BACKGROUND:Signal transducer and activator of transcription 3 hyper-IgE syndrome (STAT3-HIES) is a multisystem disorder with both immunologic and nonimmunologic 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 nonimmunologic manifestations of this disorder will further improve patient outcomes.

Signal transducer and activator of transcription 3 dominant negative (STAT3DN) disease causes an autosomal dominant hyper-IgE syndrome (AD-HIES; Job's syndrome) characterized by elevated IgE, recurrent lung and skin infections, eczematous dermatitis, mucocutaneous candidiasis, and skeletal, connective tissue, and vascular abnormalities. Since the genetic etiology identification in 2007,1,2 the diagnosis of infants with a family history of STAT3DN can be confirmed in newborns or prenatally. Although antibiotic prophylaxis targeting Staphylococcus aureus is known to decrease infectious complications in STAT3DN,3,4 the impact of early diagnosis and treatment specifically in infants with antimicrobials and antiseptics is unexamined. We retrospectively reviewed medical histories of 18 pediatric patients with STAT3DN to compare the clinical course for those with and without a family history of STAT3DN.

STAT3 dominant negative disease (STAT3 DN) is characterized by elevated IgE, recurrent skin and lung infections, skeletal, connective tissue, and vascular abnormalities. Early genetic diagnosis, especially with familial disease, allows for early intervention, which may impact natural history through minimizing infectious complications. We retrospectively reviewed medical records of 18 STAT3 DN pediatric patients born after 2007, when STAT3 genetic testing was available. Clinical features, laboratory results, infections and treatments were compared between those with STAT3 DN family history and probands. Our cohort included 8 patients with STAT3 DN diagnosed by family history (median age 9 years; range 4–14) and 10 probands (median age 13 years, range 5–14). For those with family history, one was diagnosed in utero, six by 6 months of age, and one at 2 years. Probands were diagnosed at a median age of 2 years (range 1–6 years). STAT3 mutation domains were similar between groups. Those with family history started antiseptic washes at a mean of 2.4 months and prophylactic antibiotics at 0.4 years, whereas probands initiated antiseptics at 4.5 years and prophylactic antibiotics at 3 years. Compared to probands, patients with STAT3 DN diagnosed by family history had significantly (p < 0.05) reduced rates of hospitalizations (mean 0.6 vs 6.2 times), bacterial pneumonias (13% vs 90%), >4 skin abscesses (25% vs 90%), other serious infections (0% vs 40%), recurrent ear infections and/or tympanostomy tube placement (0% vs 60%), and severe eczema (13% vs 60%). Significant differences were not seen in parenchymal lung abnormalities (13% vs 50%, p = 0.09) and non-immunologic features, such as fractures and joint hyperextensibility. Mean peak serum IgE and absolute eosinophil counts (AEC) were comparable (IgE 6,865 vs 13,317 IU/mL; AEC 1,023 vs 1,182 cells/uL in family history vs probands). Those with family history received less advanced therapies than probands, specifically immunoglobulin replacement (13% vs 60%), antifungals (25% vs 60%), and lung surgery (0% vs 40%). One proband received bone marrow transplantation. Early diagnosis and intervention positively impacts disease course and management with markedly reduced rates of infectious complications, which may decrease future morbidity and mortality in this vulnerable patient population.