Hyper IgE Syndrome (Job's syndrome) is a rare immunodeficiency marked by very high IgE levels and recurrent skin and lung infections.

This multisystem syndrome manifests predominantly during infancy or early childhood and poses diagnostic and therapeutic challenges due to its diverse clinical features and underlying genetic heterogeneity.

Pathophysiology and Genetic Basis

HIES includes two major genetic forms: an autosomal dominant variant caused mainly by mutations in the STAT3 gene and an autosomal recessive variant linked to mutations in DOCK8 or TYK2 genes. These mutations disrupt cellular immunity and cytokine signaling pathways, particularly affecting helper T-cell differentiation and the function of neutrophils and other immune cells.

As a result, affected individuals exhibit impaired defense mechanisms against bacterial and fungal pathogens, leading to recurrent and often severe infections.

Clinical Manifestations

Patients with HIES typically develop recurrent skin abscesses, commonly caused by Staphylococcus aureus, and persistent eczematous dermatitis reminiscent of atopic dermatitis. Pulmonary involvement includes frequent pneumonias, often complicated by the formation of pneumatoceles—large cystic spaces in the lungs post-infection that predispose to further infections and respiratory compromise.

Other characteristic features of autosomal dominant HIES include delayed shedding of primary teeth, skeletal issues like scoliosis and fractures from osteopenia, and vascular abnormalities such as aneurysms. Conversely, the autosomal recessive form features viral skin infections, severe allergies including asthma, and increased susceptibility to malignancies primarily due to DOCK8 deficiency.

Diagnosis

Confirmation of HIES involves clinical suspicion based on characteristic infection patterns and examination findings, supported by laboratory identification of markedly elevated serum IgE levels—often exceeding 2000 IU/mL. Genetic testing facilitates exact mutation identification, clarifying prognosis and guiding family counseling.

Radiological imaging with chest X-rays or CT scans can elucidate pulmonary complications such as pneumatoceles.

Management Approaches

Therapeutic strategies in HIES aim to control infections, manage eczema, and prevent long-term complications. Long-term prophylactic antibiotics, particularly trimethoprim-sulfamethoxazole, reduce recurrence of staphylococcal infections. Topical treatments include emollients and anti-inflammatory agents to alleviate dermatitis symptoms, while respiratory infections receive targeted antibiotic therapies as needed.

In select cases, immunomodulatory agents such as interferon gamma have been administered to boost immune responses, though experience remains limited. For patients with DOCK8 deficiency, hematopoietic stem cell transplantation offers a potential curative approach by restoring immune competence. Clinical vigilance involves monitoring lung function, skeletal health, and signs of malignancy, underscoring the importance of multidisciplinary care.

Dr. Alexandra F. Freeman, a pediatric infectious diseases physician, has extensively studied Hyper IgE Syndrome (HIES), particularly the autosomal dominant form caused by STAT3 mutations. She notes that "Hyper IgE syndrome is an uncommon primary immunodeficiency defined by high serum IgE, chronic skin and pulmonary infections, and coarse facies."

Hyper IgE Syndrome is a rare, genetically influenced immunodeficiency marked by elevated IgE and recurrent mucocutaneous and pulmonary infections. It encompasses multiple clinical and genetic variants, each with distinct features influencing prognosis and treatment. Diagnosis hinges on clinical suspicion complemented by laboratory and genetic testing.

Management focuses on infection prevention, skin care, and addressing systemic complications to enhance longevity and life quality. The evolving landscape of molecular genetics promises improved personalized therapies, emphasizing the need for ongoing research and multidisciplinary care coordination.