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

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....

Study Overview

• Status: Recruiting
• Conditions: Infections; Immune System Diseases; Pneumonia; Job Syndrome; STAT3 Transcription Factor

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 600

Contacts and Locations

• Study Contact: Name: Christine J Lafeer, R.N.; Phone Number: (301) 761-6902; Email: clafeer@niaid.nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR); Phone Number: TTY dial 711 800-411-1222; Email: ccopr@nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

primary clinical

Description

• 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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Affected adults and children; Confirmed or suspected history of a Hyper IgE syndrome
Relatives; Family members of subjects with confirmed or suspected history of a Hyper IgE syndrome

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Albert Einstein College of Medicine
• Investigators: Principal Investigator: Alexandra F Freeman, M.D., National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

General Publications

• Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, Freeman AF, Demidowich A, Davis J, Turner ML, Anderson VL, Darnell DN, Welch PA, Kuhns DB, Frucht DM, Malech HL, Gallin JI, Kobayashi SD, Whitney AR, Voyich JM, Musser JM, Woellner C, Schaffer AA, Puck JM, Grimbacher B. STAT3 mutations in the hyper-IgE syndrome. N Engl J Med. 2007 Oct 18;357(16):1608-19. doi: 10.1056/NEJMoa073687. Epub 2007 Sep 19.
• Grimbacher B, Holland SM, Gallin JI, Greenberg F, Hill SC, Malech HL, Miller JA, O'Connell AC, Puck JM. Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder. N Engl J Med. 1999 Mar 4;340(9):692-702. doi: 10.1056/NEJM199903043400904.
• Sowerwine KJ, Holland SM, Freeman AF. Hyper-IgE syndrome update. Ann N Y Acad Sci. 2012 Feb;1250:25-32. doi: 10.1111/j.1749-6632.2011.06387.x. Epub 2012 Jan 23.
• Freeman AF, Holland SM. Clinical manifestations of hyper IgE syndromes. Dis Markers. 2010;29(3-4):123-30. doi: 10.3233/DMA-2010-0734.
• Freeman AF, Avila EM, Shaw PA, Davis J, Hsu AP, Welch P, Matta JR, Hadigan C, Pettigrew RI, Holland SM, Gharib AM. Coronary artery abnormalities in Hyper-IgE syndrome. J Clin Immunol. 2011 Jun;31(3):338-45. doi: 10.1007/s10875-011-9515-9. Epub 2011 Apr 15.
• Freeman AF, Collura-Burke CJ, Patronas NJ, Ilcus LS, Darnell D, Davis J, Puck JM, Holland SM. Brain abnormalities in patients with hyperimmunoglobulin E syndrome. Pediatrics. 2007 May;119(5):e1121-5. doi: 10.1542/peds.2006-2649. Epub 2007 Apr 16.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): August 10, 2000

Study Registration Dates

• First Submitted: August 8, 2000
• First Submitted That Met QC Criteria: August 8, 2000
• First Posted (Estimated): August 9, 2000

Study Record Updates

• Last Update Posted (Actual): April 18, 2024
• Last Update Submitted That Met QC Criteria: April 17, 2024
• Last Verified: December 29, 2023

More Information

Terms related to this study

• Keywords: Natural History; Immunodeficiency; Job's Syndrome; DOCK8 Deficiency; PGM3 Deficiency; STAT3 Mutation; Hyperimmunologobulin E Syndrome; HIE Syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Immunologic Deficiency Syndromes; Disease Attributes; Disease; Hematologic Diseases; Genetic Diseases, Inborn; Leukocyte Disorders; Phagocyte Bactericidal Dysfunction; Primary Immunodeficiency Diseases; Recurrence; Syndrome; Infections; Communicable Diseases; Immune System Diseases; Reinfection; Job Syndrome
• Other Study ID Numbers: 000159; 00-I-0159

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: .We will share human data generated in this study for future research as follows:@@@@@@@@@@@@Identified data in the Biomedical Translational Research Information System (BTRIS, automatic for activities in the NIH CC)@@@@@@@@@@@@De-identified or identified data with approved outside collaborators under appropriate agreements@@@@@@@@@@@@Data will be shared through: @@@@@@@@@@@@BTRIS (automatic for activities in the NIH CC)@@@@@@@@@@@@Approved outside collaborators under appropriate individual agreements@@@@@@@@@@@@Publication and/or public presentations.@@@@@@@@@@@@Data might be shared before publication.
• IPD Sharing Time Frame: IPD is available in real time in BTRIS.
• IPD Sharing Access Criteria: Identified data in the Biomedical Translational Research Information System (BTRIS, automatic for activities in the NIH CC) are available indefinitely.@@@@@@@@@@@@De-identified or identified data with approved outside collaborators under appropriate agreements
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No