Clinical characteristics.

Autosomal dominant hyper IgE syndrome (AD-HIES) is a primary immune deficiency characterized by the classic triad of recurrent skin boils, cyst-forming pneumonias, and extreme elevations of serum IgE. It is now recognized that other common manifestations include eczema, mucocutaneous candidiasis, and several connective tissue and skeletal abnormalities. A rash in the newborn period subsequently evolves into an eczematoid dermatitis. Recurrent staphylococcal skin boils and bacterial pneumonias usually manifest in the first years of life. Pneumatocoeles and bronchiectasis often result from aberrant healing of pneumonias. Mucocutaneous candidiasis is common. A characteristic facial appearance typically emerges in adolescence. Skeletal abnormalities include osteopenia, minimal trauma fractures, and scoliosis. Vascular abnormalities 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 rarely colonic perforations, some of which are associated with diverticuli. Fungal infection of the GI tract (typically histoplasmosis, Cryptococcus, and Coccidioides) also occur infrequently. Survival is typically into adulthood, but life span is often shortened. Most deaths are associated with Gram-negative (Pseudomonas) or filamentous fungal pneumonias resulting in hemoptysis. Lymphomas occur at an increased frequency.

Diagnosis/testing.

Diagnosis requires a high index of suspicion based on clinical features. A clinical scoring system that includes both immunologic/infectious manifestations and skeletal/connective tissue abnormalities has been developed. Molecular genetic testing of STAT3, the only gene in which pathogenic variants are known to cause AD-HIES, confirms the diagnosis.

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 bleach baths are beneficial. Medications such as histamine-1 antagonists to control pruritus are helpful for more significant eczema. Optimization of calcium and vitamin D intake may be considered to improve bone health.

Surveillance: Periodic chest imaging and high clinical suspicion assist in early detection of infections. Culture of skin lesions and sputum samples helps direct therapy. Routine dental care is necessary to ensure timely removal of primary teeth to allow eruption of secondary teeth. Routine screening of adolescents for early signs of scoliosis is recommended.

Genetic counseling.

AD-HIES is inherited in an autosomal dominant manner. To date, the majority of cases have been caused by de novo pathogenic variants. Each child of an individual with AD-HIES has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family is known.

Clinical Diagnosis

Until the 2007 identification of STAT3 pathogenic variants 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.

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.

Testing

Clinical findings

• Elevated 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 individuals
• Diminished 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).

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 pathogenic variant, 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 pathogenic variants 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 pathogenic variants reported to date are protein positive and each person carries one benign allele. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) has not been shown to be sensitive for the majority of pathogenic variants.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variant in the family.

Clinical Description

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]. Pathogenic variants tend to cluster in the DNA-binding and SH2 domains with few affected individuals having pathogenic variants 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].

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 pathogenic variant in the first generation and more severe disease associated with a STAT3 constitutional pathogenic variant in the second and subsequent generations.

Prevalence

The prevalence of STAT3-deficient hyper IgE syndrome is unknown. The condition is rare. Enrichment in a specific ethnic or racial group has not been reported; gender preference is not seen.

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 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 Complications

Prophylactic 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.

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.
• 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 Risk

Molecular genetic testing of at-risk relatives of a proband with a known pathogenic variant 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 Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

Other

Parents 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.

Mode of Inheritance

Autosomal dominant hyper IgE syndrome associated with mutation of STAT3 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 de novo pathogenic variant. The majority of cases reported to date have been caused by de novo pathogenic variants. Simplex cases (i.e., a single occurrence in a family) are common.
• Individuals with some findings of hyper IgE syndrome have had mosaicism for a STAT3 pathogenic variant and have transmitted the variant to offspring [Holland et al 2007; Hsu and Holland, unpublished data]
• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include clinical evaluation and/or molecular genetic testing. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of 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 is 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 pathogenic variant.

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

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

Considerations in families with an apparent de novo pathogenic variant. 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 pathogenic variant. 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

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

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Revision History

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