Background
Autosomal dominant hyperimmunoglobulin E (IgE) syndrome (HIES) was first described as Job syndrome in 1966
and included the triad of eosinophilia, eczema, and recurrent skin and pulmonary infections (named after the biblical character Job, who was “smote with sore boils”). Elevated IgE level was recognized as a cardinal feature of the syndrome in 1972, and the name HIES was subsequently proposed.
The phenotype was later expanded to include many connective tissue and skeletal abnormalities. A scoring system that weighted both the immunologic and somatic features of the syndrome was designed to aid in the clinical diagnosis of these patients (see the table below).
Table. Scoring System for Job Syndrome (Open Table in a new window)
|
0 |
1 |
2 |
3 |
4 |
5 |
6 |
7 |
8 |
10 |
Clinical Findings |
|
|
|
|
|
|
|
|
|
|
Highest IgE (IU/mL) |
< 200 |
200-500 |
|
|
501-1000 |
|
|
|
1001-2000 |
>2000 |
Total # skin abscesses/boils |
None |
|
1-2 |
|
3-4 |
|
|
|
>4 |
|
Total # pneumonias |
None |
|
1 |
|
2 |
|
3 |
|
>3 |
|
Parenchymal lung abnormalities |
None |
|
|
|
|
|
Bronchiectasis |
|
Pneumatocele |
|
Other serious infection |
None |
|
|
|
Present |
|
|
|
|
|
Fatal infection |
None |
|
|
|
Present |
|
|
|
|
|
Highest eosinophils/uL |
< 700 |
|
|
701-800 |
|
|
>800 |
|
|
|
Newborn rash |
None |
|
|
|
Present |
|
|
|
|
|
Eczema (worst stage) |
None |
Mild |
Moderate |
|
Severe |
|
|
|
|
|
Sinusitis/otitis (# in worst year) |
1-2 |
3 |
4-6 |
|
>6 |
|
|
|
|
|
Candidiasis |
None |
Oral, vaginal |
Fingernail |
|
Systemic |
|
|
|
|
|
Retained primary teeth |
None |
1 |
2 |
|
3 |
|
|
|
>3 |
|
Scoliosis (max. curvature) |
< 10 |
|
10-14 |
|
15-20 |
|
|
|
>20 |
|
Minimal trauma fractures |
None |
|
|
|
1-2 |
|
|
|
>2 |
|
Hyperextensibility |
None |
|
|
|
Present |
|
|
|
|
|
Characteristic face |
None |
|
Mild |
|
|
Present |
|
|
|
|
Increased interalar distance |
< 1 SD |
1-2 SD |
|
>2 SD |
|
|
|
|
|
|
High palate |
None |
|
Present |
|
|
|
|
|
|
|
Congenital anomaly |
None |
|
|
|
|
Present |
|
|
|
|
Lymphoma |
None |
|
|
|
Present |
|
|
|
|
|
More recently, vascular abnormalities, including coronary aneurysm without atherosclerosis, and brain MRI abnormalities, including focal hyperintensities and Chiari I malformations, have been described. In 2007, autosomal dominant mutations in signal transducer and activator of transcription-3 (STAT3) gene were identified as the molecular cause of this disease.
See image below.
STAT3 gene is diagrammed with depiction of hotspots (areas where higher numbers of patients were noted to have mutations).