Natural History, Management, and Genetics of the Hyperimmunoglobulin E Recurrent Infection Syndrome (HIES)

Study Overview
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Brief Summary
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The Hyper IgE Syndromes (HIES) are primary immunodeficiencies resulting in eczema and recurrent skin and lung infections. Autosomal dominant Hyper IgE syndrome (AD-HIIES; Job's syndrome) is caused by STAT3 mutations, and is a multi-system disorder with skeletal, vascular, and connective tissue manifestations. Understanding how STAT3 mutations cause these diverse clinical manifestations is critical to our complete understanding of bone metabolism, bronchiectasis, dental maturation, and atherosclerosis. Bi-allelic mutations in DOCK8 cause a combined immunodeficiency previously described as autosomal-recessive Hyper IgE syndrome. These individuals suffer from extensive viral infections as well as have a high incidence of malignancy and mortality. The pathogenesis of this disease and long-term natural history is being investigated. Therefore, we seek to enroll patients and families with a confirmed or suspected diagnosis of HIES syndrome for extensive phenotypic and genotypic study as well as disease management. Patients will be carefully examined by a multidisciplinary team and followed longitudinally. Through these studies we hope to better characterize the clinical presentation of STAT3-mutated HIES, DOCK8 deficiency and other causes of the hyper IgE phenotype, and to be able to identify further genetic etiologies, as well as understand the pathogenesis of HIES. We seek to enroll 300 patients and 300 relatives....

Detailed Description
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The Hyper IgE Syndromes (HIES) are primary immunodeficiencies resulting in eczema and recurrent skin and lung infections. Autosomal dominant Hyper IgE syndrome (AD-HIES; Job's syndrome) is caused by STAT3 mutations, and is a multi-system disorder with skeletal, vascular, and connective tissue manifestations. Understanding how STAT3 mutations cause these diverse clinical manifestations is critical to our complete understanding of bone metabolism, bronchiectasis, dental maturation, and atherosclerosis. Bi-allelic mutations in DOCK8 cause a combined immunodeficiency previously described as autosomal-recessive Hyper IgE syndrome. These individuals suffer from extensive viral infections as well as have a high incidence of malignancy and mortality. The pathogenesis of this disease and long-term natural history is being investigated. Therefore, we seek to enroll patients and families with a confirmed or suspected diagnosis of HIES syndrome for extensive phenotypic and genotypic study as well as disease management. Patients will be carefully examined by a multidisciplinary team and followed longitudinally. Through these studies we hope to better characterize the clinical presentation of STAT3-mutated HIES, DOCK8 deficiency and other causes of the hyper IgE phenotype, and to be able to identify further genetic etiologies, as well as understand the pathogenesis of HIES. We seek to enroll 300 patients and 300 relatives.

Official Title
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Natural History, Management, and Genetics of the Hyperimmunoglobulin E Recurrent Infection Syndrome (HIES)

Conditions
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Infections, Pneumonia, Immune System Diseases, STAT3 Transcription Factor, Job Syndrome

Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Patients may be included in this study who: Were referred to the NIH with a diagnosis or a suspicion of Hyper IgE syndrome. Are patients referred for other immune syndromes that demonstrate some of the characteristics of HIES. Are male or female, aged Aged >=1 month for affected subjects Aged >=2 years for unaffected subjects For unaffected subjects, are able to understand and have the willingness to sign a written informed consent document. Unaffected biological relatives of HIES patients are also eligible to enroll in a separate relative cohort. EXCLUSION CRITERIA: Coronary CTA will not be performed on any patient younger than 30 years or with contraindication to IV contrast media. This includes patients with 1) creatinine value of >1.3 mg/dL, 2) history of multiple myeloma, 3) Use of metformin-containing products less than 24 hours prior to contrast media, and 4) history of significant allergic reaction to CT contrast agents despite the use of premedication. Subjects with a medical, psychiatric, or social condition which, in the opinion of the investigator, would place undue burden on the subject, NIH resources, or increase risk of participation, may be excluded.

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Affected adults and children<br>Confirmed or suspected history of a Hyper IgE syndrome | |
| Relatives<br>Family members of subjects with confirmed or suspected history of a Hyper IgE syndrome | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To clinically phenotype AD-HIES, DOCK8 deficiency, PGM3 deficiency and other related hyper IgE syndromes | established clinical phenotype of AD-HIES, DOCK8 deficiency, PGM3 deficiency and other related hyper IgE syndromes | end of study | 
| To assess quality of life on the basis of clinical and immunologic evaluations | quality of life assessments based on clinical and immunologic evaluations | end of study | 
| To understand the pathogenesis of the immunologic defect in hyper IgE syndromes as well as the diverse clinical features such as wound healing abnormalities | understanding of the pathogenesis of the immunologic defect in hyper IgE syndromes as well as the diverse clinical features such as wound healing abnormalities | end of study | 
| To identify, characterize, and treat complications of the hyper IgE syndromes as they arise | identification, characterization, and treatment of complications of the hyper IgE syndromes | end of study | 
| To identify novel genetic defects leading to hyper IgE syndromes. | identified novel genetic defects leading to hyper IgE syndromes. | end of study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Job's Syndrome, Immunodeficiency, Natural History, Hyperimmunologobulin E Syndrome, HIE Syndrome, DOCK8 Deficiency, PGM3 Deficiency, STAT3 Mutation