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Autosomal dominant hyper-IgE syndrome
A very rare primary immunodeficiency disorder characterized by the clinical triad of high serum IgE (>2000 IU/ml), recurring staphylococcal skin abscesses, and recurrent pneumonia with formation of pneumatoceles.
ORPHA:2314Classification level: Disorder
- Autosomal dominant HIES
- Autosomal dominant hyperimmunoglobulin E syndrome
- Buckley syndrome
- Hyperimmunoglobulin E syndrome type 1
- Hyperimmunoglobulin E-recurrent infection syndrome
- Job syndrome
- STAT3 deficiency
- Prevalence: 1-9 / 100 000
- Inheritance: Autosomal dominant
- Age of onset: Infancy, Neonatal
- ICD-10: D82.4
- OMIM: 147060
- UMLS: C2936739 C3489795 C3887645
- MeSH: -
- GARD: 6800
- MedDRA: -
Annual incidence is estimated at around 1/1,000,000. The syndrome affects males and females equally.
AD-HIES typically first manifests with neonatal rash but it affects the immune system, connective tissue, skeleton, and dental development, with variations in severity. Eczema, recurrent skin abscesses, pneumonia with pneumatocele formation, mucocutaneous candidiasis, elevated serum IgE levels, and eosinophilia are the most common features of immune deficiency/dysregulation. Severe recurrent respiratory infections that may lead to chronic respiratory insufficiency are frequent. A distinctive facial appearance is described (rough skin, facial asymmetry, a prominent forehead, deep-set eyes, broad nasal bridge and a fleshy nasal tip, prognathism), along with midline anomalies. Recurrent pathological fractures occur in about 50% of patients (long bones and ribs). Scoliosis of varying degrees of severity is seen in more than 60%. Anomalies of dentinogenesis are a consistent feature. Reduced resorption of primary tooth roots may lead to prolonged retention of primary teeth, which in turn prevents the appropriate eruption of permanent teeth. Vascular features (coronary and aortic aneurysms, thrombosis of the cerebellar artery and congenital patent ductus venosus) have also been reported. Ocular complications may include xanthelasmas, giant chalasias, eyelid nodules, strabismus, and retinal detachment with complicated cataracts. There is also an increased risk of autoimmune and lymphoproliferative diseases.
In 70% of patients, the phenotype is associated with heterozygous mutations of the signal transducer and activator of transcription 3 gene (STAT3; 17q21.31). STAT3 plays a key role in the signal transduction of a broad range of cytokines (control of infections caused by fungi and extracellular bacteria). The etiology in the remaining 30% is unknown.
The diagnostic hallmark is increased serum immunoglobulin E (IgE) levels exceeding 2000 U/ml, often higher than 5000 U/ml. A clinical scoring sheet has been defined to assess the probability of diagnosis. Total IgE concentration > 1000 IU/ml and weighted score of clinical features > 30 indicates AD-HIES due to STAT3 deficiency, and a dominant-negative heterozygous mutation in STAT3 provides a definitive diagnosis.
The differential diagnosis should include cystic fibrosis and chronic granulomatous disease (see these terms), as well as severe atopic dermatitis and HIV-infection. A clinically distinct autosomal recessive hyper-IgE syndrome has also been described (AR-HIES; see this term).
Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation in the family is known.
The majority of AD-HIES cases are caused by de novo mutations and are therefore sporadic but autosomal dominant transmission is characteristic for STAT3 mutations.
Management and treatment
The therapeutic approach involves prevention and management of infections with long-term administration of systemic antibiotics and antifungals. Lung abscesses may require surgery but possible complications require close attention. The role of hematopoietic stem cell transplantation (HSCT) has to be evaluated further.
Although HIES is associated with significant morbidity and mortality, adequate care, close monitoring, and patient compliance improve the prognosis and can lead to survival of 50 years of age or over.
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