Autosomal Dominant Hyperimmunoglobulin E Syndrome

Epidemiology and Etiology

Epidemiology

• Incidence: 1/1,000,000 per year
• Males and females are affected equally.

Etiology

• Has been described in both sporadic and familial forms with an autosomal dominant inheritance pattern
• 60%–70% of cases are caused by mutations in the STAT3 gene, which is responsible for the production of 1 of the signal transducers and activator of transcription (STAT) proteins. 
  • Mutations lead to the production of dysfunctional STAT3 protein (although produced in normal amounts) → defective immune response
  • Dysfunctional STAT3 blocks the maturation of immune cells, especially Th17 cells → decreasing levels of interferon-gamma and interleukin-17 → abnormal neutrophil chemotaxis → high susceptibility to infections, particularly bacterial and fungal infections of the lungs and skin 
  • STAT3 protein is also involved in the formation of cells that build and break down bone tissue → skeletal and dental abnormalities
• The cause of the other 30%–40% of cases is unknown.
• Patients with autosomal dominant hyper-IgE syndrome (AD-HIES; also known as Job’s syndrome) also have abnormally high levels of IgE (cause unknown) → eosinophilia

Clinical Presentation

Symptoms may be apparent at birth or become apparent during infancy or early childhood.

Patients present with various clinical manifestations and abnormalities:

• Characteristic facial features: broad nasal base and bridge, deep-set eyes, frontal bossing, irregularly proportioned cheeks and jaws, midline anomalies, prognathism, and generalized coarsening of the skin (known as “coarse facies”)
• Dental: failure to shed primary teeth, leading to double rows of teeth
• Skeletal: scoliosis, joint hyperextensibility, osteoporosis, and recurrent fractures 
• Ocular: xanthelasma, retinal detachment, chalazion, and strabismus
• Respiratory: Recurrent lung infections (most often by Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae) lead to air-filled cysts (pneumatoceles) in the lungs and chronic respiratory insufficiency.
• Dermatologic: Staphylococcal infections are common, presenting as eczema-like rashes, blisters, scaling, open sores, pruritus, and recurrent “cold” abscesses (lack cardinal signs of inflammation). 
• Immunological: increased susceptibility to opportunistic infections (e.g., mucocutaneous candidiasis) with very high levels of antibody IgE and eosinophilia 
• Cardiovascular: thrombosis, congenital patent ductus venosus, and coronary and aortic aneurysms
• Malignancies: lymphomas, such as anaplastic large cell lymphoma and peripheral T-cell lymphoma

Mnemonic

A helpful mnemonic of the clinical manifestations of AD-HIES is FATED: 

• F: Coarse or leonine Facies
• A: Cold staph Abscesses
• T: Retained primary Teeth
• E: Increased IgE levels
• D: Dermatologic problems (e.g., eczema)

Diagnosis and Management

Diagnosis

The diagnosis of AD-HIES is based on clinical evaluation, especially a detailed patient history and identification of characteristic findings.

• Laboratory findings:
  • Elevated IgE levels (> 2,000 IU/mL): diagnostic of AD-HIES
  • Eosinophilia on CBC > 2 standard deviations above the normal mean
• Genetic testing is available for STAT3 mutations.
• If symptoms of pneumonia are present, order computed tomography (CT) scans or X-rays of the chest to detect lung infections and the development of pneumatoceles.

Management

There is no definitive cure. Management is aimed at treating symptoms as well as preventing and managing infections.

• Long-term anti-staphylococcal prophylactic antibiotic therapy 
• High-dose IV gammaglobulin and histamine-1 antagonists for eczema
• Antibiotics and antifungal agents, depending on the nature of infections, along with periodic chest imaging and high clinical suspicion for the early detection of recurrent infections
• Surgery to drain abscesses
• Optimization of calcium and vitamin D intake to improve bone health
• Routine dental care
• Screening for scoliosis

Differential Diagnosis

The following conditions are differential diagnoses of autosomal dominant hyperimmunoglobulin E syndrome:

• Autosomal recessive hyper-IgE syndrome: a rare primary immunodeficiency disorder characterized by recurrent pulmonary and dermatological infections caused by bacteria and viruses. May present with abnormalities of the central nervous system or vessels but do not lack characteristic facial features and skeletal malformations. Can be due to mutations of the ZNF341, DOCK8, or PGM3 genes.
• Cystic fibrosis: an autosomal recessive disorder caused by mutations in the CFTR gene. Mutations lead to dysfunction of chloride channels, which results in hyperviscous mucus and the accumulation of secretions. Common presentations include chronic respiratory infections, failure to thrive, and pancreatic insufficiency. 
• Chronic granulomatous disease: a chronic disorder that is characterized by granuloma formation. This disorder is a consequence of dysfunctional phagocytic cells that are unable to produce bactericidal superoxide due to a defect in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in these cells. Presentation includes recurrent skin infections, pneumonia, and gastroenteritis.
• Atopic dermatitis: also known as allergic eczema, a chronic pruritic inflammatory skin disease that occurs most frequently in children, but also in adults. Often associated with elevated IgE and a personal or family history of atopy. Presents with intense pruritus, papulovesicular lesions on extensor surfaces, and lichenification on flexural areas
• HIV infection and AIDS: caused by a single-stranded RNA virus in the Retroviridae family. Transmitted through the exchange of body fluids such as semen and blood. Presentation is marked by a deterioration of the immune system, beginning with constitutional symptoms such as lymphadenopathy, and advancing into AIDS-defining illnesses such as opportunistic infections.