Clinical trial NCT00006150: Natural History, Management, and Genetics of the Hyperimmunoglobulin E Recurrent Infection Syndrome (HIES)
Official title: Natural History, Management, and Genetics of the Hyperimmunoglobulin E Recurrent Infection Syndrome (HIES)
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Infections
Pneumonia
Immune System Diseases
STAT3 Transcription Factor
Job Syndrome
Keywords: DOCK8 Deficiency
PGM3 Deficiency
STAT3 Mutation
Job's Syndrome
Immunodeficiency
Natural History
Hyperimmunologobulin E Syndrome
HIE Syndrome
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
Collaborators: name: Albert Einstein College of Medicine
First posted: 2000-08-09
Enrollment: 600
Sex: ALL
Minimum age (years): 1
Maximum age (years): 120
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: primary clinical

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.

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.

Primary outcomes:
measure: To clinically phenotype AD-HIES, DOCK8 deficiency, PGM3 deficiency and other related hyper IgE syndromes
timeFrame: end of study
measure: To assess quality of life on the basis of clinical and immunologic evaluations
timeFrame: end of study
measure: To understand the pathogenesis of the immunologic defect in hyper IgE syndromes as well as the diverse clinical features such as wound healing abnormalities
timeFrame: end of study
measure: To identify, characterize, and treat complications of the hyper IgE syndromes as they arise
timeFrame: end of study
measure: To identify novel genetic defects leading to hyper IgE syndromes.
timeFrame: end of study
Secondary outcomes:
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Institute of Allergy and Infectious Diseases (NIAID)
name: Alexandra F Freeman, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Freeman AF, Holland SM. Clinical manifestations of hyper IgE syndromes. Dis Markers. 2010;29(3-4):123-30. doi: 10.3233/DMA-2010-0734.
citation: 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.
citation: 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.
citation: 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.
citation: 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.