Definition/General
Introduction:
Hyper-IgE syndrome (HIES), also known as Job syndrome, is a rare primary immunodeficiency characterized by extremely elevated IgE levels, recurrent infections, and eczematous dermatitis
Two main forms exist: autosomal dominant HIES (STAT3 mutations) and autosomal recessive HIES (DOCK8, TYK2 mutations)
Features distinctive facial and skeletal abnormalities.
Origin:
Results from mutations affecting immune cell signaling pathways
AD-HIES: STAT3 mutations (85% cases) affecting Th17 cell development
AR-HIES: DOCK8 mutations (severe immunodeficiency), TYK2 mutations, SPINK5 mutations
Leads to defective immune responses and characteristic syndromic features.
Classification:
Classified into two main forms: Autosomal dominant HIES (AD-HIES, STAT3 mutations)
Autosomal recessive HIES (AR-HIES, DOCK8, TYK2 mutations)
Classical HIES (full syndrome)
Atypical HIES (incomplete features)
NIH scoring system for diagnosis.
Epidemiology:
Very rare disorder with less than 300 cases reported
AD-HIES more common than AR-HIES
Equal gender distribution
Characteristic facial features develop with age
Variable severity within families.
Clinical Features
Presentation:
Markedly elevated IgE (>2000 IU/mL)
Recurrent skin and lung infections
Chronic eczematous dermatitis
Characteristic facial features (coarse, asymmetric)
Skeletal abnormalities (scoliosis, fractures)
Dental problems (retained primary teeth).
Symptoms:
Recurrent staphylococcal abscesses
Pneumonia with pneumatocele formation
Severe eczema from infancy
Candidiasis (mucocutaneous)
Bone fractures with minimal trauma
Joint hyperextensibility
Growth retardation.
Risk Factors:
Family history (autosomal dominant)
De novo mutations (common)
Characteristic facial features
Early onset eczema
Recurrent abscesses
Pneumatoceles.
Screening:
IgE levels (markedly elevated >2000 IU/mL)
Eosinophil count (elevated)
NIH scoring system
Th17 cell assessment
Genetic testing
Immunological workup.
Master Hyper-IgE Syndrome Pathology with RxDx
Access 100+ pathology videos and expert guidance with the RxDx app
Gross Description
Appearance:
Bone marrow aspirate shows normal to increased cellularity
Eosinophilia (increased eosinophils)
Normal other lineages
No specific morphological abnormalities
Reactive changes due to chronic infections.
Characteristics:
Eosinophilic infiltration in bone marrow
Normal hematopoietic architecture
Increased plasma cells (IgE-producing)
Reactive lymphoid elements
No dysplastic changes.
Size Location:
Lymphadenopathy (reactive)
Hepatosplenomegaly may be present
Normal bone marrow distribution
Skin involvement (eczema, abscesses)
Pulmonary involvement (pneumatoceles).
Multifocality:
Systemic immune dysfunction
Multi-organ involvement
Chronic inflammatory state
Recurrent infections
Progressive complications.
Microscopic Description
Histological Features:
Normal to increased bone marrow cellularity
Eosinophilia (>5% of nucleated cells)
Increased plasma cells
Normal other lineages
Reactive lymphoid aggregates.
Cellular Characteristics:
Morphologically normal eosinophils
Increased eosinophil precursors
IgE-producing plasma cells
Normal T and B cell morphology
Activated immune cells.
Architectural Patterns:
Preserved bone marrow architecture
Increased eosinophilic areas
Normal sinusoidal pattern
Reactive changes
No fibrosis.
Grading Criteria:
Diagnosis by NIH scoring system: IgE >2000 IU/mL (major criterion)
Recurrent infections
Eczema
Characteristic facial features
Skeletal abnormalities
Score >40 suggests HIES.
Immunohistochemistry
Positive Markers:
Major basic protein highlights eosinophils
CD138 shows increased plasma cells
IgE shows elevated plasma cells
CD3/CD20 show lymphoid cells
MPO shows granulopoiesis.
Negative Markers:
Th17 markers reduced (AD-HIES)
IL-17 production decreased
Some cytokine receptors may be abnormal
Viral markers variable.
Diagnostic Utility:
Demonstrates eosinophilia
Shows increased IgE plasma cells
Confirms reactive changes
Assesses immune cell populations
Excludes other disorders
Supports clinical diagnosis.
Molecular Subtypes:
AD-HIES (STAT3 mutations)
AR-HIES (DOCK8, TYK2 mutations)
Atypical forms
Different clinical severities
Variable immune defects.
Molecular/Genetic
Genetic Mutations:
STAT3 mutations (AD-HIES, 85% cases)
DOCK8 mutations (AR-HIES, severe form)
TYK2 mutations (AR-HIES, mycobacterial infections)
SPINK5 mutations (Netherton syndrome overlap)
PGM3 mutations (rare).
Molecular Markers:
Markedly elevated IgE (>2000 IU/mL)
Eosinophilia (peripheral and marrow)
Defective Th17 responses (AD-HIES)
Impaired cytokine signaling
Reduced specific antibodies.
Prognostic Significance:
AD-HIES better prognosis
AR-HIES more severe complications
DOCK8 deficiency worst outcomes
Early diagnosis improves management
Malignancy risk increased
BMT consideration in severe cases.
Therapeutic Targets:
Antimicrobial prophylaxis
Antifungal agents
Immunoglobulin replacement
Topical corticosteroids
Bone marrow transplantation (severe AR-HIES)
Supportive care.
Differential Diagnosis
Similar Entities:
Atopic dermatitis
Wiskott-Aldrich syndrome
Omenn syndrome
Chronic granulomatous disease
Netherton syndrome
Aspergillosis (allergic bronchopulmonary).
Distinguishing Features:
HIES: Extremely high IgE
HIES: Characteristic facial features
HIES: Pneumatoceles
AD: Normal IgE
WAS: Small platelets
WAS: Immunodeficiency
CGD: Granulomas
CGD: Normal IgE
Omenn: SCID features.
Diagnostic Challenges:
Confirming genetic diagnosis
Distinguishing AD vs AR forms
NIH scoring interpretation
Atypical presentations
Family screening
Treatment selection.
Rare Variants:
Atypical HIES (incomplete features)
Late-onset HIES
HIES with normal IgE (rare)
Autosomal recessive variants
Overlapping syndromes.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Bone marrow aspirate and biopsy from [site], adequate for evaluation
Diagnosis
Hyper-IgE Syndrome (Job Syndrome)
Classification
Classification: Primary immunodeficiency with eosinophilia and elevated IgE
Bone Marrow Cellularity
Cellularity: [X]% for age, with eosinophilia and increased plasma cells
Lineage Assessment
Eosinophils: increased ([X]% of nucleated cells). Plasma cells: increased. Other lineages: normal
Morphological Features
Shows eosinophilia and increased plasma cells with reactive changes
Special Studies
IgE levels: [correlation required]
Genetic testing: recommend STAT3, DOCK8 analysis
NIH scoring: recommend clinical assessment
Clinical Correlation
Findings consistent with hyper-IgE syndrome. Recommend genetic counseling
Final Diagnosis
Bone marrow showing eosinophilia and reactive changes consistent with hyper-IgE syndrome