DiagnosisClinical Diagnosis Until the 2007 identification of STAT3 mutations as the cause of most cases of autosomal dominant hyper-IgE syndrome (AD-HIES), diagnosis was primarily made through the long-standing classic triad of recurrent skin boils, cyst-forming pneumonias, and extreme elevations of serum concentration of immunoglobulin E (IgE). A clinical scoring system was devised by the NIH group who recognized AD-HIES to be a multisystem disorder [Grimbacher et al 1999b]. Diagnosis now combines a high index of suspicion based on clinical features (as delineated in the clinical scoring system; see Table 1) with molecular genetic testing of STAT3 [Holland et al 2007, Minegishi et al 2007]. 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.Scoring system components include both immunologic/infectious manifestations and skeletal/connective tissue abnormalities. Scores are weighted to reflect the severity of a finding and to emphasize findings that are specific for AD-HIES. In order to have a high likelihood of being affected with AD-HIES, individuals should have a combination of both immunologic/infectious features and non-immunologic features. In the NIH clinical feature scoring system, a score of:>40 is suggestive of AD-HIES; 20-40 is considered indeterminate;<20 is considered unlikely to indicate AD-HIES. Table 1. Scoring System with Clinical and Laboratory Tests for Individuals in Kindreds with HIESView in own windowClinical FindingPoints ^{101234567810Highest serum-IgE level (IU/mL) 2<200200-500501-1,0001,001-2,000>2,000Skin abscessesNone1-23-4>4Pneumonia (episodes over lifetime)None123>3Parenchymal lung anomaliesAbsentBronchiectasisPneumatocoeleRetained primary teethNone123>3Scoliosis, maximum curvature<10°10°-14º15°-20°>20°Fractures with minor traumaNone1-2>2Highest eosinophil count (cells/μL) 3<700700-800>800Characteristic faceAbsentMildly presentPresentMidline anomaly 4AbsentPresentNewborn rashAbsentPresentEczema (worst stage)AbsentMildModerateSevereUpper-respiratory infections per year1-234-6>6CandidiasisNoneOralFingernailsSystemicOther serious infectionsNoneSevereFatal infectionAbsentPresentHyperextensibilityAbsentPresentLymphomaAbsentPresentIncreased nasal width 5<1 SD1-2 SD>2 SDHigh palateAbsentPresentYoung-age correction>5 years2-5 years1-2 years≤1 yearFrom Grimbacher et al [1999b]1. The entry in the furthest-right column is assigned the maximum points allowed for each finding.2. Normal <130 IU/mL3. 700/μL = 1 standard deviation (SD), 800/μL = 2 SD above the mean value for normal individuals.4. For example, cleft palate, cleft tongue, hemivertebrae, other vertebral anomaly (see Grimbacher et al [1999a]).5. Compared with age- and sex-matched controls [Farkas 1994] Immunologic/infectious features include elevation of serum concentration of IgE, eosinophilia, recurrent skin abscesses (often “cold,” manifesting little inflammatory reaction), pneumonias, destructive parenchymal lung lesions following infection, other serious or fatal infections, newborn rash, eczema, sinusitis or otitis and mucocutaneous candidiasis. Non-immune features include three or more retained primary teeth, scoliosis, bone fractures following minimal trauma, hyperextensibility of joints, characteristic facial appearance, increased nasal width, high palate, congenital skeletal anomalies and lymphoma. Not all features need to be present to diagnose AD-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 diagnosis. TestingClinical findingsElevated serum concentration of IgE. Serum IgE (normally <130 IU/mL in adults) is typically above 2000 IU/mL, but can be variable and may decrease in adulthood to normal levels. Eosinophilia >700/μL. Present in the majority of individualsDiminished memory T and B cells Near absence of IL-17 producing Th17 cell differentiation [Ma et al 2008, Milner et al 2008, Renner et al 2008]Chest imaging revealing pneumatocoeles or bronchiectasis, especially following recurrent pneumonias Spine imaging demonstrating scoliosis in approximately two thirds of individuals older than age 16 years Reduced bone density in approximately 50% of individuals Chiari 1 malformations in approximately 20% of persons, and brain MRI T₂-weighted focal hyperintensities in approximately 70%Protein analysis. Protein analysis is of limited diagnostic value (see Testing Strategy).Molecular Genetic TestingGene. STAT3 is the only gene in which mutations are known to cause autosomal dominant hyper-IgE syndrome (AD-HIES).Evidence for locus heterogeneity. A small percentage (<5%) of individuals meeting the clinical criteria for AD-HIES do not have identifiable STAT3 mutations, suggesting the existence of additional, as-yet unidentified loci. Table 2. Summary of Molecular Genetic Testing Used in Autosomal Dominant Hyper IgE SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Gene and Test Method 1Test AvailabilitySTAT3Sequence analysis Missense mutations, splice mutations and small in-frame deletions>95% 2ClinicalSequence analysis of select exonsMutations in exons 9-23 3Unknown1. The ability of the test method used to detect a mutation that is present in the indicated gene2. More than 95% of individuals with findings typical of signal transducer and activator of transcription 3 (STAT3)-deficient hyper IgE syndrome (NIH clinical scores >40 with points coming from both immune and non-immune categories) have a STAT3 mutation encoding an altered, expressed protein. 3. Exons analyzed may vary by laboratory.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a proband. History and physical examination using the scoring system (including both immune and non-immune categories) outlined in Clinical Diagnosis may suggest the diagnosis. Perform screening blood work to detect elevated serum concentration of IgE and eosinophilia. Other serum immunoglobulins and neutrophil/lymphocyte counts should be in the normal to near-normal range.For clinicians with access to research flow cytometry, greatly diminished Th17 cell number may be indicative of, but not definitive for, HIES. Individuals with a high clinical suspicion should have STAT3 sequencing performed. If sequence analysis does not identify a disease-causing mutation, cDNA analysis may be considered. An in-frame deletion that spans exons 22 and 23 has been reported; detected by cDNA analysis, the deletion would have been missed by standard genomic sequencing [Schimke et al 2010]. However, to date, no mutations that are out-of-frame, involve the entire gene, or otherwise result in haploinsufficiency have been reported. Protein analysis is of limited diagnostic value, as all mutations reported to date are protein positive and each person carries one normal allele. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) has not been shown to be sensitive for the majority of mutations. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in STAT3.}

Natural History Autosomal dominant hyper IgE syndrome (AD-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. Immunologic characteristics. Individuals with AD-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 [Hill & Quie 1974, Chamlin et al 2002, Eberting et al 2004].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, pneumatocoeles, and bronchiectasis are common complications. Staphylococcal infections outside of the lung and skin, such as osteomyelitis or liver abscess, occur much less frequently. Mucocutaneous candidiasis affecting the oropharynx, vagina, fingernails, and toenails is common. Opportunistic infections may occur, including Pneumocystis jiroveci pneumonia, disseminated histoplasmosis and Cryptococcus, and secondary infection of the pneumatocoeles with molds such as Aspergillus fumigatus or Scedosporium species. Decreased central memory T-cell formation may lead to increased incidence of varicella zoster virus (VZV) reactivation and modestly increased levels of circulating Epstein-Barr virus (EBV) [Siegel et al 2011].Non-immunologic characteristics. Individuals with AD-HIES have several connective tissue, skeletal, and vascular abnormalities. A characteristic facial appearance typically emerges by adolescence characterized by facial asymmetry, deep-set eyes, a broad nose, and prominent skin pores [Borges et al 1998; Grimbacher et al 1999a]. A high arched palate is common, as are oral mucosal variants including palatal 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 osteopenia, minimal trauma fractures, and scoliosis. Scoliosis typically develops through childhood and adolescence, and may require surgical correction. Joint hyperextensibilty 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.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 middle-sized arterial tortuosity 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 infrequently associated with subarachnoid hemorrhage. Symptoms of esophageal dysmotility are present in more than 50% of individuals and manifest as gastrointestinal reflux disease and dysphagia. Upper endoscopy frequently shows eosinophilic esophagitis. Diverticuli can occur at a relatively young age and may be associated with bowel perforation [Stover et al 2010]. Isolated colonic perforations have also been described. Major causes of morbidity and mortality. Survival is typically into adulthood, but a shortened life span is typical. Most deaths of individuals with AD-HIES are associated with Gram-negative (Pseudomonas) or filamentous fungal pneumonias (most commonly Aspergillus) infecting damaged lung parenchyma (i.e., pneumatocoeles, bronchiectasis) [Freeman et al 2007b]. Fungi may invade the pulmonary vasculature leading to massive hemoptysis, or may disseminate to multiple organs. Complications of arterial aneurysms have included myocardial infarction related to coronary artery aneurysm and subarachnoid hemorrhage related to intracranial aneurysm [Fathi et al 2011]. Lymphomas occur at an increased frequency and treatment has been successful with standard chemotherapy. Other malignancies have been reported [Leonard et al 2004].

Genotype-Phenotype Correlations No heritable differences in phenotype have been identified in individuals with STAT3-deficient hyper IgE syndrome [Heimall et al 2011]. Mutations tend to cluster in the DNA-binding and SH2 domains with few affected individuals having mutations in the transactivation domain and only one to date in the N-terminal domain [Holland et al 2007; Minegishi et al 2007; Renner et al 2008; Holland et al, unpublished].

Differential DiagnosisAtopic dermatitis. Individuals with severe atopic dermatitis are often suspected of having HIES because of the shared elevation of serum concentration of IgE, and many individuals with atopic dermatitis have recurrent staphylococcal skin infections. However, the other features of AD-HIES are typically not present, and individuals with severe atopic dermatitis often have increased numbers and severity of allergies (e.g., environmental, food that may lead to anaphylaxis) than do individuals with AD-HIES.Autosomal recessive hyper IgE syndrome (AR-HIES) is a distinct clinical disorder, characterized by elevated serum concentration of IgE, severe eczema, and recurrent skin and lung infections [Renner et al 2004]. It differs from STAT3-deficient hyper IgE syndrome by an increased incidence of neurologic abnormalities, an increased occurrence of viral infections of the skin (e.g., Molluscum contagiosum, warts), and absence of the non-immunologic findings of AD-HIES (e.g., retention of primary teeth) [Renner et al 2004]. Mutations in DOCK8 have now been identified as a cause of AR-HIES. Combined immunodeficiency associated with DOCK8 mutations is characterized by eczema, allergies, sinopulmonary infections, and viral skin infections including herpes simplex virus (HSV), varicella-zoster virus (VZV), Molluscum contagiosum, and human papillomavirus (HPV) [Zhang et al 2009, Engelhardt et al 2009]. Affected individuals have 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.TYK2 deficiency. A single report of human TYK2 deficiency described moderately high serum concentration of IgE in conjunction with disseminated bacillus Calmette-Guérin (BCG) 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].Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder caused by mutations in WAS. Similar to HIES, eczema and recurrent infections are present, but WAS has associated thrombocytopenia, a high incidence of autoimmune disease and lymphoma in later childhood and adulthood, and typically more opportunistic infections than seen in HIES. Wiskott-Aldrich syndrome occurs in males, although there have been isolated cases of affected females with skewed X-inactivation resulting in the disease phenotype [Parolini et al 1998]. Thrombocytopenia with small platelets is a distinguishing feature.Netherton syndrome is an autosomal recessive disorder caused by mutations in SPINK5. Netherton syndrome is associated with elevated IgE and rash; however, the rash is typically more ichthyotic in appearance with associated trichorrhexis invaginata (bamboo hair). Frequently an enteropathy is present with failure to thrive. Omenn syndrome also presents in the newborn period with rash and typically elevated serum IgE. Omenn syndrome is a form of SCID (severe combined immunodeficiency) that can result from mutations in RAG1 or RAG2, DCLRE1C (previously known as Artemis), IL2RG, and additional combined immunodeficiency genes that allow residual functional activity. Affected infants are usually sicker than those with HIES and have associated lymphadenopathy, hepatosplenomegaly, and opportunistic infections. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with hyper IgE syndrome (HIES), the following evaluations are recommended: Dermatologic examination Chest imaging Evaluation for scoliosis Dental examination for possible retention of primary teeth Treatment of ManifestationsCurrently, there is no cure or targeted treatment for AD-HIES, and the mainstay of therapy is prevention of staphylococcal abscesses and pneumonias with anti-staphylococcal prophylactic 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. Prophylactic antibiotics targeting Staphylococcus aureus and other pyogenic bacteria are primarily used to prevent the pneumonias and their complications. If structural damage to the lungs (e.g., bronchiectasis and/or pneumatocoeles) occurs, the breadth of antimicrobial coverage is usually extended, as these structural abnormalities become secondarily infected with Gram-negative bacteria (e.g., Pseudomonas) or fungi (e.g., Aspergillus). The combination of prophylactic antimicrobials and aggressive diagnosis and treatment of pneumonias helps to diminish these secondary lung parenchymal abnormalities. Continued use of antifungal agents to control mucocutaneous candidiasis and to prevent pulmonary disease may be necessary. The skin disease of eczema and recurrent boils is usually well controlled with antiseptic therapies such as diluted bleach baths (~1/2 - 1 cup of bleach per bath tub of water for 15 minutes 3 times weekly) or frequent swimming in a chlorinated pool. Adequate skin lubrication is needed with frequent bleach baths. Medications such as histamine-1 antagonists to control pruritus are helpful for more significant eczema. Intravenous or subcutaneous immunoglobulin is used with anecdotal improvement for some individuals, especially those who fail to make protective levels of specific antibodies following vaccination challenge; but prospective, randomized controlled studies of immunoglobulin supplementation have not been performed. There is no known treatment or prevention for the non-immunologic characteristics. As many individuals have osteopenia and minimal trauma fractures, optimizing of calcium and vitamin D intake is prudent. The role of medications such as bisphosphonates for persons with AD-HIES with osteoporosis is largely unexplored. Optimal blood pressure management seems appropriate in light of the arterial abnormalities.Anti-platelet or anticoagulation therapies may be considered for individuals with significant coronary artery aneurysms to prevent myocardial infarction related to clotting with aneurysm.However, any anti-clotting therapies need to be weighed against the risk of hemoptysis, a recognized complication of fungal or bacterial lung disease in individuals with AD-HIES.The role of hematopoietic cell transplantation (HSCT) in AD-HIES remains unknown. An adult treated for lymphoma with HSCT had improvement of many of the clinical features of HIES and decreasing IgE concentrations, but then died of transplant-related complications [Nester et al 1998]. A young girl with recurrent infections had full engraftment and reduction of serum IgE concentration that rebounded with the cessation of immunosuppression [Gennery et al 2000]. Recently, two unrelated affected teenagers who received HSCT for non-Hodgkin lymphoma were reported. Their immunologic and non-immunologic features, such as osteoporosis and course facial skin, were corrected [Goussetis et al 2010]. Prevention of Secondary ComplicationsProphylactic antimicrobials are used to decrease the number of boils and pneumonias. Aberrant healing from pyogenic pneumonias leads to bronchiectasis and pneumatocoeles; therefore, prevention of these pneumonias may lead to better preservation of lung parenchyma and decreased risk of secondary, more difficult to treat pulmonary infections. The role of prophylactic antifungals to prevent pulmonary mold infections is unknown.Osteoporosis and minimal trauma fractures are frequent findings. The effect of calcium and vitamin D supplementation is not known. SurveillanceIndividuals with AD-HIES often lack systemic signs of infection and feel better than one would expect when actively infected; therefore, a high index of suspicion for infection is necessary to permit recognition of pneumonias and institution of antibiotic treatment prior to development of extensive lung damage.Periodic chest imaging is helpful, especially if pneumonias have occurred, to assess whether structural lesions to the lung (e.g., pneumatocoeles) have formed. Because the microbiology of damaged lung tissue may change over time, it is important to obtain sputum samples intermittently and with acute infections, to direct therapy. Sputum samples should be obtained for microbiology during lung infections.Scoliosis screening of adolescents is indicated to guide any necessary intervention. Dental visits should ensure that primary teeth are removed in a timely fashion if necessary to allow secondary teeth to emerge.Periodic laboratory monitoring should be performed for individuals on chronic antimicrobial therapy. Individuals with AD-HIES have an increased incidence of lymphoma, which should be considered in the evaluation of lymphadenopathy, masses, or bony lesions.Evaluation of Relatives at RiskMolecular genetic testing of at-risk relatives of a proband with a known pathogenic mutation allows for early diagnosis.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 options, 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 AD-HIES.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.OtherParents have reported anecdotally 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.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Autosomal Dominant Hyper IgE Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSTAT317q21​.2Signal transducer and activator of transcription 3STAT3base-NIH
Resource of Asian Primary Immunodeficiency Diseases (RAPID)
STAT3 homepage - Mendelian genesSTAT3Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Autosomal Dominant Hyper IgE Syndrome (View All in OMIM) View in own window 102582SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3; STAT3 147060HYPER-IgE RECURRENT INFECTION SYNDROME, AUTOSOMAL DOMINANTNormal allelic variants. STAT3 has 24 exons. There are normal splice variants (see Table A, STAT3); there are also rare allelic variants in healthy populations.Pathologic allelic variants. Mutations identified to date include missense mutations, single amino-acid in-frame deletions, and splice mutations of exon 12 resulting in a ten amino-acid in-frame deletion at the start of the DNA binding domain [Renner et al 2008; Hsu, unpublished]. There are several hotspot mutations in the SH2 and DNA binding domain. Four recurrent mutations occur at CpG dinucleotides: c.1144C>T, c.1145G>A, c.1268G>A, and c.1909G>A (see Table 3) as well as a recurrent three-base in-frame deletion, c.1387_1389delGTG. The first three account for 64 of 97 identified mutations within the DNA binding domain (66%) while the last represents 27 of 55 mutations in the SH2 domain (49%). When the recurrent deletion is included, these five changes account for 61% of mutations identified in STAT3. Two unrelated individuals were identified with a 3.9-kb deletion spanning exons 22 and 23 resulting in an in-frame deletion of 53 amino acids [Schimke et al 2010]. Table 3. Selected STAT3 Pathologic Allelic Variants View in own windowDNA Nucleotide ChangeProtein Amino Acid Change Reference Sequencesc.1144C>T ^{1p.Arg382TrpNM_139276​.2
NP_644805​.1 c.1145G>A 1p.Arg382Glnc.1268G>A 1p.Arg423Glnc.1387_1389delGTGp.Val463delc.1909G>A 1p.Val637MetSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. Recurrent mutations; see Pathologic allelic variants.Normal gene product. Signal transducer and activator of transcription 3 (STAT3) is a major signal transduction protein involved in many diverse pathways such as wound healing, immunity, cancer, and vascular remodeling.Abnormal gene product. Expression of a mutated gene product is the rule; thus missense mutations, in-frame splice mutations, and in-frame insertions/deletions have been associated with AD-HIES. Null alleles have not been detected, consistent with the hypothesis that dominant interfering mutations are required to produce the condition. 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.}