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STAT3 Hyper IgE Syndrome

Synonyms: Job Syndrome, STAT3-Deficient Hyper-IgE Syndrome, STAT3 Deficiency, STAT3-HIES, STAT3 Loss-of-Function Hyper-IgE Syndrome (STAT3 LOF HIES)

, BA, , PNP-BC, APNG, , MD, , MD, and , MD.

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Initial Posting: ; Last Update: March 26, 2020.

Estimated reading time: 22 minutes

Summary

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.

Diagnosis

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).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of STAT3-HIES, molecular genetic testing approaches can include single-gene testing (especially if there is a positive family history) or, more typically, the use of a multigene panel:

  • Single-gene testing. Sequence analysis of STAT3 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. Since STAT3-HIES occurs through a dominant-negative mechanism (see Molecular Genetics), the detection of a large intragenic deletion or duplication is unexpected; however, one in-frame deletion of exons 22 and 23 has been reported [Schimke et al 2010]. Therefore, while it is unlikely to identify a disease-causing variant, testing for intragenic deletions or duplication may be considered.
  • A multigene panel that includes STAT3 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the diagnosis of STAT3-HIES is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in STAT3 Hyper IgE Syndrome

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
STAT3Sequence analysis 3>99% 4
Gene-targeted deletion/duplication analysis 51 reported 6
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Data derived from Human Gene Mutation Database [Stenson et al 2017]

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

An in-frame deletion of exons 22 and 23 has been reported [Schimke et al 2010].

7.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

Clinical Characteristics

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.

Presentation

Individuals with STAT3-HIES typically manifest in the newborn period with a rash, often diagnosed as eosinophilic pustulosis. The rash evolves into an eczematoid dermatitis that is often driven by staphylococcal infection [Chamlin et al 2002, Eberting et al 2004].

Immunologic Characteristics

Recurrent skin and sinopulmonary infections are noted in early childhood.

  • Recurrent staphylococcal boils usually manifest in the first few years of life, and may be "cold," lacking the cardinal features of inflammation, warmth, redness, and pain.
  • Recurrent pneumonias begin as well in the first few years, with the most common bacterial isolates being Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae. Abnormal healing of these pneumonias frequently leads to pneumatoceles and bronchiectasis.
  • Staphylococcal infections outside of the skin and lung, such as osteomyelitis or liver abscess, occur but much less frequently.
  • Mucocutaneous candidiasis affecting the oropharynx, vagina, fingernails, and toenails is common.
  • Opportunistic infections including Pneumocystis jiroveci pneumonia, disseminated histoplasmosis and Cryptococcus, and secondary infection of the pneumatoceles with molds such as Aspergillus fumigatus or Scedosporium species may occur. Histoplasmosis most frequently disseminates to the intestinal tract and can mimic inflammatory bowel disease. Coccidioides and Cryptococcus have caused meningitis [Odio et al 2015].
  • Decreased central memory T-cells may lead to increased incidence of varicella zoster virus (VZV) reactivation and modestly increased levels of circulating Epstein-Barr virus [Siegel et al 2011].

Nonimmunologic Characteristics

Individuals with STAT3-HIES may have several additional nonimmunologic findings.

Facial. A characteristic facial appearance including facial asymmetry, deeply set eyes, a broad nose, and prominent skin pores typically emerges by adolescence [Borges et al 1998, Grimbacher et al 1999a].

Oral findings include a high arched palate and oral mucosal variants including prominent palatine ridges [Domingo et al 2008]. Failure of primary teeth exfoliation is common; secondary tooth development is normal if the primary teeth are removed.

Skeletal abnormalities include osteoporosis, minimal trauma fractures, scoliosis, joint hyperextensibility, and craniosynostosis.

  • Osteoporosis and minimal trauma fractures start in early childhood.
  • Scoliosis typically develops through childhood and adolescence, and may require surgical correction.
  • Joint hyperextensibility is common, and adults may have degenerative joint disease.
  • Varying degrees of craniosynostosis can be seen, although surgical correction is rarely required. Skull radiographs often have a "beaten copper" appearance. Mild craniosynostosis is frequently noted in skull imaging.

Brain imaging reveals Chiari 1 malformations in approximately 20% of individuals and focal hyperintensities prominent on T2-weighted images in approximately 70% of individuals.

  • The focal hyperintensities are usually localized to the white matter and tend to increase in number with age.
  • Both the Chiari 1 malformations and the hyperintensities are usually asymptomatic [Freeman et al 2007a].

Vascular abnormalities including tortuosity of middle-sized arteries and aneurysms have been described [Ling et al 2007, Freeman et al 2011, Chandesris et al 2012]. The coronary arteries have been the most completely studied.

  • The combination of tortuosity and dilation is found in approximately 50% of affected individuals; either abnormality is present in approximately 70%.
  • Clinical sequelae have been rare but include myocardial infarction.

Cerebral artery aneurysm has also been described and is infrequently associated with subarachnoid hemorrhage.

Gastrointestinal issues vary [Arora et al 2017]:

  • Symptoms of esophageal dysmotility are present in more than 50% of individuals and manifest as gastrointestinal reflux and dysphagia.
  • Upper endoscopy frequently shows eosinophilic esophagitis.
  • Diverticula can occur at a relatively young age and may be associated with bowel perforation [Stover et al 2010].
  • Spontaneous intestinal perforations have also been described.
  • Significant gastrointestinal bleeds can occur from aneurysms and Dieulafoy lesions (abnormally large artery in the lining of the gastrointestinal system).

Major Causes of Morbidity and Mortality

Survival is typically into adulthood, but a shortened life span was typical in the past. Most individuals are now living into or past the sixth decade.

  • Most deaths of individuals with STAT3-HIES are associated with gram-negative (Pseudomonas) or filamentous fungal pneumonias (most commonly Aspergillus) infecting damaged lung parenchyma (i.e., preexisting pneumatoceles, bronchiectasis) [Freeman et al 2007b]. Fungi may invade the pulmonary vasculature leading to massive hemoptysis, or may disseminate to multiple organs.
  • Myocardial infarction may be related to coronary artery aneurysms and subarachnoid hemorrhage may be related to intracranial aneurysms [Fathi et al 2011].
  • Lymphomas occur at an increased frequency; treatment with standard chemotherapy has been successful.

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.

Differential Diagnosis

Table 2.

Disorders with Elevated Serum Concentration of IgE to Consider in the Differential Diagnosis of STAT3 Hyper IgE Syndrome

Gene(s)DisorderMOIAdditional Clinical Features of Differential Disorder
Overlapping w/STAT3-HIESDistinguishing from STAT3-HIES
CARD14 1
FLG 2
Atopic dermatitis 3AD
AR 4
Recurrent staphylococcal skin infections
  • Absence (typically) of other features of AD-HIES
  • Individuals w/severe atopic dermatitis often have more (& more severe) allergies (e.g., environmental, food that may lead to anaphylaxis) than those w/AD-HIES.
CARD11Immunodeficiency 11B w/atopic dermatitis 5 (OMIM 617638)ADEarly-onset eczema (frequently)↑ viral skin infections; variable hypogammaglobulinemia
DCLRE1C
RAG1
RAG2
Omenn syndrome 6 (OMIM 603554)ARPresents in newborn period w/rash & typically ↑ serum IgE
  • Affected infants are usually sicker than those w/HIES.
  • Lymphadenopathy, hepatosplenomegaly, opportunistic infections
DOCK8DOCK8 deficiency (DOCK8 AR HIES 7; OMIM 243700)AR
  • Eczema
  • Recurrent skin & lung infections 8
  • ↑ occurrence of viral skin infections (e.g., Molluscum contagiosum, warts); ↑ malignancies (lymphoma, squamous cell CA); ↑ vasculitis
  • Absence of nonimmunologic findings of STAT3-HIES (e.g., retention of primary teeth) 8
IL6STIL6ST deficiency 9 (OMIM 618523)AR
  • Recurrent skin & lung infections
  • Craniosynostosis & scoliosis
Limited cases but potentially more serious infections
PGM3PGM3 deficiency 10 (OMIM 615816)ARRecurrent skin & sinopulmonary infections; bone defects incl scoliosis
  • Developmental delays (common)
  • Cytopenias w/lymphopenia & neutropenia
SPINK5Netherton syndrome (OMIM 256500)ARRash
  • Rash typically more ichthyotic in appearance w/assoc trichorrhexis invaginata (bamboo hair)
  • Enteropathy w/failure to thrive frequently present
WASWiskott-Aldrich syndrome (see WAS Disorders)XLEczema & recurrent infections
  • Thrombocytopenia w/small platelets; high incidence of autoimmune disease & lymphoma in later childhood & adulthood; typically more opportunistic infections than in HIES
  • Typically seen in males (isolated cases of affected females w/skewed X-inactivation resulting in disease phenotype reported)
ZNF341ZNF341 deficiency 11 (OMIM 618282)AREczema & recurrent infectionsFewer nonimmunologic manifestations; stronger inflammatory responses w/infection

AD = autosomal dominant; AR = autosomal recessive; HIES = hyper IgE syndrome; MOI = mode of inheritance; XL = X-linked

1.
2.

OMIM 605803

3.

Atopic dermatitis has many causes (many of which are unknown); FLG- and CARD14-related atopic dermatitis represent selected examples of heritable atopic dermatitis.

4.

Atopic dermatitis caused by FLG pathogenic variants can be inherited in an autosomal dominant or autosomal recessive manner; atopic dermatitis caused by CARD14 pathogenic variants is inherited in an autosomal dominant manner.

5.
6.

Omenn syndrome is a form of SCID (severe combined immunodeficiency) that can result from pathogenic variants in RAG1, RAG2, DCLRE1C (previously known as Artemis), IL2RG, and additional combined immunodeficiency genes that allow residual functional activity.

7.

Most individuals initially described as having autosomal recessive hyper IgE were found to have biallelic pathogenic variants in DOCK8. DOCK8 deficiency is a combined immunodeficiency characterized by eczema, allergies, sinopulmonary infections, and viral skin infections including herpes simplex virus, varicella-zoster virus, Molluscum contagiosum, and human papillomavirus [Zhang et al 2009, Engelhardt et al 2009]. Affected individuals are at increased risk for malignancy; squamous cell carcinomas and lymphoma have been reported. DOCK8 deficiency is frequently associated with lymphopenia which often progresses with age, and serum IgM levels may be low or undetectable. Eosinophilia and IgE are both variable, but can be extremely elevated.

8.
9.
10.
11.

Note: A single report of human TYK2 deficiency described moderately high serum concentration of IgE in conjunction with disseminated bacillus Calmette-Guérin infection and susceptibility to viral and other infections [Minegishi et al 2006]. However, subsequent reports of TYK2 deficiency have not been associated with the AR-HIES phenotype [Kilic et al 2012, Kreins et al 2015].

Management

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.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with STAT3 Hyper IgE Syndrome

System/ConcernEvaluationComment
SkinDermatologic examinationNewborn rash & eczema during childhood; often improves w/age
PulmonaryChest imagingDetection of bronchiectasis & pneumatoceles
SkeletalEvaluation for scoliosis & osteoporosis
  • Scoliosis typically progresses through adolescence.
  • Osteoporosis can be present in children & adults; DEXA screening recommended.
DentalDental examination for possible retention of primary teeth
VascularScreening for coronary artery & cerebral artery aneurysms
  • Aneurysms much more common in adults than in children
  • Screening by brain MRA & heart CTA or coronary artery MRA every 3 yrs recommended for adolescents & adults
OtherConsultation w/clinical geneticist &/or genetic counselor

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].

Table 4.

Treatment of Manifestations in Individuals with STAT3 Hyper IgE Syndrome

Manifestation/
Concern
TreatmentConsiderations/Other
Eczema &
recurrent boils
Topical antiseptics, e.g., dilute bleach baths 1 & chlorhexidine; frequent swimming in a chlorinated poolAdequate skin lubrication is needed after bleach.
Anti-staphylococcal prophylaxis, e.g., w/2x/day TMP/SMX
Histamine-1 antagonists (e.g., hydroxyzine) to control pruritusHelpful for more significant eczema
Recurrent
pneumonias
Antibiotic prophylaxis, typically w/2x/day TMP/SMXTargeting Staphylococcus aureus & other pyogenic bacteria to prevent the pneumonias & their complications
In Coccidioides endemic regions use of prophylactic antifungals (e.g., fluconazole) can be considered.To prevent disseminated severe infection
  • If structural damage to the lungs (e.g., bronchiectasis &/or pneumatoceles) has occurred, the breadth of antimicrobial coverage may need to be extended, incl antifungals, as these structural abnormalities become secondarily infected w/gram-negative bacteria (e.g., Pseudomonas) or fungi (e.g., Aspergillus).
  • In the setting of bronchiectasis, consideration of azithromycin to prevent exacerbations if no mycobacterial infection present
Sputum samples for bacteria, fungi, & mycobacteria (typically nontuberculous) should be obtained for microbiology during lung infections to help guide antimicrobial choice.
Intravenous or subcutaneous IgG replacement can be considered.Has been used w/anecdotal improvement for some individuals, esp those who fail to make protective levels of specific antibodies following vaccination challenge; prospective, randomized controlled studies of immunoglobulin supplementation have not been performed.
Airway clearance w/bronchiectasisAirway clearance techniques incl airway clearance devices, hypertonic saline nebulizers.
Chronic mucocutaneous
candidiasis
Antifungal prophylaxisConsider fluconazole prophylaxis if living in a Coccidioides endemic region.
Osteoporosis &
Minimal trauma
fractures
Optimize calcium & vitamin D intakeThe role of bisphosphonates for those w/this disorder w/osteoporosis is unclear; some improvement seen in bone density but unclear improvement in fractures [Sowerwine et al 2014].
Arterial
aneurysms
Optimal blood pressure management
Antiplatelet or anticoagulation therapies may be considered for individuals w/significant coronary artery aneurysms to prevent myocardial infarction related to clotting within the aneurysm.This must be weighed against risk of hemoptysis, a complication of fungal or bacterial lung disease in individuals w/STAT3-HIES.

TMP/SMX = trimethoprim/sulfamethoxazole

1.

1/2 - 1 cup bleach per bathtub of water for 15 minutes 3 times weekly

Surveillance

Table 5.

Recommended Surveillance for Individuals with STAT3 Hyper IgE Syndrome

System/ConcernEvaluationFrequency
SkinDermatology exam & culture of skin lesionsAs needed
PulmonaryHigh index of suspicion for infectionLifelong
Periodic chest imagingWith ↑ pulmonary symptoms
Sputum samplesWith ↑ pulmonary symptoms
SkeletalScoliosis evaluationThrough adolescence
DentalMonitor for emergence of secondary teeth & possible need for removal of primary teethEvery 6-12 mos during childhood
Vascular
  • Brain MRA for cerebral aneurysm
  • CTA or MRA for coronary artery aneurysm
Every 3 yrs in adults
OtherMonitor for lymphadenopathy, or masses due to ↑ incidence of lymphomaAnnually

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

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

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 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 is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

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 decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Job Research Foundation
    459 Columbus Avenue
    Suite 509
    New York NY 10024
    Email: info@jobresearchfoundation.org
  • Canadian Immunodeficiencies Patient Organization (CIPO)
    362 Concession Road 12
    RR #2
    Hastings Ontario K0L 1Y0
    Canada
    Phone: 877-262-2476 (toll-free)
    Fax: 866-942-7651 (toll-free)
    Email: info@cipo.ca
  • International Patient Organisation for Primary Immunodeficiencies (IPOPI)
    Firside
    Main Road
    Downderry Cornwall PL11 3LE
    United Kingdom
    Phone: +44 01503 250 668
    Fax: +44 01503 250 668
    Email: info@ipopi.org
  • Jeffrey Modell Foundation/National Primary Immunodeficiency Resource Center
    747 Third Avenue
    New York NY 10017
    Phone: 866-463-6474 (toll-free); 212-819-0200
    Fax: 212-764-4180
    Email: info@jmfworld.org
  • European Society for Immunodeficiencies (ESID) Registry
    Dr. Gerhard Kindle
    University Medical Center Freiburg Centre of Chronic Immunodeficiency
    Engesserstr. 4
    79106 Freiburg
    Germany
    Phone: 49-761-270-34450
    Email: esid-registry@uniklinik-freiburg.de
  • Primary Immunodeficiency Diseases Registry at USIDNET
    40 West Chesapeake Avenue
    Suite 308
    Towson MD 21204-4803
    Phone: 866-939-7568
    Fax: 410-321-0293
    Email: contact@usidnet.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

STAT3 Hyper IgE Syndrome: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for STAT3 Hyper IgE Syndrome (View All in OMIM)

102582SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3; STAT3
147060HYPER-IgE RECURRENT INFECTION SYNDROME 1, AUTOSOMAL DOMINANT; HIES1

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.

Table 6.

Notable STAT3 Pathogenic Variants

Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment [Reference]
NM_139276​.2
NP_644805​.1
c.1144C>Tp.Arg382TrpRecurrent & most frequently observed pathogenic variants [Holland et al 2007]
c.1145G>Ap.Arg382Gln
c.1268G>Ap.Arg423Gln
c.1387_1389delGTGp.Val463del
c.1909G>Ap.Val637Met

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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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Chapter Notes

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
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