Stat3 Hyper Ige Syndrome

Clinical characteristics.

STAT3 hyper IgE syndrome (STAT3-HIES) is a primary immune deficiency syndrome characterized by elevated serum IgE, eczema, and recurrent skin and respiratory tract infections, together with several nonimmune features. This disorder typically manifests in the newborn period with a rash (often diagnosed as eosinophilic pustulosis) that subsequently evolves into an eczematoid dermatitis. Recurrent staphylococcal skin boils and bacterial pneumonias usually manifest in the first years of life. Pneumatoceles and bronchiectasis often result from aberrant healing of pneumonias. Mucocutaneous candidiasis is common. Nonimmune features may include retained primary teeth, scoliosis, bone fractures following minimal trauma, joint hyperextensibility, and characteristic facial appearance, which typically emerges in adolescence. Vascular abnormalities have been described and include middle-sized artery tortuosity and aneurysms, with infrequent clinical sequelae of myocardial infarction and subarachnoid hemorrhage. Gastrointestinal (GI) manifestations include gastroesophageal reflux disease, esophageal dysmotility, and spontaneous intestinal perforations (some of which are associated with diverticuli). Fungal infections of the GI tract (typically histoplasmosis, Cryptococcus, and Coccidioides) also occur infrequently. Survival is typically into adulthood, with most individuals now living into or past the sixth decade. Most deaths are associated with gram-negative (Pseudomonas) or filamentous fungal pneumonias resulting in hemoptysis. Lymphomas occur at an increased frequency.

Diagnosis/testing.

The diagnosis of STAT3-HIES is established in a proband with typical clinical findings and a heterozygous dominant-negative pathogenic variant in STAT3 identified by molecular genetic testing.

Management.

Treatment of manifestations: The mainstay of treatment is prevention of staphylococcal abscesses and pneumonias with anti-staphylococcal prophylactic antibiotics as well as early aggressive treatment of infections. Use of antibiotics and antifungal agents depends on the nature of the infection and the extent of involvement. Antiseptic therapies for the skin such as dilute bleach baths and chlorhexidine are beneficial. Medications such as histamine-1 antagonists to control pruritus are helpful for more significant eczema. There is no known treatment or prevention for the nonimmunologic characteristics, although optimization of calcium and vitamin D intake may be considered to improve bone health. The role of hematopoietic cell transplantation (HSCT) in STAT3-HIES is emerging; while successful transplant recipients have improved infection phenotype, the effect of HSCT on the nonimmunologic aspects of the disease remains unclear.

Surveillance: Periodic chest imaging and high clinical suspicion assist in early detection of lung infections. Culture of skin lesions and sputum samples helps direct therapy. Routine screening of adolescents for early signs of scoliosis is recommended. Dental monitoring is necessary to ensure timely removal of primary teeth to allow eruption of secondary teeth. Evaluation for coronary artery and cerebral aneurysms every three years in adulthood is recommended as well as monitoring for lymphadenopathy due to increased incidence of lymphoma.

Genetic counseling.

STAT3-HIES is inherited in an autosomal dominant manner. The majority of affected individuals have the disorder as the result of a de novo pathogenic variant. Each child of an individual with STAT3-HIES has a 50% chance of inheriting the pathogenic variant. Prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible once the STAT3 pathogenic variant in the family has been identified.

Suggestive Findings

STAT3 hyper IgE syndrome (STAT3-HIES) should be suspected in individuals with the following findings:

• Newborn rash and typically eczematous rash at least through childhood
• Recurrent skin boils (often "cold," manifesting little inflammatory reaction)
• Cyst-forming pneumonias
• Mucocutaneous candidiasis
• Nonimmune features such as three or more retained primary teeth, scoliosis, bone fractures following minimal trauma, hyperextensibility of joints, characteristic facial appearance, increased nasal width, high palate
• Laboratory test results showing:
  • Elevations of serum concentration of immunoglobulin E (IgE) to levels above 2000 IU/mL (normal <100 IU/mL in adults);
  • Eosinophilia (>700/μL);
  • Diminished circulating memory T and B cells and near absence of IL-17-producing Th17 cells.

Note: Not all features need to be present to suspect STAT3-HIES, and because features accrue over time, the clinical diagnosis can be uncertain in young children. Moreover, early institution of effective prophylactic antibiotics can attenuate or prevent many of the infectious complications that would otherwise facilitate suspicion of the diagnosis.

A clinical scoring system was devised by the NIH group who recognized STAT3-HIES (then known as autosomal dominant HIES) to be a multisystem disorder [Grimbacher et al 1999b]. Woellner et al [2010] have developed guidelines that include the NIH clinical feature scoring system as well as determination of IL-17-producing T cells.

However, molecular genetic testing for STAT3 pathogenic variants, readily available on a clinical basis, is the only reliable diagnostic approach. Prior to the genetic diagnosis, a HIES scoring system was developed to assist in the diagnosis [Grimbacher et al 1999b]. The scoring system components included both immunologic/infectious manifestations and skeletal / connective tissue abnormalities. The scoring system may still be helpful in identifying individuals in whom to perform genetic testing, or for considering the diagnosis if resources do not allow for genetic testing.

Establishing the Diagnosis

The diagnosis of STAT3 hyper IgE syndrome (STAT3-HIES) is established in a proband with typical clinical findings and a heterozygous dominant-negative pathogenic variant in STAT3 identified by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of STAT3-HIES is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with atypical clinical findings in whom the diagnosis of STAT3-HIES has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

STAT3 hyper IgE syndrome (STAT3-HIES) is a primary immune deficiency syndrome characterized by elevated serum IgE, eczema, and recurrent skin and respiratory tract infections, together with several connective tissue and skeletal abnormalities.

Genotype-Phenotype Correlations

No genotype-phenotype correlations for STAT3 missense pathogenic variants have been identified.

Penetrance

Intrafamilial variability is minimal and penetrance appears to be complete.

Nomenclature

Dominant-negative pathogenic variants in STAT3 were identified as the cause of autosomal dominant hyper IgE syndrome (AD-HIES) and "Job syndrome" in 2007. Since this time, other clinically overlapping dominant genetic disorders have been characterized and the term AD-HIES is no longer specific to the dominant-negative STAT3 phenotype. Multiple terms are currently used to refer to the dominant-negative STAT3 phenotype: STAT3-HIES (used in this GeneReview), STAT3-mutated HIES, dominant-negative STAT3, LOF STAT3, and STAT3 LOF.

Prevalence

The prevalence of STAT3-HIES is unknown. The condition is rare, likely around 1:1,000,000 population. Enrichment in a specific ethnic or racial group has not been reported.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with STAT3 hyper IgE syndrome (STAT3-HIES), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Currently, there is no complete cure or targeted treatment for STAT3-HIES. The mainstay of therapy is prevention of staphylococcal abscesses and pneumonias with prophylactic anti-staphylococcal antibiotics as well as early aggressive treatment of infections. It is important to institute antibiotic therapy at the earliest sign of infection. Many affected individuals progress from minor to major infection rapidly, and systemic signs of infection may be minimal.

There is no known treatment or prevention for the nonimmunologic characteristics.

The role of hematopoietic cell transplantation (HSCT) in STAT3-HIES is emerging. It is clear that successful transplant recipients have improved infection phenotype. The effect of HSCT on the nonimmunologic aspects of the disease remains unclear [Goussetis et al 2010, Patel et al 2015, Yanagimachi et al 2016].