Definition/General
Introduction:
Hyper-IgM syndrome (HIGM) is a group of primary immunodeficiency disorders characterized by elevated or normal IgM levels with deficient IgG, IgA, and IgE production
It results from defects in immunoglobulin class switching
The most common form is X-linked HIGM due to CD40L deficiency.
Origin:
Results from defects in immunoglobulin class switch recombination
X-linked HIGM1: CD40L (CD154) mutations
Autosomal HIGM2: AID (AICDA) mutations
HIGM3: CD40 mutations
HIGM4: unknown gene
HIGM5: UNG mutations
Leads to inability to produce non-IgM antibodies.
Classification:
Classified by genetic defect: HIGM1 (X-linked, CD40L deficiency, 65% cases)
HIGM2 (AID deficiency, 15% cases)
HIGM3 (CD40 deficiency, rare)
HIGM4 (unknown gene, rare)
HIGM5 (UNG deficiency, rare)
Intrinsic vs extrinsic B cell defects.
Epidemiology:
Rare disorder with incidence 2 per million males (X-linked form)
X-linked form most common (65%)
Male predominance in X-linked form
Equal gender in autosomal forms
Early onset infections.
Clinical Features
Presentation:
Recurrent sinopulmonary infections
Opportunistic infections (X-linked form)
Neutropenia (common)
Lymphadenopathy
Autoimmune manifestations
No lymphoid hyperplasia (unlike CVID).
Symptoms:
Recurrent pneumonia and sinusitis
Pneumocystis pneumonia (X-linked)
Cryptosporidium diarrhea
Oral ulcers
Autoimmune cytopenias
Sclerosing cholangitis
Growth retardation.
Risk Factors:
X-linked inheritance (maternal transmission)
Family history of immunodeficiency
Male gender (X-linked form)
Consanguinity (autosomal forms)
Early onset infections.
Screening:
Immunoglobulin levels (high IgM, low IgG/IgA)
CD40L expression (flow cytometry)
B cell subsets
Vaccine responses
Genetic testing
T cell function.
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Gross Description
Appearance:
Bone marrow aspirate shows variable cellularity
B cells present
Plasma cells may be increased (IgM-producing)
Normal T cells
Possible neutropenia.
Characteristics:
Normal to increased B cells
IgM-producing plasma cells
Absent IgG/IgA plasma cells
Normal bone marrow architecture
Reactive changes due to infections.
Size Location:
Lymph nodes variable (enlarged but no germinal centers)
Splenomegaly may be present
Normal bone marrow distribution
Hepatomegaly (infections, autoimmunity).
Multifocality:
Systemic class switch defect
All lymphoid organs affected
Absent germinal centers
IgM-predominant responses
Opportunistic infections.
Microscopic Description
Histological Features:
Normal to increased B cells
IgM-positive plasma cells increased
IgG/IgA plasma cells absent
Normal T cells
Absent germinal centers (lymph nodes).
Cellular Characteristics:
B cells morphologically normal
Plasma cells predominantly IgM-positive
Normal T cell morphology
Neutropenia may be present
Reactive lymphoid cells.
Architectural Patterns:
Preserved bone marrow architecture
Normal cellular distribution
Absent germinal center formation (lymphoid organs)
Reactive follicular hyperplasia without germinal centers.
Grading Criteria:
Diagnosis by immunoglobulin pattern: IgM >150 mg/dL (or normal)
IgG <250 mg/dL
IgA <10 mg/dL
CD40L expression absent (X-linked)
Class switch defect demonstrated.
Immunohistochemistry
Positive Markers:
CD19 and CD20 show normal B cells
CD3 shows normal T cells
IgM shows increased plasma cells
CD138 highlights plasma cells
MPO shows granulopoiesis.
Negative Markers:
CD40L absent (X-linked form)
IgG and IgA plasma cells absent
Germinal center markers absent (CD21, CD23)
Memory B cell markers reduced.
Diagnostic Utility:
Demonstrates CD40L deficiency
Shows IgM plasma cell predominance
Confirms absent class switching
Identifies B cell populations
Excludes other immunodeficiencies
Guides genetic testing.
Molecular Subtypes:
X-linked HIGM1 (CD40L deficiency)
Autosomal HIGM2 (AID deficiency)
HIGM3 (CD40 deficiency)
HIGM5 (UNG deficiency)
Different clinical severities.
Molecular/Genetic
Genetic Mutations:
CD40LG mutations (X-linked HIGM1, Xq26)
AICDA mutations (HIGM2, autosomal recessive)
CD40 mutations (HIGM3, autosomal recessive)
UNG mutations (HIGM5, autosomal recessive)
Over 100 CD40L mutations described.
Molecular Markers:
Absent CD40L expression (X-linked)
Defective class switch recombination
Normal somatic hypermutation (most forms)
Elevated IgM levels
Absent specific antibodies
T cell dysfunction (X-linked).
Prognostic Significance:
X-linked form worst prognosis
Opportunistic infections life-threatening
Autosomal forms milder
Early BMT improves outcomes
IVIG prevents infections
Neutropenia complicates course.
Therapeutic Targets:
Immunoglobulin replacement (IVIG/SCIG)
Bone marrow transplantation (X-linked form)
Antimicrobial prophylaxis
G-CSF (neutropenia)
Gene therapy (experimental)
Supportive care.
Differential Diagnosis
Similar Entities:
Common variable immunodeficiency
X-linked agammaglobulinemia
Selective IgA deficiency
Transient hypogammaglobulinemia
Secondary immunodeficiency
Autoimmune lymphoproliferative syndrome.
Distinguishing Features:
HIGM: Elevated IgM
HIGM: CD40L deficiency
HIGM: Class switch defect
CVID: Low all immunoglobulins
XLA: Absent B cells
SIgAD: Isolated IgA deficiency
THI: Transient nature.
Diagnostic Challenges:
Confirming genetic subtype
Distinguishing HIGM variants
CD40L expression testing
Functional studies
Carrier detection
Treatment selection.
Rare Variants:
Atypical HIGM
Late-onset HIGM
HIGM with autoimmunity
Transient CD40L deficiency
Somatic reversion.
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-IgM Syndrome
Classification
Classification: Primary immunodeficiency with class switch defect
Bone Marrow Cellularity
Cellularity: [X]% for age, with normal B cells and IgM-predominant plasma cells
Lineage Assessment
B cells: normal numbers. Plasma cells: IgM-positive predominant, IgG/IgA-positive absent. T cells: normal
Morphological Features
Shows normal B cells with IgM-predominant plasma cells and absent class switching
Special Studies
CD40L expression: [absent/present]
Immunoglobulin studies: IgM predominant, absent IgG/IgA plasma cells
Genetic testing: recommend HIGM gene panel
Clinical Correlation
Findings consistent with hyper-IgM syndrome. Recommend genetic counseling
Final Diagnosis
Bone marrow showing class switch defect consistent with hyper-IgM syndrome