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

NCT ID: NCT00006150

Last Updated: 2026-01-08

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 600 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2000-08-10

Brief Summary

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

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.

Conditions

Infections; Pneumonia; Immune System Diseases; STAT3 Transcription Factor; Job Syndrome

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Affected adults and children

Confirmed or suspected history of a Hyper IgE syndrome

No interventions assigned to this group

Relatives

Family members of subjects with confirmed or suspected history of a Hyper IgE syndrome

No interventions assigned to this group

Eligibility Criteria

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.

• Minimum Eligible Age: 1 Month
• Maximum Eligible Age: 120 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Albert Einstein College of Medicine

OTHER

Sponsor Role: collaborator

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Alexandra F Freeman, M.D.

Role: PRINCIPAL_INVESTIGATOR

National Institute of Allergy and Infectious Diseases (NIAID)

Locations

National Institutes of Health Clinical Center

Bethesda, Maryland, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Jean M Ulrick

Role: CONTACT

julrick@niaid.nih.gov

(301) 221-0855

Facility Contacts

For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)

Role: primary

ccopr@nih.gov

800-411-1222 ext. TTY dial 711

References

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.

Reference Type: BACKGROUND

PMID: 22268731 (View on PubMed)

Freeman AF, Holland SM. Clinical manifestations of hyper IgE syndromes. Dis Markers. 2010;29(3-4):123-30. doi: 10.3233/DMA-2010-0734.

Reference Type: BACKGROUND

PMID: 21178271 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 21494893 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 17438082 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 10053178 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 17881745 (View on PubMed)

Related Links

https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2000-I-0159.html

NIH Clinical Center Detailed Web Page

Other Identifiers

00-I-0159

Identifier Type: -

Identifier Source: secondary_id

000159

Identifier Type: -

Identifier Source: org_study_id