Hyperimmunoglobulinemia E 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.
