston, TX, USA Baylor College of Medicine, Department of Pediatrics, Section of Immunology, Allergy and Rheumatology, Houston, TX, USA Correspondence should be addressed to C. M. Davis; carlad@bcm.edu Received 11 May 2021; Accepted 5 August 2021; Published 24 September 2021 Academic Editor: Claudio Pignata Copyright © 2021 A. Chin et al. $is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Elevated IgE has been long recognized as an important clinical marker of atopy but can be seen in a myriad of conditions. $e discovery of autosomal dominant STAT3 deficiency marked the first recognition of hyper-IgE syndrome (HIES) and the first primary immunodeficiency linked to elevated IgE. Since then, genomic testing has increased the number of defects with associated mutations causing hyper-IgE syndrome and atopic diseases with FLG, DOCK8, SPINK5, and CARD11, among others. A spectrum of recurrent infections and atopy are hallmarks of elevated IgE with significant phenotypic overlap between each underlying condition. As treatment is predicated on early diagnosis, genomic testing is becoming a more commonly used diagnostic tool. We present a 6-year-old male patient with markedly elevated IgE and severe atopic dermatitis presenting with staphylococcal bacteremia found to have a heterozygous variant in FLG (p.S3247X) and multiple variants of unknown significance in BCL11B, ZAP70, LYST, and PTPRC. We review the genetic defects underpinning elevated IgE and highlight the spectrum of atopy and immunodeficiency seen in patients with underlying mutations. Although no one mutation is completely causative of the constellation of symptoms in this patient, we suggest the synergism of these variants is an impetus of disease. 1. Introduction 2. Case Presentation IgE, an immunoglobulin produced primarily by B-cells and A 6-year-old male with eczema since the age of two was plasma cells, is an important mediator of allergic disease. El- hospitalized for an acute eczema flare with low-grade fever evated IgE is commonly seen in patients with atopic dermatitis, and rigors. On arrival, the patient presented with a low- food allergy, and asthma [1]. Higher, markedly elevated serum grade fever of 99.4 F with a physical exam notable for diffuse IgE above 2000 IU/ml tends to be associated with severe atopy erythroderma with xerosis and open impetiginous lesions driven by mutations of the epithelial skin barrier or inborn throughout the arms, trunk, and face. $ere were no pus- errors of immunity as seen in HIES [1, 2]. Patients with these tules, vesicles, draining wounds, or extensive denudation. underlying conditions present with overlapping phenotypes Before this, his eczema had been reasonably controlled with that pose a diagnostic challenge [3]. Early diagnosis and dif- triamcinolone cream and frequent hydration with emol- ferentiation between these conditions are of priority as man- lients. $ere was no history of recurrent viral or fungal agement and prognosis can differ. $is case highlights clinical infections involving the respiratory or sinus tracts. $ere was and diagnostic considerations when approaching a patient with no personal or family history of fractures, skeletal abnor- severe atopic dermatitis and very elevated IgE. malities, cognitive abnormalities, or vasculitis. Further 2 Case Reports in Immunology history elicited no known food allergies in the patient, but an dermatitis predisposes patients to the atopic march and can egg allergy in the patient’s father. become a nidus for infection. $is infectious phenotype Initial lab testing showed leukocytosis (14,700 cells/μL) varies drastically, however, with some patients never ex- with 27.6% eosinophils and blood cultures positive for periencing infections and others with persistent skin in- methicillin-sensitive Staphylococcus aureus. He was treated fections. Mutations involving epithelial barrier proteins, with intravenous clindamycin and eventually transitioned to such as filaggrin (FLG), SPINK5, FLG-2, SPRR3, and CLDN1, oral clindamycin for a fourteen-day course. $is initial have become associated with severe atopic dermatitis [5]. infection resolved; however, three months later, the patient Dysregulation of the innate and adaptive immune responses returned with recurrence of eczematous flares and suspected via changes in pattern-recognition receptors, antimicrobial superinfection. He was treated with a fourteen-day course of peptides, the $2 pathway, IL-1, and TSLP have also been oral clindamycin and cephalexin and a five-day course of linked with atopic dermatitis [5]. HIES, on the other hand, prednisone. $e patient’s IgE drawn at this time was has been generally associated with loss of function in STAT3 7,460 IU/ml. Food allergen panel was significant for very protein, resulting in a dysregulated immune response that high specific IgE to peanuts, egg whites, soybean, hazelnut, commonly appears with eczematous skin breakdown and walnuts, almonds, and cashews. Chest imaging showed no predisposition to sinopulmonary infections [1]. What was pathology. A hyper-IgE NIH score [3] was 27 once a monogenic syndrome associated with STAT3, HIES (IgE> 2000 �10 points, eosinophil count >800 � 6 points, has evolved to encapsulate an ever-growing list of gene mild characteristic facial features � 2 points, severe defects, which are thought to contribute to specific patient eczema � 4 points, history of severe nonpulmonary clinical features (see Table 1). Currently, the International infection � 4 points, and increased nasal width � 1 point). Union of Immunological Societies has designated patho- Despite topical steroids, topical clobetasol, topical genic defects in DOCK8, SPINK5, PGM3, ZNF341, IL6ST, tacrolimus, and aggressive skincare, the patient continued to IL6R, ERBB2IP, TGFBR1, TGFBR2, and CARD11/14 genes have recurrent eczematous flares associated with cutaneous as causative of HIES [6]. Although each of these genetic Staphylococcus aureus infection. Prophylactic cephalexin deficiencies has unique characteristics, the severity of the disease is based on a spectrum of atopic and infectious abated some symptoms, and the patient had no additional episodes of bacteremia. Repeat serum IgE level at this time features with specific therapeutic implications for the mu- was improved, but still markedly elevated at 3,464 IU/ml. A tations with the poorest outcomes due to severe infection or HIES targeted genetic panel was negative, indicating that the malignancy (Figure 1(a)). Other primary immunodefi- patient had no detectable pathogenic variants associated ciencies such as Wiskott–Aldrich syndrome (WAS gene), with STAT3, DOCK8, TYK2, and SPINK5. Given this IPEX syndrome (FOXP3 gene), and TYK2 deficiency also negative finding, whole exome sequencing (WES) with present with eczematous lesions and elevated IgE similar to chromosomal microarray was performed. Nonsynonymous HIES but are not officially included under the HIES umbrella variants of unknown clinical significance were found in the [1, 4]. genes BCL11B, ZAP70, LYST, and PTPRC, all inherited from the patient’s mother, all of which are related to the immune system or immunodeficiency. WES revealed heterozygosity 3.1. Clinical Considerations for Markedly Elevated IgE. Approaching these conditions with understanding the of a pathogenic variant of the filaggrin gene (p.S3247X). $e father’s WES showed a similar heterozygous mutation in spectrum of atopy may be help parse out key distinguishing features (Figure 1(b)). In STAT3-deficient HIES, IgE is filaggrin despite only reporting alopecia totalis and egg and chicken allergy. Chromosomal microarray analysis showed a produced in a rather nonspecific manner due to dysregu- lated immune activation [7]. On the other hand, IgE in copy number gain of chromosome region 15q13.3, which did not contain genes associated with immune function. In atopic dermatitis and DOCK8-deficient patients is more allergen specific. As such, severe FLG-associated atopic addition to prophylactic antibiotics, the patient was started on dupilumab (200 mg every 2 weeks), resulting in fewer dermatitis and DOCK8 deficiency present with more severe environmental and food allergies compared to those with eczematous flares with no reported adverse events. At this STAT3-associated HIES. In addition, DOCK8 deficiency time, the patient is off of dupilumab, but utilizes ultraviolet therapy every other day, topical steroids, and tacrolimus and FLG null-mutations are associated with early onset asthma [8, 9]. Heterozygous FLG deficiency, such as the with nightly wet wraps, and still requires intermittent oral antibiotics for eczema control. mutation seen in this patient, is generally associated with milder atopy. $e few cases of HIES due to PGM3, CARD11/14, and SPINK5 defects can also present with 3. Discussion atopic dermatitis and food allergy [1, 4, 9]. Since its discovery in 1966, IgE has become an important Recurrent skin infections can be seen in almost all conditions associated with elevated IgE; however, the se- clinical marker of atopy and HIES [1]. Severe atopic der- matitis and HIES can be phenotypically difficult to distin- verity, location, and overall burden of infection differ. Patients with atopic dermatitis frequently present with guish clinically as both conditions can present with severe minor superinfections that rarely progress to invasive in- eczematous skin lesions with overlapping infections, fection [10]. $is patient’s staphylococcal bacteremia is markedly elevated IgE (>2000 IU/mL), and eosinophilia consistent with a presentation of STAT3-deficient and [1–4]. $e epithelial breakdown that occurs in atopic Case Reports in Immunology 3 Table 1: Phenotypes of genes involved in patients with markedly elevated IgE levels. FLG PGM3 STAT 3 CARD11/14 SPINK5 DOCK8 Skin Yes Yes Yes Yes Yes Yes Respiratory No Yes Yes No Yes Yes Musculoskeletal No Yes Yes No No No Allergies Yes Yes Yes Yes Yes Yes Neuro No Yes Yes No Yes Yes Hem/onc No No Yes No Yes Yes GI No No Yes Yes Yes Yes Systemic complication of infection, Hyper-reactivity to environmental rare association with cancers stimulus (food, inhalant allergens, (cutaneous T-cell lymphomas) irritants, infection) Treatment: Consideration of bone Treatment: Biologics, marrow transplant Immunotherapies Mild Severe Dry skin, pruritus, eczema Cutaneous infections –viral, bacterial Treatment: Topical steroids, Emollients, Lubrication, Treatment: Antimicrobials Avoidance of trigger (a) FLG +/- PGM3 STAT3 FLG -/- CARD11/14 SPINK5 DOCK8 Asthma Allergic Rhinitis Food Allergies Dermatitis (b) Figure 1: (a) Spectrum of disease in patients with elevated IgE. (b) Genetically defined markedly elevated IgE. ZNF341-deficient HIES, prompting a deeper genetic in- recently reported loss-of-function variants in SPINK5, vestigation. $is patient had mutations affecting the immune CARD11, and CARD14 are not only associated with severe system as described in the next section. atopic dermatitis but also include sinopulmonary infec- Known genetic defects in HIES, STAT3, and ZNK341 tions [1, 9]. Given these differences, patient management deficiency can be distinguished from other etiologies by the can vary drastically. In STAT3-deficient patients, routine presence of primarily staphylococcal abscesses, boils, and use of prophylactic antibiotics is common, whereas it is pneumatoceles [3]. DOCK8 deficiency leads to a wide range generally not recommended in patients with atopic der- of severe bacterial and viral infections involving multiple matitis [1, 10]. Prophylactic antibacterials and antifungals organs [4, 9]. $e severity of infections, inflammatory are also used in DOCK8-deficient patients; however, the conditions, and occurrence of malignancy in DOCK8- severity of infection and degree of immunodeficiency deficient patients results in an increased risk of mortality, as prompt the use of IgG supplementation and hematopoietic well as significantly decreased quality of life [9]. $e stem cell treatment [9]. 4 Case Reports in Immunology T-cells and most cδ T-cells [15, 16]. Ablation of this protein Clinical scores have been developed to help physicians differentiate HIES from other conditions when genetic in mice skin led to enhanced $2 activation and subsequent development of atopic dermatitis, indicating the role for testing was not broadly available. $e NIH scoring system utilizes 21 clinical and laboratory findings including the suppression of $1 cytokines [16, 17]. Heterozygous mu- presence of increased serum IgE (>10 times normal), ec- tations in ZAP70, a tyrosine kinase expressed on the surface zema, blood eosinophilia, and characteristic facies [11]. In of T-cells, are associated with elevated IgE due to TCR addition, reduced $17 cell counts can be incorporated for signaling defects and CD8 immunodeficiency due to the improved sensitivity [11]. Scores ≥40 are considered the termination of thymic development [1, 18]. $is patient had cutoff for the diagnosis of HIES, whereas scores below 20 mutations in LYST, associated with the immunodeficiency Chediak–Higashi ´ syndrome and PTPRC, which encodes make the diagnosis unlikely. Scores between 20 and 40 result in inconclusive judgments as to the role of the immune CD45 and functions as a signaling gatekeeper in T-cells. All three of the abovementioned genes have been reported to be system in a patient’s presentation, as in this patient. Genetic testing can be helpful in determining how large a role the associated with eczema and immune deficiencies [19]. Given this association with both eczema and impaired T-cell immune system versus defective barrier function is playing in recurrent infections. Because the sensitivity and specificity function, there is the potential pathophysiological synergism of the HIES scores for STAT3-deficient HIES diagnosis have of all of these variants in this patient, causing severe eczema not been fully validated, the NIH scoring system should be and recurrent skin infections. $is warrants further protein used with caution. $e presence of food allergies, a feature functional testing. not included in the NIH-HIES scoring system, is present in With the advent of next-generation genomic sequencing up to 85% of DOCK8-associated HIES, but only in 37% of and molecular diagnostics, multigene panels have emerged as new clinically available tools for physicians. $ese panels STAT3-deficient HIES [9]. Similarly, unlike STAT3-defi- cient HIES, PGM3-associated HIES is correlated with in- typically include several targeted genes that detect high-yield mutations. For elevated IgE, proprietary panels typically creased, not decreased, levels of $17 [12]. Ultimately, the phenotypes associated with each of these gene defects as- include 3-4 genes that pertain to HIES diagnoses. $is can be problematic as many disorders can underlie elevated IgE and sociated with HIES have a wide range of system involvement that is difficult to capture in a single score (Table 1). may go undetected with these tests. Alternatively, using comprehensive genomic testing with whole exome se- quencing (WES) or whole genome sequencing (WGS) offers 3.2. Genetic Considerations for Markedly Elevated IgE. a less biased approach that may be beneficial in diagnosing $e use of genetic testing is generally recommended in the patients with specific primary immunodeficiency or patients workup of inborn errors of primary immunodeficiency [2]. with an altered immune system predisposing to infection Genetic testing of this patient revealed a paternally inherited [20]. $e diagnostic yield of using these sequencing tech- heterozygous mutation in FLG associated with epidermal niques to uncover subtle or overt immune defects should be barrier function and maternally inherited variants of un- further explored in patients with suspected HIES. known significance (VUS) in BCL11B, ZAP70, LYST, and PTPRC associated with immunity. FLG defects are classically 4. Conclusions associated with severe atopic dermatitis; however, the pathogenicity of this patient’s heterozygous mutation is less $is case highlights the clinical spectrum of atopy and clear [13]. FLG mutation carriers tend to have a much milder infectious phenotypes among patients presenting with phenotype [13]. In addition, the type of FLG variant may also markedly elevated IgE and the potential for synergistic dictate a level of phenotypic heterogeneity. For example, the genetic mutations to contribute to severe disease. Ulti- p.R501X and p.S761fs genotypes are associated with the most mately, the use of whole exome sequencing facilitated the severe disease [14]. $is patient’s c.9740C> A mutation, diagnosis of FLG deficiency and unveiled several addi- otherwise known as the p.S3247X genotype, is a common tional genetic factors that may contribute to this patient’s variant that has a relatively weak association with atopic phenotype through the alteration of his adaptive immu- dermatitis [14]. nity. With an increasing number of immunologic and $e discrepancy of this patient’s clinical severity with his atopic diseases associated with elevated serum IgE levels, known FLG variant highlights the contributory effect of the definitive diagnosis of these conditions becomes other genetic mutations associated with elevated IgE or uncertain from a strictly clinical basis. $e use of next- infection [4, 5, 9]. In this case, the patient’s father exhibited generation gene sequencing, choosing targeted gene only mild allergy with no cutaneous symptoms despite panels, or whole exome sequencing will need further having the same heterozygous FLG variant as the patient. exploration, but provides an avenue to diagnose patients Studies exploring synergism between multiple polymor- early in their disease course, offering opportunities for phisms are limited, especially when considering the con- timely intervention. tribution of skin barrier function and immunity. $e VUS should be considered when the clinical phenotype of eczema Data Availability appears out of proportion with known genetic mutations. $e BCL11B gene has been shown to play a role in epidermal $e patient medical information used to support the find- development and is required for the development of αβ ings of this study is included within the article. Case Reports in Immunology 5 England Journal of Medicine, vol. 365, no. 14, pp. 1315–1327, Conflicts of Interest [14] S. P. Smieszek, S. Welsh, C. Xiao et al., “Correlation of age-of- Carla M. Davis is a consultant for Moonlight $erapeutics. onset of atopic dermatitis with Filaggrin loss-of-function variant status,” Scientific Reports, vol. 10, no. 1, pp. 1–11, 2020. Acknowledgments [15] H. Hosokawa, M. Romero-Wolf, M. A. Yui et al., “Bcl11b sets pro-T cell fate by site-specific cofactor recruitment and by Carla M. Davis received research grant support from the repressing Id2 and Zbtb16,” Nature Immunology, vol. 19, National Institutes of Health/National Institute of Allergy no. 12, pp. 1427–1440, 2018. and Infectious Disease (Consortium of Food Allergy Re- [16] Z. Wang, L.-j. Zhang, G. Guha et al., “Selective ablation of search/Consortium of Eosinophilic Gastrointestinal Re- ctip2/Bcl11b in epidermal Keratinocytes triggers atopic der- matitis-like skin inflammatory responses in adult mice,” PLoS searchers), DBV Technologies, Aimmune $erapeutics, One, vol. 7, no. 12, Article ID e51262, 2012. Regeneron Pharmaceuticals, and the Scurlock Foundation. [17] D. Fang, K. Cui, G. Hu et al., “Bcl11b, a novel GATA3- interacting protein, suppresses $1 while limiting $2 cell References differentiation,” Journal of Experimental Medicine, vol. 215, no. 5, pp. 1449–1462, 2018. [1] M. J. Ponsford, A. Klocperk, F. Pulvirenti et al., “Hyper-IgE in [18] I. Schim van der Loeff, L.-Y. Hsu, M. Saini, A. Weiss, and the allergy clinic—when is it primary immunodeficiency?” B. Seddon, “Zap70 is essential for long-term survival of naive Allergy, vol. 73, no. 11, pp. 2122–2136, 2018. CD8 T cells,” =e Journal of Immunology, vol. 193, no. 6, [2] P.-C. Stadler, E. D. Renner, J. Milner, and A. Wollenberg, pp. 2873–2880, 2014. “Inborn error of immunity or atopic dermatitis: when to be [19] S. Kohler, ¨ L. Carmody, N. Vasilevsky et al., “Expansion of the concerned and how to investigate,” =e Journal of Allergy and human phenotype ontology (HPO) knowledge base and re- Clinical Immunology: In Practice, vol. 9, no. 4, pp. 1501–1507, sources,” Nucleic Acids Research, vol. 47, pp. D1018–D1027, [3] L. F. Schimke, J. Sawalle-Belohradsky, J. Roesler et al., “Di- [20] H. A. F. Yska, K. Elsink, T. W. Kuijpers, G. W. J. Frederix, agnostic approach to the hyper-IgE syndromes: immunologic M. E. Van Gijn, and J. M. Van Montfrans, “Diagnostic yield of and clinical key findings to differentiate hyper-IgE syndromes next generation sequencing in genetically undiagnosed pa- from atopic dermatitis,” Journal of Allergy and Clinical Im- tients with primary immunodeficiencies: a systematic review,” munology, vol. 126, no. 3, pp. 611–617, 2010. Journal of Clinical Immunology, vol. 39, no. 6, pp. 577–591, [4] Q. Zhang, B. Boisson, V. Beziat, ´ A. Puel, and J.-L. Casanova, 2019. “Human hyper-IgE syndrome: singular or plural?” Mam- malian Genome, vol. 29, no. 7-8, pp. 603–617, 2018. [5] L. Bin and D. Y. M. Leung, “Genetic and epigenetic studies of atopic dermatitis,” Allergy, Asthma & Clinical Immunology, vol. 12, no. 1, pp. 1–14, 2016. [6] S. G. Tangye, W. Al-Herz, A. Bousfiha et al., “Human inborn errors of immunity: 2019 update on the classification from the international union of immunological Societies expert com- mittee,” Journal of Clinical Immunology, vol. 40, no. 1, pp. 24–64, 2020. [7] A. C. Boos, B. Hagl, A. Schlesinger et al., “Atopic dermatitis, STAT3- and DOCK8-hyper-IgE syndromes differ in IgE- based sensitization pattern,” Allergy, vol. 69, no. 7, pp. 943–953, 2014. [8] M. W. Tenn and A. K. Ellis, “$e clinical relevance of filaggrin mutations,” Annals of Allergy, Asthma, & Immunology, vol. 117, no. 5, pp. 483–489, 2016. [9] T. Al-Shaikhly and H. D. Ochs, “Hyper IgE syndromes: clinical and molecular characteristics,” Immunology & Cell Biology, vol. 97, no. 4, pp. 368–379, 2019. [10] J. Kim, B. E. Kim, and D. Y. M. Leung, “Pathophysiology of atopic dermatitis: clinical implications,” Allergy and Asthma Proceedings, vol. 40, no. 2, pp. 84–92, 2019. [11] C. Woellner, E. M. Gertz, A. A. Schaffer ¨ et al., “Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome,” =e Journal of Allergy and Clinical Immunology, vol. 125, no. 2, pp. 424–432, 2010. [12] J. J. Lyons, J. D. Milner, and S. D. Rosenzweig, “Glycans instructing immunity: the emerging role of altered glyco- sylation in clinical immunology,” Frontiers in Pediatrics, vol. 3, p. 54, 2015. [13] A. D. Irvine, W. H. I. McLean, and D. Y. M. Leung, “Filaggrin mutations associated with skin and allergic diseases,” New http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Case Reports in Immunology Hindawi Publishing Corporation

Very Elevated IgE, Atopy, and Severe Infection: A Genomics-Based Diagnostic Approach to a Spectrum of Diseases

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Copyright © 2021 A. Chin et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi Case Reports in Immunology Volume 2021, Article ID 2767012, 5 pages https://doi.org/10.1155/2021/2767012 Case Report Very Elevated IgE, Atopy, and Severe Infection: A Genomics-Based Diagnostic Approach to a Spectrum of Diseases 1 1 2 A. Chin, S. Balasubramanyam, and C. M. Davis Baylor College of Medicine, Department of Internal Medicine Houston, Houston, TX, USA Baylor College of Medicine, Department of Pediatrics, Section of Immunology, Allergy and Rheumatology, Houston, TX, USA Correspondence should be addressed to C. M. Davis; carlad@bcm.edu Received 11 May 2021; Accepted 5 August 2021; Published 24 September 2021 Academic Editor: Claudio Pignata Copyright © 2021 A. Chin et al. $is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Elevated IgE has been long recognized as an important clinical marker of atopy but can be seen in a myriad of conditions. $e discovery of autosomal dominant STAT3 deficiency marked the first recognition of hyper-IgE syndrome (HIES) and the first primary immunodeficiency linked to elevated IgE. Since then, genomic testing has increased the number of defects with associated mutations causing hyper-IgE syndrome and atopic diseases with FLG, DOCK8, SPINK5, and CARD11, among others. A spectrum of recurrent infections and atopy are hallmarks of elevated IgE with significant phenotypic overlap between each underlying condition. As treatment is predicated on early diagnosis, genomic testing is becoming a more commonly used diagnostic tool. We present a 6-year-old male patient with markedly elevated IgE and severe atopic dermatitis presenting with staphylococcal bacteremia found to have a heterozygous variant in FLG (p.S3247X) and multiple variants of unknown significance in BCL11B, ZAP70, LYST, and PTPRC. We review the genetic defects underpinning elevated IgE and highlight the spectrum of atopy and immunodeficiency seen in patients with underlying mutations. Although no one mutation is completely causative of the constellation of symptoms in this patient, we suggest the synergism of these variants is an impetus of disease. 1. Introduction 2. Case Presentation IgE, an immunoglobulin produced primarily by B-cells and A 6-year-old male with eczema since the age of two was plasma cells, is an important mediator of allergic disease. El- hospitalized for an acute eczema flare with low-grade fever evated IgE is commonly seen in patients with atopic dermatitis, and rigors. On arrival, the patient presented with a low- food allergy, and asthma [1]. Higher, markedly elevated serum grade fever of 99.4 F with a physical exam notable for diffuse IgE above 2000 IU/ml tends to be associated with severe atopy erythroderma with xerosis and open impetiginous lesions driven by mutations of the epithelial skin barrier or inborn throughout the arms, trunk, and face. $ere were no pus- errors of immunity as seen in HIES [1, 2]. Patients with these tules, vesicles, draining wounds, or extensive denudation. underlying conditions present with overlapping phenotypes Before this, his eczema had been reasonably controlled with that pose a diagnostic challenge [3]. Early diagnosis and dif- triamcinolone cream and frequent hydration with emol- ferentiation between these conditions are of priority as man- lients. $ere was no history of recurrent viral or fungal agement and prognosis can differ. $is case highlights clinical infections involving the respiratory or sinus tracts. $ere was and diagnostic considerations when approaching a patient with no personal or family history of fractures, skeletal abnor- severe atopic dermatitis and very elevated IgE. malities, cognitive abnormalities, or vasculitis. Further 2 Case Reports in Immunology history elicited no known food allergies in the patient, but an dermatitis predisposes patients to the atopic march and can egg allergy in the patient’s father. become a nidus for infection. $is infectious phenotype Initial lab testing showed leukocytosis (14,700 cells/μL) varies drastically, however, with some patients never ex- with 27.6% eosinophils and blood cultures positive for periencing infections and others with persistent skin in- methicillin-sensitive Staphylococcus aureus. He was treated fections. Mutations involving epithelial barrier proteins, with intravenous clindamycin and eventually transitioned to such as filaggrin (FLG), SPINK5, FLG-2, SPRR3, and CLDN1, oral clindamycin for a fourteen-day course. $is initial have become associated with severe atopic dermatitis [5]. infection resolved; however, three months later, the patient Dysregulation of the innate and adaptive immune responses returned with recurrence of eczematous flares and suspected via changes in pattern-recognition receptors, antimicrobial superinfection. He was treated with a fourteen-day course of peptides, the $2 pathway, IL-1, and TSLP have also been oral clindamycin and cephalexin and a five-day course of linked with atopic dermatitis [5]. HIES, on the other hand, prednisone. $e patient’s IgE drawn at this time was has been generally associated with loss of function in STAT3 7,460 IU/ml. Food allergen panel was significant for very protein, resulting in a dysregulated immune response that high specific IgE to peanuts, egg whites, soybean, hazelnut, commonly appears with eczematous skin breakdown and walnuts, almonds, and cashews. Chest imaging showed no predisposition to sinopulmonary infections [1]. What was pathology. A hyper-IgE NIH score [3] was 27 once a monogenic syndrome associated with STAT3, HIES (IgE> 2000 �10 points, eosinophil count >800 � 6 points, has evolved to encapsulate an ever-growing list of gene mild characteristic facial features � 2 points, severe defects, which are thought to contribute to specific patient eczema � 4 points, history of severe nonpulmonary clinical features (see Table 1). Currently, the International infection � 4 points, and increased nasal width � 1 point). Union of Immunological Societies has designated patho- Despite topical steroids, topical clobetasol, topical genic defects in DOCK8, SPINK5, PGM3, ZNF341, IL6ST, tacrolimus, and aggressive skincare, the patient continued to IL6R, ERBB2IP, TGFBR1, TGFBR2, and CARD11/14 genes have recurrent eczematous flares associated with cutaneous as causative of HIES [6]. Although each of these genetic Staphylococcus aureus infection. Prophylactic cephalexin deficiencies has unique characteristics, the severity of the disease is based on a spectrum of atopic and infectious abated some symptoms, and the patient had no additional episodes of bacteremia. Repeat serum IgE level at this time features with specific therapeutic implications for the mu- was improved, but still markedly elevated at 3,464 IU/ml. A tations with the poorest outcomes due to severe infection or HIES targeted genetic panel was negative, indicating that the malignancy (Figure 1(a)). Other primary immunodefi- patient had no detectable pathogenic variants associated ciencies such as Wiskott–Aldrich syndrome (WAS gene), with STAT3, DOCK8, TYK2, and SPINK5. Given this IPEX syndrome (FOXP3 gene), and TYK2 deficiency also negative finding, whole exome sequencing (WES) with present with eczematous lesions and elevated IgE similar to chromosomal microarray was performed. Nonsynonymous HIES but are not officially included under the HIES umbrella variants of unknown clinical significance were found in the [1, 4]. genes BCL11B, ZAP70, LYST, and PTPRC, all inherited from the patient’s mother, all of which are related to the immune system or immunodeficiency. WES revealed heterozygosity 3.1. Clinical Considerations for Markedly Elevated IgE. Approaching these conditions with understanding the of a pathogenic variant of the filaggrin gene (p.S3247X). $e father’s WES showed a similar heterozygous mutation in spectrum of atopy may be help parse out key distinguishing features (Figure 1(b)). In STAT3-deficient HIES, IgE is filaggrin despite only reporting alopecia totalis and egg and chicken allergy. Chromosomal microarray analysis showed a produced in a rather nonspecific manner due to dysregu- lated immune activation [7]. On the other hand, IgE in copy number gain of chromosome region 15q13.3, which did not contain genes associated with immune function. In atopic dermatitis and DOCK8-deficient patients is more allergen specific. As such, severe FLG-associated atopic addition to prophylactic antibiotics, the patient was started on dupilumab (200 mg every 2 weeks), resulting in fewer dermatitis and DOCK8 deficiency present with more severe environmental and food allergies compared to those with eczematous flares with no reported adverse events. At this STAT3-associated HIES. In addition, DOCK8 deficiency time, the patient is off of dupilumab, but utilizes ultraviolet therapy every other day, topical steroids, and tacrolimus and FLG null-mutations are associated with early onset asthma [8, 9]. Heterozygous FLG deficiency, such as the with nightly wet wraps, and still requires intermittent oral antibiotics for eczema control. mutation seen in this patient, is generally associated with milder atopy. $e few cases of HIES due to PGM3, CARD11/14, and SPINK5 defects can also present with 3. Discussion atopic dermatitis and food allergy [1, 4, 9]. Since its discovery in 1966, IgE has become an important Recurrent skin infections can be seen in almost all conditions associated with elevated IgE; however, the se- clinical marker of atopy and HIES [1]. Severe atopic der- matitis and HIES can be phenotypically difficult to distin- verity, location, and overall burden of infection differ. Patients with atopic dermatitis frequently present with guish clinically as both conditions can present with severe minor superinfections that rarely progress to invasive in- eczematous skin lesions with overlapping infections, fection [10]. $is patient’s staphylococcal bacteremia is markedly elevated IgE (>2000 IU/mL), and eosinophilia consistent with a presentation of STAT3-deficient and [1–4]. $e epithelial breakdown that occurs in atopic Case Reports in Immunology 3 Table 1: Phenotypes of genes involved in patients with markedly elevated IgE levels. FLG PGM3 STAT 3 CARD11/14 SPINK5 DOCK8 Skin Yes Yes Yes Yes Yes Yes Respiratory No Yes Yes No Yes Yes Musculoskeletal No Yes Yes No No No Allergies Yes Yes Yes Yes Yes Yes Neuro No Yes Yes No Yes Yes Hem/onc No No Yes No Yes Yes GI No No Yes Yes Yes Yes Systemic complication of infection, Hyper-reactivity to environmental rare association with cancers stimulus (food, inhalant allergens, (cutaneous T-cell lymphomas) irritants, infection) Treatment: Consideration of bone Treatment: Biologics, marrow transplant Immunotherapies Mild Severe Dry skin, pruritus, eczema Cutaneous infections –viral, bacterial Treatment: Topical steroids, Emollients, Lubrication, Treatment: Antimicrobials Avoidance of trigger (a) FLG +/- PGM3 STAT3 FLG -/- CARD11/14 SPINK5 DOCK8 Asthma Allergic Rhinitis Food Allergies Dermatitis (b) Figure 1: (a) Spectrum of disease in patients with elevated IgE. (b) Genetically defined markedly elevated IgE. ZNF341-deficient HIES, prompting a deeper genetic in- recently reported loss-of-function variants in SPINK5, vestigation. $is patient had mutations affecting the immune CARD11, and CARD14 are not only associated with severe system as described in the next section. atopic dermatitis but also include sinopulmonary infec- Known genetic defects in HIES, STAT3, and ZNK341 tions [1, 9]. Given these differences, patient management deficiency can be distinguished from other etiologies by the can vary drastically. In STAT3-deficient patients, routine presence of primarily staphylococcal abscesses, boils, and use of prophylactic antibiotics is common, whereas it is pneumatoceles [3]. DOCK8 deficiency leads to a wide range generally not recommended in patients with atopic der- of severe bacterial and viral infections involving multiple matitis [1, 10]. Prophylactic antibacterials and antifungals organs [4, 9]. $e severity of infections, inflammatory are also used in DOCK8-deficient patients; however, the conditions, and occurrence of malignancy in DOCK8- severity of infection and degree of immunodeficiency deficient patients results in an increased risk of mortality, as prompt the use of IgG supplementation and hematopoietic well as significantly decreased quality of life [9]. $e stem cell treatment [9]. 4 Case Reports in Immunology T-cells and most cδ T-cells [15, 16]. Ablation of this protein Clinical scores have been developed to help physicians differentiate HIES from other conditions when genetic in mice skin led to enhanced $2 activation and subsequent development of atopic dermatitis, indicating the role for testing was not broadly available. $e NIH scoring system utilizes 21 clinical and laboratory findings including the suppression of $1 cytokines [16, 17]. Heterozygous mu- presence of increased serum IgE (>10 times normal), ec- tations in ZAP70, a tyrosine kinase expressed on the surface zema, blood eosinophilia, and characteristic facies [11]. In of T-cells, are associated with elevated IgE due to TCR addition, reduced $17 cell counts can be incorporated for signaling defects and CD8 immunodeficiency due to the improved sensitivity [11]. Scores ≥40 are considered the termination of thymic development [1, 18]. $is patient had cutoff for the diagnosis of HIES, whereas scores below 20 mutations in LYST, associated with the immunodeficiency Chediak–Higashi ´ syndrome and PTPRC, which encodes make the diagnosis unlikely. Scores between 20 and 40 result in inconclusive judgments as to the role of the immune CD45 and functions as a signaling gatekeeper in T-cells. All three of the abovementioned genes have been reported to be system in a patient’s presentation, as in this patient. Genetic testing can be helpful in determining how large a role the associated with eczema and immune deficiencies [19]. Given this association with both eczema and impaired T-cell immune system versus defective barrier function is playing in recurrent infections. Because the sensitivity and specificity function, there is the potential pathophysiological synergism of the HIES scores for STAT3-deficient HIES diagnosis have of all of these variants in this patient, causing severe eczema not been fully validated, the NIH scoring system should be and recurrent skin infections. $is warrants further protein used with caution. $e presence of food allergies, a feature functional testing. not included in the NIH-HIES scoring system, is present in With the advent of next-generation genomic sequencing up to 85% of DOCK8-associated HIES, but only in 37% of and molecular diagnostics, multigene panels have emerged as new clinically available tools for physicians. $ese panels STAT3-deficient HIES [9]. Similarly, unlike STAT3-defi- cient HIES, PGM3-associated HIES is correlated with in- typically include several targeted genes that detect high-yield mutations. For elevated IgE, proprietary panels typically creased, not decreased, levels of $17 [12]. Ultimately, the phenotypes associated with each of these gene defects as- include 3-4 genes that pertain to HIES diagnoses. $is can be problematic as many disorders can underlie elevated IgE and sociated with HIES have a wide range of system involvement that is difficult to capture in a single score (Table 1). may go undetected with these tests. Alternatively, using comprehensive genomic testing with whole exome se- quencing (WES) or whole genome sequencing (WGS) offers 3.2. Genetic Considerations for Markedly Elevated IgE. a less biased approach that may be beneficial in diagnosing $e use of genetic testing is generally recommended in the patients with specific primary immunodeficiency or patients workup of inborn errors of primary immunodeficiency [2]. with an altered immune system predisposing to infection Genetic testing of this patient revealed a paternally inherited [20]. $e diagnostic yield of using these sequencing tech- heterozygous mutation in FLG associated with epidermal niques to uncover subtle or overt immune defects should be barrier function and maternally inherited variants of un- further explored in patients with suspected HIES. known significance (VUS) in BCL11B, ZAP70, LYST, and PTPRC associated with immunity. FLG defects are classically 4. Conclusions associated with severe atopic dermatitis; however, the pathogenicity of this patient’s heterozygous mutation is less $is case highlights the clinical spectrum of atopy and clear [13]. FLG mutation carriers tend to have a much milder infectious phenotypes among patients presenting with phenotype [13]. In addition, the type of FLG variant may also markedly elevated IgE and the potential for synergistic dictate a level of phenotypic heterogeneity. For example, the genetic mutations to contribute to severe disease. Ulti- p.R501X and p.S761fs genotypes are associated with the most mately, the use of whole exome sequencing facilitated the severe disease [14]. $is patient’s c.9740C> A mutation, diagnosis of FLG deficiency and unveiled several addi- otherwise known as the p.S3247X genotype, is a common tional genetic factors that may contribute to this patient’s variant that has a relatively weak association with atopic phenotype through the alteration of his adaptive immu- dermatitis [14]. nity. With an increasing number of immunologic and $e discrepancy of this patient’s clinical severity with his atopic diseases associated with elevated serum IgE levels, known FLG variant highlights the contributory effect of the definitive diagnosis of these conditions becomes other genetic mutations associated with elevated IgE or uncertain from a strictly clinical basis. $e use of next- infection [4, 5, 9]. In this case, the patient’s father exhibited generation gene sequencing, choosing targeted gene only mild allergy with no cutaneous symptoms despite panels, or whole exome sequencing will need further having the same heterozygous FLG variant as the patient. exploration, but provides an avenue to diagnose patients Studies exploring synergism between multiple polymor- early in their disease course, offering opportunities for phisms are limited, especially when considering the con- timely intervention. tribution of skin barrier function and immunity. $e VUS should be considered when the clinical phenotype of eczema Data Availability appears out of proportion with known genetic mutations. $e BCL11B gene has been shown to play a role in epidermal $e patient medical information used to support the find- development and is required for the development of αβ ings of this study is included within the article. 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