Clinical features, genetics, treatment, and long-term outcomes of STAT3 hyper-IgE syndrome: a single-center cohort analysis

Abstract

Background:

STAT3 hyper-IgE syndrome (STAT3-HIES) is a multisystem disorder with both immunologic and non-immunologic manifestations.

Objective:

We sought to characterize the spectrum of clinical manifestations, genetics, treatment approaches, and long-term outcomes of patients with STAT3-HIES.

Methods:

Clinical features, laboratory findings, treatment, and survival were reviewed in the largest single-center STAT3-HIES cohort (n = 164) prospectively followed under a natural history protocol (NCT00006150).

Results:

In addition to the classic skin, lung, dental, and musculoskeletal manifestations captured in the 1999 scoring system, we comprehensively characterized disease phenotypes across multiple organ systems, including previously underrecognized features. Lung disease remained the major morbidity with both infectious and parenchymal complications. During longitudinal follow-up, age-related vascular and skeletal degeneration emerged and significantly affected quality of life in patients 45 years and older. No genotype-phenotype correlations were identified. In terms of management, optimal supportive measures, including antimicrobials and immunoglobulin replacement therapy, tailored to disease features and individual risk factors, remained the primary approach. Dupilumab was used primarily for the eczematous dermatitis and demonstrated significant clinical benefit. In highly selected cases (n = 6), allogeneic hematopoietic stem cell transplantation was performed and showed reduction in infection burden. The median overall survival was 55 years, significantly shorter than that of the general United States population, and was not affected by sex, variant location, or proband status.

Conclusions:

STAT3-HIES is a multisystem disorder that requires multidisciplinary care. Early diagnosis and supportive measures have altered its natural history. Recognition and improved understanding of the non-immunologic manifestations of this disorder will further improve patient outcomes.

Graphical Abstract

Capsule summary

STAT3-HIES is a multisystem disorder without genotype-phenotype correlations. Age-related degenerative conditions emerge in adulthood and significantly affected quality of life. Early diagnosis and multidisciplinary supportive care have improved long-term outcomes.

Introduction

Job’s syndrome was first described in 1966 in two unrelated girls with recurrent “cold” staphylococcal abscesses and eczema(1). Subsequently, high serum IgE levels and an expanded phenotype were added(2–4). Autosomal dominant hyper-IgE syndrome (AD-HIES) was defined as a disorder with diverse clinical features affecting the immune system, dentition, skeleton, vasculature, brain, and gastrointestinal tract(5). In 1999, a scoring system based on characteristic clinical and laboratory findings from patients evaluated at the National Institutes of Health (NIH) was developed to support clinical diagnosis and facilitate genetic investigation(6). In 2007, germline dominant-negative (DN) variants in STAT3 were confirmed in most patients with classical autosomal dominant phenotype(7–9). The complex clinical phenotype reflects the pleiotropic roles of STAT3(10). A number of additional rare genetic syndromes impacting the STAT3 pathway were subsequently identified, with significant phenotypic overlap, including upstream receptors (i.e., IL6R(11), IL6ST(12,13)), a transcriptional regulator (i.e., ZNF341(14,15)), and an interacting partner (i.e., ERBIN(16)). The shared clinical phenotypes among these disorders have been attributed to impaired interleukin-6 (IL-6) and IL-11 signaling through STAT3(17). Moreover, several other genetic disorders with different underlying pathomechanisms result in elevated IgE and atopy, with and without risk for distinct infectious, inflammatory, and syndromic features, such as DOCK8 deficiency and CARD11 DN disease(18).

Since the initial description of the NIH cohort(4–6), we have phenotyped and followed 164 patients with STAT3-HIES, representing an expansion of the original cohort. Leveraging standardized, longitudinal evaluations, we identified evolving clinical features and age-associated degeneration. Over time, our treatment strategies have evolved, as have the complications observed, offering valuable insights into disease mechanisms and guiding the continued improvement of patient care.

Methods

Human subjects

Patients were enrolled under an Institutional Review Board-approved prospective natural history protocol (NCT00006150)(7). The term STAT3-HIES is used to specifically indicate the genetic etiology in this cohort. Eligible patients had (1) compatible clinical features, (2) germline pathogenic/likely pathogenic heterozygous STAT3 variants, and (3) evaluation at the NIH Clinical Center between 2005 and 2023, corresponding to our current electronic medical record system. All participants/guardians provided informed consent. Details of patient evaluation, genetic testing, variant validation, and statistical analysis are described in the Supplements.

Results

Demographics

We analyzed 164 patients with STAT3-HIES, including 59 familial cases from 20 kindreds (Figure S1), and 105 sporadic cases. Ninety-two patients (56.1%) were female. The median age at first study evaluation was 13 years of age (range 1 month-62 years), while the median age at diagnosis was 6 years of age (range prenatal period-54 years).

STAT3 variants and functional validation

We identified 56 unique germline heterozygous STAT3 variants, including 27 in the DNA binding domain, 23 in the SH2 domain, and 6 in the transactivation domain (Figure 1A). These variants included missense (n = 51), in-frame indels (n = 3), and splice site variants (n = 2). Two hotspots, R328 and V637, affected 49 (29.9%; including five kindreds) and 26 (15.9%; including three kindreds) patients, respectively. All variants were absent from the population database gnomAD v4.1.0, and CADD scores for all missense variants (median 29, range 25–34) were above the 99% confidence threshold for STAT3 mutation significance cutoff (16.4) (Figure 1B). Novel variants are described in the Supplements.

Figure 1.

STAT3 variants underlie AD-HIES.

(A) Schematic representation of STAT3 variants. Missense variants are shown in the upper part, and others (splice site variants and deletions) are depicted in the lower part. The number of kindreds with each variant is indicated in parentheses. Hotspots are highlighted in red. Novel variants identified in our cohort are labeled in blue. Abbreviations for domains: NT, N-terminal; CC, coiled-coil; DBD, DNA-binding domain; LD, linker domain; SH2, Src homology 2; TA, transactivation.

(B) Graph showing the predicted Combined Annotation Dependent Depletion (CADD) scores (v1.6) and minor allele frequency (MAF) of STAT3 missense variants with the most severe consequence on the MANE transcript identified in both our study cohort and gnomAD v4.1. The 99% mutation significance cutoff for STAT3 is indicated by a blue dashed line.

Clinical manifestations

Skin and soft tissue.

Newborn rash, typically presenting within days of birth, was reported in 137 patients (83.5%) (Figure 2A; Table 1) and is likely underreported, particularly in adult patients without parental input of neonatal history. Recurrent skin abscesses were seen in 134 patients (81.7%), and necrotizing fasciitis was diagnosed in seven patients (4.3%) (Supplemental Table 1). Twenty-six patients (16%) reported local cutaneous adverse reactions to pneumococcal polysaccharide vaccines, including severe large local reactions with ulcerations (Figure 2B). In some, this led to inpatient admission and treatment with antimicrobials/corticosteroids. No similar local reactions were observed following other routine vaccinations.

Figure 2.

Clinical phenotypes of STAT3-HIES.

(A) Schematic representation of STAT3-HIES clinical phenotypes. *Prevalence may vary based on endemic exposure. PPSV, pneumococcal polysaccharide vaccine; EoE, eosinophilic esophagitis; ABPA/M, allergic bronchopulmonary aspergillosis/mycosis.

(B) Representative clinical images of selected phenotypes: (a) a 48-year-old female with scoliosis, pneumatoceles, aspergillomas (arrow), and bronchiectasis; (b) a 70-year-old female with bilateral hip replacement, left shoulder replacement, and cervical spine stabilization; (c) a 27-year-old male with tracheal diverticuli (top, arrow) and then 3 years later with Staphylococcus aureus infection (bottom, arrow); (d) a 18-year-old male with an aphthous ulcer on his tongue (arrow); (e) a 28-year-old male with eczematous dermatitis pre- and 1-year post-dupilumab therapy; (f) a 29-year-old female with a large local reaction at the injection site following pneumococcal polysaccharide vaccination; (g) a 33-year-old male with T2-weighted focal hyperintensities on brain magnetic resonance imaging (arrow).

(C) Common clinical features based on STAT3 variant location.

(D) Distribution of infections based on pathogens.

(E) Emerging aging-associated phenotypes.

(F) Comparison of the Karnofsky Performance Status (KPS) scale between two different age groups. ****, p < 0.0001.

Table 1.

Characteristic clinical phenotypes of STAT3-HIES

Variable (median, Q1-Q3; n, %)	All, n = 164	DBD variants, n = 89	SH2 or TA domain variants, n = 75	R382 variants, n = 49	V637 variants, n = 26
Age (years)	29 (20–42)	29 (21–42)	29 (20–42)	28 (18–39)	29 (19–41)
Female (%)	92 (56.1)	46 (51.7)	46 (61.3)	25 (51.0)	14 (53.8)
NIH HIES score	71 (59–78)	71 (61–79)	70 (59–78)	74 (63–80)	73 (63–81)
Newborn rash	137 (83.5)	77 (86.5)	60 (80.0)	41 (83.7)	22 (84.6)
Severe eczematous dermatitis	99 (60.4)	55 (61.8)	44 (58.7)	28 (57.1)	17 (65.4)
Skin abscesses (> 4)	134 (81.7)	75 (84.3)	59 (78.7)	44 (89.8)	21 (80.8)
Mucocutaneous candidiasis	135 (82.3)	75 (84.3)	60 (80.0)	42 (85.7)	21 (80.8)
Pneumonias (> 3)	124 (75.6)	67 (75.3)	57 (76.0)	39 (79.6)	20 (76.9)
Bronchiectasis	110 (67.1)	61 (68.5)	49 (65.3)	35 (71.4)	19 (73.1)
Pneumatocele	78 (47.6)	42 (47.2)	36 (48.0)	24 (49.0)	15 (57.7)
Scoliosis1	98 (67.1) (n = 146)	56 (71.8) (n = 78)	42 (61.8) (n = 68)	34 (85.0) (n = 40)	16 (61.5)
Fractures with minimal trauma (> 2)	73 (44.5)	39 (43.8)	34 (45.3)	24 (49.0)	12 (46.2)
Retained primary teeth2	128 (85.3) (n = 150)	65 (82.3) (n = 79)	63 (88.7) (n = 71)	37 (90.2) (n = 41)	25 (96.2)
Lymphoma	11 (6.7)	8 (9.0)	3 (4.0)	7 (14.3)	1 (3.8)
Fatal infections	13 (7.9)	6 (6.7)	7 (9.3)	1 (2.0)	0 (0.0)

Abbreviations: HIES, hyper-IgE syndrome; Q1, first quartile; Q3, third quartile; DBD, DNA-binding domain; SH2, Src homology 2; TA, transactivation; NIH, National Institutes of Health.

^1.In individuals age ≥ 10 years. Scoliosis is diagnosed based on a Cobb angle > 10°.

^2.In individuals age ≥ 9 years.

Allergy and atopy.

Eczematous rash was present in 158 patients (96.3%), with the majority (n = 99, 62.7%) experiencing severe rash during the disease course (Figure 2B, 2C). Although many patients carried a clinical diagnosis of asthma prior to enrollment in our study, the diagnosis was confirmed by demonstration of reversible airflow obstruction on pulmonary function testing in only 41 patients (25.0%). A history of food allergy was self-reported in 67 patients (40.9%), including 13 (7.9%) who had anaphylaxis (Supplemental Table 2). Other organ-specific atopic manifestations included allergic bronchopulmonary aspergillosis (ABPA, n = 8, 4.9%) and eosinophilic esophagitis (EoE, n = 10, 6.1%), as described below.

Respiratory system.

Recurrent pneumonias were reported in 124 patients (75.6%) (Figure 2D), with bronchiectasis present in 110 (67.1%) and pneumatoceles in 78 (47.6%). The bacterial causes of acute pneumonias were not always identified microbiologically, but common pathogens included Staphylococcus aureus, Haemophilus influenzae, Streptococcus pneumoniae, and Mycoplasma species. The median age at first diagnosis of bronchiectasis/pneumatoceles was 13 years (range 1–28 years). Chronic infections were frequent among the 115 patients with parenchymal lung abnormalities, including Pseudomonas in 51 (44.3%), nontuberculous mycobacteria in 19 (16.5%), and Aspergillus in 55 patients (47.8%), the latter manifesting as mycetoma in 32 and as ABPA in 8 patients(19), respectively. Other pathogens underlying chronic lung infections included E. coli, Staphylococcus aureus, Klebsiella species, and Scedosporium species. Pneumocystis jirovecii pneumonia occurred in seven patients (4.3%), with five presenting during infancy.

Forty-two patients (25.6%) underwent lung surgeries, complicated by bronchopleural fistulae in almost half (20/42, 47.6%). An additional four patients developed bronchopleural fistulae following spontaneous pneumothoraces related to parenchymal lung disease. Paratracheal cysts, likely related to underlying tracheal diverticula, were identified on chest computed tomography in 39 patients (23.8%) (Figure 2B). Four patients had mediastinal or laryngeal infections, potentially associated with these cysts.

Extrapulmonary fungal infections.

Chronic mucocutaneous candidiasis (CMC) was seen in 135 patients (82.3%), including onychomycosis in 56 (34.1%). Endemic extrapulmonary dimorphic fungal infections were diagnosed in 10 patients (6.1%), including seven with Histoplasma and three with Coccidioides (all with meningitis). Histoplasma infections were diverse: intestinal disease (n = 2), pulmonary disease with an hemophagocytic lymphohistiocytosis-like hyperinflammation (n = 1), pulmonary/bone marrow/bone disease (n = 1), liver disease (n = 1), oral disease (n = 1), and laryngeal disease (n = 1). There were four patients with Cryptococcus infections (three with meningitis and one with esophageal disease).

Viral infections.

Thirty-five patients (21.3%) reported herpes zoster, with onset as early as the first decade of life and typically affected a single dermatome(20). Other viral infections are described in the Supplements.

Other severe infections.

Invasive bacterial infections included osteomyelitis and/or septic arthritis in 27 (16.5%), liver abscesses in four (associated with Staphylococcus aureus endocarditis in one), and renal abscesses in two patients. Invasive group A streptococcal infections occurred in two patients, causing pericarditis in one and meningitis in another. Orbital abscesses were reported in two patients and mastoiditis with subdural abscess in one. Pneumococcal sepsis was seen in one patient. Nine patients had Staphyloccocus aureus bacteremia and/or sepsis, and at least four others had bacteremias related to central venous access. Enteric bacteremias were associated with pyelonephritis in one patient, and biliary abnormalities in two others. One patient developed mesenteric adenitis due to Mycobacterium avium complex. Clostridioides difficile infection was uncommon (5.5%) despite prevalent antibiotics use.

Malignancy.

Eleven patients (6.7%) were diagnosed with lymphoma. In addition to the ten previously reported cases of non-Hodgkin lymphoma (all tested cases were EBV-negative)(21), one additional patient developed EBV-positive Hodgkin lymphoma. No lymphoma-related death occurred, and all achieved remission after chemotherapy without relapse during follow-up (range 2–29 years).

Oral and dental abnormalities.

Among patients ≥ 9 years (n = 150), 128 (85.3%) had retained primary dentition, of whom 108 (84.4%) underwent tooth extraction(22–24). Secondary tooth loss due to decay was also common; 16 adult patients had either received or been evaluated for dentures, including two patients in their third decades. Recurrent non-infectious aphthous ulcers were a frequent cause of mouth pain (n = 83, 50.6%) (Figure 2B). Nine patients had tongue masses prompting biopsy: most showed increased eosinophils and/or granulation tissue. Two patients had traumatic ulcerative granuloma with stromal eosinophilia, and two had pyogenic granulomas.

Skeletal and joint abnormalities.

Minimal trauma fractures were common (n = 117, 71.3%), with 73 patients having two or more fractures. Among 150 patients with DEXA results, 88 met the diagnosis of osteoporosis (58.7%) (Figure 2A). Scoliosis was diagnosed in 98 patients (67.1% aged ≥ 10 years), 18 of whom underwent surgery. Surgery was generally well tolerated, but several required revisions and one had hardware removal for infection. Severe scoliosis (i.e., Cobb angle > 20°) was associated with a higher likelihood of concurrent parenchymal lung abnormalities (odds ratio 2.96, p = 0.06) and the need for supplemental oxygen or non-invasive positive airway pressure support (odds ratio 4.52, p = 0.02). Hyperextensibility of peripheral joints was also common (72.6%). Craniosynostosis occured but was not systematically assessed, and it rarely required surgical correction.

Gastrointestinal diseases.

Ninety-two patients (56.1%) had gastrointestinal complications. Fifty-three (32.3%) reported gastroesophageal reflux disease. Among them, 10 had upper endoscopy, with two showing erosive esophagitis. One patient had non-dysplastic Barrett esophagus and three required surgical fundoplication for management of severe reflux. Dysphagia was reported in 34 patients (20.7%), including 10 with EoE. Gastrointestinal ulcers were identified in 17 patients (10.4%). Gastrointestinal bleeding occurred in 14 patients (8.5%), mostly from ulcer-related hemorrhage. One patient had bleeding from a small bowel Dieulafoy lesion, another had presumed Dieulafoy-related bleeding, and one experienced bleeding from a superior mesenteric artery aneurysm. Ten patients (6.1%) had bowel perforations, including eight without an identifiable immediate cause and two associated with intestinal lymphoma. Ten patients had cholecystectomies, largely for gallstone-related disease. Nine required hernia repairs, primarily for inguinal hernias, with two needing repeated surgical corrections.

Autoimmune diseases.

In addition to the 10 patients with lupus or lupus-like disease previously reported(25), one further patient developed lupus, for a total of 11 patients (6.7%). Among them, five patients had associated chronic kidney disease, which progressed to end-stage renal failure in one patient.

Cardiovascular and other vasculature abnormalities.

Hypertension was seen in 31.1% of the entire cohort, and 38.1% in those ≥ 18 years. Coronary artery abnormalities occurred in 73/129 patients (56.6%) with coronary artery imaging available, including 58 with tortuous coronary arteries, 52 with coronary dilatations, and four with coronary artery aneurysms. Three patients with coronary artery abnormalities had myocardial infarctions and were maintained on anticoagulation and/or antiplatelet agents. Cerebral artery aneurysms were found in three patients: one after subarachnoid hemorrhage, and two identified prospectively, one of which required coiling. One patient each had hepatic artery aneurysm, mesenteric artery aneurysm, splenic artery aneurysm, and right internal carotid artery aneurysm.

Brain manifestations and mental/behavioral health.

T2-weighted focal hyperintensities (previously termed unidentified bright objects) were found in 99/140 patients (70.7%), including as early as 7 years (Figure 2B). The hyperintensities tended to be more discrete in younger patients and became more confluent with age. Type I Chiari malformations were found in 27 patients (16.5%), but were largely asymptomatic; only one received surgical intervention. Mental health disorders were seen at frequencies similar to the general United States population(26,27). Anxiety was diagnosed in 30 (18.3%) and depression in 36 patients (22.0%). Attention deficit hyperactivity disorder was reported in 16 patients (9.8%), and dyslexia in two.

Women’s health.

Seventy female patients were 13 years or older. Because reduced STAT3 signaling has been linked to peripartum cardiomyopathy in mice(28), we monitored cardiac function of 20 patients with prior pregnancy, and peripartum cardiomyopathy was not observed. Pregnancy-related complications included worsening of lung disease (n = 2), postpartum uterine hemorrhage leading to hysterectomy (n = 1), and infection of Cesarean section wound (n = 1). Nineteen women (27.1%) experienced breast abscesses and two had therapeutic breast reduction surgeries(29). Vulvo-vaginal aphthous ulcers requiring medical intervention were reported in four and vulvo-vaginal bacterial abscesses in five. Five patients had hysterectomies for various reasons (e.g., cancer predisposition, menorrhagia, and fibroids).

Aging cohort.

Twenty-eight patients (female 57.1%) were 45 years or older (Figure 2E). The Karnofsky performance status (KPS) was negatively correlated with age (Spearman rho −0.47, p < 0.0001), and the aging cohort had a significantly lower median KPS than the younger cohort (median 70 vs. 80, p < 0.0001) (Figure 2F). Degenerative joint disease became increasingly common with age, including eight and four patients requiring spine (not for scoliosis) or peripheral joint surgery, respectively (Figure 2B). Chronic pain was reported by 17 patients (60.7%), and 12 (42.9%) experienced mobility limitations. In addition, memory loss was reported by seven patients over 45 years (25.0%).

Others.

Additional manifestations are detailed in Supplemental text and Supplemental Table 3.

Genotype-phenotype correlations.

The median NIH HIES score was 71 (range 10–96). No apparent genotype-phenotype correlations were observed based on STAT3 variants locations (DNA binding domain vs. others) or hotspot status (R328 vs. V637 vs. others) (Figure 2C; Table 1–3), as was described in a smaller cohort(30). We did not find any association between specific variants and time to parenchymal lung abnormalities.

Table 3.

Less recognized phenotypes of STAT3-HIES.

Variables (n, %)	All, n = 164	DBD variants, n = 89	SH2 or TA domain variants, n = 75	R382 variants, n = 49	V637 variants, n = 26
Intestinal perforation	10 (6.1)	6 (6.7)	4 (5.3)	6 (12.2)	2 (7.7)
Gastrointestinal bleeding	14 (8.5)	7 (7.9)	7 (9.3)	3 (6.1)	0 (0.0)
Necrotizing fasciitis	7 (4.3)	3 (3.4)	4 (5.3)	2 (4.1)	1 (3.8)
Joint replacement surgery	7 (4.3)	1 (1.1)	6 (8.0)	0 (0.0)	1 (3.8)
Degenerative spine surgery	8 (4.9)	6 (6.7)	2 (2.7)	3 (6.1)	0 (0.0)
Clinical autoimmunity1	13 (7.9)	9 (10.1)	4 (5.3)	6 (12.2)	1 (3.8)
Coronary artery abnormalities2	73 (56.6) (n = 129)	36 (51.4) (n = 70)	37 (62.7) (n = 59)	19 (54.3) (n = 35)	13 (56.5) (n = 23)
Vascular aneurysm	9 (5.5)	1 (1.1)	8 (10.7)	1 (2.0)	2 (7.7)
Herpes zoster infection	35 (21.3)	22 (24.7)	13 (17.3)	11 (22.4)	6 (23.1)
PPSV23-related reactions	26 (54.2) (n = 48)	11 (47.8) (n = 23)	15 (60.0) (n = 25)	5 (35.7) (n = 14)	6 (66.7) (n = 9)
Aphthous ulcers	83 (50.6)	40 (44.9)	43 (57.3)	23 (46.9)	12 (46.2)

Abbreviations: HIES, hyper-IgE syndrome; DBD, DNA-binding domain; SH2, Src homology 2; TA, transactivation; PPSV23, pneumococcal polysaccharide vaccine 23-valent.

^1.Clinical autoimmunity includes lupus or -like diseases (n = 11) and autoimmune thyroid diseases (n = 2).

^2.Coronary artery abnormalities include tortuous artery, dilation, and aneurysms detected on coronary computed tomography angiography.

Laboratory findings

Where applicable, we analyzed serum total IgE levels before dupilumab therapy and cell counts prior to hematopoietic stem cell transplantation (HSCT). Serum total IgE levels were significantly elevated in most patients at initial evaluation (> 2000 IU/mL, 82.9%) but declined over time (Figure 3A; Supplemental Table 4), consistent with prior observations(5). Absolute lymphocyte counts mostly remained within normal limits. Mean absolute eosinophil counts were at the upper end of the normal range (Figure S3). Across the cohort, absolute eosinophil counts were positively correlated with serum total IgE levels (correlation coefficient 0.412, p < 0.001). Compared to age- and sex-matched controls, total CD3⁺ T cell counts were higher in patients through early adulthood, mainly due to higher CD3⁺CD4⁺ T cells (Figure 3B, S3). Within the CD3⁺CD4⁺ T cell compartments, we observed higher naïve CD4⁺ cells but lower effector memory CD4⁺ T cells until late adulthood (Figure 3C, S3). Similar findings were seen within the CD3⁺CD8⁺ T cell compartments (Figure S3). Although total CD19⁺ B cell counts were comparable to healthy controls (Figure S3), both total memory and switched memory compartments were significantly smaller throughout life (Figure 3D, 3E). NK cell counts were also consistently lower than controls (Figure 3F).

Figure 3.

Trajectory of serum total IgE and peripheral blood immune cell subsets along the disease course. (A) Serum total IgE. (B) CD3⁺CD4⁺ T cells. (C) CD3⁺CD4⁺CD45RA⁻CD62L⁻ T cells (i.e., CD4⁺ effector memory T cells). (D) CD20⁺CD27⁺ B cells (i.e., memory B cells). (E) CD20⁺CD27⁺IgM⁻ B cells (i.e., classs-witched memory B cells). (F) Natural killer (NK) cells. The shaded gray area indicates a statistically significant difference between patients and healthy controls.

Treatments

Antimicrobial prophylaxis.

One hundred fifty-eight patients (96.3%) were on chronic antibiotics, typically commencing after diagnosis. The few patients not on chronic antibiotics had either a minimal infection burden or, in one case, a history of recurrent Clostridioides difficile infection. Trimethoprim/sulfamethoxazole (TMP/SMX) was the most commonly used agent, with 135 patients (82.3%) on it at some point. Fifty-five patients (33.5%) were on azithromycin, primarily for chronic lung disease. Thirteen patients (7.9%) were on β-lactams, and 15 patients (9.1%) were on doxycycline, largely due to recurrent infections with TMP/SMX-resistant Staphylococcus aureus.

One hundred eighteen patients (72.0%) were on chronic antifungals: thirty-five on fluconazole for CMC suppression (n = 25), Coccidioides suppression or prophylaxis (n = 10). Fifteen patients were on itraconazole for either mold prophylaxis, mostly in the context of pneumatoceles, or for secondary prophylaxis after disseminated histoplasmosis (n = 1). Sixty-two were on posaconazole, largely for prior or chronic pulmonary aspergillosis. Twenty-two had been treated with voriconazole for pulmonary molds including Scedosporium, and two were on chronic inhaled voriconazole for chronic airway mold suppression (Aspergillus and Scedosporium). Two were on chronic “swish and swallow” amphotericin for azole-resistant oral and/or esophageal Candida species.

Immunoglobulin replacement therapy (IgRT).

Seventy-four patients (45.1%) were initiated on IgRT, typically due to poor specific antibody responses and/or recurrent infections despite antibiotic prophylaxis. Of those, 23 patients (31.1%) subsequently discontinued IgRT, due to lack of efficacy (n = 11), limited access to care (n = 5), HSCT (n = 2), adverse event (n = 1), or unknown reasons (n = 4). We observed insignificantly higher rates of parenchymal lung abnormalities among those who initiated IgRT later (odds ratio 1.07 per one-year increase in age, 95% confidence interval 0.97–1.19, p = 0.180).

Dupilumab.

Twenty-eight patients (17.1%) received dupilumab for eczematous dermatitis (n = 24), ABPA/mycoses (n = 2), severe persistent asthma (n = 1), or eosinophilic esophagitis (n = 1). The median age of initiation was 22 years (range 2–51). All reported significant improvements in dermatitis (Figure 2B), with markedly reduced need for topical steroids, and, in many cases, decreased antibiotics use for skin infections. One patient had improvement in ABPA, while another had improvement in eosinophilic esophagitis. Serum total IgE levels declined after dupilumab initiation. Treatment was discontinued in four patients due to intolerance/adverse events (n = 3) (Supplements) or inability to obtain insurance coverage (n = 1).

Bone and dental/oral therapies.

Treatment for osteoporosis included standard calcium and vitamin D supplementation with bisphosphonates (e.g., alendronate, zoledronic acid), administered to 24 patients. Aphthous ulcers were frequently treated with topical corticosteroids and/or anesthetics.

HSCT and solid organ transplantation.

Six patients (median age 16 years; range 7–20 years) underwent HSCT(31,32). One died at 16 years (4.5 months post-HSCT) from cryptogenic organizing pneumonia. Peri-HSCT complications included Aspergillus-infected pneumatocele with bronchopleural fistulae requiring resection (n = 1) and gastrointestinal bleeding during conditioning (n = 1). Although all patients had a decreased infection burden after HSCT, one developed new bronchiectasis with Pseudomonas aeruginosa infection and worsening of scoliosis. Another developed avascular necrosis of the left knee, and three had fractures (Supplements).

One patient had double lung transplantation at 27 years, complicated by post-transplant disseminated Aspergillus infection with obliteration of the right pulmonary artery, and died from progressive allograft vasculopathy three years later. One patient underwent a living donor kidney transplant at 26 years for end-stage lupus nephritis and was alive nine years later, but had worsened lung disease, including respiratory failure, renal insufficiency, and BK and cytomegalovirus viremias.

Overall survival and outcomes

At last follow-up, the median age was 26 years (range 1–72 years). Twenty-one deaths (12.5%) occurred (median age 41, range 10–63 years). The leading causes of death were pulmonary disease and/or infection (13/21, 61.9%), including progression of chronic pulmonary disease in 10 patients and acute infection in three (sepsis not otherwise specified, Staphylococcus aureus pneumonia, and SARS-CoV-2 with secondary infection). The median overall survival was 55 years, shorter than the general United States population (median 81 years; Figure 4A). We explored the association between overall survival and several factors, including sex, STAT3 hotspot variants (R382 and V637), and proband status, but found no significant differences (Figure 4B–D). IgRT use was associated with a non-significant improved overall survival (hazard ratio 0.52, 95% confidence interval 0.17–1.58, p = 0.248).

Figure 4.

Overall survival of STAT3-HIES patients compared to the United States general population. (A) Entire cohort. (B) Stratified based on sex. (C) Stratified based on hotspot variants. (D) Stratified based on proband status. Estimates for patients are based on the Kaplan-Meier estimator for left-truncated, right-censored data. The shaded area represents the 95% confidence interval.

Discussion

Since its initial description in 1966(1) and its association with extremely elevated serum IgE levels in 1972(2,3), AD-HIES has been recognized as a multisystem disorder(4), with its classic spectrum of manifestations summarized in the 1999 NIH scoring system(5,6). Although this scoring system was originally designed to facilitate genetic linkage analyses by recruiting phenotypically similar patients(6), it has since become the most widely used clinical tool for documenting the phenotypes of affected patients and has also been applied to other disorders under the broader HIES umbrella(11–13,15).

The identification of STAT3 DN variants underlying most cases of AD-HIES has greatly advanced our understanding of this disorder(7,8). The widespread tissue expression and diverse biological functions of STAT3 explain the spectrum of clinical phenotypes observed. Importantly, this has enabled the recruitment of genetically defined patients, allowing us to substantially expand the original NIH cohort and continue systematic phenotyping over the past two decades(33–39), culminating in the present study. The broader spectrum of phenotypes described here extends beyond those captured in the 1999 scoring system, and includes manifestations that were present in the original cohort but are more clearly recognized in this expanded study (e.g., necrotizing fasciitis), as additional cases were identified. In addition, some findings became apparent only through longitudinal follow-up, particularly age-related vascular abnormalities and joint/spine degeneration. Despite these observations, our intention was not to propose a new scoring system. The 1999 scoring system effectively captures the core features of STAT3-HIES, as demonstrated across multiple independent cohorts(40–42) (Supplemental Table 5), and has proven to be a useful tool in practice(7,41,43). Rather, we aim to increase awareness of these additional manifestations when caring for affected patients. In the current era, however, genetic testing can and should be pursued in individuals with any suggestive features rather than waiting for characteristic complications to develop, as earlier molecular diagnosis may improve management and outcomes(44).

Among these manifestations, lung disease remains the primary cause of morbidity and mortality and is characterized by early-onset, recurrent pyogenic pulmonary infections, followed by parenchymal structural abnormalities and chronic infection with Gram-negative bacteria (e.g., Pseudomonas) and molds (e.g. Aspergillus). Moreoever, many manifestations of STAT3-HIES center on epithelial barriers. T_H17 defects are thought to underlie the epithelial Staphylococcus-related infections and CMC(45,46). Epithelial abnormalities also affect the gastrointestinal tract, including ulcers, perforations, endemic fungal infections, particularly Histoplasma, although the underlying mechanisms remain poorly defined(37). However, despite most infections occuring at epithelial barriers, visceral bacterial abscesses (e.g., liver abscesses), osteomyelitis, and other severe infections (e.g., pericarditis, Coccidioides meningits, necrotizing fasciitis) were also increased.

Since its initial description, antimicrobial therapy has remained the cornerstone of management for STAT3-HIES, extending overall survival into late adulthood(40). Over time, antimicrobial strategies have become increasingly tailored based on disease features and individual risk factors (Table 4)(47). In addition, IgRT should be considered in patients with breakthrough infections and/or poor specific antibody responses despite bacterial prophylaxis. For non-infectious manifestations, improved understanding of both immune and non-immune mechanisms may further enhance patient care. For example, recurrent aphthous ulcers affect approximately half of patients, a prevalence similar to that observed in STAT1 gain-of-function disease(48). These ulcers are particularly problematic in children, as they are painful and can significantly impair oral intake. In our practice, they are typically managed with topical analgesics/corticosteroids. Given the elevated STAT1 signaling in STAT3-HIES patients, targeted therapies (e.g., topical Jakinibs), may represent effective options(49). Epithelial abnormalities have also received increasing attention, particularly in the context of lung disease. In clinical practice, various airway clearance strategies should be implemented, while future efforts should focus on developing therapies targeting epithelial dysfunction(50–53). Lastly, premature skeletal and vascular degeneration was observed during our longitudinal follow-up, which have not been well described in other STAT3-HIES cohorts(40–42) (Supplemental Table 5). They occurred at younger-than-expected ages, likely reflecting abnormal tissue remodeling due to defective STAT3 signaling(54). Management currently relies primarily on supportive multidisciplinary care. Given the diverse clinical manifestations of STAT3-HIES, a detailed discussion of each feature is beyond the scope of this report; therefore, we summarize our approach to the evaluation and management of the core disease features in Table 4.

Table 4.

How we evaluate and manage STAT3-HIES

Clinical manifestations	How we evaluate	How we manage
Oral and dental manifestations
Dental abnormalities	Twice yearly dental evaluations to assess Retention of primary teeth and the appropriate timing of extraction. Decay of secondary teeth.	Antibiotic prophylaxis (e.g. amoxicillin/clavulanate) around tooth extractions and other oral surgeries, typically 48 hours for primary teeth and 5–7 days for secondary teeth. Referral to Orthodontics as indicated.
Mucocutaneous candidiasis	Obtain fungal culture with antifungal susceptibility testing in cases of persistent Candida infection despite antifungal therapy.	Consider suppressive antifungal therapy for Candida onychomycosis or recurrent oropharyngeal disease requiring repeated treatment. Fluconazole is typically the first line agent if no resistance; posaconazole can be used when there is concern for concurrent mold infection.
Aphthous ulcers	Obtain HSV PCR for initial episode or atypical appearance.	Symptomatic pain relief with Magic mouthwash or topical corticosteroids (e.g. triamcinolone dental ointment)
Non-allergic skin/soft tissue manifestations
Newborn rash	Obtain bacterial cultures from skin lesions or nose to assess S. aureus carriage and antibiotics susceptibility.	Use chlorhexidine washes to reduce S. aureus colonization. Initiate TMP/SMX prophylaxis around 2 months of age.
Recurrent skin abscesses	If breakthrough infections occur despite TMP/SMX prophylaxis, consider obtaining a nasal culture for S. aureus with antibiotics susceptibility testing to evaluate for resistance.	Use antiseptics to decrease S. aureus colonization (e.g., dilute bleach baths, chlorhexidine washes, or swimming in chlorinated pools). Initiate TMP/SMX prophylaxis at 5–6 mg/kg/day of the TMP component divided twice daily (max 160 mg TMP/dose). Consider dupilumab to improve skin barrier integrity and reduce the risk of secondary infections.
Allergic manifestations
Eczematous rash	Obtain clinical history and perform physical exam.	Use antiseptics (e.g. dilute bleach baths, chlorhexidine washes) in addition to antibiotic prophylaxis (e.g., TMP/SMX) and topical therapies. Low threshold to consider dupilumab.
Eosinophilic esophagitis	Obtain relevant clinical history (e.g., dysphagia, food impaction) and proceed with upper endoscopy as indicated.	Consider swallowed corticosteroids or dupilumab in biopsy-proven cases.
Food allergy	Obtain clinical history and only proceed with allergen-specific IgE testing if history is suggestive of an IgE-mediated hypersensitivity	In confirmed cases, avoid culprit food and prescribe epinephrine autoinjectors.
Lung manifestations
Recurrent pneumonia	Education regarding minimal systemic signs at start of pneumonia, and low clinical threshold to look for pneumonia with chest imaging.	Obtain sputum cultures (induced or bronchoscopy if needed) during infection to guide antibiotics use. Ensure compliance with TMP/SMX prophylaxis at 5–6 mg/kg/day of the TMP component divided twice daily (max 160 mg TMP/dose). Strong consideration for IgRT.
Bronchiectasis	Chest CT imaging every 1–2 years with PFTs and 6-minute walk test.	Sputum culture monitoring for bacteria, fungi and mycobacteria in patients with chronic infection/colonization, which can guide treatment choices during exacerbation. Airway clearance with oscillatory devices, albuterol, hypertonic saline aerosols, or aerobic exercise. Consider azithromycin (in adults, 250 mg daily), if no evidence of nontuberculous mycobacteria colonization.
Pneumatocele	Chest CT imaging to assess for thickened walls or debris suggestive of infection	If not infected, consider itraconazole antifungal prophylaxis. Minimize mold exposures (e.g., avoiding mulching and hay exposure).
Aspergillus lung infection	Chest CT imaging to assess for Aspergilloma.	Lifelong antifungals (e.g., posaconazole) typically due to increased risk of hemoptysis and further spread with local invasion.
Prolonged bronchopleural fistula	Awareness of the risk of this complication before lung surgery.	Consider endobronchial valves.
ABPA/M	Follow revised ISHAM-ABPA working group consensus criteria but emphasize the importance to look for compatible chest CT imaging findings.	Anti-mold antifungals (e.g., posaconazole) and initiate systemic corticosteroids. Low threshold for anti-type 2 biologies (e.g., dupilumab) as steroid-sparing agent, due to negative consequences of prolonged corticosteroid use with increased risk of fractures and potential worsening of infections.
Musculoskeletal manifestations
Scoliosis	Annual physical exam screen, more frequent if scoliosis is present. Low threshold to obtain radiographic evaluation.	Referral to Orthopedics. When surgical correction is needed, consider additional S. aureus prophylaxis (e.g., linezolid), starting pre-operatively and continuing for 7–10 days post-operatively.
Minor trauma fractures	Obtain DEXA scan and vitamin D levels	Optimize Vitamin D and calcium intake. Consider medical therapy (e.g. bisphosphonates) in patients with fractures or osteoporosis on DEXA scan.
Osteoarthritis	Low threshold for radiographic evaluation	Low threshold for physical therapy and orthopedics referral. With surgical correction/joint replacement, consider additional S. aureus prophylaxis (e.g., linezolid), starting 1–2 days pre-operatively and continuing 7–10 days post-operatively.
Other manifestations
Endemic mycoses	Low threshold to look for disseminated Coccidioides, Histoplasma and Cryptococcal disease.	Azole prophylaxis for patients traveling to or residing in Coccidioides endemic regions. Consideration of azole prophylaxis for those with high-risk activities for Histoplasma exposure (e.g. residing in highly endemic regions).
Vascular abnormalities: e.g., cerebral or coronary artery	Brain MRA and coronary artery screening (e.g., cardiac MRI) beginning in adolescence, with follow-up imaging every 3 years, unless clinical concerns warrant earlier evaluation.	Consider anti-platelet agents for coronary artery aneurysm. Optimize blood pressure management as appropriate. Avoid estrogen supplementation or other pro-thrombotic agents, when possible, particularly in patients with vascular abnormalities.
Clinical autoimmunity: e.g., lupus-like manifestations	Clinical assessment and yearly urinalysis screening for proteinuria.	Referral to Rheumatology.
Lymphoma	Low threshold for imaging, annual blood tests (e.g., LDH, uric acid), and biopsy if indicated.	Referral to Hematology/Oncology. Patients typically respond well to standard chemotherapy regimen.

Abbreviations: HSV, herpes simplex virus; PCR, polymerase chain reaction; TMP/SMX, trimethoprim/sulfamethoxazole; IgRT, immunoglobulin replacement therapy; PFT, pulmonary function test; CT, computed tomography; ABPA/M, allergic bronchopulmonary aspergillosis/mycosis; ISHAM, International Society for Human and Animal Mycology; DEXA, dual-energy X-ray absorptiometry; MRA, magnetic resonance angiogram; MRI, magnetic resonance imaging; LDH, lactate dehydrogenase.

Several important areas warrant further investigations. First, HSCT has been increasingly used for STAT3-HIES(32); however, its impact on non-immunologic manifestations, especially tissue remodeling including vascular abnormalities, requires longer follow-up. Second, although STAT3-HIES is classified as a primary atopic disorder with skewed type 2 immunity and elevated IgE levels(55,56), mast cell-mediated manifestations (e.g., food allergy, anaphylaxis) appear less prominent than in individuals with severe atopy and comparably elevated IgE. This difference is attributed to impaired IgE-mediated mast cell degranulation and mediator-induced vascular permeability(57,58). While increased T_H2 cells have been observed in the peripheral blood of some patients(56), the mechanisms driving organ-specific atopic manifestations (e.g., eczematous dermatitis, EoE, and potentially lung inflammation) warrant further investigations. Dupilumab has been shown to improve eczematous dermatitis and appears to reduce secondary skin infections, presumably through restoration of skin integrity and antimicrobial peptide production(59–62). Its therapeutic potential may further extend to other tissues affected by type 2 inflammation(59,60), which requires further evaluation. In addition, incorporation of patient-reported outcome measures will be essential, as quality of life is significantly impacted by chronic pain, vascular, and skeletal complications.

While this represents the largest single-center prospective cohort, our study has limitations; missing data are inevitable, especially for events that occurred at other centers. The natural history design of this study was not developed to address specific therapies, such as antimicrobial prophylaxis, IgRT, or HSCT(32).

Conclusion

STAT3-HIES is a multisystem disorder with evolving non-immunologic impacts. The broad clinical manifestations emphasizes the diverse functions of STAT3. Increased genetic testing will enable earlier diagnosis and supportive care. Such interventions may mitigate bronchiectasis and pneumatoceles due to recurrent pneumonias, and enable earlier identification of severe scoliosis that compromises lung function. Survival beyond the 6^th decade will require better understanding of vascular disease, skeletal degeneration, and intestinal complications.

Table 2.

Detailed lung phenotypes of STAT3-HIES.

Variable (n, %)	All, n = 164	DBD variants, n = 89	SH2 or TA domain variants, n = 75	R382 variants, n = 49	V637 variants, n = 26
Asthma	41 (25.0)	22 (24.7)	19 (25.3)	11 (22.4)	5 (19.2)
ABPA/ABPM	9 (5.5)	7 (7.9)	2 (2.7)	3 (6.1)	1 (3.8)
Tracheal diverticuli	39 (23.8)	18 (20.2)	21 (28.0)	10 (20.8)	8 (30.8)
Aspergillus infection	55 (33.5)	32 (36.0)	23 (30.7)	17 (34.7)	9 (34.6)
Pseudomonas infection	51 (31.1)	29 (32.6)	22 (29.3)	17 (34.7)	9 (34.6)
Non-tuberculous mycobacterial infection	19 (11.6)	10 (11.2)	9 (12.0)	4 (8.2)	2 (7.7)
Lung parenchyma surgery	42 (25.6)	19 (21.4)	23 (30.7)	10 (20.4)	9 (34.6)
Prolonged bronchopulmonary fistula (> 2 weeks)	20 (12.2)	14 (15.7)	6 (8.0)	9 (18.4)	2 (7.7)
Long-term oxygen supplementation	12 (7.3)	5 (5.6)	7 (9.3)	1 (2.0)	3 (11.5)
Non-invasive ventilation	12 (7.3)	4 (4.5)	9 (12.0)	2 (4.1)	2 (7.7)

Abbreviations: HIES, hyper-IgE syndrome; DBD, DNA-binding domain; SH2, Src homology 2; TA, transactivation; ABPA/ABPM, allergic bronchopulmonary aspergillosis/mycosis.

Key Messages.

• STAT3-HIES is a multisystem disorder with broad immunologic and non-immunologic manifestations, without genotype-phenotype correlations.

• Age-related degenerative conditions emerge in adulthood and significantly affected quality of life.

• Early diagnosis and multidisciplinary supportive care have improved long-term outcomes.

Abbreviations:

ABPA

allergic bronchopulmonary aspergillosis

AD

autosomal dominant

CMC

chronic mucocutaneous candidiasis

DEXA

dual-energy X-ray absorptiometry

DN

dominant negative

EBV

Epstein-Barr virus

HIES

hyper-IgE syndrome

HSCT

hematopoietic stem cell transplantation

IgRT

immunoglobulin replacement therapy

IL

interleukin

KPS

Karnofsky performance status

NIH

National Institutes of Health

STAT3

signal transducer and activator of transcription 3

TMP/SMX

trimethoprim/sulfamethoxazole