Clinical analysis of hyperimmunoglobulin E syndrome in children with STAT3 and DOCK8 mutations in different genotypes

Introduction

Background

Hyperimmunoglobulin E syndrome (HIES) is a rare primary immunodeficiency disorder characterized by a marked susceptibility to infections caused by specific pathogens, the presence of eczema, and elevated serum levels of immunoglobulin E (IgE), with an annual incidence of <1/10⁶ (1). In 1966, Davis et al. (2) first described it as Job’s syndrome. The autosomal dominant form of HIES (AD-HIES) is typical of Job’s syndrome, mostly sporadic, and involves both immune and non-immune system manifestations (3). The autosomal recessive form of HIES (AR-HIES) primarily affects the immune system, demonstrates higher susceptibility to cutaneous viral infections, and is more commonly observed in children born to consanguineous parents. However, the heterogeneous clinical presentation of HIES among individuals, coupled with the potential for significant comorbidities, presents considerable challenges in its diagnosis and management.

Rationale and knowledge gap

HIES has complex clinical manifestations and multisystem involvement. The published literature, both domestic and international, consists mainly of case reports; large-scale clinical studies are relatively scarce. In 2007, it was identified that AD-HIES is primarily due to dominant-negative heterozygous mutations in the signal transducer and activator of transcription-3 (STAT3) gene, accounting for 70% of all HIES cases (3). A hallmark feature of HIES is the significantly elevated serum levels of IgE, which result from dysregulated IgE production. Mutations in the STAT3 gene disrupt the interleukin (IL)-21 (IL-21)-mediated inhibition of IgE class-switching in B cells, leading to an uncontrolled synthesis of IgE. HIES is distinguished by notable cutaneous abnormalities, predominantly presenting as chronic eczema accompanied by recurrent bacterial or fungal infections. The impaired skin barrier function observed in HIES can be partially attributed to mutations in the STAT3 gene, which impede the production of T helper 17 (Th17) cytokines, including IL-17 and IL-22. These cytokines are crucial for epithelial defense by promoting the release of antimicrobial peptides and maintaining skin barrier integrity. AR-HIES is significantly rarer than AD-HIES and results from mutations in genes such as dedicator of cytokinesis 8 (DOCK8), phosphoglucomutase 3 (PGM3), or, less commonly, tyrosine kinase 2 (TYK2) genes (4). DOCK8 deficiency disrupts T cell-B cell interactions, impairs immune cell trafficking (migration), and compromises the response to pathogens. Patients with AR-HIES typically manifest as a severe form of immunodeficiency, characterized by recurrent bacterial, viral, and fungal infections. In contrast to AD-HIES, AR-HIES is largely devoid of most non-immunologic features (e.g., skeletal or connective tissue abnormalities); however, it exhibits a higher incidence of malignancies. The other single-gene disorders with a HIES phenotype include tyrosine kinase 2 (TYK2), glucose phosphomutase 3 (PGM3), serine peptidase inhibitor Kazal Type 5 (SPINK5), and IL-6 signal transduction (IL-6ST). The diagnosis of HIES is based on a comprehensive assessment of clinical features and laboratory parameters, as there is currently no singular definitive diagnostic test available. Genetic testing can confirm the diagnosis, but there is currently no cure for the underlying defect.

Objective

This study analyzed the clinical characteristics of 25 HIES cases, focusing on the two main genetic subtypes (STAT3 and DOCK8 mutations) and their correlation with genetic variations, to improve clinical diagnosis and management. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-278/rc).

Methods

Cases were diagnosed using the National Institutes of Health HIES scoring system (5) (based on clinical and laboratory findings) combined with genetic testing. We retrospectively analyzed clinical data from seven children with STAT3 mutation-induced HIES treated at Children’s Hospital of Nanjing Medical University between August 2014 and March 2021. Using “Hyperimmunoglobulin E Syndrome” and “DOCK8 gene mutation” as search terms, 18 cases of DOCK8 mutation-associated HIES in China were retrieved from Wanfang Data. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Approval for the study was granted by the ethics committee of Children’s Hospital of Nanjing Medical University (No. 202412018-1), and individual consent for this retrospective analysis was waived.

Statistical analysis

All data were analyzed using SPSS/PASW version 20.0 statistical software. The normality of continuous variables was assessed using the Shapiro-Wilk test. Data that did not follow a normal distribution are presented as median with interquartile range (IQR).

Results

General characteristics

They were divided into the STAT3 group and the DOCK8 group according to the gene mutation type. Among 25 children, the STAT3 group included five males and two females; the DOCK8 group included four males and 14 females. The age of onset ranged from two days to eight months (STAT3 group) and half months to three years (DOCK8 group) (Table 1). The ages of the diagnosis were six months to 11 years and the median age was 7.5 (3.75–10.25) years in the STAT3 group. The ages of the diagnosis were 15 months to 14 years and the median age was 6.35 years (range: 3.43–9 years) in the DOCK8 group. None of the STAT3 group cases were from consanguineous families; while in the DOCK8 group, one case was adopted, one was an orphan, and two were from consanguineous unions.

Clinical manifestation

Atopic diseases

All 25 cases had eczema or atopic dermatitis; one case in the DOCK8 group had asthma.

Skin and pulmonary infections

In the STAT3 group, six cases had skin abscesses [including one perianal abscess, one local abscess at the Bacillus Calmette-Guérin (BCG) vaccination site, and two with fungal infections]. In the DOCK8 group, two cases had skin abscesses; six had mucocutaneous fungal infections (two oral, two chronic nail); one had flat warts, seven had molluscum contagiosum, and one had varicella complicated by encephalitis and myelitis.

All 25 cases had recurrent pulmonary infections. In the STAT3 group, one case had pyopneumothorax; imaging showed severe airway and parenchymal lung damage in five cases, manifesting as two with lung cysts, two with pulmonary bullae, and two with bronchiectasis. One bronchiectasis case had left main bronchomalacia (confirmed by bronchoscopy); another showed extensive ciliary shedding and absent ciliary microtubule structure on bronchial mucosal biopsy, with pulmonary function tests indicating mixed ventilation dysfunction (severe restrictive and moderate obstructive) and a positive bronchodilation test. In the DOCK8 group, one case had interstitial pneumonia, one had tuberculosis (TB) with mediastinal lymph node involvement, and three had bronchiectasis (Figure 1A,1B).

Figure 1 Imaging manifestations of the cases with HIES. (A,B) Cavity, lung cyst with infection, bronchiectasis. (C) Several cystic low-density shadows in the liver, liver abscess. HIES, hyperimmunoglobulin E syndrome.

Other infections

In the STAT3 group, one patient had multiple giant liver abscesses (Figure 1C), three patients had recurrent otitis media, one patient had cervical lymph node infection, one patient had neck lymphangioma with infection, and one patient had infectious arthritis.

In the DOCK8 group, 11 patients had recurrent otitis media, five patients had sinusitis, three patients had conjunctivitis, and seven patients had stomatitis.

Facial, skeletal, and dental abnormalities

In the STAT3 group, five patients had distinctive facial features; three patients had metacarpophalangeal joint hypermobility, one patient had scoliosis, and five patients had delayed deciduous tooth exfoliation. In the DOCK8 group, one patient had distinctive facial features; two patients had metacarpophalangeal joint hypermobility, three patients had scoliosis, and one patient had a clavicle fracture from a fall; two patients had delayed deciduous tooth exfoliation.

Vascular calcification

One case in the DOCK8 group had calcification of neck vessels.

Laboratory examinations

Immunological tests

In the STAT3 group, six cases had elevated serum total IgE and eosinophil (EOS) counts (EOS ratio up to 28%); one case had normal levels. Among six cases tested for allergens, five cases had positive food allergen results; one case had positive inhalation allergen results (dust mites) at 12.2 years of age, with recurrent cough and sputum but no wheezing. In the DOCK8 group, all 18 cases had elevated serum total IgE; 17 cases had elevated EOS counts/proportions (up to 77%); four cases had positive food allergen tests, and six cases had food allergies. In the STAT3 group, one case had significantly decreased immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin A (IgA) [complicated by immune thrombocytopenic purpura (ITP)]; one case had decreased CD4⁺ T cells. In the DOCK8 group, one case had significantly elevated IgG (complicated by severe autoimmune hemolysis); 15 cases had decreased IgM; 12 cases had decreased CD4⁺ T cells.

Pathogen examination

In the STAT3 group, four cases had Staphylococcus aureus infection (pus culture), three cases had Mycoplasma pneumoniae (MP) infection (IgM antibody/sputum-MP-cDNA), one case had Hemophilus influenzae infection (sputum culture), and one case had TB infection (TB-DNA positive in BCG vaccination site abscess discharge).

In the DOCK8 group, one case had Staphylococcus aureus (pus culture), one case had Hemophilus influenzae infection (sputum culture), and one case had TB infection (acid-fast stain positive in mediastinal lymph node biopsy). Four cases had fungal infections: one with Pneumocystis carinii (bronchoalveolar lavage fluid metagenomic testing) and three cases with Candida albicans (one from the exudate of vulva rash and two from onychomycosis culture). Viral infections included two cases of herpes simplex virus (HSV), three of human papillomavirus (HPV), one of molluscum contagiosum virus (MCV), one of varicella-zoster virus (VZV), six of Epstein-Barr virus (EBV), one of cytomegalovirus (CMV), one of measles virus (MV), and one of hepatitis B virus (HBV).

Gene sequencing

All STAT3 group cases had STAT3 mutations: five spontaneous mutations, one with confirmed sequencing (unknown mutation site), and one with no parental testing. Six cases had missense variants (two unreported; one with a heterozygous variant inherited from the father).

All DOCK8 group cases had homozygous or compound heterozygous DOCK8 mutations, including large-fragment deletions, missense mutations, or frameshift mutations (four unreported). One case inherited a mutation from the father, one from the mother, and nine from both parents.

Treatment and follow-up

In the STAT3 group, all cases received active anti-infective therapy: one case with prophylactic cotrimoxazole, two with regular intravenous immunoglobulin (IVIG) supplementation (400 mg/kg/month), and four with local abscess drainage, two with bronchoscope alveolar lavage. All were discharged after treatment. Follow-up findings: case 1, which was followed for three years and 11 months, had recurrent pneumonia with mild bronchial dilatation; case 2, which was followed for three years, had recurrent skin infection, lymphadenitis, otitis media, and no lung parenchymal abnormalities; case 3, which was followed for four years and five months, had pulmonary bulla/cysts, recurrent skin abscesses, right cervical lymphangioma with infection, lymphadenitis, and liver abscess; case 4, which was followed for four years and nine months, had recurrent pulmonary infection, underwent thoracoscopic pulmonary cyst excision and partial lobectomy, with worsening bronchiectasis; case 5, which was followed for one year, had recurrent pneumonia and rash and underwent excision of a pulmonary cyst, but the cyst recrudesced after surgery; case 6, which was followed for two years, had recurrent pneumonia, rash and skin infection, while lung cysts became bigger compared to the previous; case 7, which was followed for one and a half years, had recurrent pneumonia and recovered from a right pulmonary abscess with anti-infection treatment.

Six cases in the DOCK8 group were followed up, receiving anti-infective (antibacterial, antifungal, antituberculosis, antiviral), antiallergic, glucocorticoid, IVIG, and supportive therapies. Eczema, skin and pulmonary infections compared to the previous were controlled. Two cases underwent allogeneic hematopoietic stem cell transplantation (HSCT), achieving immune reconstitution; post-transplant, peripheral blood EOS percentage and serum IgE levels decreased significantly, with disease-free survival.

Discussion

Key findings

Distinguishing between the two forms of HIES clinically is challenging due to significant overlap in their initial symptoms (e.g., respiratory infections, eczema, cutaneous infections, elevated IgE, eosinophilia). Genetic testing for the detection of variants in STAT3 or DOCK8 remains the gold standard for diagnosis. Currently, there is no treatment that can cure the basic defect of HIES. Immune reconstitution is the fundamental treatment for the eradication of primary immunodeficiency disease (PIDs), and HSCT may be a key curative approach for HIES.

Strengths and limitations

HIES poses considerable diagnostic and management challenges owing to its phenotypic variability, clinical overlap with other atopic and immunodeficiency disorders, and the complexity of the underlying genetic mutations. Despite significant advancements in genetic testing, challenges such as delayed diagnosis, misdiagnosis, and suboptimal management continue to be prevalent issues that negatively impact patient outcomes (6). Even after diagnosis, managing HIES remains challenging owing to the lack of standardized treatment guidelines and the variability in disease progression. Therefore, there is an urgent need for molecular diagnosis via genetic testing to serve as a definitive diagnostic tool. The cornerstone of the treatment for HIES is the early administration of broad-spectrum antibiotics/antifungal agents to control skin and lung infections, as well as the surgical drainage of abscesses. The role of HSCT is currently under active investigation, and HSCT can only correct the immunodeficiency in most cases.

Comparison with similar research

The median age of diagnosis in our STAT3 group (7.5 years) was earlier than in the US Immune Deficiency Network (USIDNET) cohort (85 cases, 13.8 years) (7), Shanghai cohort (17 cases, 10.35 years) (8), but later than the Chongqing cohort (20 cases, 5.31 years) (9). Chinese cohorts had higher mortality rates (17.65% Shanghai, 15% Chongqing), but no deaths occurred in our STAT3 group. The prevalence, mutational spectrum and molecular pathogenesis of HIES remain incompletely understood.

The core clinical features of HIES—eczema (atopic dermatitis), recurrent skin/lung infections—are early diagnostic clues, as initial symptoms of both subtypes overlap. In our STAT3 group, and 100% had eczema, 85.7% skin abscesses, and 100% pneumonia—proportions similar to the Shanghai cohort.

The STAT3 group had more Staphylococcus aureus infections, while the DOCK8 group had more cutaneous viral infections (HSV, HPV, EBV). Candida albicans was a common cause of mucocutaneous infections in both groups (two onychomycosis cases in STAT3 group; six mucocutaneous fungal infections in DOCK8 group).

All cases in both groups had recurrent pulmonary infections. STAT3-deficient HIES frequently develops pneumatoceles (two cases with pulmonary cysts, two with bullae in our series). DOCK8-deficient HIES often leads to recurrent pulmonary infections with bronchiectasis (three cases in our DOCK8 group). Unlike the low chronic otitis media incidence reported in the Shanghai cohort, our STAT3 group had three cases and the DOCK8 group had 11 cases.

Non-immune features are typical of AD-HIES, including distinctive facial features (e.g., rough appearance, prominent forehead, sunken eyes, widened nasal base, and craniosynostosis), skeletal abnormalities (10) (e.g., scoliosis, fractures, osteoporosis and joint hypermobility), dental abnormalities (deciduous tooth retention), vascular abnormalities (e.g., coronary aneurysm, lymphocytic myocarditis). These typically appear in late childhood/early adolescence. Our STAT3 group frequently had rough facial features, joint hypermobility, and delayed deciduous tooth exfoliation—consistent with the established literature. The results of one study indicated that in 6.5% of cases, HIES was complicated by malignant tumors (particularly lymphomas) (11). Lymphoma, vascular abnormalities and scoliosis were absent or less prevalent in Chinese AD-HIES. Our STAT3 group had one scoliosis case, no malignancies/vascular abnormalities; the DOCK8 group had three scoliosis cases and one vascular calcification case.

Patients with DOCK8-deficient HIES demonstrate elevated food allergen-specific IgE levels and a more prominent allergic phenotype compared to those with STAT3-deficient HIES, who typically exhibit attenuated allergic manifestations (5). In our study, five cases tested positive for food allergens, and one tested positive for inhaled allergens in STAT3 group; 10 cases tested positive for food allergens in DOCK8 group.

The majority of STAT3 mutation had normal immunoglobulin concentration and normal numbers and function of T cells. In our STAT3 group, four cases had slightly increased IgG, one case had elevated IgM, one case had decreased IgG/IgM/IgA, and three cases had slightly decreased CD4⁺ T cells. DOCK8 deficiency often causes low IgM and cellular immunodeficiency (e.g., lymphocytopenia, particularly T-cell lymphopenia). In our DOCK8 group, 15 cases had decreased IgM and 12 had decreased CD4⁺ T cells.

Secondary pulmonary infections can also be caused by Aspergillus and Pseudomonas aeruginosa. Duréault et al. (12) reported that 17.5% of 74 STAT3-deficient cases in a French cohort had chronic allergic aspergillosis. Saikia et al. (13) reported TB or mycobacterial infection in five of 27 (18.5%) STAT3-HIES cases in an Indian cohort. In two Chinese cohorts, BCG-associated adverse events were reported in 37.5% (Shanghai cohort) and 38.8% (Chongqing cohort) of vaccinated infants, including local abscesses/ulceration at the BCG injection site and disseminated BCG disease. In our STAT3 group, three cases had MP infection, one case had Haemophilus influenzae infection, and one case had TB. MP may be a key pathogen in Chinese AD-HIES children.

Explanations of findings

STAT3 serves as a crucial component in various cytokine signaling pathways, including IL-6, IL-10, IL-21, and IL-22. Additionally, it plays a vital role in the differentiation of Th17 cells and exerts inhibitory control over excessive IgE production. STAT3 mutations disrupt downstream signaling of IL-6, IL-10, and IL-21, resulting in impaired inflammatory responses and defective neutrophil recruitment. This culminates in the hallmark “cold” staphylococcal abscesses observed in HIES patients. The STAT3 modulates IL-11 signaling and the production of matrix metalloproteinases (MMPs), processes critical for the physiological shedding of primary dentition and the ossification of cranial sutures. STAT3 activation mediated by IL-6 regulates osteopontin (OPN) gene expression, and its significant dysregulation in STAT3-deficient HIES may contribute to the pathogenesis of dental/facial manifestations (14).

Most of HIES patients have extremely high levels of IgE (due to impaired IL-10 and IL-21 signals), but levels of IgE begin to rise after birth and decline or may normalize in adulthood; thus, normal or IgE levels <2,000 IU/mL do not rule out HIES. Eosinophilia is present in over 90% of patients, typically with absolute counts around 700/µL. In our study, six STAT3 cases had serum IgE >2,000 IU/mL and elevated EOSs; all DOCK8 cases had elevated IgE, and 17 cases had elevated EOSs. But there was no association between increased blood EOS count with increased IgE. Nandy et al. (15) reported a case of a boy with HIES who had recurrent liver abscess and no eczema or eosinophilia, and had increased IgE levels after resolution of symptoms.

The STAT3 deficiency immunophenotype includes high IgE, eosinophilia, severely reduced Th17 cells, and low memory B cells. Th17 cells play a critical role in IL-17 and IL-22 secretion and are susceptible to extracellular bacteria Staphylococcal and Candida infections. The DOCK8 deficiency immunophenotype included high IgE levels, eosinophilia, and reduced T/natural killer (NK) cells (16). The DOCK8 gene regulates actin cytoskeleton organization and STAT3 nuclear translocation. Its role in modulating STAT3 function and Th17 differentiation provides a molecular basis explaining the overlapping clinical features between AD-HIES (STAT3-deficient) and DOCK8 deficiency. Recurrent pulmonary infections in children with HIES are primarily caused by Staphylococcus aureus and less commonly, Streptococcus pneumoniae. Recurrent pulmonary infections in children with HIES are mainly caused by Staphylococcus aureus or more rarely Streptococcus pneumoniae. Impaired clearance of pneumococci due to poor response to IL-17A may cause increased rates of pneumococcal respiratory infections in AD-HIES patients (17). DOCK8 mutations disrupt the regulation of the actin cytoskeleton, leading to defective T cell activation, impaired differentiation of Th17 cells, and an increased susceptibility to viral and bacterial infections. In our DOCK8 group, one case had Haemophilus influenzae, one had TB, and one had Pneumocystis carinii.

Loss-of-function mutations in the STAT3 gene are responsible for AD-HIES. The majority of these mutations are missense mutations. In the STAT3 group, five cases were spontaneous mutation, including one case with whose father carries a pathogenic mutation, two cases with R382W/Q amino acid change, and two cases of V637M mutation; two cases mutation were not reported, including one case was c.1859C>T, which the pathogenicity of the variant c.1859C>G at the same position as this variant has been reported in the literature which was associated with high IgE syndrome (Table 1). The DOCK8 is a large gene, and deletion mutations of large segments of the DOCK8 gene occur more frequently (18), which may be associated with frequent homologous recombination (19). DOCK8 deficiency manifests as combined immunodeficiency, autoimmunity, and impaired adaptive immunity. The DOCK8 group had homozygous or compound heterozygous mutations, encompassing large segment deletion mutations, frameshift mutations, or missense mutations. Four of these mutations were not reported. One case with paternal inheritance, one case with maternal inheritance, and nine cases with biallelic inheritance (from both parents). Deng et al. (20) reported two HIES cases in Chinese children; case 2 had both onychomycosis and scoliosis, which were more severe than case 1. They believed that differences in mutation positions might cause clinical phenotypic differences, and the same mutations often showed similar phenotypes.

Implications and actions needed

The diagnosis of HIES is established through the comprehensive integration of clinical characteristics, immunological biomarkers, and confirmatory genetic testing. This approach is critical for differentiating HIES from more prevalent atopic disorders, as both share overlapping features such as eczema, elevated IgE levels, and recurrent infections. Genetic testing plays a decisive role in diagnosing HIES and differentiating it from atopic disorders. Identification of variants in STAT3 and DOCK8 by genetic testing remains the optimal diagnostic method. The correlation between STAT3 genotype and phenotype requires further study. In this study, the cases in the STAT3 group were strongly suspected of immunodeficiency primarily due to elevated serum IgE levels and recurrent severe skin abscesses or pulmonary infections (and eczema), yet experienced a delayed final diagnosis. The earlier age at diagnosis (before one year of age) for case 2 and case 7 in the STAT3 group is likely attributable to heightened awareness of primary immunodeficiency presenting with recurrent eczema, skin abscesses, and elevated IgE levels, coupled with the widespread availability of genetic sequencing techniques.

Effective management of HIES requires a comprehensive strategy that addresses infections, immune dysregulation, and the overall well-being of affected individuals. There is currently no treatment that can cure the basic defect of HIES. Early administration of broad-spectrum antibiotics/antifungals aims to control skin and pulmonary infections and surgical drainage of the abscess is the cornerstone of HIES therapy. The Chongqing Center recommends lifelong prophylactic administration of trimethoprim-sulfamethoxazole (TMP-SMX) and itraconazole to all patients with AD-HIES for prevention of bacterial and fungal infections (9). Antimicrobial and antiviral prophylaxis is recommended for DOCK8 deficiency. Pulmonary disease has the greatest impact on patients’ quality of life (21), and the pulmonary symptoms (e.g., dyspnea, decreased exercise tolerance) are most likely to affect the quality of life of patients with STAT3 deficiency. High-dose IVIG replacement therapy, possessing immunomodulatory and anti-inflammatory properties, reduces the frequency of recurrent pneumonia and improves eczematous dermatitis. Stentzel et al. (22) reported that Staphylococcus aureus-specific IgG was significantly decreased in STAT3-HIES patients, and immunoglobulin substitution treatment increased Staphylococcus aureus-specific IgG, which indicated the role of humoral immunity in the clearance of Staphylococcus aureus. Subcutaneous injection of interferon-γ (IFN-γ) has been demonstrated to reduce IgE production and improve neutrophil chemotaxis and alleviate viral skin infection, but recombinant IFN-γ has been reported to cause autoimmune thrombocytopenic adverse effects. The monoclonal anti-IgE antibody omalizumab does not target the underlying immunodeficiency associated with AD-HIES; however, it effectively manages allergic inflammation and enhances quality of life. Patients with AR-HIES, particularly those carrying DOCK8 mutations, often exhibit severe systemic anaphylactic symptoms as a consequence of elevated allergen-specific IgE levels. Immune reconstitution is the fundamental treatment for the eradication of PIDs, and HSCT may be an important means to cure HIES. HSCT seeks to substitute the impaired immune system with healthy stem cells obtained from a donor, thereby restoring normal immune function. Emerging evidence indicates successful HSCT in select cases of AD-HIES (23,24). Furthermore, the timing and selection of candidates for HSCT are crucial factors, as late pulmonary complications such as bronchiectasis and emphysema may persist or even progress despite the intervention. Additionally, the risks associated with HSCT, including graft-versus-host disease (GVHD) and complications related to the transplant procedure, must be meticulously evaluated. Recent research has underscored the critical role of the gut microbiome in immune regulation. This suggests that therapies aimed at modulating the microbiome, such as probiotics, prebiotics, and fecal microbiota transplantation (FMT), may provide a novel approach to managing HIES (25). In addition to the previously mentioned strategies, supportive care measures play a vital role in the management of HIES. This encompasses addressing various complications, including recurrent skin infections, pulmonary issues, skeletal abnormalities, and growth retardation.

The prognosis of HIES is variable and influenced by several factors, including the specific underlying genetic mutation, the severity of clinical manifestations, the presence of comorbidities, and the effectiveness of therapeutic interventions (26). The long-term advantages of HIES management include the stabilization of severe pulmonary involvement and the eradication of recurrent skin infections and abscesses. Biological or gene therapy may alter the prognosis of this syndrome in the future.

Conclusions

This study provides a summary of patients with HIES from clinical, immunological, and genetic aspects. Clinical distinction between STAT3- and DOCK8-HIES is difficult due to overlapping initial symptoms, such as respiratory infections, eczema, skin infections, together with increased serum IgE levels and increased eosinophilia. Improving awareness of the disease, early testing of total IgE, and genetic testing are key to early diagnosis and helpful for treatment of HIES.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-278/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-278/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-278/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-278/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the ethics committee of Children’s Hospital of Nanjing Medical University (No. 202412018-1) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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