hyper-IgE Research Articles

Disseminated Talaromyces marneffei Infection With STAT3-Hyper-IgE Syndrome: A Case Series and Literature Review.

Little is known about the clinical characteristics of talaromycosis with hyper-immunoglobulin E syndrome (HIES). We conducted a multicenter retrospective study, which included 7 hospitals from 2016 to 2022. Five consecutive cases of human immunodeficiency virus (HIV)-negative patients with systemic Talaromyces marneffei infections due to STAT3-HIES were identified. A systematic literature review of original articles published in English identified an additional 7 cases. Clinical characteristics and laboratory parameters were collected. Forty-two percent (5/12) of patients were young adults. The main symptoms of 10 patients were similar: fever (75%), cough (75%) and dyspnea (33%), but two patients mainly had gastrointestinal symptoms. Most patients had a history of infections since infancy. T marneffei was cultured from the bronchoalveolar lavage fluid (50%) and 25% of patients were next-generation sequencing positive. Eight patients had significantly elevated serum immunoglobulin E, increased B cells and decreased natural killer cells. There were ten different STAT3 mutations, three of which were reported for the first time in this study. Chest computed tomography examinations showed multiple exudations with cavities in the lungs. Voriconazole combined with thymosin was effective. Despite given antifungal agents, most had poor outcomes and the case fatality rate was as high as 25%. STAT3-HIES is most likely a susceptibility factor for T marneffei infections among HIV-negative patients, which has a high case fatality rate. Increased awareness among clinicians is necessary to help in early diagnosis.

Ovarian tissue cryopreservation in the pediatric with rare diseases- experience from China's first and the largest ovarian tissue cryobank.

There is limited information about the efficacy of ovarian tissue cryopreservation (OTC) in children. In the present study, we report eight patients with rare diseases who underwent OTC in China's first and largest ovarian tissue cryobank. Data from girls with rare diseases who underwent OTC between September 2020 and November 2022 were retrospectively analyzed. We also compared the number of cryopreserved cortex pieces, follicle number, and AMH in those with rare diseases and age-matched children with non-rare diseases who also underwent OTC in our cryobank. The median age of the children was 5.88 ± 3.52 (range 2-13) years old. Unilateral oophorectomy was undertaken via laparoscopy in all of the children. The diseases in the 8 patients were: 4 mucopolysaccharidoses (MPS I two cases, IVA two cases), 1 Diamond-Blackfan anemia (DBA), 1 Fanconi anemia (FA), 1 hyperimmunoglobulin E syndrome (HIES), 1 Niemann-Pick disease. The number of cryopreserved cortex pieces was 17.13 ± 6.36, and the follicle count per 2mm biopsy was 447.38 ± 524.35. No significant difference in age, the count of cryopreserved cortex pieces, follicle number per 2mm biopsy, and AMH level was seen between the 20 children with non-rare diseases and those with rare diseases. The reports help practitioners counsel girls with rare diseases about fertility preservation. The demand for OTC in pediatrics will likely grow as a standard of care.

Hyper‐IgE syndrome presenting with early life craniosynostosis in monozygotic twin sisters

<scp>Hyper‐IgE</scp> syndrome presenting with early life craniosynostosis in monozygotic twin sisters

Treatment of patients with atopic dermatitis and extremely high immunoglobulin E: world experience and own clinical observation

Atopic dermatitis is a chronic inflammatory skin disease characterized by a recurrent course, difficulty in individual selection of therapy, especially in patients with severe course. When examining and treating such patients, one of the routine diagnostic methods is to determine the level of total immunoglobulin E in the blood serum. The article is devoted to the analysis of available world practice data on published clinical cases of the use of biological therapy with dupilumab in real clinical practice in patients with severe atopic dermatitis, in whom high and very high levels of immunoglobulin E. The appointment of biological therapy for this cohort of patients often raises significant concerns. However, the use of a monoclonal antibody against IL-4/IL-13 proved effective, did not lead to serious adverse reactions in such patients and was accompanied by a decrease in the level of immunoglobulin E during treatment. It was noted that immunosuppressive treatment prior to biological therapy led to the development of adverse events in these patients. A separate group of patients with genetically determined hyper-IgE syndrome and severe atopic dermatitis is described, in which the positive experience of using dupilumab is also noted. The author presents his own clinical case of a patient with severe atopic dermatitis and a high level of immunoglobulin E receiving successful targeted therapy after a preliminary thorough examination except for lymphoproliferative and autoimmune diseases. Against the background of dupilumab therapy, there was a pronounced clinical regression of skin symptoms, a decrease in the level of immunoglobulin E, an increase in the patient’s quality of life, and the absence of side effects.

A novel STAT3 splice-site variant in a kindred with autosomal dominant hyper IgE syndrome

Background: Dominant negative STAT3 loss-of-function is the most common genetic cause of hyper-IgE syndrome (HIES). Patients may present with a host of both immune and non-immune manifestations, including connective tissue abnormalities, recurrent infections, malignant predisposition, and biochemical evidence of elevated serum IgE or eosinophilia. Aim: To describe a novel splice-site variant in STAT3 resulting in HIES. Methods: Case report of two family members with HIES. Results: A proband and his son presented with neonatal-onset pustular rash, recurrent skin and sinopulmonary infections and elevated serum IgE and were diagnosed with AD-HIES. They were identified to harbor a novel splice-site variant in the DNA-binding domain (DBD) of STAT3: c.1110-3C&gt;G, predicted to result in defective splicing in exon 12. Interestingly, a number of other patients with AD-HIES have mutations affecting the same splice-site, suggesting this may be a hot-spot for mutagenesis. Conclusion: Splice-site mutations in the DBD of STAT3 are increasingly identified as a cause of AD-HIES. Future work is required to delineate whether patients with splice-site mutations have unique clinical characteristics, supporting efforts for genotype-phenotype correlation in this disease. Statement of Novelty: We present a novel splice-site mutation in the DNA-binding domain of STAT3 leading to autosomal dominant hyper-IgE syndrome.

Haematopoietic Stem Cell Transplantation (HSCT) for Primary Immune System Disorders in Children: A Single Centre Experience.

To determine the outcomes of allogeneic HSCT in children with primary immune system disorders (PID). Descriptive Cross-sectional study. Place and Duration of the Study: Armed Forces bone marrow transplant centre / National Institute of Bone Marrow Transplant (AFBMTC / NIBMT), Rawalpindi, Pakistan, from October 2012 to December 2021. Data of all cases undergoing HSCT for immune system disorders were analysed for variables affecting outcome and overall survival in the first 180 days after allogeneic HSCT. All patients presenting to AFBMTC / NIBMT with PID, age <12 years. Patients with organ dysfunction secondary to repeated infections were excluded from the study. Data of all patients and their donors undergoing HSCT for immune system disorders were analysed for variables affecting outcome and overall survival in the first 180 days after allogeneic bone marrow transplant. Neutrophil engraftment was defined as absolute neutrophil count ≥0.5 × 109/L for 3 consecutive days, while platelet engraftment as platelet count ≥20 × 109/L without platelet transfusion for one week. Overall survival (OS) was taken as time from the date of HSCT till day + 180 post-transplant. A total of 42children including 29 boys and 13 girls underwent HSCT for PID. The mean age was 2.1±2.8 years. Underlying diagnosis was haemophagocytic lymphohistiocytosis (HLH), severe immune deficiency (SCID), leukocyte adhesion defect (LAD), X-linked agammaglobulinemia, chronic granulomatous disease (CGD) and Job's syndrome in 18 (42.9%), 16 (38.1%), 3(7.1%), 2 (4.8%), 2 (4.8%) and 1 (2.4%) patients respectively. Thirty-one (73.8%) children had fully HLA-matched donors while 11 (26.2%) had haplo-matched donors. Major immediate post-transplant complications were febrile neutropenia, mucositis and SOS/VOD in 31 (73.8%), 9 (21.4%) and 4 (10.0%) cases, respectively. Eight (19.0%) had CMV reactivation, acute GVHD was seen in 17 (40.4%) cases, while 1 (2.3%) case had chronic GVHD. Twelve (28.6%) patients died, out of which 5 had graft failure, 3 had VOD, 2 had pneumonia, 1 had severe GVHD, and 1 died due to seizures. Overall survival (OS) in this study was 71.4% with survival reaching up to 80.6% in fully matched HSCT. HLH and SCID were the commonest immune disorders requiring HSCT. Graft failure leading to neutropenic sepsis was the commonest cause of mortality. OS was better in fully matched HSCT as compared to haplo-identical HSCT. Immune deficiency, Severe combined immunodeficiency, Haematopoietic stem cell transplantation.

Idiopathic non-cirrhotic portal hypertension in a patient with Talaromyces marneffei infection: a case report

BackgroundThe 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 presentationWe 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.ConclusionIn 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.

Allergic Bronchopulmonary Aspergillosis in Patients with Dominant Negative IL6ST

Pathogenic variants in IL6ST cause a Hyper-IgE syndrome (HIES) that presents similarly to STAT3 dominant negative (DN) HIES. Severe structural lung disease with bronchiectasis and pneumatoceles is a major driver of morbidity in this disease. We describe clinical characteristics of four patients with heterozygous IL6ST variants with presentations consistent with allergic bronchopulmonary aspergillosis (ABPA).

The signal transducer and activator of transcription 3 at the center of the causative gene network of the hyper-IgE syndrome.

The hyper-IgE syndrome (HIES) is characterized by atopic dermatitis with extremely high serum IgE levels and diminished inflammatory responses, in combination with bacterial and fungal infections followed by pneumatocele formation. These immunological manifestations are frequently associated with nonimmunological abnormalities, including characteristic face, pathological fracture, and retention of deciduous teeth. We previously identified that major causal variants of the HIES are dominant-negative variants in the signal transducer and activator of transcription 3 (STAT3) gene. Several new causative variants of HIES have been identified, interestingly, most of which are functionally associated with STAT3. These include a zinc finger transcription factor ZNF341 as well as IL-6 family cytokine receptors, IL6ST, and IL-6R. In this review, I will outline the pathological mechanisms of new causative variants, in which STAT3 is at the center of the causative gene network.

Combined immunodeficiency due to DOCK8 deficiency. State of the art

Combinedimmunodeficiency (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 varicella-zoster 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.

Germline Mosaicism in STAT3: A Pitfall for Genetic Diagnosis, Counseling, and Therapy of Hyper-IgE Syndrome.

Germline Mosaicism in STAT3: A Pitfall for Genetic Diagnosis, Counseling, and Therapy of Hyper-IgE Syndrome.

Hyper-IgE syndrome with recurrent infections — An autosomal dominant multisystem disorder

Hyper IgE syndrome (HIES) is a rare disorder characterized by eczema, recurrent infections of the skin and lungs, typically with Staphylococcus aureus, Candida albicans and certain viruses, and elevated levels of serum IgE. Other clinical manifestations include characteristic facies (prominent forehead, broad nasal bridge and facial asymmetry), chronic eczematous dermatitis, retained primary dentition, recurrent pathological fractures, hyper-extensibility and scoliosis. The respiratory system involvement in HIES has been reported with HRAD. Here we presented a case of HIES with rare associations of Hyperreactive airway disease.

Multiplex Proteomic Evaluation in Inborn Errors with Deregulated IgE Response.

(1) Background: Atopic dermatitis constitutes one of the most common inflammatory skin manifestations of the pediatric population. The onset of many inborn errors occurs early in life with an AD-like picture associated with a deregulated IgE response. The availability of proteomic tests for the simultaneous evaluation of hundreds of molecules allows for more precise diagnosis in these cases. (2) Methods: Comparative genomic hybridization microarray (Array-CGH) analysis and specific IgE evaluation by using allergenic microarray (ISAC) and microarray (ALEX2) systems were performed. (3) Results: Proteomic investigations that use multiplex methods have proven to be extremely useful to diagnose the sensitization profile in inborn errors with deregulated IgE synthesis. Four patients with rare diseases, such as recessive X-linked ichthyosis (RXLI, OMIM 308100), Comel-Netherton syndrome (NS, OMIM256500), monosomy 1p36 syndrome (OMIM: 607872), and a microduplication of Xp11.4 associated with extremely high levels of IgE: 7.710 kU/L, 5.300 kU/L, 1.826 kU/L, and 10.430 kU/L, respectively, were evaluated by micro- and macroarray multiplex methods. Polyreactivity to both environmental and food allergens was observed in all cases, including the first described case of association of X-chromosome microduplication and HIE. (4) Conclusions: Extensive use of proteomic diagnostics should be included among the procedures to be implemented in inborn errors with hyper-IgE.

Autoimmune myositis and autoimmune hemolytic anemia in two sisters with DOCK8-deficient hyper-IgE syndrome.

Autoimmune myositis and autoimmune hemolytic anemia in two sisters with DOCK8-deficient hyper-IgE syndrome.

STAT3 mutation-associated airway epithelial defects in Job syndrome

Job syndrome is a disease of autosomal dominant hyper-IgE syndrome (AD-HIES). Patients harboring STAT3 mutation are particularly prone to airway remodeling and airway infections. Airway epithelial cells play a central role as the first line of defense against pathogenic infection and express high levels of STAT3. This study thus interrogates how AD-HIES STAT3 mutations impact the physiological functions of airway epithelial cells. This study created human airway basal cells expressing 4 common AD-HIES STAT3 mutants (R382W, V463del, V637M, and Y657S). In addition, primary airway epithelial cells were isolated from a patient with Job syndrome who was harboring a STAT3-S560del mutation and from mice harboring a STAT3-V463del mutation. Cell proliferation, differentiation, barrier function, bacterial elimination, and innate immune responses to pathogenic infection were quantitatively analyzed. STAT3 mutations reduce STAT3 protein phosphorylation, nuclear translocation, transcription activity, and protein stability in airway basal cells. As a consequence, STAT3-mutated airway basal cells give rise to airway epithelial cells with abnormal cellular composition and loss of coordinated mucociliary clearance. Notably, AD-HIES STAT3 airway epithelial cells are defective in bacterial killing and fail to initiate vigorous proinflammatory responses and neutrophil transepithelial migration in response to an experimental model of Pseudomonas aeruginosa infection. AD-HIES STAT3 mutations confer numerous abnormalities to airway epithelial cells in cell differentiation and host innate immunity, emphasizing their involvement in the pathogenesis of lung complications in Job syndrome. Therefore, therapies must address the epithelial defects as well as the previously noted immune cell defects to alleviate chronic infections in patients with Job syndrome.

Diagnostic challenge in a series of eleven patients with hyper IgE syndromes.

Hyper IgE syndromes (HIES) is a heterogeneous group of Inborn Errors of Immunity characterized by eczema, recurrent skin and lung infections associated with eosinophilia and elevated IgE levels. Autosomal dominant HIES caused by loss of function mutations in Signal transducer and activator of transcription 3 (STAT3) gene is the prototype of these disorders. Over the past two decades, advent in genetic testing allowed the identification of ten other etiologies of HIES. Although Dedicator of Cytokinesis 8 (DOCK8) deficiency is no more classified among HIES etiologies but as a combined immunodeficiency, this disease, characterized by severe viral infections, food allergies, autoimmunity, and increased risk of malignancies, shares some clinical features with STAT3 deficiency. The present study highlights the diagnostic challenge in eleven patients with the clinical phenotype of HIES in a resource-limited region. Candidate gene strategy supported by clinical features, laboratory findings and functional investigations allowed the identification of two heterozygous STAT3 mutations in five patients, and a bi-allelic DOCK8 mutation in one patient. Whole Exome Sequencing allowed to unmask atypical presentations of DOCK8 deficiency in two patients presenting with clinical features reminiscent of STAT3 deficiency. Our study underlies the importance of the differential diagnosis between STAT3 and DOCK8 deficiencies in order to improve diagnostic criteria and to propose appropriate therapeutic approaches. In addition, our findings emphasize the role of NGS in detecting mutations that induce overlapping phenotypes.

Association of hyper IgE with herpetic viral encephalitis and ecthyma gangrenosum in a male Egyptian patient

There are two forms of hyper-immunoglobulin E syndromes (HIES): a dominant form (AD-HIES) is caused by mutations in signal transducer and activator of transcription 3 (STAT3), and a recessive form (AR-HIES) is caused by mutations in dedicator of cytokinesis 8 (DOCK8). DOCK8 autosomal recessive hyper IgE syndrome (AR-HIES) patients have a more symptomatic neurologic disease than those with STAT3 deficiency. Involvement of the central nervous system in patients with HIES has been rarely reported. Being a rare primary immuno-deficiency, the disease may be underdiagnosed and under-reported. In the central nervous system abnormalities with definite neurologic manifestations, very few articles were published previously which may vary from hemiplegia to partial facial nerve paralysis in children and acute disseminated encephalomyelitis (ADEM), but viral encephalitis has not been reported. Herein, we describe a 21-year-old male with hyper-immunoglobulin E syndrome presented with fever, pneumonia, skin abscesses, and altered consciousness who proved to have herpetic viral encephalitis. The purpose of this study is to emphasize that neurologic complications with herpetic viral encephalitis may occur in patients with hyper IgE syndrome. In the case series, no cases of hyper IgE were described to have viral encephalitis, and to the best of our knowledge, this is the first description of herpes simplex encephalitis in a patient with hyper IgE syndrome.

Hyper IgE syndrome with autoimmune hemolytic anemia in Saudi Arabia

Background: Hyper IgE syndrome (HIES) is a rare primary immunodeficiency disorder characterized by elevated serum immunoglobulin E (IgE) levels. Autosomal dominant and autosomal recessive forms of HIES have been reported. Autosomal recessive HIES typically includes a history of asthma, atopic dermatitis, food allergy, and recurrent viral infection. HIES diagnosis requires genetic study, which is time-consuming and not always feasible. Case Presentation: We report the case of an 8-year-old female. The patient recently presented to our emergency department with pallor and syncope. Upon examination, the hemoglobin level was 4.9 g/dl. Direct antiglobulin test showed a positive result. The patient had an admitting diagnosis of autoimmune hemolytic anemia, a rare complication of autosomal recessive HIES. The patient is a known case of asthma, herpetiformis dermatitis, nut allergy, and allergic rhinitis. HIES was the first possible diagnosis, which was further confirmed by clinical presentation and a high serum IgE count. The patient was referred to a tertiary care center for genetic counseling and further follow-up. Conclusion: HIES is a rare immune deficiency disorder that can be inherited in either an autosomal dominant or recessive pattern. Although these two types show similar clinical presentations, certain features remain distinct, providing a valuable insight into the final diagnosis even without the gene study results. To the best of our knowledge, no study has evaluated HIES in general, and no case report has evaluated autosomal recessive HIES in Saudi Arabia. This case study will guide the medical community in the early-stage diagnosis and management of HIES.

Dupilumab in the treatment of genodermatosis: A systematic review.

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 immunoglobulinE levels and cytokine normalization have also been documented. In conclusion, Dupilumab may have a potential therapeutic role in certain genodermatoses skewed towards Thelper 2 (Th2) immunity, including Netherton syndrome, epidermolysis bullosa pruriginosa, hyper-IgE syndrome, Hailey-Hailey disease, and severe eczema associated with some genetic disorders.

The role of flexible bronchoscopy in the diagnostic pathway of children with unexplained peripheral eosinophilia.

Many possible underlying causes can be seen in children with unexplained peripheral eosinophilia (UPE) with suspected pulmonary involvement. Here, we aimed to demonstrate the clinical characteristics and diagnoses of children evaluated for UPE who underwent diagnostic bronchoscopy. Thirty-one children who underwent diagnostic bronchoscopy for UPE between 2006-2018 were included. Demographic characteristics, bronchoscopy findings and final diagnosis, and treatments were evaluated. The median age at the time of diagnosis was 5 (0.25-17.5) years. The final diagnoses of 26 patients were as follows: immunodeficiency (n=6); hyper-IgE syndromes (n=4), DOCK8 deficiency + HES (idiopathic hypereosinophilic syndrome; n=1), and severe combined immunodeficiency (n=1), HES (n=3), idiopathic chronic eosinophilic pneumonia (ICEP; n=3), idiopathic pulmonary hemosiderosis (n=1), B cell lymphoma (n=1). In one child, an integrin α3 mutation + cytomegalovirus (CMV) pneumonia was detected. Congenital pneumonia was found in one patient, and parasitic infection in another. In two, eosinophilia was attributed to underlying asthma and atopy. In four, the underlying reasons could not be elucidated. Two children with HES and one with ICEP were lost to follow-up. There was no significant relationship between the peripheral eosinophil count at the time of diagnosis and the percentage of bronchoalveolar lavage eosinophils (BAL). Bronchoscopy contributed to the management of 14 (53.9%) patients. Bronchoscopy has potential diagnostic contribution in patients with UPE suspected of having pulmonary involvement. Numerous various underlying causes may be present in this patient group. There is no relation between peripheral eosinophil count and BAL eosinophil percentage.