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].

Surveillance

Evaluation of Relatives at Risk

Molecular genetic testing of at-risk relatives of a proband with a known STAT3 pathogenic variant allows for early diagnosis and prompt initiation of treatment and preventive measures.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Cessation of prophylactic antimicrobials is often advised during pregnancy. This may increase the risk of infection and should be taken into consideration. There have been pregnancies without complication, but also instances in which lung disease has worsened after pregnancy, potentially from limited antimicrobial use, delayed radiographic diagnosis, and impaired pulmonary clearance.

Risks associated with pregnancy should be discussed with affected females who have pulmonary compromise, severe scoliosis, or other complications of STAT3-HIES.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Parents have reported that due to the severe eczema of their child, there have been occasions when the health care providers have alerted Child Protective Services reporting that the child is not being kept clean. While skin hygiene is very important, in spite of the best efforts of caregivers, sometimes the skin flares are severe. Questions about parental neglect/abuse have also arisen when a toddler or young child appears with evidence of repeated fractures. Health care providers who are attuned to these possibilities can serve as important advocates for the parents and family.

Mode of Inheritance

STAT3 hyper IgE syndrome (STAT3-HIES) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• The majority of individuals with STAT3-HIES reported to date have had the disorder as the result of a de novo pathogenic variant; simplex cases (i.e., a single occurrence in a family) are common.
• Some individuals diagnosed with STAT3-HIES have an affected parent.
• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include clinical evaluation and/or molecular genetic testing.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or mosaicism in a parent. * Individuals with some findings of hyper IgE syndrome have had somatic and germline mosaicism for a STAT3 pathogenic variant and have transmitted the variant to offspring [Holland et al 2007, Hsu et al 2013].
  * Misattributed parentage can also be explored as an alternative explanation for an apparent de novo pathogenic variant.
• The family history of some individuals diagnosed with STAT3-HIES may appear to be negative because of failure to recognize the disorder in family members with a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
• Note: If the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the variant and may be mildly affected [Holland et al 2007, Hsu et al 2013].

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known STAT3 pathogenic variant that cannot be detected in the leukocyte DNA of either parent and the parents are clinically unaffected, the recurrence risk to sibs is still greater than that of the general population because of the possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with STAT3-HIES has a 50% chance of inheriting the STAT3 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the STAT3 pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the STAT3 pathogenic variant has been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic testing for STAT3-HIES are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

STAT3 encodes signal transducer and activator of transcription 3 (STAT3), a major signal transduction protein involved in many diverse pathways such as wound healing, immunity, cancer, and vascular remodeling.

Expression of an abnormal gene product with a dominant-negative effect is associated with STAT3 hyper IgE syndrome (STAT3-HIES). Its complex immunologic and somatic features reflect STAT3's critical role in signaling for the gp130-dependent cytokines including IL-6 (inflammation, fever, CRP elevation, wound healing), IL-11 (tooth deciduation), IL-23 (IL-17 production), and TNF (vascular remodeling and wound healing).

Mechanism of disease causation. Almost all cases of STAT3-HIES are caused by missense variants that interfere with STAT3 function, conferring a dominant-negative effect that leads to impaired STAT3 signaling. In-frame splice variants and in-frame insertions/deletions have also been reported, as well as a single in-frame deletion of exons 22 and 23 [Schimke et al 2010].

Null alleles have not been detected, consistent with the dominant-negative mechanism. Homozygous Stat3 knockout mice are embryonic lethal while the heterozygous mice are reported to be phenotypically normal [Takeda et al 1997], supporting the dominant-negative mechanism of disease.

STAT3-specific laboratory considerations. The STAT3 mechanism of disease complicates variant interpretation. It is important to note that dominant gain-of-function variants cause lymphoproliferation, autoimmunity, lung disease, and infection (see Genetically Related Disorders). These variants have been reported in the same codons as the dominant-negative variants, meaning that determining whether a missense variant in STAT3 will confer a dominant-negative or gain-of-function effect cannot be based on codon alone.

Cancer and Benign Tumors

Somatic variants in STAT3 are associated with multiple cancers. Of the hematologic malignancies, activating pathogenic variants in STAT3 occur most frequently in T-cell large granular lymphocyte leukemia [Koskela et al 2012]. Somatic STAT3 variants have also been described in skin cancers including melanomas, gastrointestinal cancers, and neural tumors [Shahmarvand et al 2018].

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Revision History

• 26 March 2020 (ha) Comprehensive update posted live
• 7 June 2012 (me) Comprehensive update posted live
• 23 February 2010 (me) Review posted live
• 16 July 2009 (jp) Original submission