Hyper IgE Syndrome (HIES)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at NSU

Phagocyte immunodeficiencies (click to enlarge the image):

Hyper-IgE syndrome (HIES) is a complex primary immunodeficiency characterized by atopic dermatitis associated with extremely high serum IgE levels and susceptibility to infections of the lung and skin with extracellular bacteria.

HIES is associated with heterozygous dominant-negative mutations in the signal transducer and activator of transcription 3 (STAT3) and severe reductions of T(H)17 cells.

Genetic basis:

- Dominant-negative mutations in the signal transducer and activator of transcription 3 (STAT3) gene result in the classical multisystem form of HIES
- A null mutation in the tyrosine kinase 2 (TYK2) gene causes an autosomal recessive HIES associated with viral and mycobacterial infections

Signal transduction for multiple cytokines, including IL-6 and IL-23, is was defective, resulting in impaired TH17 function.

Clinical features of HIES

- Recurrent infections of the lower respiratory system and skin
- Chronic eczema
- Extremely elevated IgE levels
- Eosinophilia

The level of IgE increases during childhood until about 10 years of age. At age 10, the total IgE reaches a value that is typically maintained throughout adult life.

The patients with HIES are not neutropenic. Neutrophils engulf and kill bacteria normally but they do have intermittent chemotactic defects in 80% of cases. Inflammatory cytokine production is impaired and inflammation is minimal leading to cold (non inflamed) abscesses.

Nonimmunological abnormalities include:

- distinctive facial appearance
- fracture following minor trauma
- scoliosis
- hyperextensive joints
- retention of deciduous teeth

In HIES, there is hypertelorism, prominent mandible, broad nasal bridge, wide nasal tip, and increased interalar distance (a larger distance between alae nasi) ("boxer's nose").

In HIES, lung abscesses are almost always staphylococcal. A pneumatocele often develops, and becomes a substrate for superinfections with Aspergillus and Pseudomonas.

Patients with HIES characteristically will have a pneumatocele on chest X-ray.

Laboratory findings in HIES

- IgE is usually above 2000 IU/ml
- T cell dysfunction may underlie the excessive production of IgE
- IgG is normal
- Antibody responses to polysaccharide and protein antigens are abnormal
- Eosinophilia is common

A combination of 5 clinical features predicted STAT3 mutations with 85% accuracy.

Diagnostic guidelines for STAT3-deficient HIES:

- Possible: IgE greater than 1000 IU/mL plus a weighted score of clinical features greater than 30 based on recurrent pneumonia, newborn rash, pathologic bone fractures, characteristic face, and high palate.

- Probable: These characteristics plus lack of T(H)17 cells or a family history for definitive HIES.

- Definitive: These characteristics plus a dominant-negative heterozygous mutation in STAT3.

How to make the diagnosis of HIES from a practical point of view?

A clinical diagnosis is made based on the classic manifestations and laboratory tests such as elevated IgE levels and hypereosinophilia. A specific confirmatory diagnosis would require demonstration of one of the following genetic defects:

- dominant mutations in signal transducer and activator of transcription 3 (STAT3)
- mutations in the tyrosine-kinase 2 gene (Tyk2)
- autosomal recessive mutations in DOC8

However, no commercial labs are offering these tests as of year 2010. Research laboratories might be willing to perform the assays.

Treatment of HIES

Anti-staphylococcal antibiotics long-term.
The prognosis is generally good for those who undergo treatment.

Conditions with elevated IgE

Atopic dermatitis, Asthma, ABPA, and allergic fungal sinusitis
Infections (parasites, HIV, TB, EBV, and CMV)
Malignancy (IgE myeloma and lymphoma)
Churg-Strauss syndrome
Kimura’s disease, painless, unilateral cervical lymphadenopathy or subcutaneous masses in the head or neck region

Immunodeficiency diseases with elevated IgE

Hyper IgE syndrome (HIES)
Wiskott-Aldrich syndrome (WAS)
Omenn syndrome
DiGeorge syndrome (DGS)
Netherton syndrome, form of ichthyosis associated with SPINK5
Nezelof syndrome, congenital hypoplasia of the thymus with retention of normal parathyroid function (in contrast to complete DiGeorge syndrome in which there is absence of the parathyroids)


Hyper-IgE syndrome. Yoshiyuki Minegishia. Current Opinion in Immunology, 2009.
Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome. J Allergy Clin Immunol. 2010 Feb;125(2):424-432.e8.

No comments: