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Background: Hyper-IgE syndrome (HIES) constitutes a group of rare primary immunodeficiency disorders. The diagnosis relies on the National Institutes of Health (NIH) scoring system, incorporating clinical and laboratory data. Scores greater than or equal to 15 raise a strong suspicion of the disease. In an isolated Israeli population, Zinc Finger 341 deficiency, a subtype of HIES, has a carrier incidence of 1:20, but the prevalence of the clinical syndrome within this community remains unknown., Objective: To estimate the prevalence of potentially undiagnosed HIES cases within this population by using the NIH scoring criteria., Methods: This retrospective cohort study obtained requisite clinical and laboratory data for NIH score computation from the electronic medical records of Clalit Health Services for the isolated village under scrutiny in comparison to a neighboring village. Subsequently, clinical scores were assigned to each subject, enabling comparative analysis of suspected diagnosis rates between the 2 populations., Results: Among the 29,390 studied subjects, 12 had a documented diagnosis of HIES. All were in the study village, and none were from the control village (0.08% vs 0%, P < .01). Within the study village, 235 individuals (1.62%) had an NIH score greater than or equal to 15 and were suspected with having HIES almost doubled compared with the control group at 130 individuals (0.87%) (P < .001)., Conclusion: This is the first time the NIH clinical score system has been used for population screening. The significant disparity in the prevalence of suspected, undiagnosed cases between the study village and the control village strongly suggests the potential utility of this tool for preliminary screening., Competing Interests: Disclosures The authors have no conflicts of interest to report., (Copyright © 2024 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The hyper-immunoglobulin E syndrome (HIES) is a primary immunodeficiency disease originally described as Job syndrome. The fundamental causative variant of the HIES is an autosomal dominant mutation in the signal transducer and activator of transcription 3 (STAT3) gene. It is characterized by recurrent staphylococcal cold skin abscess, sinopulmonary infection, eczema, head and face anomalies, frequent bone fractures, eosinophilia and extremely high serum IgE levels (IgE ≥ 2000 IU/mL). However, multiple other genetic defects are also known as HIES-like disorders. Apart from infectious manifestations, STAT3, DOCK8 and TYK2 gene mutations are associated with various malignancies. The most common malignancies reported in these patients are lymphomas, including Hodgkin's and non-Hodgkin's lymphomas (NHL) of B and T cells. This systematic review aimed to investigate the prevalence of malignancies in HIES and the factors associated with malignancy in these patients. In this survey, all articles published until April 1st, 2023, in Scopus, PubMed and Web of Science databases based on three groups of keywords related to HIES syndrome and malignancy were reviewed by three different researchers. Finally, 26 articles were evaluated from which 24 papers were meta-analyzed. In the current study, the demographic information of 1133 patients with HIES, which was mentioned in 24 articles enrolled in the project, was collected, and the information related to patients who had malignancy was analyzed and meta-analyzed. A total of 96 patients out of 1133 studied patients had at least one type of malignancy, the overall prevalence of malignancies reported in the articles was 6.5% (95% confidence interval 4.1-9%), and the total prevalence of malignancy in patients with NHL type and patients with squamous cell carcinoma (SCC) was 2.9% (95% confidence interval 1.7-4.4%) and 2.2% (95% confidence interval 0.3-4.1%), respectively. The results of this study indicated that in 6.5% of cases, HIES was complicated with malignancy, and considering the higher rate of these malignancies in women as well as in DOCK8 mutation sufferers, it is necessary for physicians to be aware of this association and includes malignancy screening in follow-up and periodic examinations of these patients. Indeed, more studies in this field will help to clarify the precise figures and predisposing factors of the relationship between HIES and malignancy., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: Hyper IgE syndromes (HIES) are a group of rare primary immunodeficiency characterized by high levels of serum IgE, cold abscesses, pulmonary infections, and eczema. ZNF341 deficiency was described in 2018 in 11 patients clinically diagnosed previously with HIES. Eight of those patients, all offspring of consanguineous couples, are from three families who live in a Muslim village in Israel which has approximately 15,000 residents., Objective: Our study aimed to evaluate the prevalence of ZNF341 mutation in the population of the village., Methods: Three hundred DNA samples of females were included in the study. The samples belong to females that were referred to the Meir Medical Center for prenatal genetic testing before pregnancy, during 2017-2019: 200 samples were from the village, and 100 samples of Muslim females were from other villages.All samples were tested by Sanger sequencing for the ZNF341 mutation (c.904C>T, NM&#95;001282933.1)., Results: Heterozygous nonsense mutation in ZNF341 was found in ten samples (5%) of the study group compared to zero in the control group (p<0.01)., Conclusion: The carrier frequency of the mutation in ZNF341 in the studied village population is 1:20. This high frequency is probably due to founder mutation and consanguineous marriages., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lachover-Roth, Lagovsky, Shtorch-Asor, Confino-Cohen, Reinstein and Garty.)

Background: Autosomal-dominant signal transducer and activator of transcription 3 (STAT3) deficiency predisposes to recurrent bacterial pneumonia, complicated by bronchiectasis and cavitations. Aspergillosis is a major cause of morbidity in these patients. However, its diagnosis, classification, and treatment are challenging., Objective: We aimed to assess the prevalence and describe the clinical, mycological, and radiological presentation and related therapy and outcome of Aspergillus infections of the respiratory tract in the STAT3-deficient patients of the National French cohort., Methods: We performed a retrospective study of all pulmonary aspergillosis cases in STAT3-deficient patients (n = 74). Clinical and mycological data were collected up to October 2015 and imaging was centralized., Results: Twenty-one episodes of pulmonary aspergillosis in 13 (17.5%) STAT3-deficient patients were identified. The median age at first episode was 13 years (interquartile range, 10-26 years). Ninety percent of patients had previous bronchiectasis or cavitations. Infections were classified as follows: 5 single aspergilloma, 9 chronic cavity pulmonary aspergillosis, 5 allergic bronchopulmonary aspergillosis-like disease, and 2 mixed forms of concomitant allergic bronchopulmonary aspergillosis-like disease and chronic cavity pulmonary aspergillosis. No invasive aspergillosis cases were identified. Aspergillus species were isolated in 71% of episodes and anti-Aspergillus antibodies in 93%. Eleven episodes were breakthrough infections. Antifungal treatment was prolonged, with a median of 13 months, and 6 patients (7 episodes) required surgery, with a high rate of postsurgical complications. One patient died and 6 had a relapse., Conclusions: Chronic and allergic forms of aspergillosis occurred in 17.5% of STAT3-deficient patients, mostly in lung cavities. Almost half had recurrences, despite prolonged antifungal treatment and/or surgery., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Hyper-IgE syndromes (HIES) are distinct diseases characterized by recurrent cutaneous and lung infections, eczema, and elevated serum IgE level., Methods: In this study, clinical manifestations, immunologic findings, and genetic studies of all patients with HIES in the Iranian national registry database were evaluated., Results: A total of 129 HIES patients with a median age of 14.0 (9.0-24.0) years were followed up for a total of 307.8 patient-years. Genetic studies showed heterozygous STAT3 mutations in 19 patients and homozygous DOCK8 mutation in 16 patients. The mean of National Institutes of Health score in STAT3-deficient patients was higher than in patients with DOCK8 mutation (P = 0.001). It was shown that the presence of pneumatocele and hematologic complication were significantly frequent in STAT3-deficient cases compared to patients with DOCK8 deficiency (P = 0.001 and P = 0.002, respectively). Moreover, the median IgE serum levels were higher in patients with STAT3 gene mutation than in patients with DOCK8 gene mutation (P = 0.02). The eosinophils' count was enhanced in patients with DOCK8 deficiency than in patients with STAT3 gene defects (P = 0.02)., Conclusion: Specific molecular study of STAT3 and DOCK8 mutations in patients with HIES clinical phenotype could help the physician to definitively characterize the disease. Since HIES showed the highest rate of unsolved combined immunodeficiency, investigation of other genetic and environmental factors could also help in understanding the mechanism of remaining patients as well as providing strategy into therapeutic modalities., (© 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Autosomal dominant hyper-IgE syndrome (AD-HIES) is a rare condition., Objective: Data from the USIDNET Registry provide a resource to examine the characteristics of patients with rare immune deficiency diseases., Methods: A query was submitted to the USIDNET requesting deidentified data for patients with physician-diagnosed AD-HIES through July 2016., Results: Data on 85 patients diagnosed with AD-HIES (50 males; 35 females) born between 1950 and 2013, collected by 14 physicians from 25 states and Quebec, were entered into the USIDNET Registry by July 2016. Cumulative follow-up was 2157 years. Of these patients, 45.9% had a family history of HIES. The complications reported included skin abscesses (74.4%), eczema (57.7%), retained primary teeth (41.4%), fractures (39%), scoliosis (34.1%), and cancer (7%). Reported allergic diseases included food (37.8%), environmental (18%), and drugs (42.7%). The mean serum IgE level was 8383.7 kU/mL and was inversely correlated to the patient's age. A total of 49.4% had eosinophilia; 56% were known to be on trimethoprim-sulfamethoxazole, 26.6% on antifungal coverage, and 30.6% on immunoglobulin replacement therapy. Pneumonias were more commonly attributed to Staphylococcus aureus (55.3%) or Aspergillus fumigatus (22.4%); 19.5% had a history of lung abscess; these were most often associated with Pseudomonas aeruginosa (P Fisher's exact test = .029) or A. fumigatus (P Fisher's exact test = .016). Lung abscesses were significantly associated with drug reactions (P χ 2  = .01; odds ratio: 4.03 [1.2-12.97]), depression (P Fisher's exact test = .036), and lower Karnofsky index scores (P Mann-Whitney = .007)., Discussion: Data from the USIDNET Registry summarize the currently reported clinical characteristics of a large cohort of subjects with AD-HIES., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Immigrants from undeveloped countries are a growing problem in Europe. Spain has become a frequent destination for immigrants (20% of whom are children) because of its geographic location and its historic and cultural links with Africa and Latin America. Eosinophilia is frequent in adult immigrants, travelers and expatriates coming from tropical areas. However, there are few studies that focus on the incidence and causes of tropical eosinophilia and hyper-IgE in immigrant children.We evaluated, prospectively, the prevalence and causes of eosinophilia and hyper-immunoglobulin E (IgE) in 362 immigrant children coming from Sub-Saharan Africa, Northern Africa and Latin America to Salamanca, Spain, between January 2007 and December 2011.Absolute eosinophilia and hyper-IgE were present in 22.9% and 56.8% of the analyzed children, respectively. The most frequent causes of absolute eosinophilia were filariasis (52.6%), strongyloidiasis (46.8%) and schistosomiasis (28.9%). Filariasis (41.9%), strongyloidiasis (29.6%) and schistosomiasis (22.2%) were the most frequent causes of increased levels of IgE. The area under the ROC curve showed similar values between eosinophil count and IgE levels in the diagnosis of helminthiasis (69% [95% confidence interval (CI) 63%-74%] vs 67% [95% CI 60%-72%], P = 0.24). Eosinophilia and hyper-IgE have a high value as biomarkers of helminthiasis in children coming from tropical and subtropical areas.

Background: Severe atopic conditions associated with elevated serum IgE are heterogeneous with few known causes. Nearly every patient with autosomal-dominant hyper-IgE syndrome (AD-HIES) due to signal transducer and activator of transcription 3 (STAT3) mutations has a history of eczematous dermatitis and elevated IgE; however, clinical atopy has never been systematically studied., Objective: Understanding of genetic determinants of allergic disease may lead to novel therapies in controlling allergic disease., Methods: We conducted clinical evaluation of the rates of food allergies and anaphylaxis in patients with AD-HIES, a cohort of patients with no STAT3 mutation but with similar histories of elevated IgE and atopic dermatitis, and healthy volunteers with no history of atopy. Morphine skin prick testing, ImmunoCAP assays for allergen-specific IgE, and basophil activation were measured. A model of systemic anaphylaxis was studied in transgenic mice carrying an AD-HIES mutation. STAT3 was silenced in LAD2 and primary human mast cells to study the role of STAT3 in signaling and degranulation after IgE cross-linking., Results: Food allergies and anaphylaxis were markedly diminished in patients with AD-HIES compared with a cohort of patients with no STAT3 mutation but with similar histories of elevated IgE and atopic dermatitis. Morphine skin prick testing and basophil activation were diminished in patients with AD-HIES, whereas mice carrying an AD-HIES mutation were hyporesponsive to systemic anaphylaxis models. Rapid mast cell STAT3 serine727 phosphorylation was noted after IgE cross-linking, and inhibition of STAT3 signaling in mast cells lead to impaired FcεRI-mediated proximal and distal signaling, as well as reduced degranulation., Conclusion: This study serves as an example for how mutations in specific atopic pathways can lead to discrete allergic phenotypes, encompassing increased risk of some phenotypes but a relative protection from others., (Published by Mosby, Inc.)

Purpose: Autosomal recessive hyper-IgE syndrome is a rare combined immunodeficiency characterized by susceptibility to viral infections, atopic eczema, high serum IgE and defective T cell activation. The genetic etiologies are diverse. Null mutations in DOCK8 and TYK2 are responsible for many cases. This study aims to provide a detailed clinical and immunological characterization of the disease and explore the underlying genetic defects among a large series of patients followed by a single center. The available data might improve our understanding of the disease pathogenesis and prognosis., Methods: Clinical data of twenty-five patients diagnosed with AR-HIES were collected. Seventeen patients screened for STAT3, TYK2 and DOCK8 mutations., Results: Sinopulmonary infections, dermatitis, hepatic disorders, cutaneous and systemic bacterial, fungal and viral infections were the most common clinical features. The rate of hepatic disorders and systemic infections were high. Twelve patients died with a median age of 10 years. CMV infection was the only statistically significant predicting factor for poor prognosis (early death). Three novel DOCK8 mutations and two large deletions were found in thirteen patients. No mutations found in STAT3 or TYK2 genes., Conclusion: Autosomal recessive hyper-IgE syndrome is a combined immunodeficiency disease characterized by high morbidity and mortality rate. The different genetic background and environmental factors may explain the more severe phenotypes seen in our series. DOCK8 defect is the most common identified genetic cause. Patients with no identified genetic etiology are likely to carry mutations in the regulatory elements of genes tested or in novel genes that are yet to be discovered.

Autosomal dominant deficiency of signal transducer and activator of transcription 3 (STAT3) is the main genetic etiology of hyper-immunoglobulin (Ig) E syndrome. We documented the molecular, cellular, and clinical features of 60 patients with heterozygous STAT3 mutations from 47 kindreds followed in France. We identified 11 known and 13 new mutations of STAT3. Low levels of interleukin (IL)-6-dependent phosphorylation and nuclear translocation (or accumulation) of STAT3 were observed in Epstein-Barr virus-transformed B lymphocytes (EBV-B cells) from all STAT3-deficient patients tested. The immunologic phenotype was characterized by high serum IgE levels (96% of the patients), memory B-cell lymphopenia (94.5%), and hypereosinophilia (80%). A low proportion of IL-17A-producing circulating T cells was found in 14 of the 15 patients tested. Mucocutaneous infections were the most frequent, typically caused by Staphylococcus aureus (all patients) and Candida albicans (85%). Up to 90% of the patients had pneumonia, mostly caused by Staph. aureus (31%) or Streptococcus pneumoniae (30%). Recurrent pneumonia was associated with secondary bronchiectasis and pneumatocele (67%), as well as secondary aspergillosis (22%). Up to 92% of the patients had dermatitis and connective tissue abnormalities, with facial dysmorphism (95%), retention of decidual teeth (65%), osteopenia (50%), and hyperextensibility (50%). Four patients developed non-Hodgkin lymphoma. The clinical outcome was favorable, with 56 patients, including 43 adults, still alive at the end of study (mean age, 21 yr; range, 1 mo to 46 yr). Only 4 patients died, 3 from severe bacterial infection (aged 1, 15, and 29 yr, respectively). Antibiotic prophylaxis (90% of patients), antifungal prophylaxis (50%), and IgG infusions (53%) improved patient health, as demonstrated by the large decrease in pneumonia recurrence. Overall, the prognosis of STAT3 deficiency may be considered good, provided that multiple prophylactic measures, including IgG infusions, are implemented.

This study represents the first epidemiological study based on the national registry of primary immunodeficiencies (PID) in Korea. Patient data were collected from 23 major hospitals. A total of 152 patients with PID (under 19 yr of age), who were observed from 2001 to 2005, have been entered in this registry. The period prevalence of PID in Korea in 2005 is 11.25 per million children. The following frequencies were found: antibody deficiencies, 53.3% (n = 81), phagocytic disorders, 28.9% (n = 44); combined immunodeficiencies, 13.2% (n = 20); and T cell deficiencies, 4.6% (n = 7). Congenital agammaglobulinemia (n = 21) and selective IgA deficiency (n = 21) were the most frequently reported antibody deficiency. Other reported deficiencies were common variable immunodeficiencies (n = 16), X-linked agammaglobulinemia (n = 15), IgG subclass deficiency (n = 4). Phagocytic disorder was mostly chronic granulomatous disease. A small number of patients with Wiskott-Aldrich syndrome, hyper-IgE syndrome, and severe combined immunodeficiency were also registered. Overall, the most common first manifestation was pneumonia. This study provides data that permit a more accurate estimation PID patients in Korea.

Skin manifestations are prevalent in primary immunodeficiency disorders (PID). In a large proportion of patients, they manifest as presenting signs and serve as important factors for the early diagnosis of PID. Only a few studies describing the spectrum of skin disorders in PID are available. The objective of the current study was to determine the prevalence and characteristics of skin manifestations in children with PID. Participants were 128 pediatric patients with PID (aged <16 years) registered prospectively over 6 years. Skin manifestations were observed in 61 patients (48%), and those manifestations were the presenting features in 50 (39% of total PID and 82% of those with skin lesions). Skin infections were the most prevalent manifestations, seen in 39 patients (30%), followed by eczemas in 24 (19%). Skin infections were significantly more prevalent in those with congenital defects in phagocyte number, function, or both, as well as in those with well-defined immunodeficiencies. Although widely present in all participants with PID, eczema was a consistent feature (100%) in patients with hyper IgE syndrome and Wiskott-Aldrich syndrome (WAS). Erythroderma of infancy with diffuse alopecia was seen exclusively in patients with severe combined immunodeficiency disorders, telangiectasia in patients with ataxia telangiectasia, and partial albinism with silvery gray hair in those with Chediak-Higashi syndrome. Autoimmune skin manifestations were observed in 6% of reported cases of PID. This study highlights the importance of awareness of skin manifestations of PID to assist in the early diagnosis and management of these disorders., (© 2011 Wiley Periodicals, Inc.)

Objective: To characterize the dermatitis, the newborn rash, and cutaneous findings in hyper-IgE syndrome, also known as Job's syndrome., Design: Prospective and retrospective evaluation and treatment of cutaneous manifestations in patients with a clinical diagnosis of hyper-IgE syndrome (HIES). Analysis of the newborn rash encountered in this population., Setting: Dermatology clinic at the National Institutes of Health, Bethesda, Md., Patients: Forty-three patients seen in our clinic between January 1998 and August 2003 who had a clinical diagnosis of HIES., Interventions: The UK Working Party's Diagnostic Criteria for Atopic Dermatitis were used to assess for atopic dermatitis in this population. To assess the newborn rash, we performed a retrospective chart review and an in-person or telephone interview of the parent or caregiver of each patient., Results: Twenty-eight (65%) of 43 patients fulfilled the criteria for atopic dermatitis. Thirty-five (81%) of 43 patients reported a newborn rash. Eight (19%) of 43 were born with the rash; 23 (53%) of 43 had acquired the rash within 7 days; 32 (74%) of 43 within 14 days; 34 (79%) of 43 within 30 days; and 35 (81%) of 43 had the rash within 35 days of birth., Conclusions: The dermatitis in HIES resembles classic atopic dermatitis but may have distinctive features. A newborn rash is almost always a presenting sign of HIES. After the newborn period, skin findings include retroauricular fissures, external otitis, infected dermatitis of the axillae and groin, folliculitis of the upper back and shoulders, cutaneous abscesses, mucocutaneous candidiasis, and in some patients pitted scarring of the face.

Hyperimmunoglobulinemia E (HIGE) is associated with various conditions such as atopy, dermatitis, hypersensitivity reactions, and certain parasitic infections. In the course of vaccination initiatives in the province of Napo, eastern Ecuador, blood samples were collected from one of the two remaining rural subgroups of Huaorani Indians who in 1979 were reported to have the world's highest concentrations of IgE. One subgroup of Huaorani, the Dicaron, lives in a protected Amazonian region which has reportedly suffered from extensive pollution after petroleum industry exploration. Plasma was collected from 31 members of the Dicaron (age range 15-75 years), eight non-Dicaron Huaorani, and 16 Quichua Indians from the same province, and tested for IgE, IgG, IgM, IgA, and immunoglobulin allotypes. Subjects were examined for evidence of filariasis, a group of parasitic diseases associated with HIGE. Mean IgE concentration in the Dicaron was measured by CAP ELISA at 11,850 IU/mL (range 5000-33,000) while IgA and IgM concentrations were within normal limits compared to North American controls. IgG levels were slightly elevated and there was no evidence of filariasis. Compared to the Quichua and non-Dicaron Huaorani, two other Amerindian tribes in the Ecuadorian Amazon, the highest concentrations of IgE were recorded from the Dicaron who live within the allegedly polluted section of the Amazon. We conclude that an unexplained HIGE syndrome exists among only one subgroup of Huaorani, the Dicaron. Other eastern Ecuadorian Amerindians, such as the Quichua and resettled Huaorani, have IgE concentrations expected in a population with intestinal helminthiasis. Environmental factors cannot be excluded as the cause of HIGE in the Dicaron.