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DOCK8 deficiency is the most common cause of autosomal recessive hyper-IgE syndrome (AR-HIES). The clinical spectrum is wide resulting in combined immunodeficiency, atopy, autoimmunity, and malignancies. To study the clinical and molecular profile of 20 patients with DOCK8 deficiency. Four hundred and eight patients with various inborn errors of immunity (IEIs) were diagnosed in the Pediatric Immunology Unit of our hospital during the study period of February 2017 to August 2023. Based on the clinical and immunological phenotype, DOCK8 deficiency was suspected in 31 patients. Genetic studies confirmed DOCK8 deficiency in 20 patients, and their profile was analyzed in detail. Twenty patients from 17 kindreds were diagnosed with DOCK8 deficiency. The female-to-male ratio was 1.2:1. The mean age at onset of symptoms and diagnosis was 9.8 and 69.8 months, respectively. Thirteen out of 17 families (76%) reported consanguinity. Eczema was the presenting manifestation in 19 patients (95%). Mucocutaneous manifestations included oromucosal hyperpigmentation (n = 8), scalp seborrhoea (n = 2), psoriasis (n = 2), and alopecia (n = 1). The spectrum of infections included pneumonia (n = 14), otitis media (n = 6), gastrointestinal infections (n = 6), cutaneous viral infections (n = 5), oral candidiasis (n = 4), and meningoencephalitis (n = 2). Three patients had developed bronchiectasis. Four patients had autoimmune manifestations including autoimmune hemolytic anemia (n = 2) and vasculitis (n = 2). The whole exome sequencing showed deletions (8 kindreds) as the most common mutation in the DOCK8 gene. Overall, 11 of these mutations were novel. Ten patients were on monthly intravenous immunoglobulin therapy and antibiotic prophylaxis at the time of writing this paper. Three patients underwent hematopoietic stem cell transplants elsewhere, two of whom succumbed to post-transplant complications and one is doing well. Nine patients died during the study period. We present one of the largest single-center experiences on DOCK8 deficiency from India. A significant delay in the diagnosis contributed to poor outcomes in our cohort. [ABSTRACT FROM AUTHOR]

Elevated serum IgE levels serve as a critical marker for uncovering hidden immunological disorders, particularly inborn errors of immunity (IEIs), which are often misdiagnosed as common allergic conditions. IgE, while typically associated with allergic diseases, plays a significant role in immune defense, especially against parasitic infections. However, extremely high levels of IgE can indicate more severe conditions, such as Hyper-IgE syndromes (HIES) and disorders with similar features, including Omenn syndrome, Wiskott-Aldrich syndrome, and IPEX syndrome. Novel insights into the genetic mutations responsible for these conditions highlight their impact on immune regulation and the resulting clinical features, including recurrent infections, eczema, and elevated IgE. This narrative review uniquely integrates recent advances in the genetic understanding of IEIs and discusses how these findings impact both diagnosis and treatment. Additionally, emerging therapeutic strategies, such as hematopoietic stem cell transplantation (HSCT) and gene therapies, are explored, underscoring the potential for personalized treatment approaches. Emphasizing the need for precise diagnosis and tailored interventions aims to enhance patient outcomes and improve the quality of care for those with elevated IgE levels and associated immunological disorders. [ABSTRACT FROM AUTHOR]

Hyper-IgE Syndrome (HIES) is a rare inborn error of immunity (IEI) characterised by elevated levels of serum IgE, recurrent bacterial infections on the skin, eczema and recurrent pneumonia which leads to the formation of lung cysts. DOCK8 Immunodeficiency Syndrome (DIDS) is characterised by severe allergy, chronic infections and early-onset cancer. Diagnosis of both HIES and DIDS depends on the clinical characteristics of patients, laboratory immunological findings as well as genetic analysis before coming up with the appropriate treatment strategy. Despite some overlapping phenotypes, DIDS has been reclassified as a combined immunodefiency (CID) separate from HIES. This review discusses both STAT3-HIES and DIDS through its clinical presentations, mutational and immunological profile to explore any overlapping or distinctive features that resulted in the reclassification of DIDS as a CID. This review also explores current treatment plans and prospective strategies moving forward. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to describe the clinical, immunological, and genetic features of patients with DOCK8 deficiency (DOCK8‐Def) in a tertiary care center for children. Methods: Retrospective chart review of patients' clinical, immunological, and genetic characteristics with DOCK8‐Def. Genetic analysis was performed with targeted‐ or whole‐exome sequencing; we also assessed DOCK8 protein expression and a lymphoproliferation assay and analyzed survival by the Kaplan–Meier method. Results: We described 11 patients from 8 unrelated kindreds. The median age at symptoms' onset was 10 months (range 1–54 months). The median follow‐up time was 53.4 months (4.8–118.8). All patients presented eczema and recurrent sinopulmonary and cutaneous infections. Besides those symptoms, the most frequent manifestations were bronchiectases (8/11), food allergies (6/11), and severe infections (6/11). Infrequent characteristics were detection of CMV in bronchial lavage, C. parvum‐driven sclerosing cholangitis, Takayasu vasculitis, neurological syndromes, pulmonary tuberculosis, and lymphomatoid granulomatosis. Conclusion: DOCK8‐Def has a broad spectrum of manifestations, including allergy, autoimmunity, inflammation, infection, and cancer. The hallmark of this inborn error of immunity is IEI‐associated eczema with eosinophilia and increased IgE. Here, we report six new mutations causing human DOCK8 deficiency and symptoms previously unrecognized to occur in DOCK8‐Def. Therefore, an early diagnosis of DOCK8‐Def is essential to facilitate an adequate treatment such as HSCT. [ABSTRACT FROM AUTHOR]

Abstract Background STAT3 hyperimmunoglobulin E syndrome (STAT3-HIES) also referred to as autosomal dominant HIES (AD-HIES) is an inborn error of immunity characterized by the classic triad of eczema, frequent opportunistic infections, and elevated serum IgE levels. As a consequence of lung sequels due to repeated infections and impaired tissue healing, patients may require interventional pulmonary procedures. Method Four patients with dominant-negative STAT3 mutations who had received interventional pulmonary procedures were enrolled. The demographic, clinical, and molecular characteristics were gathered through a medical record search. All reported STAT3-HIES patients in the literature requiring pulmonary procedures as part of their treatment were reviewed. Result Recurrent episodes of pneumonia and lung abscess were the most prevalent symptoms. The most common non-immunological features were scoliosis, failure to thrive, and dental problems such as primary teeth retention and disseminated decays. Bronchiectasis, lung abscess, pneumatocele, and cavitary lesion were the most prevalent finding on high-resolution computed tomography at the earliest recording. All patients underwent pulmonary surgery and two of them experienced complications. Conclusion Patients with STAT3-HIES have marked pulmonary infection susceptibility which may necessitate thoracic surgeries. Since surgical procedures involve a high risk of complication, surgical options are recommended to be utilized only in cases of drug resistance or emergencies.

Autosomal dominant hyper-IgE syndrome (AD-HIES) is an inborn error of immunity (IEI) caused by a dominant-negative mutation in the signal transducer and activator of transcription 3 (STAT 3). This disease is characterized by chronic eczematoid dermatitis, recurrent staphylococcal skin abscesses, pneumonia, pneumatoceles, and extremely high serum IgE levels. Loss-of-function STAT3 mutations may also result in distinct non-immunologic features such as dental, facial, skeletal, and vascular abnormalities, central nervous system malformations and an increased risk for bone fractures. Prophylactic treatment of Candida infections and prophylactic antimicrobial therapy for staphylococcal skin infections and sinopulmonary infections are essential. An awareness of the oral and maxillofacial features of HIES may facilitate early diagnosis with genetic counselling and may improve future patient care. This study describes oral, dental, and maxillofacial manifestations in 14 patients with genetically defined AD-HIES. We also review the literature and propose recommendations for the complex care of patients with this rare primary immunodeficiency.

BackgroundDedicator of cytokinesis 8 (DOCK8) deficiency is the main cause of the autosomal recessive hyper-IgE syndrome (HIES). We previously reported the selective loss of group 3 innate lymphoid cell (ILC) number and function in a Dock8-deficient mouse model. In this study, we sought to test whether DOCK8 is required for the function and maintenance of ILC subsets in humans.MethodsPeripheral blood ILC1-3 subsets of 16 DOCK8-deficient patients recruited at the pretransplant stage, and seven patients with autosomal dominant (AD) HIES due to STAT3 mutations, were compared with those of healthy controls or post-transplant DOCK8-deficient patients (n = 12) by flow cytometry and real-time qPCR. Sorted total ILCs from DOCK8- or STAT3-mutant patients and healthy controls were assayed for survival, apoptosis, proliferation, and activation by IL-7, IL-23, and IL-12 by cell culture, flow cytometry, and phospho-flow assays.ResultsDOCK8-deficient but not STAT3-mutant patients exhibited a profound depletion of ILC3s, and to a lesser extent ILC2s, in their peripheral blood. DOCK8-deficient ILC1-3 subsets had defective proliferation, expressed lower levels of IL-7R, responded less to IL-7, IL-12, or IL-23 cytokines, and were more prone to apoptosis compared with those of healthy controls.ConclusionDOCK8 regulates human ILC3 expansion and survival, and more globally ILC cytokine signaling and proliferation. DOCK8 deficiency leads to loss of ILC3 from peripheral blood. ILC3 deficiency may contribute to the susceptibility of DOCK8-deficient patients to infections.

Monogenic inherited skin diseases are a group of clinically rare diseases that include nearly 1000 phenotypically distinct disorders. Through the concerted efforts of researchers in dermatological sciences and related disciplines worldwide, many advances have been made in the etiology and pathogenesis of these diseases in the last 30 years. However, it is important to note that the treatment of the majority of monogenic inherited skin diseases remains a challenge for clinicians. Dupilumab is a fully human monoclonal IgG4 antibody that specifically binds to the α subunit of the IL-4 receptor, thereby inhibiting the IL-4 and IL-13 signaling pathway. It was first approved for the treatment of moderate-to-severe atopic dermatitis (AD) and has been used worldwide. In recent years, the drug has been successfully used to treat some monogenic inherited skin diseases with AD-like clinical manifestations, such as hyper-IgE syndrome and Netherton syndrome, with good efficacy. The drug was later tried for the treatment of other monogenic inherited skin diseases, such as Hailey-Hailey syndrome and epidermolysis bullosa pruriginosa, where it was also proven to be effective. In this paper, we review literature reports related to dupilumab for the treatment of monogenic inherited skin diseases in recent years, focusing on its efficacy, safety and possible therapeutic mechanisms. We aim to provide a possible scientific basis for the future application of this drug in the field of rare monogenic inherited skin diseases.

Abstract Background The etiopathogenesis of idiopathic non-cirrhotic portal hypertension (INCPH) is so far poorly understood. Altered immunity, blood diseases, infections, congenital defects and drug exposure have been documented in a part of patients with INCPH owing to increased recognition of the disorder in patients with HIV, or various haematological disorders or autoimmune diseases. We aim to discuss the possible etiopathogenesis of INCPH. Case presentation We reported that a patient with intestinal infection of T. Marneffei and hyper-IgE syndrome, a group of rare primary immunodeficiency disorders, was finally diagnosed with INCPH for gastroesophageal variceal bleeding. The diagnosis was mainly based on histopathological features. Transjugular intrahepatic portosystemic shunt was performed and there was no recurrence of melena during the six-month follow-up. Conclusion In the context of immunodeficiency, INCPH may associated with intestinal infections. Thus, screening for enterogenic infection and immunological disorders in patients with unexplained portal hypertension is necessary.

Background: STAT3 hyperimmunoglobulin E syndrome (STAT3-HIES) also referred to as autosomal dominant HIES (AD-HIES) is an inborn error of immunity characterized by the classic triad of eczema, frequent opportunistic infections, and elevated serum IgE levels. As a consequence of lung sequels due to repeated infections and impaired tissue healing, patients may require interventional pulmonary procedures. Method: Four patients with dominant-negative STAT3 mutations who had received interventional pulmonary procedures were enrolled. The demographic, clinical, and molecular characteristics were gathered through a medical record search. All reported STAT3-HIES patients in the literature requiring pulmonary procedures as part of their treatment were reviewed. Result: Recurrent episodes of pneumonia and lung abscess were the most prevalent symptoms. The most common non-immunological features were scoliosis, failure to thrive, and dental problems such as primary teeth retention and disseminated decays. Bronchiectasis, lung abscess, pneumatocele, and cavitary lesion were the most prevalent finding on high-resolution computed tomography at the earliest recording. All patients underwent pulmonary surgery and two of them experienced complications. Conclusion: Patients with STAT3-HIES have marked pulmonary infection susceptibility which may necessitate thoracic surgeries. Since surgical procedures involve a high risk of complication, surgical options are recommended to be utilized only in cases of drug resistance or emergencies. [ABSTRACT FROM AUTHOR]

Hyper-IgE syndrome (HIES) in adult patients is a very rare occurrence with heterogeneous clinical manifestations. Most of the previously described cases were from developed countries, capable of performing comprehensive testing to pinpoint the underlying genetic defect. Such a facility is often unavailable in resource-limited countries, creating a great diagnostic challenge. Nevertheless, several important clinical clues can significantly aid in hypothesis formulation, such as the presence of primary immunodeficiency, eosinophilia, and a history of atopy. We describe the process of diagnosing HIES on an 18-year-old Asian male through systematic symptom analysis and strategic use of a simple laboratory examination. [ABSTRACT FROM AUTHOR]

Craniosynostosis, hyper-IgE syndrome, Job's syndrome Available treatments include immunoglobulin substitution and antimicrobial prophylaxis, and also HSCT, although this later treatment has no impact on the musculoskeletal aspects of the syndrome. Keywords: craniosynostosis; hyper-IgE syndrome; Job's syndrome EN craniosynostosis hyper-IgE syndrome Job's syndrome 1 7 7 05/02/23 20230401 NES 230401 PEER REVIEW The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/pai.13944. Hyper-IgE syndrome presenting with early life craniosynostosis in monozygotic twin sisters. [Extracted from the article]

Background: The etiopathogenesis of idiopathic non-cirrhotic portal hypertension (INCPH) is so far poorly understood. Altered immunity, blood diseases, infections, congenital defects and drug exposure have been documented in a part of patients with INCPH owing to increased recognition of the disorder in patients with HIV, or various haematological disorders or autoimmune diseases. We aim to discuss the possible etiopathogenesis of INCPH. Case presentation: We reported that a patient with intestinal infection of T. Marneffei and hyper-IgE syndrome, a group of rare primary immunodeficiency disorders, was finally diagnosed with INCPH for gastroesophageal variceal bleeding. The diagnosis was mainly based on histopathological features. Transjugular intrahepatic portosystemic shunt was performed and there was no recurrence of melena during the six-month follow-up. Conclusion: In the context of immunodeficiency, INCPH may associated with intestinal infections. Thus, screening for enterogenic infection and immunological disorders in patients with unexplained portal hypertension is necessary. [ABSTRACT FROM AUTHOR]

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Summary: Dupilumab interferes with the signaling pathways of IL‐4 and IL‐13 and is effective in treating atopic dermatitis. Specific genodermatoses, including Netherton syndrome, epidermolysis bullosa pruriginosa, and hyper‐IgE syndrome, are Th2 skewed diseases with activation of type 2 inflammation. We performed this systematic review to investigate the therapeutic role of dupilumab in the treatment of genodermatosis. A systematic search was conducted of the PubMed, Embase, Web of Science, and Cochrane databases from inception to December 13, 2021. The review included studies with relevant terms including "dupilumab," "genodermatosis", "Netherton syndrome", "ichthyosis", "epidermolysis bullosa" and "hyper‐IgE syndrome". The initial search yielded 2,888 results, of which 28 studies and 37 patients with genodermatosis were enrolled. The assessed genodermatoses included Netherton syndrome, epidermolysis bullosa pruriginosa, hyper‐IgE syndrome, Hailey‐Hailey disease, and severe eczema associated with genetic disorders. Most of the reported cases showed significant clinical improvement after the initiation of dupilumab treatment without major adverse events. Decreased immunoglobulin E levels and cytokine normalization have also been documented. In conclusion, Dupilumab may have a potential therapeutic role in certain genodermatoses skewed towards T helper 2 (Th2) immunity, including Netherton syndrome, epidermolysis bullosa pruriginosa, hyper‐IgE syndrome, Hailey‐Hailey disease, and severe eczema associated with some genetic disorders. [ABSTRACT FROM AUTHOR]

Hyper-IgE syndrome (HIES) is a rare group of primary immunodeficiency diseases characterized by elevated IgE levels, eosinophilia, recurrent pyoderma, ear infection, eczematous dermatitis, and pulmonary infection. The treatment depends on the clinical presentation of the disease. The eczematous skin lesions usually respond to a topical steroid, calcineurin inhibitors, and sometimes, based on severity, systemic drugs are given. The secondary infections are usually treated with oral and topical antibiotics. We are describing a case of HIES who presented with severe recalcitrant itchy oozy eczematous skin lesions which did not respond to conventional systemic drugs and were later on controlled with injection omalizumab. In addition, we have discussed the HIES in detail in the current article.

Autosomal recessive hyper-IgE syndrome caused by DOCK8 gene mutation is an immunodeficiency. However, the presentation of a tumour-like lesion of the lip in autosomal recessive hyper-IgE syndrome has not yet been reported. This article reports the case of a 20-year-old man with autosomal recessive hyper-IgE syndrome who presented with a tumour-like lesion of the lip, and hyperplasia and erosion of the gingiva. The clinical manifestations included coarse face and neck skin, a diffuse tumour-like lesion on the upper lip showing a reddish erosive nodular surface with yellowish-white exudation, erosive buccal mucosa, and severe periodontitis. The swollen gingival and palatal mucosa indicated nodular hyperplasia and redness with pseudomembrane. The patient had a significantly increased peripheral blood eosinophil count and serum IgE level and an abnormal T lymphocyte count. His oral lesions improved markedly after prednisolone acetate use and local symptomatic treatment for 2 years. However, the patient unfortunately died of a cerebral infection 6 months after the oral lesions had resolved. The novel features of the labial tumour-like lesion described here extend our understanding of the manifestations of autosomal recessive hyper-IgE syndrome. [ABSTRACT FROM AUTHOR]

Hyper-IgE syndrome (HIES) is a rare group of primary immunodeficiency diseases characterized by elevated IgE levels, eosinophilia, recurrent pyoderma, ear infection, eczematous dermatitis, and pulmonary infection. The treatment depends on the clinical presentation of the disease. The eczematous skin lesions usually respond to a topical steroid, calcineurin inhibitors, and sometimes, based on severity, systemic drugs are given. The secondary infections are usually treated with oral and topical antibiotics. We are describing a case of HIES who presented with severe recalcitrant itchy oozy eczematous skin lesions which did not respond to conventional systemic drugs and were later on controlled with injection omalizumab. In addition, we have discussed the HIES in detail in the current article. [ABSTRACT FROM AUTHOR]

Ran Zhao,1,* Chao Wang,1,* Chao Sun,1 Kun Jiang,1 Shengnan Wu,2 Fen Pan,2 Zeyu Zeng,1 Yijing Hu,1 Xiaoyan Dong1 1Department of Respiratory, Shanghai Children’s Hospital, Shanghai Jiaotong University, Shanghai, 200062, People’s Republic of China; 2Clinical Laboratory of Shanghai Children’s Hospital, Shanghai Jiaotong University, Shanghai, 200062, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoyan DongDepartment of Respiratory, Shanghai Children’s Hospital, Shanghai Jiaotong University, No. 355 Luding Road, Shanghai, 200062, People’s Republic of ChinaEmail dongxy@shchildren.com.cnPurpose: Autosomal dominant hyper-IgE syndrome (HIES) is a rare primary immune deficiency syndrome caused mainly by mutations in the signal transducer and activator of transcription 3 (STAT3) gene. More information on STAT3 mutations is still needed, and further investigation is warranted. A girl with HIES carrying a novel STAT3 mutation who had no obvious apparent symptoms but presented with a severe necrotizing pulmonary infection is described here. We analysed dynamic changes in blood cells and a series of inflammatory factors in the bronchoalveolar lavage fluid (BALF) before and after each bronchoscopic lavage to relieve her severe pulmonary abscess.Patients and Methods: Whole-exome sequencing and Sanger sequencing were used to identify novel STAT3 mutations. Flow cytometry was used for immune analysis of Th17 cells and inflammatory cytokines.Results: A novel de novo mutation in STAT3 (c.1552C>T, p.Arg518*) was identified in this patient. The number of eosinophils decreased after each bronchoscopy procedure. Elevated interleukin (IL)-8 and IL-1β levels were detected in her right lung BALF in the acute phase, but they were reduced after four bronchoscopic lavage procedures and the administration of antimicrobial medicine.Conclusion: More information on STAT3 mutations is needed to investigate the relationship between the genotype and HIES phenotype. Bronchoscopic lavages are recommended instead of surgery to relieve acute severe pulmonary abscesses and necrotizing pulmonary infections in paediatric patients with HIES.Keywords: hyper-IgE syndrome, infection, lung alveolar lavage fluid, pulmonary infection

Abstract Background STAT3 hyper-IgE syndrome (STAT3-HIES) is a rare primary immunodeficiency that clinically overlaps with atopic dermatitis. In addition to eczema, elevated serum-IgE, and recurrent infections, STAT3-HIES patients suffer from characteristic facies, midline defects, and retained primary teeth. To optimize dental management we assessed the development of dentition and the long-term outcomes of dental treatment in 13 molecularly defined STAT3-HIES patients using questionnaires, radiographs, and dental investigations. Results Primary tooth eruption was unremarkable in all STAT3-HIES patients evaluated. Primary tooth exfoliation and permanent tooth eruption was delayed in 83% of patients due to unresorbed tooth roots. A complex orthodontic treatment was needed for one patient receiving delayed extraction of primary molars and canines. Permanent teeth erupted spontaneously in all patients receiving primary teeth extraction of retained primary teeth during average physiologic exfoliation time. Conclusions The association of STAT3-HIES with retained primary teeth is important knowledge for dentists and physicians as timely extraction of retained primary teeth prevents dental complications. To enable spontaneous eruption of permanent teeth in children with STAT3-HIES, we recommend extracting retained primary incisors when the patient is not older than 9 years of age and retained primary canines and molars when the patient is not older than 13 years of age, after having confirmed the presence of the permanent successor teeth by radiograph.

BackgroundHyper-immunoglobulin E (IgE) syndromes (HIES) are a group of primary immune deficiencies disorders (PID) characterized by elevated serum IgE, eczema, recurrent skin, or respiratory system infections and may also be accompanied by some connective tissues and skeletal abnormalities. Currently, there is no complete cure or targeted treatment for HIES. Omalizumab is a humanized recombinant monoclonal antibody against IgE, reducing the level of free IgE, inhibiting the binding of IgE to receptors on the surface of effector cells, and reducing the activation of inflammatory cells and the release of multiple inflammatory mediators. However, the effect of omalizumab in treating HIES remains unknown. Herein, we described a case of an AD-HIES patient with chronic airway disease who benefited from omalizumab treatment.Case PresentationA 28-year-old Chinese woman was admitted for recurrent cough for 7 years, markedly elevated serum IgE level, and recurrent pneumonia caused by multiple pathogens, such as Pneumocystis jirovecii, Cytomegalovirus, Staphylococcus aureus, Aspergillus, and Mycobacterium tuberculosis. She had eczema-dermatitis, skin abscess, slightly traumatic fracture since childhood, and developed asthma and allergic bronchopulmonary aspergillosis (ABPA) lately. Using whole-exome sequencing, the STAT3 (c.1294G>T, p.Val432Leu) missense mutation for the autosomal dominant hyper-IgE syndrome was identified, and omalizumab was prescribed at 300 mg every 2 weeks. The patient responded well with the improvement of respiratory symptoms and lung function tests. The level of serum IgE remained stable on follow-up.ConclusionOmalizumab treatment proved beneficial in the case of HIES, especially with chronic airway disease, for which therapeutic options are limited. However, larger-scale prospective studies and long-term follow-up are required to establish the efficacy and safety of this therapeutic intervention.

DOCK8 deficiency is the most common cause of autosomal recessive hyper-IgE syndrome (AR-HIES). The clinical spectrum is wide resulting in combined immunodeficiency, atopy, autoimmunity, and malignancies. To study the clinical and molecular profile of 20 patients with DOCK8 deficiency. Four hundred and eight patients with various inborn errors of immunity (IEIs) were diagnosed in the Pediatric Immunology Unit of our hospital during the study period of February 2017 to August 2023. Based on the clinical and immunological phenotype, DOCK8 deficiency was suspected in 31 patients. Genetic studies confirmed DOCK8 deficiency in 20 patients, and their profile was analyzed in detail. Twenty patients from 17 kindreds were diagnosed with DOCK8 deficiency. The female-to-male ratio was 1.2:1. The mean age at onset of symptoms and diagnosis was 9.8 and 69.8 months, respectively. Thirteen out of 17 families (76%) reported consanguinity. Eczema was the presenting manifestation in 19 patients (95%). Mucocutaneous manifestations included oromucosal hyperpigmentation (n = 8), scalp seborrhoea (n = 2), psoriasis (n = 2), and alopecia (n = 1). The spectrum of infections included pneumonia (n = 14), otitis media (n = 6), gastrointestinal infections (n = 6), cutaneous viral infections (n = 5), oral candidiasis (n = 4), and meningoencephalitis (n = 2). Three patients had developed bronchiectasis. Four patients had autoimmune manifestations including autoimmune hemolytic anemia (n = 2) and vasculitis (n = 2). The whole exome sequencing showed deletions (8 kindreds) as the most common mutation in the DOCK8 gene. Overall, 11 of these mutations were novel. Ten patients were on monthly intravenous immunoglobulin therapy and antibiotic prophylaxis at the time of writing this paper. Three patients underwent hematopoietic stem cell transplants elsewhere, two of whom succumbed to post-transplant complications and one is doing well. Nine patients died during the study period. We present one of the largest single-center experiences on DOCK8 deficiency from India. A significant delay in the diagnosis contributed to poor outcomes in our cohort., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Abstract Hyperimmunoglobulin E (IgE) syndrome (HIES) is a rare disease with an unclear prognosis. We report a case of HIES comorbid with chronic pulmonary aspergillosis (CPA). A 19‐year‐old male was referred to our department with a medical history of bacterial pneumonia and skin infection. Laboratory data showed an elevated eosinophil count and serum IgE level. Chest computed tomography (CT) showed a pneumatocele and bronchiectasis. On the basis of the clinical and laboratory findings and genetic mutation analysis, we diagnosed him as having HIES. Fourteen months later, he complained of blood‐tinged sputum and haemoptysis. Chest CT showed pneumatocele wall thickening, fungus ball and consolidation. Serum Aspergillus precipitating antibody and serum galactomannan Aspergillus antigen were positive, and Aspergillus fumigatus was detected in the sputum. We diagnosed CPA and treated him using antifungal agents and bronchial artery embolization. CPA is a complication that requires attention in patients with HIES.

Combined immunodeficiency (CID) due to DOCK8 deficiency is an inborn error of immunity (IBD) characterized by dysfunctional T and B lymphocytes; The spectrum of manifestations includes allergy, autoimmunity, inflammation, predisposition to cancer, and recurrent infections. DOCK8 deficiency can be distinguished from other CIDs or within the spectrum of hyper-IgE syndromes by exhibiting profound susceptibility to viral skin infections, associated skin cancers, and severe food allergies. The 9p24.3 subtelomeric locus where DOCK8 is located includes numerous repetitive sequence elements that predispose to the generation of large germline deletions and recombination-mediated somatic DNA repair. Residual production DOCK8 protein contributes to the variable phenotype of the disease. Severe viral skin infections and varicellazoster virus (VZV)-associated vasculopathy, reflect an essential role of the DOCK8 protein, which is required to maintain lymphocyte integrity as cells migrate through the tissues. Loss of DOCK8 causes immune deficiencies through other mechanisms, including a cell survival defect. In addition, there are alterations in the response of dendritic cells, which explains susceptibility to virus infection and regulatory T lymphocytes that could help explain autoimmunity in patients. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment; it improves eczema, allergies, and susceptibility to infections. [ABSTRACT FROM AUTHOR]

Background: TYK2 deficiency is a rare primary immunodeficiency disease caused by loss‐of‐function mutations of TYK2 gene, which is initially proposed as a subset of hyper‐IgE syndrome (HIES). However, accumulating evidence suggests TYK2‐deficient patients do not necessarily present with HIES characteristics, indicating a vacuum of knowledge on the exact roles of TYK2 in human immune system. Method: Pathogenic effects of patients were confirmed by qRT‐PCR, Western blot, and protein stability assays. The responses to cytokines including IFN‐α/β/γ, IL‐6, IL‐10, IL‐12, and IL‐23 of peripheral blood mononuclear cells (PBMCs) from these patients were detected by Western blot, qRT‐PCR, and flow cytometry. The differentiation of T and B cells was detected by flow cytometry. Results: We described five more TYK2‐deficient cases presenting with or without hyper‐IgE levels, atopy, and distinct pathogen infection profile, which are caused by novel TYK2 mutations. These mutations were all found by high‐throughput sequencing and confirmed by Sanger sequencing. The patients showed heterogeneous responses to various cytokine treatments, including IFN‐α/β/γ, IL‐6, IL‐10, IL‐12, and IL‐23. The homeostasis of lymphocytes is also disrupted. Conclusion: Based on our findings, we propose that TYK2 works as a multi‐tasker in orchestrating various cytokine signaling pathways, differentially combined defects which account for the expressed clinical manifestations. [ABSTRACT FROM AUTHOR]

Hyper-IgE syndromes and chronic mucocutaneous candidiasis constitute rare primary immunodeficiency syndromes with an overlapping clinical phenotype. In recent years, a growing number of underlying genetic defects have been identified. To characterize the underlying genetic defects in a large international cohort of 275 patients, of whom 211 had been clinically diagnosed with hyper-IgE syndrome and 64 with chronic mucocutaneous candidiasis, targeted panel sequencing was performed, relying on Agilent HaloPlex and Illumina MiSeq technologies. The targeted panel sequencing approach allowed us to identify 87 (32 novel and 55 previously described) mutations in 78 patients, which generated a diagnostic success rate of 28.4%. Specifically, mutations in DOCK8 (26 patients), STAT3 (21), STAT1 (15), CARD9 (6), AIRE (3), IL17RA (2), SPINK5 (3), ZNF341 (2), CARMIL2/RLTPR (1), IL12RB1 (1), and WAS (1) have been detected. The most common clinical findings in this cohort were elevated IgE (81.5%), eczema (71.7%), and eosinophilia (62.9%). Regarding infections, 54.7% of patients had a history of radiologically proven pneumonia, and 28.3% have had other serious infections. History of fungal infection was noted in 53% of cases and skin abscesses in 52.9%. Skeletal or dental abnormalities were observed in 46.2% of patients with a characteristic face being the most commonly reported feature (23.1%), followed by retained primary teeth in 18.9% of patients. Targeted panel sequencing provides a cost-effective first-line genetic screening method which allows for the identification of mutations also in patients with atypical clinical presentations and should be routinely implemented in referral centers. [ABSTRACT FROM AUTHOR]

Background: Granulomatous lymphocytic interstitial lung disease (GLILD) has been increasingly recognized in children affected with primary immunodeficiencies (PIDs). In this study, we aimed to better characterize the spectrum of pediatric PIDs coexisting with GLILD including clinical and immunological predictors, thoracic imaging findings, and histopathologic features. Methods: We respectively reviewed records of six representative cases of children, three of them affected with common variable immunodeficiency (CVID) and three with syndromic immunodeficiencies, in whom a diagnosis of GLILD was established based on clinical, radiological, and histopathologic findings. Clinical and immunological predictors for GLILD were also analyzed in the patients studied. Results: All the children with GLILD had a history of autoimmune phenomena, organ-specific immunopathology, and immune dysregulation. Defective B-cell maturation and deficiency of memory B cells were found in all the children with GLILD. The radiological and histopathological features consistent with the diagnosis of GLILD, granulomatous disease, and lymphoid hyperplasia, were accompanied by chronic airway disease with bronchiectasis in children with CVID and syndromic PIDs. Conclusions: Our study shows that both CVID and syndromic PIDs may be complicated with GLILD. Further studies are required to understand the predictive value of coexisting autoimmunity and immune dysregulation in the recognition of GLILD in children with PIDs. [ABSTRACT FROM AUTHOR]

Hyper‐IgE syndromes (HIES) are a heterogeneous group of rare primary immunodeficiency diseases classically characterized by the triad of atopic dermatitis, and recurrent cutaneous and pulmonary infections. Autosomal dominant, loss‐of‐function STAT3 pathogenic variants are the most common genetic cause, which lead to deficiency of Th17 lymphocytes, impaired interferon gamma production, and IL‐10 signal transduction, and an unbalanced IL‐4 state. Dupilumab, a monoclonal antibody to the IL‐4a receptor, inhibits both IL‐4 and IL‐13, and has been shown to improve atopic dermatitis and other manifestations of HIES including asthma and allergic bronchopulmonary aspergillosis. We present a pediatric patient with HIES who presented predominantly with eosinophilic folliculitis, recurrent cutaneous infections, and other non‐eczematous findings and achieved sustained clearance with dupilumab. [ABSTRACT FROM AUTHOR]

BackgroundRecurrent bacterial and fungal infections, eczema, and increased serum IgE levels characterize patients with the hyper-IgE syndrome (HIES). Known genetic causes for HIES are mutations in signal transducer and activator of transcription 3 (STAT3) and dedicator of cytokinesis 8 (DOCK8), which are involved in signal transduction pathways. However, glycosylation defects have not been described in patients with HIES. One crucial enzyme in the glycosylation pathway is phosphoglucomutase 3 (PGM3), which catalyzes a key step in the synthesis of uridine diphosphate N-acetylglucosamine, which is required for the biosynthesis of N-glycans.ObjectiveWe sought to elucidate the genetic cause in patients with HIES who do not carry mutations in STAT3 or DOCK8.MethodsAfter establishing a linkage interval by means of SNPchip genotyping and homozygosity mapping in 2 families with HIES from Tunisia, mutational analysis was performed with selector-based, high-throughput sequencing. Protein expression was analyzed by means of Western blotting, and glycosylation was profiled by using mass spectrometry.ResultsMutational analysis of candidate genes in an 11.9-Mb linkage region on chromosome 6 shared by 2 multiplex families identified 2 homozygous mutations in PGM3 that segregated with disease status and followed recessive inheritance. The mutations predict amino acid changes in PGM3 (p.Glu340del and p.Leu83Ser). A third homozygous mutation (p.Asp502Tyr) and the p.Leu83Ser variant were identified in 2 other affected families, respectively. These hypomorphic mutations have an effect on the biosynthetic reactions involving uridine diphosphate N-acetylglucosamine. Glycomic analysis revealed an aberrant glycosylation pattern in leukocytes demonstrated by a reduced level of tri-antennary and tetra-antennary N-glycans. T-cell proliferation and differentiation were impaired in patients. Most patients had developmental delay, and many had psychomotor retardation.ConclusionImpairment of PGM3 function leads to a novel primary (inborn) error of development and immunity because biallelic hypomorphic mutations are associated with impaired glycosylation and a hyper-IgE-like phenotype.

The efficacy of dupilumab in pediatric patients with severe eczema presenting in the setting of elevated immunoglobulin E (IgE) levels and recurrent bacterial skin infections is not well-understood. Here we present the case of a child with elevated IgE levels in whom dupilumab treatment led to remarkable control of his eczema and recurrent skin infections. We also review the use of dupilumab in other patients with molecularly proven cases of hyper IgE (HIGE) syndrome. Our case supports the notion that dupilumab may have a seminal application in treating severe eczema that occurs in the setting of elevated IgE levels and recurrent bacterial skin infections.

BackgroundInborn errors of immunity (IEI) present with a large phenotypic spectrum of disease, which can pose diagnostic and therapeutic challenges. Suppressor of cytokine signaling 1 (SOCS1) is a key negative regulator of cytokine signaling, and has recently been associated with a novel IEI. Of patients described to date, it is apparent that SOCS1 haploinsufficiency has a pleiotropic effect in humans.ObjectiveWe sought to investigate whether dysregulation of immune pathways, in addition to STAT1, play a role in the broad clinical manifestations of SOCS1 haploinsufficiency.MethodsWe assessed impacts of reduced SOCS1 expression across multiple immune cell pathways utilizing patient cells and CRISPR/Cas9 edited primary human T cells.ResultsSOCS1 haploinsufficiency phenotypes straddled across the International Union of Immunological Societies classifications of IEI. We found that reduced SOCS1 expression led to dysregulation of multiple intracellular pathways in immune cells. STAT1 phosphorylation is enhanced, comparably with STAT1 gain-of-function mutations, and STAT3 phosphorylation is similarly reduced with concurrent reduction of Th17 cells. Furthermore, reduced SOCS1 E3 ligase function was associated with increased FAK1 in immune cells, and increased AKT and p70 ribosomal protein S6 kinase phosphorylation. We also found Toll-like receptor responses are increased in SOCS1 haploinsufficiency patients.ConclusionsSOCS1 haploinsufficiency is a pleiotropic monogenic IEI. Dysregulation of multiple immune cell pathways may explain the variable clinical phenotype associated with this new condition. Knowledge of these additional dysregulated immune pathways is important when considering the optimum management for SOCS1 haploinsufficient patients.

Abstract Asthma and anaphylaxis are two atypical presentations of hyper‐IgE syndrome (HIES). Early diagnosis and management of HIES can improve quality of life of patients through minimizing orthodontic problems and other complications related to this disorder.

Background: Inborn errors of immunity (IEI) present with a large phenotypic spectrum of disease, which can pose diagnostic and therapeutic challenges. Suppressor of cytokine signaling 1 (SOCS1) is a key negative regulator of cytokine signaling, and has recently been associated with a novel IEI. Of patients described to date, it is apparent that SOCS1 haploinsufficiency has a pleiotropic effect in humans. Objective: We sought to investigate whether dysregulation of immune pathways, in addition to STAT1, play a role in the broad clinical manifestations of SOCS1 haploinsufficiency. Methods: We assessed impacts of reduced SOCS1 expression across multiple immune cell pathways utilizing patient cells and CRISPR/Cas9 edited primary human T cells. Results: SOCS1 haploinsufficiency phenotypes straddled across the International Union of Immunological Societies classifications of IEI. We found that reduced SOCS1 expression led to dysregulation of multiple intracellular pathways in immune cells. STAT1 phosphorylation is enhanced, comparably with STAT1 gain-of-function mutations, and STAT3 phosphorylation is similarly reduced with concurrent reduction of Th17 cells. Furthermore, reduced SOCS1 E3 ligase function was associated with increased FAK1 in immune cells, and increased AKT and p70 ribosomal protein S6 kinase phosphorylation. We also found Toll-like receptor responses are increased in SOCS1 haploinsufficiency patients. Conclusions: SOCS1 haploinsufficiency is a pleiotropic monogenic IEI. Dysregulation of multiple immune cell pathways may explain the variable clinical phenotype associated with this new condition. Knowledge of these additional dysregulated immune pathways is important when considering the optimum management for SOCS1 haploinsufficient patients. [ABSTRACT FROM AUTHOR]

Biallelic variants in IL6ST , encoding GP130, cause a recessive form of hyper-IgE syndrome (HIES) characterized by high IgE level, eosinophilia, defective acute phase response, susceptibility to bacterial infections, and skeletal abnormalities due to cytokine-selective loss of function in GP130, with defective IL-6 and IL-11 and variable oncostatin M (OSM) and IL-27 levels but sparing leukemia inhibitory factor (LIF) signaling. Our aim was to understand the functional and structural impact of recessive HIES-associated IL6ST variants. We investigated a patient with HIES by using exome, genome, and RNA sequencing. Functional assays assessed IL-6, IL-11, IL-27, OSM, LIF, CT-1, CLC, and CNTF signaling. Molecular dynamics simulations and structural modeling of GP130 cytokine receptor complexes were performed. We identified a patient with compound heterozygous novel missense variants in IL6ST (p.Ala517Pro and the exon-skipping null variant p.Gly484_Pro518delinsArg). The p.Ala517Pro variant resulted in a more profound IL-6– and IL-11–dominated signaling defect than did the previously identified recessive HIES IL6ST variants p.Asn404Tyr and p.Pro498Leu. Molecular dynamics simulations suggested that the p.Ala517Pro and p.Asn404Tyr variants result in increased flexibility of the extracellular membrane–proximal domains of GP130. We propose a structural model that explains the cytokine selectivity of pathogenic IL6ST variants that result in recessive HIES. The variants destabilized the conformation of the hexameric cytokine receptor complexes, whereas the trimeric LIF-GP130-LIFR complex remained stable through an additional membrane-proximal interaction. Deletion of this membrane-proximal interaction site in GP130 consequently caused additional defective LIF signaling and Stüve-Wiedemann syndrome. Our data provide a structural basis to understand clinical phenotypes in patients with IL6ST variants. [Display omitted] [ABSTRACT FROM AUTHOR]

Asthma and anaphylaxis are two atypical presentations of hyper-IgE syndrome (HIES). Early diagnosis and management of HIES can improve quality of life of patients through minimizing orthodontic problems and other complications related to this disorder. [ABSTRACT FROM AUTHOR]

Some severe asthmatic patients experience frequent bacterial respiratory tract infections, which contribute significantly to their disease burden, and often are attributed to their use of systemic corticosteroids and comorbid bronchiectasis. We report a case of a 58-year-old woman who had prednisone-dependent asthma and exacerbations with intense mixed eosinophilic and neutrophilic bronchitis. Autosomal dominant hyper-IgE syndrome, which is a primary immunodeficiency characterized by elevated IgE, eosinophilia, and recurrent infections, caused by a novel pathogenic mutation in STAT3 was identified as the cause of her airway disease. We believe that this is the first report of the demonstration of an IL-5 driven eosinophilia that is associated with a STAT3 mutation that was treated successfully with an anti-IL5 biological. [ABSTRACT FROM AUTHOR]

Background: Phosphoglucomutase‐3 (PGM3) deficiency is a congenital disorder of glycosylation (CDG) with hyperimmunoglobulin IgE, atopy, and a variable immunological phenotype; most reported patients display dysmorphic features. The aim of the study was to characterize the genotype and phenotype of individuals with newly identified compound heterozygous variants in the phosphate‐binding domain of PGM3 in order to better understand phenotypic differences between these patients and published cases. Methods: We analyzed PGM3 protein expression, PGM3 enzymatic activity, the presence of other gene variants within the N‐glycosylation pathway, and the clinical and immunological manifestations of two affected siblings. Results: Patients belonged to a non‐consanguineous family, presenting with atopic dermatitis, elevated levels of IgE, and CD4+ lymphopenia (a more severe phenotype was observed in Patient 2), but lacked dysmorphic features or neurocognitive impairment. Compound heterozygous PGM3 variants were identified, located in the phosphate‐binding domain of the enzyme. PGM3 expression was comparable to healthy donors, but L‐PHA binding in naïve‐CD4+ cells was decreased. Examination of exome sequence identified the presence of one additional candidate variant of unknown significance (VUS) in the N‐glycosylation pathway in Patient 2: a variant predicted to have moderate‐to‐high impact in ALG12. Conclusions: Our analysis revealed that L‐PHA binding is reduced in naïve‐CD4+ cells, which is consistent with decreased residual PGM3 enzymatic activity. Other gene variants in the N‐glycosylation pathway may modify patient phenotypes in PGM3 deficiency. This study expands the clinical criteria for when PGM3 deficiency should be considered among individuals with hyper‐IgE. [ABSTRACT FROM AUTHOR]

Introduction and Importance: Hyper-IgE syndrome (HIES), also known as Job syndrome, is a rare immunodeficiency disorder characterized by elevated immunoglobulin E levels and recurrent infections. Diagnosing and managing HIES in resource-limited settings is challenging due to the lack of advanced diagnostic tools. This report highlights the necessity of clinical evaluation and basic laboratory investigations for diagnosing HIES., Case Presentation: A 3-year-old male presented with fever, cough, and widespread pustular lesions. He had a history of recurrent respiratory infections and otitis media. Physical examination revealed characteristic facial features, skin findings, and laboratory investigations showed elevated immunoglobulin E levels (>3000 IU/ml) and leukocytosis. A clinical diagnosis of HIES was made, and the patient responded well to antibiotics, antihistamines, and topical steroids., Clinical Discussion: HIES is caused by genetic mutations affecting immune function, primarily involving STAT3 and DOCK8 genes. Diagnosis in resource-limited settings relies on clinical features and basic investigations. Challenges include the unavailability of genetic testing. Management includes antibiotics and symptomatic relief adapted to available resources., Conclusion: Diagnosing and managing HIES in resource-limited settings requires adaptation of clinical approaches to available resources. This case underscores the importance of clinical vigilance and basic diagnostic tools in diagnosing rare immunodeficiencies., Competing Interests: The authors declare no conflicts of interest.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Hyper-IgE syndrome (HIES) or Job syndrome is a rare immunodeficiency characterized by elevated levels of IgE and recurrent infections, eczema, and connective tissue abnormalities. Patients with HIES are prone to recurrent pyogenic and opportunistic infections due to impaired immune responses. Here, we present the case of an 11-year-old female diagnosed with HIES, who was admitted to the hospital with bacterial pneumonia and leg pain associated with a history of osteopenia. The patient's clinical course included fever, cough, throat pain, and leg pain. Management involved a rigorous course of antibiotics, antifungals, and cultures of pertinent pathogens, along with imaging of the lower extremity. This case underscores the importance of appropriate management strategies for patients with HIES and their comorbidities to mitigate the risk of infections and improve patient outcomes., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Elashmawy et al.)

Introduction: Hyper-IgE Syndrome (HIES) is a rare inborn error of immunity (IEI) characterized by a constellation of symptoms related to susceptibility to Staphylococcal skin and pulmonary infections, eczema, raised serum IgE (>2,000 IU/ml), craniofacial anomalies, and recurrent bone fractures. Data on HIES from the Indian subcontinent is scarce and restricted to small case series and case reports. This is the first compilation of national data on HIES.Materials and Methods: A total 103 cases clinically diagnosed and treated as HIES were analyzed from nine centers. Cases with clinical and/or molecular diagnosis of DOCK8 deficiency were not included. Patients were divided into two groups: group I for whom a heterozygous rare variant of STAT3 was identified, and group II, with clinical features similar to those of AD STAT3 deficiency, but without any genetic diagnosis.Results: Genetic diagnosis was available in 27 patients (26.2%) and all harbored rare variants in the STAT3 gene. Majority of these STAT3 HIES patients presented with recurrent skin abscesses (77.7%) or pneumonia (62.9%) or both (59.2%). Other features included eczema (37%), candidiasis (55.5%), facial dysmorphism (55.5%), recurrent fractures (11.1%), and retained primary teeth (7.4%). Mycobacterial infections were seen in a significant 18.5%. Mortality was seen in three subjects (11.1%). A similar trend in the clinical presentation was observed when all the 103 patients were analyzed together. Twenty percent of patients without a rare variant in the STAT3 gene had an NIH score of ≥40, whereas, 51.9% of STAT3 HIES subjects had scores below the cut off of ≥40. TH17 cell numbers were low in 10/11 (90.9%) STAT3 HIES tested. Rare variants observed were 8 in exon 21; 8 in exon 13; 3 in exon 10; 2 in exon 15, and one each in exon 6, 16, 17, 19, 22, and splice site downstream of exon 12. Seven variants were novel and included F174S, N567D, L404Sfs*8, G419 =, M329K, T714I, R518X, and a splice site variant downstream of exon 12.Conclusions: The report includes seven novel STAT3 variants, including a rare linker domain nonsense variant and a CC domain variant. Mycobacterial diseases were more frequent, compared to western literature.