Hyper-IgE syndrome

Hyper-IgE syndrome
ICD-10	D82.4
ICD-9	288.1
OMIM	29572 147060
DiseasesDB	29572
eMedicine	derm/845  ped/1074
MeSH	D007589

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2]

Synonyms and keywords: Job-Buckley syndrome; Job syndrome; Buckley syndrome.

Overview

Hyper IgE syndrome (HIES) is a heterogeneous 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 it was named as Job's syndrome.

• The criterai 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 is caused due to mutations in STAT 3 and Tyrosine kinase 2 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 phosphorylate STAT proteins.
• The STATs 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.
• T cell defects —
  • STAT3 plays a crucial role in the differentiation of naïve 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 resonsible 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.

Disease	IgM levels	IgG levels	IgA levels	IgE levels	B cell defect	T cell defect
IgM deficiency	↓	-	-	-	-	-
IgA deficiency	-	-	↓	-	-	-
IgG deficiency	-	↓	-	-	-	-
IgE deficiency	-	-	-	↓	-	-
Hypoproteinemia/Proteinuria	↓	↓	↓	↓	-	-
Comined Immunodeficiency	↓	↓	↓	↓	+	+
X linked agammaglobulinemia	↓	↓	↓	↓	+	-
Hyperimmunoglobulin M syndrome	↑	↓	↓	↓	+	-
Common variable immunodeficiency	↓	↓	↓	↓	+	-
Wiskott-Aldrich syndrome	↓	↓	↑	↑	-	+
Hyper IgE syndrome	-	-	-	↑	-	+

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 alongwith laboratory findings..

• Serum IgE levels above 2,000 IU/ml(100 times greater than normal).
• Increased levels of eosinophills 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.

Clinical findings	Points*
	0	1	2	3	4	5	6	7	8	10
Highest serum-IgE level (international units/mL)¶	<200	200 to 500			501 to 1000				1001 to 2000	>2000
Skin abscesses	None		1 to 2		3 to 4				>4
Pneumonia (episodes over lifetime)	None		1		2		3		>3
Parenchymal lung anomalies	Absent						Bronchiectasis		Pneumatocele
Retained primary teeth	None	1	2		3				>3
Scoliosis, maximum curvature	<10°		10 to 14°		15 to 20°				>20°
Fractures with minor trauma	None				1 to 2				>2
Highest eosinophil count (cells/microL)Δ	<700			700 to 800			>800
Characteristic face	Absent		Mildly present			Present
Midline anomaly◊	Absent					Present
Newborn rash	Absent				Present
Eczema (worst stage)	Absent	Mild	Moderate		Severe
Upper respiratory infections per year	1 to 2	3	4 to 6		>6
Candidiasis	None	Oral	Fingernails		Systemic
Other serious infections	None				Severe
Fatal infection	Absent				Present
Hyperextensibility	Absent				Present
Lymphoma	Absent				Present
Increased nasal width§	<1 SD	1 to 2 SD		>2 SD
High palate	Absent		Present
Young-age correction	>5 years			2 to 5 years		1 to 2 years		≤1 year

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 pneumonias.
• 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, hyperextensibility, and degenerative joint disease.

Laboratory Findings

Elevated IgE is the hallmark of HIES, usually > 10 times normal. However, patients younger than 6 months of age may have very low to non-detectable IgE levels. Eosinophilia is also a common finding with greater than 90% of patients having eosinophil elevations greater than two standard deviations above the normal mean.

Treatment

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 .
• 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.
• 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.
• 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.