Study of Clinical Features and Genetics of Hyperimmunoglobulin E Recurrent Infection

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 multisystem 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. Mutations in DOCK8 cause many cases
of autosomalrecessive 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 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 HIES 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.

- INCLUSION CRITERIA:

Patients must be referred to the NIH with a diagnosis or a suspicion of Hyper IgE syndrome.
Family members of probands and patients referred for other immune syndromes that
demonstrate some of the characteristics of HIES may also be evaluated under this protocol.
Male and female patients will be accepted. An inclusion age range will be constructed to
accommodate at-risk infants born into affected families as well as to be able to examine
the members of extended families. The extent of evaluation will be tailored to the patient
s needs, age, and conditions. The cutaneous manifestations of HIE are often present at
birth and need management from that time on.

Because this is often an AD disorder, it is important to evaluate family members. Family
members will have labs drawn for genetic testing and additional labs as clinically
indicated. Selected family members will have EBV cell lines made and all family members
will receive a genetic-oriented physical examination with close examination of their
palates, hyper-extensibility, etc. If on this evaluation any information is uncovered which
suggests abnormalities related to Hyper IgE syndrome, then further workup would include
chest X-ray or CT, possible spine films, dental evaluation, dermatology consult, and other
consults or procedures deemed necessary for that particular relative. For the recessive
forms of HIES, such as DOCK8 deficiency and PGM3 deficiency, family members may be
evaluated as possible donors if a hematopoietic stem cell transplant is necessary.

EXCLUSION CRITERIA:

Pregnant women are excluded only from any procedure or test that may endanger the pregnancy
or the fetus due to the risk from radiographic studies, anesthesia, or certain biopsies. We
have seen flares of skin disease during pregnancy and therefore believe that

enrolling and following these patients during pregnancy is appropriate.

Coronary CT angiography will not be performed on any patient with contraindication to IV
contrast media. This includes patients with: 1) creatinine value of greater than 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.