Hyper-IgE syndrome
Synonyms and keywords: Job-Buckley syndrome; Job syndrome; Buckley syndrome

# Overview
Hyper IgE syndrome (HIES) is a group of disorders characterized by recurrent staphylococcal infections, unusual eczema-like skin rashes, severe lung infections that result in pneumatoceles (balloon-like lesions that may be filled with air or pus or scar tissue) and very high concentrations of serum IgE. Some patients have an autosomal dominant form of the disease. These patients have problems with their bones including recurrent fractures and scoliosis. Many patients with autosomal dominant hyper IgE syndrome fail to lose their baby teeth and have two sets of teeth simultaneously.

# Historical Perspective
- HIES was first described by Davis et al in 1966 and  was named as Job's syndrome.
- The criteria included triad of eczema, recurrent skin and lung infections and high serum IgE .

# Classification
Hyper IgE syndrome is classified into 2 types:
- Autosomal dominant
- Autosomal recessive

# Pathophysiology
- Hyper IgE syndrome may be caused due to mutations in STAT3 and TYK2 genes.
- Signal transducer and activator of transcription 3 (STAT3) is a cytoplasmic protein and a component of the JAK-STAT pathway of signal transduction.
- The binding of various cytokines to their receptors on the cell surface results in activation of JAK proteins, which in turn phosphorylates STAT proteins.
- These STAT proteins then form dimers, translocate to the nucleus, bind to specific sites on the DNA, and activate target genes.
- Tyrosine kinase 2 (TYK2) is part of the JAK family of kinases that are associated with cytokine receptors.
- A deletion in TYK2 resulting in a truncated protein that is associated with abnormal signaling for type I interferon, IL-6, IL-10, IL-12, and IL-23.
- Both STAT3 and TYK2 defects lead to impaired Th17 function.
- A defect in Th17 function, results in decreased neutrophil proliferation and chemotaxis, decreased inflammation, and increased susceptibility to Candida and bacterial infections.

## Pathogenesis:
- Neutrophil chemotactic defect:
Th17 cell production of IL-17 is involved in neutrophil chemotaxis and proliferation .
Defective Th17 leads to defects in neutrophil chemotaxis and proliferation .
Interferon (IFN)-gamma production is also decreased which results in cutaneous and pulmonary infections.
Defect in neutrophil chemotaxis results in cutaneous cold abscess formation, in which signs of acute inflammation are absent.
- Th17 cell production of IL-17 is involved in neutrophil chemotaxis and proliferation .
- Defective Th17 leads to defects in neutrophil chemotaxis and proliferation .
- Interferon (IFN)-gamma production is also decreased which results in cutaneous and pulmonary infections.
- Defect in neutrophil chemotaxis results in cutaneous cold abscess formation, in which signs of acute inflammation are absent.
- T cell defects
STAT3 plays a crucial role in the differentiation of naive T cells into IL-17 producing CD4+ T cells (Th17 cells).
Th17 cells are involved in the response to fungal and extracellular bacterial infections.
These cells are significantly reduced or absent in patients with HIES.
- STAT3 plays a crucial role in the differentiation of naive T cells into IL-17 producing CD4+ T cells (Th17 cells).
- Th17 cells are involved in the response to fungal and extracellular bacterial infections.
- These cells are significantly reduced or absent in patients with HIES.
- B cell defects and abnormal IgE regulation
B cells are responsible for the synthesis of IgE.
A defect in the B cells leads to abnormal synthesis of IgE.
IgE regulation involves T cell stimulation, appropriate cytokine production, and the ability of B cells to class switch toward the production of IgE.
Thus, defects in IFN-gamma production or regulation contribute to the elevated levels of IgE.
- B cells are responsible for the synthesis of IgE.
- A defect in the B cells leads to abnormal synthesis of IgE.
- IgE regulation involves T cell stimulation, appropriate cytokine production, and the ability of B cells to class switch toward the production of IgE.
- Thus, defects in IFN-gamma production or regulation contribute to the elevated levels of IgE.

# Causes
- Hyper IgE syndrome is caused due to mutations in the signal transducer and activator of transcription 3 (STAT3) and tyrosine kinase 2 (TYK2) gene.
- STAT 3 gene is essential for the differentiation of helper T cells, mutation causes autosomal dominant type.
- Tyrosine kinase 2 (TYK2) gene mutation causes autosomal recessive type.

# Differentiating Hyper-IgE syndrome from Other Diseases
Hyper IgE syndrome can be differentiated from other diseases of the same kind by measuring the serum IgE levels.

# Epidemiology and Demographics
- Incidence of hyper IgE syndrome is less than 1 in 100,000 individuals.

# Screening
Screening is not recommended for hyper IgE syndrome.

# Natural History, Complications, and Prognosis

## Natural History
- Patients of hyper IgE syndrome are born with pustular or eczematoid rashes, or they may appear in first month of life.
- Recurrent eczema, boils and skin abscesses.
- Recurrent infections such as chronic otitis media, sinusitis, pneumonias, mucocutaneous infections, neurological and systemic.
- Hyperextensible joints/recurrent bone fractures, and distinctive coarse faces( prominent forehead, deep-set eyes, broad nasal bridge, and wide interalar distance) in early childhood.
- Eczema complicated by mucocutaneous candidiasis involving the mouth and diaper areas.
- Skeletal abnormalities include scoliosis, osteopenia, minimal trauma fractures, hyperextensibility, and degenerative joint disease.
- Retained primary teeth past the age of normal dental exfoliation.

## Complications
- Pustular and eczematoid rashes usually begin within the first month of life, usually affecting the face and scalp.
- Recurrent pneumonias start in childhood.
- Recurrent lung infections cause bronchiectasis and formation of pneumatocoeles that lead to secondary infections such as fungal and gram negative bacterial infections resulting in pulmonary vessels rupture and haemoptysis.
- Mucocutaneous candidiasis is common, manifesting typically as oral thrush, vaginal candidiasis or onychomycosis.
- Skeletal abnormalities include scoliosis, osteopenia, minimal trauma fractures, hyperextensibility, and degenerative joint disease.
- Chiari 1 malformations are common.
- Arterial aneurysms are fairly common. Aneurysms can be present in brain circulation or Aorta. It can lead to myocardial infarction or stroke.
- Malignancies such as squamous cell carcinoma, cutaneous T-cell lymphoma/leukemia, Burkitt lymphoma, Hodgkin's and non-Hodgkin's lymphoma .
- Systemic vasculitis.

## Prognosis
Infectious pulmonary complications are the leading cause of death in patients with HIES, followed by lymphoma:
- Prognosis depends on the complications arising from the disease.
- Pneumatoceles can become colonized with fungi and gram-negative bacteria, including A. fumigatus and P. aeruginosa.
- Infected pneumatoceles can cause subsequent pneumonia, systemic infection, or sudden pulmonary hemorrhage.
- Vascular invasion by fungi may give rise to mycotic aneurysms with subsequent hemorrhagic complications in the lungs and other organs.
- Patients developing lymphoma have a poor prognosis, with death resulting from superimposed infections.

# Diagnosis

## Diagnostic Criteria
Diagnosis requires clinical interepretation of symptoms along with laboratory findings.
- Serum IgE levels above 2,000 IU/ml (100 times greater than normal).
- Increased levels of eosinophils with normal levels of neutrophils and lymphocytes.
- A scoring system devised by NIH for the diagnosis of hyper IgE syndrome, score >30 suggests the presence of the disease.

## History and Symptoms
- Patients of hyper IgE syndrome are born with pustular or eczematoid rashes, or they may appear in first month of life.
- Recurrent eczema, boils and skin abscesses.
- Recurrent infections such as chronic otitis media, sinusitis, pneumonias, mucocutaneous infections, neurological and systemic.
- Hyperextensible joints/recurrent bone fractures, and distinctive coarse faces( prominent forehead, deep-set eyes, broad nasal bridge, and wide interalar distance) in early childhood.
- Eczema complicated by mucocutaneous candidiasis involving the mouth and diaper areas.
- Skeletal abnormalities include scoliosis, osteopenia, minimal trauma fractures, hyperextensibility, and degenerative joint disease.
- Retained primary teeth past the age of normal dental exfoliation.

## Physical Examination
- Coarse facial features( prominent forehead, deep-set eyes, broad nasal bridge, and wide interalar distance).
- Dental abnormalities- retained primary teeth.
- Facial pain (sinusitis), ear pain and discharge (otitis media).
- Purulent sputum producing cough or dry cough due to recurrent pneumonia.
- Eczematous dermatitis and lichenification affect the face, trunk, and extremities.
- Boils and multiple skin abscesses.
- Purpural rash.
- Skeletal abnormalities include scoliosis, osteopenia , minimal trauma fractures, hyper-extensible and degenerative joint disease.

## Laboratory Findings
- Serum IgE levels above 2,000 IU/ml(100 times greater than normal).
- Increased levels of eosinophills ( >700) with normal levels of neutrophils and lymphocytes.

## Electrocardiogram
There are no ECG findings associated with IgM defiicency.

## X-ray
There are no specific findings for IgM deficiency on x ray but signs of lung disease may be present.
- Increased bronchovascular markings in bronchitis.
- Lung hyperinflation with flattened hemidiaphragms in emphysema.
- Consolidation in pneumonia.
- Tram track opacities in bronchiectasis.

## Echocardiography or Ultrasound
There are no echocardiography/ultrasound findings associated with hyper IgE syndrome.

## CT scan
- There are no CT scan findings associated with hyper IgE syndrome.
- Changes of chronic lung disease, if present will be visible on CT and can help differentiate the cause and extent of the disease.
- Chronic sinusitis- mucosal thickening, complete opacification, bone remodeling and thickening due to osteitis, and polyposis.

## MRI
There are no MRI findings associated with hyper IgE syndrome.
However, signs of chronic lung disease or chronic sinsuitis may be present.

## Other Imaging Findings
There are no other imaging findings associated with hyper IgE syndrome.

## Other Diagnostic Studies
There are no other diagnostic studies associated with hyper IgE syndrome.

# Treatment

## Medical Therapy
Treatment of hyper IgE syndrome includes prevention of infections, administering prohphylactic antibiotics, treating current infections and bone marrow transplant.
- Skin care with antiseptic wash prevents infection with bacterias and fungi.
Eczematous dermatitis is treated with a topical corticosteroid, a moisturizing cream, and an antihistamine .
- Eczematous dermatitis is treated with a topical corticosteroid, a moisturizing cream, and an antihistamine .
- Prophylactic administration of trimethoprim-sulfamethoxazole is useful in the prevention of cutaneous staphylococcal infections, including abscesses, as well as sinusitis, otitis media, and pneumonia.
5 to 8 mg/kg/day of the trimethoprim component administered orally in two divided daily doses, or from 0 to 6 months, 120 mg/day; 6 months to 5 years, 240 mg/day; 6 to 12 years, 480 mg/day; and >12 years, 960 mg/day.
- 5 to 8 mg/kg/day of the trimethoprim component administered orally in two divided daily doses, or from 0 to 6 months, 120 mg/day; 6 months to 5 years, 240 mg/day; 6 to 12 years, 480 mg/day; and >12 years, 960 mg/day.
- Treatment of active infections:
Pneumonia and deep-seeded abscesses caused by S aureus are treated intravenously with nafcillin and with vancomycin if it is methicillin-resistant.
Lung abscesses superinfected with Aspergillus species require intravenous amphotericin B.
P aeruginosa, requires an aminoglycoside and a third-generation cephalosporin or another synergistic antibiotic.
- Pneumonia and deep-seeded abscesses caused by S aureus are treated intravenously with nafcillin and with vancomycin if it is methicillin-resistant.
- Lung abscesses superinfected with Aspergillus species require intravenous amphotericin B.
- P aeruginosa, requires an aminoglycoside and a third-generation cephalosporin or another synergistic antibiotic.
- Bone marrow transplantation (BMT) is also being studied to be used for treatment.

## Surgery
Surgery is not recommended for the treatment of hyper IgE syndrome.

## Primary Prevention
There are no established measures for the primary prevention of hyper IgE syndrome.

## Secondary Prevention
Secondary prevention includes prevention of infections by:
- Avoidance- reduce exposure to others with potentially contagious illnesses, proper hand washing and immunization of family members and close contacts.
- Vaccination with conjugate vaccines - conjugated pneumococcal vaccine, conjugated haemophillus influenza B and conjugated meningococcal vaccine administered to prevent infections.
- Use of prophylactic broad spectrum antibiotics.
- Skin care with antiseptic wash prevents infection with bacterias and fungi.