Hyper IgE Syndrome: An Update on Clinical Aspects and the Role of Signal Transducer and Activator of Transcription 3

Michelle L. Paulson; Alexandra F. Freeman; Steven M. Holland


Curr Opin Allergy Clin Immunol. 2008;8(6):527-533. 

In This Article

Clinical Manifestations

HIES is a multisystem disease with varied clinical manifestations ( Table 1 ). Affected individuals may have some but not all the features of HIES, depending on the age at which they are examined.


A rash in the newborn period is usually the first clinical manifestation of HIES. The rash typically starts on the face and scalp in the first few weeks of life, and is usually pustular and eczematoid.[11,12] Biopsies show eosinophilic infiltrates and bacterial cultures typically grow Staphylococcus aureus. The rash of HIES often persists throughout childhood, but can be controlled with antistaphylococcal therapies, consisting of antibiotics, topical antiseptics such as diluted bleach, or both.

Boils also begin early in life and are nearly universal, unless antistaphylococcal therapies are initiated early. Classic signs of inflammation, such as warmth and tenderness are variable, sometimes resulting in the 'cold' abscesses reported in the initial description of Job's syndrome.[1] However, frank pus is recovered on aspiration and S. aureus is typically cultured. The boils abate with good skin staphylococcal control, but problem areas, such as the axilla and groin, may persist.


Recurrent pyogenic pneumonias start in early childhood. The most common infecting organisms are S. aureus, Streptococcus pneumoniae, and Haemophilus influenzae.[3,4] Similar to the variability seen with the boils, the extent of pneumonia may be out of proportion to the systemic signs of illness (e.g. fever and purulent sputum), leading to delayed diagnosis. Cough is surprisingly diminished in HIES pneumonias. Bronchoscopy may be needed to establish the specific bacterial diagnosis and also assists in clearance of copious but viscous pus. Pneumatocele formation and bronchiectasis typically follow these pyogenic pneumonias. Structural abnormalities tend not to subside, but serve as sites for future infections with Gram-negative bacteria (typically Pseudomonas), molds (usually Aspergillus or Scedosporium), or nontuberculous mycobacteria.[4,13] These secondary infections cause morbidity and mortality due to hemoptysis, extrapulmonary dissemination or both.[13] Surgical resection of these cysts is controversial, as the site of future serious infection may be removed, but the expansion and healing of the residual lung may be impaired, leading to difficult postoperative management.

Other Infections

Mucocutaneous candidiasis is common in HIES, typically manifesting as thrush, vaginal candidiasis and onychomycosis.[4] Much less frequently, disseminated histoplasmosis and cryptococcosis occur, typically in isolated nonpulmonary locations such as in the intestine or tongue.[14,15] Pneumocystis jiroveci pneumonia (PCP) has been described, occurring both as the initial pulmonary infection in infants and following a course similar to that in infants with congenital HIV, and in older individuals complicating chronic lung disease.[16]

Craniofacial Abnormalities

HIES has a characteristic facial appearance that develops during childhood and adolescence, characterized by asymmetry, broad nose, and deep-set eyes with a prominent forehead.[3,4] However, despite the typical facies that can be recognized by the human eye, statistical anthropometric precision has been difficult to achieve except for nasal alar width. The facial skin often has a coarse, porous texture. Both craniosynostosis and Chiari I malformations occur, but typically do not require surgical correction.[17,18,19]

Musculoskeletal Abnormalities

Musculoskeletal abnormalities in HIES include scoliosis, minimal trauma fractures, osteopenia, hyperextensibility and degenerative joint disease.[4] Scoliosis is common, and often appears during adolescence, similar to the case with idiopathic scoliosis, but may also be associated with leg length discrepancy or is worsened by lung damage or resections. Minimal trauma fractures occur in about half of individuals with HIES, and frequently involve the ribs and long bones. Osteopenia and osteoporosis also occur, but appear to be independent of the minimal trauma fractures. Osteoclast-mediated bone resorption is abnormal in HIES and likely relates to osteopenia and fractures.[20,21] Despite this, bone healing after fractures or surgery is typically normal. Hyperextensibility of the small and large joints is frequent and may contribute to early degenerative joint disease, especially in the cervical spine.

Dental Abnormalities

Most individuals with HIES fail to exfoliate their primary teeth normally, often requiring surgical extraction of some or all primary teeth to allow the secondary teeth to emerge normally.[4,22] Characteristic variations of the oral mucosa, tongue, roof of mouth and cheeks include central depressions of the tongue that may relate to Candida infections and central band-like protrusions of the palate.[23]

Vascular Abnormalities

Vascular abnormalities are newly recognized in HIES.[13,17,24,25] A coronary artery aneurysm resulting in myocardial infarction (MI) in one HIES man prompted a closer examination of arterial abnormalities in others.[24] Computed tomography and MRI show that coronary artery tortuosity, dilation, and aneurysm formation are common. However, except for the one report of MI, all have been asymptomatic (Gharib, et al. unpublished data). One woman had bilateral berry aneurysms of the carotids and another had a middle cerebral artery mycotic aneurysm.[13] Lacunar infarctions have been described at a younger age than is typical (in the fourth decade of life), and T2-weighted hyperintensities, which may reflect small vessel abnormalities, are frequently observed on brain MRI at a much younger age than is typical.[17]


HIES is associated with an increased rate of non-Hodgkin's lymphoma (NHL), the majority of which is B-cell origin and aggressive histology.[26] Several individuals responded to treatment and were apparently cured, but there was an increased mortality, which may in part be due to delayed diagnosis. Other reported malignancies have included Hodgkin's lymphoma, leukemia, and cancers of the vulva, liver and lung.[27]

Laboratory Abnormalities

The two most consistent laboratory abnormalities in HIES are eosinophilia and elevated serum IgE. Age-adjusted IgE elevation may be present at birth in cord blood and typically peaks at levels substantially above 2000 IU/ml. Over time, however, the serum IgE may decline, even into the normal range in some adults, despite persistent symptoms of HIES.[4] Eosinophilia is common but does not correlate with the IgE level. Serum IgG, IgA, and IgM are usually normal, although mild deficiencies may be present in some individuals. Lymphocyte phenotyping often shows diminished memory T cells (CD45RO+).[3]