Clinical 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).

More recently, a more precise clinical scoring system was devised by the NIH group who recognized AD-HIES to be a multisystem disorder [Grimbacher et al 1999]. Diagnosis now combines a high index of suspicion based on clinical features, as delineated in the clinical scoring system, with molecular genetic testing of STAT3 [Holland et al 2007, Minegishi et al 2007].

Scoring system components include both immunologic/infectious manifestations and skeletal/connective tissue abnormalities. Scores are weighted according to the severity of each 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 published scoring system, a score higher than 40 is suggestive of AD-HIES, a score of 20 to 40 is considered indeterminate, and a score of less than 20 is considered unlikely to indicate AD-HIES.

• Immunologic/infectious features. 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. 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.

Testing

Clinical findings:

• Elevated serum concentration of IgE. Serum IgE (normally <130 IU/mL in adults) 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 individuals

• Diminished memory T and B cells

• Near absence of IL-17 producing Th17 cell differentiation [Milner et al 2008, Ma et al 2008, Renner et al 2008]

• Chest imaging revealing pneumatocoeles or bronchiectasis, especially following recurrent pneumonias

• Spine imaging demonstrating scoliosis in approximately 2/3 of individuals older than age 16 years

• Reduced bone density in approximately 50% of individuals as determined by Dexa scan

• Brain MRI revealing Chiari 1 malformations in approximately 20% of persons, and T2 weight focal hyperintensities in approximately 70%

Molecular Genetic Testing

Gene. STAT3 is the only gene known to be associated with autosomal dominant hyper-IgE syndrome (AD-HIES).

Other loci. A small percentage (<5%) of individuals meeting the clinical criteria for AD-HIES do not have identifiable STAT3 mutations, suggesting additional, as-yet unidentified loci.

Clinical testing

• Sequence analysis. More than 95% of individuals with findings typical of STAT3-deficient hyper IgE syndrome (NIH clinical scores >40) have a STAT3 mutation encoding an altered, expressed protein.

• Sequence analysis of select exons is available clinically.

Research testing

• Deletion/duplication analysis. To date, there are no reports of large deletions resulting in null alleles.

Table 1. Summary of Molecular Genetic Testing Used in Hyper IgE Syndrome

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Gene and Test Method 1	Test Availability
STAT3	Sequence analysis of genomic DNA or cDNA	Missense mutations, splice mutations and small in-frame deletions	>95%	Clinical
	Sequence analysis of select exons	Mutations in exons 9-23	Unknown
	Deletion/duplication analysis 2	Partial- and whole-gene deletions	Unknown	Research only

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene; individuals who do not fulfill diagnostic criteria by the NIH scoring system are less likely to have identifiable STAT3 mutations.

2. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA, a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

Testing Strategy

To confirm/establish the diagnosis in a proband

• History and physical focusing on features that distinguish individuals with AD-HIES from persons with allergic diseases (such as severe atopic dermatitis) and other immunodeficiencies. Certain features, such as the documented newborn rash, recurrent boils and pyogenic pneumonias, and the presence of connective tissue, skeletal, or dental abnormalities, increase likelihood of AD-HIES. Positive family history is helpful when present, but most cases are simplex (i.e., a single occurrence in a family).

• 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.

• STAT3 molecular genetic testing for individuals with a high clinical suspicion

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) Disorders

No 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 and pneumatocoeles and bronchiectasis are common complications.

Staphylococcal infections outside of the lung and skin, such as osteomyelitis or liver abscess, occur 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.

Non-immunologic characteristics. Individuals with AD-HIES have several connective tissue, skeletal, and vascular abnormalities.

A characteristic facial appearance typically develops in adolescence characterized by facial asymmetry, deep-set eyes, a broad nose, and prominent skin pores [Borges et al 1998]. A high arched palate is common, as are oral mucosal variants including palatal ridges. 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.

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]. 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.

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 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 and life-threatening 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.

Lymphomas occur at an increased frequency with an increase in relative risk of 259. 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. 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, unpublished; Holland et al 2007; Minegishi et al 2007; Renner et al 2008].

Penetrance

Intrafamilial variability is minimal and penetrance appears to be complete.

Anticipation

Anticipation has not been observed in STAT3-deficient hyper IgE syndrome.

Although some reports suggest increasing severity of AD-HIES in successive generations, it is likely that these were instances of milder disease associated with mosaicism for a STAT3 mutation in the first generation and more severe disease associated with a STAT3 germline mutation in the second and subsequent generations.

Prevalence

The prevalence of STAT3-deficient hyper IgE syndrome is unknown, but the condition is rare. There does not appear to be a predominance in any ethnic or racial group, and no gender preference has been reported.

Evaluations 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 Manifestations

Currently, 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) 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 preventative 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.

• 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. Only two reports have appeared in the literature. One individual who was treated for lymphoma with HSCT showed improvement of many of the clinical features of HIES and decreasing IgE concentrations, but then died of pulmonary fibrosis secondary to the transplant [Nester et al 1998]. In the other individual, engraftment occurred; however, serum concentration of IgE returned to elevated levels within several years of transplantation; whether there was partial amelioration of symptoms is undetermined [Gennery et al 2000].

Surveillance

Individuals 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.

• Since 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.

Testing of Relatives at Risk

Molecular 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.

Therapies Under Investigation

Trials currently under way at the National Institute of Allergy and Infectious Disease (NIAID), National Institutes of Health (NIH):

• A randomized placebo-controlled trial of ranitidine in the prevention of infections. Anecdotal reports suggest that histamine 2 antagonist therapy decreases the number of infections.

• An open-label investigation of omalizumab therapy for HIES

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Risks of pregnancy should be discussed with affected females who have pulmonary compromise or other complications of AD-HIES.

Genetics clinics and primary immunodeficiency clinics, staffed by genetics professionals and immunologists respectively, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

The Immune Deficiency Foundation (IDF) and Jeffrey Modell Foundation maintain Web sites with links to immunology centers with expertise in this condition (see Consumer Resources).

Mode of Inheritance

Autosomal dominant hyper IgE syndrome associated with STAT3 mutations is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Some individuals diagnosed with autosomal dominant hyper IgE syndrome have an affected parent.

• A proband with autosomal dominant hyper IgE syndrome often has the disorder as the result of a new gene mutation. The majority of cases reported to date have been caused by de novo mutations. Simplex cases (i.e., a single occurrence in a family) are common.

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include clinical evaluation and/or molecular genetic testing. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Mosaicism may also lead to a milder phenotype. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

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

• If a parent of the proband is affected, the risk to the sibs is 50%.

• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low, but not entirely absent. The risk to the sibs of a proband with unaffected parents is higher than that of the general population because of the possibility of germline mosaicism in a parent.

Offspring of a proband. Each child of an individual with autosomal dominant hyper IgE syndrome has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Literature Cited

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Suggested Reading

1. Freeman AF, Holland SM. The hyper-IgE syndromes. Immunol Allergy Clin North Am. 2008;28:277–91. [PMC free article: PMC2683262] [PubMed: 18424333]
2. Grimbacher B, Puck JM, Holland SM (2007) Hyper-IgE syndrome. In: Ochs H, Smith HIE, Puck JM (eds) Primary Immunodeficiency Diseases: a Molecular and Genetic Approach, 2 ed. Oxford University Press, NY, pp 496-504.

Revision History

• 23 February 2010 (me) Review posted live

• 16 July 2009 (jp) Original submission