What is the management approach for Hyper-IgE syndrome as an autosomal dominant genetic condition?

Management of Autosomal Dominant Hyper-IgE Syndrome (AD-HIES)

The management of autosomal dominant Hyper-IgE syndrome should focus primarily on aggressive prevention and treatment of infections, with prophylactic antibiotics and antifungals as the cornerstone of therapy, while addressing specific complications like skeletal abnormalities and considering HSCT in selected cases. 1, 2

Pathophysiology and Clinical Features

• AD-HIES is primarily caused by heterozygous mutations in STAT3, characterized by elevated IgE levels, recurrent skin and pulmonary infections, and distinctive connective tissue and skeletal abnormalities 1
• The syndrome features a characteristic facial appearance with coarse/asymmetric features that becomes more prominent with age, along with hyperextensible joints, bone fragility, scoliosis, and delayed shedding of primary teeth 1, 3
• Both forms of HIES (autosomal dominant and recessive) are associated with defective development and function of IL-17–producing TH17 cells, which play a critical role in protection against Candida species 1, 4

Infection Management (Primary Focus)

• The main cause of mortality in AD-HIES is severe infections, with patients experiencing progressive decrease of lung function due to recurrent pneumonias 1, 2
• Aggressive therapeutic and prophylactic antibiotic therapy is indicated as the first-line approach to prevent life-threatening complications 1
• Antifungal prophylaxis should be considered, particularly for patients with recurrent Candida infections 1, 2
• Regular pulmonary function monitoring is essential to track disease progression and adjust antimicrobial strategies accordingly 2

Skeletal and Dental Management

• Patients require close monitoring for scoliosis development and fracture risk, as they can experience bone fractures with relatively minor trauma 1, 2
• Retained primary teeth should be extracted to prevent dental complications due to failure of root resorption 1, 3
• Preventive measures for skeletal complications should be implemented, including appropriate physical activity guidance and bone health monitoring 2

Immunoglobulin Replacement Therapy

• IVIG supplementation should be considered when impaired specific antibody responses are demonstrated, though evidence regarding efficacy is mixed 1, 2
• Some studies show clinical improvement with high-dose IVIG, while others fail to demonstrate improvement in immunologic function 1, 2
• The decision to initiate IVIG should be based on the patient's specific antibody response profile and infection history 2

Hematopoietic Stem Cell Transplantation (HSCT)

• HSCT should be considered as a potentially curative option for AD-HIES 1, 2
• While early reported cases of HSCT for AD-HIES showed recurrence of clinical manifestations, more recent cases have demonstrated successful outcomes 1
• The timing of HSCT is critical and should be considered before the development of significant irreversible complications, particularly lung damage 2

Monitoring and Follow-up

• Regular monitoring for lymphoma development is necessary as patients have an increased risk of malignancy 1, 5
• Frequent follow-up with pulmonary function tests, imaging studies, and immunological assessments is recommended to detect complications early 2, 6
• Immunological parameters should be regularly assessed as they may help predict disease course and guide management decisions 6

Special Considerations

• Family members sharing the same STAT3 mutation can present with different severity of clinical symptoms, necessitating individualized monitoring approaches 1, 6
• Intermediate or variant phenotypes of AD-HIES have been described in patients with somatic mosaicism for STAT3 mutations, which may affect treatment decisions 1
• The management approach differs significantly from autosomal recessive HIES (caused by DOCK8 mutations), which requires more focus on viral infections and has different skeletal manifestations 1, 7