Definition/General
Introduction:
Severe combined immunodeficiency (SCID) represents a group of primary immunodeficiency disorders characterized by severe defects in both T and B cell function
It results from various genetic mutations affecting lymphocyte development and function
SCID is a pediatric emergency requiring immediate treatment.
Origin:
Results from mutations in multiple genes affecting lymphocyte development
Common genes include IL2RG (X-linked SCID), JAK3, RAG1/RAG2, ADA, and others
The defects occur at different stages of lymphocyte development
T cell deficiency is universally present
B and NK cell involvement varies by subtype.
Classification:
Classified by immunological phenotype: T-B-NK- (X-linked, JAK3 deficiency)
T-B-NK+ (RAG1/2, DCLRE1C deficiency)
T-B+NK- (IL7RA deficiency)
T-B+NK+ (CD3 deficiency)
ADA-SCID and PNP-SCID (metabolic defects).
Epidemiology:
Incidence approximately 1 in 50,000-100,000 births
X-linked form most common (45-50%)
Male predominance in X-linked form
Equal gender distribution in autosomal forms
Fatal without treatment within first year
Newborn screening now available.
Clinical Features
Presentation:
Severe, recurrent infections from early infancy
Failure to thrive and growth retardation
Persistent diarrhea
Chronic thrush and skin infections
Lymphadenopathy absence
Live vaccine reactions (BCG, rotavirus).
Symptoms:
Recurrent pneumonia and sepsis
Opportunistic infections (PCP, CMV, candida)
Persistent diarrhea and malabsorption
Skin rashes and eczema
Graft-versus-host disease from maternal T cells
Developmental delays.
Risk Factors:
Family history of early infant deaths
Consanguineous parents
Male gender (X-linked form)
Previous affected siblings
Maternal T cell engraftment
Live vaccine exposure.
Screening:
Newborn screening (TREC assay)
Lymphocyte subset analysis
Proliferation studies
Immunoglobulin levels
Bone marrow examination
Genetic testing
Enzyme assays (ADA, PNP).
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Gross Description
Appearance:
Bone marrow aspirate shows variable cellularity
Markedly reduced lymphoid elements
Normal erythropoiesis and granulopoiesis
Normal megakaryopoiesis
Absence of lymphoid aggregates.
Characteristics:
Paucity of lymphocytes in bone marrow
Normal other hematopoietic lineages
No thymic shadow on chest imaging
Lymph node hypoplasia
Splenic atrophy.
Size Location:
Diffuse lymphoid depletion
Absent thymus or rudimentary thymus
Small lymph nodes
Reduced splenic size
Normal bone marrow architecture.
Multifocality:
Systemic lymphoid depletion
All lymphoid organs affected
Variable severity by SCID type
Progressive deterioration without treatment
Opportunistic pathogen colonization.
Microscopic Description
Histological Features:
Markedly reduced lymphocytes in bone marrow (<5% of normal)
Normal cellularity other lineages
Absence of plasma cells
No germinal centers in lymph nodes
Thymic dysplasia or aplasia.
Cellular Characteristics:
Severe T cell deficiency (CD3+ <300/μL)
Variable B cell numbers (functional defect)
NK cell deficiency in some types
Normal morphology residual lymphocytes
Increased susceptibility markers.
Architectural Patterns:
Preserved bone marrow architecture
Lymphoid organ hypoplasia
Absent paracortical areas (T cell zones)
Reduced follicular structures
No inflammatory infiltrates.
Grading Criteria:
Severity by T cell count: Severe (<300/μL)
Proliferation response (<10% normal)
Immunoglobulin levels (variable)
NK cell function (varies by type)
Survival without treatment (<1 year).
Immunohistochemistry
Positive Markers:
CD34 shows normal stem cells
MPO highlights granulopoiesis
Glycophorin A shows erythropoiesis
CD61 identifies megakaryocytes
Reticulin shows normal architecture.
Negative Markers:
CD3 markedly reduced (T cells)
CD20 variable (B cells)
CD56 reduced in some types (NK cells)
Plasma cell markers absent
Germinal center markers absent.
Diagnostic Utility:
Demonstrates severe T cell deficiency
Quantifies residual lymphoid cells
Shows normal other lineages
Confirms architectural preservation
Identifies SCID subtype
Monitors treatment response.
Molecular Subtypes:
X-linked SCID (IL2RG mutations)
JAK3-SCID
RAG1/2-SCID
ADA-SCID
Artemis-SCID
IL7RA-SCID
CD3 component deficiencies.
Molecular/Genetic
Genetic Mutations:
IL2RG mutations (X-linked, 45-50%)
JAK3 mutations (autosomal recessive)
RAG1/RAG2 mutations (V(D)J recombination defect)
ADA mutations (metabolic defect)
DCLRE1C mutations (Artemis deficiency)
Multiple other genes.
Molecular Markers:
Absent or reduced protein expression
Defective cytokine signaling
Impaired V(D)J recombination
Metabolic dysfunction (ADA/PNP)
DNA repair defects
Radiosensitivity (some types).
Prognostic Significance:
X-linked form good transplant outcomes
ADA-SCID excellent gene therapy results
RAG deficiency increased malignancy risk
Artemis deficiency radiosensitive
Early diagnosis improves outcomes
Maternal T cell GvHD worse prognosis.
Therapeutic Targets:
Bone marrow transplantation (curative)
Gene therapy (successful for some types)
Enzyme replacement (ADA-SCID)
Antimicrobial prophylaxis
IVIG replacement
Isolation precautions.
Differential Diagnosis
Similar Entities:
DiGeorge syndrome (22q11.2 deletion)
Combined immunodeficiency (less severe)
Omenn syndrome (leaky SCID)
Reticular dysgenesis
Cartilage-hair hypoplasia
Secondary immunodeficiency.
Distinguishing Features:
SCID: Severe T cell deficiency
SCID: Early onset infections
SCID: Normal facial features
DiGeorge: Cardiac defects
DiGeorge: Hypocalcemia
Omenn: Activated T cells
Omenn: Erythroderma
CID: Milder phenotype.
Diagnostic Challenges:
Identifying SCID subtype
Distinguishing from secondary causes
Recognizing maternal T cell GvHD
Genetic testing complexity
Urgent treatment needs
Family counseling.
Rare Variants:
Omenn syndrome (leaky SCID)
Atypical SCID with residual function
Late-onset SCID
SCID with granulomas
Radiosensitive SCID
SCID with autoimmunity.
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
Severe Combined Immunodeficiency (SCID)
Classification
Classification: Primary immunodeficiency with severe T cell defect
Bone Marrow Cellularity
Cellularity: [X]% for age (normal), with severe lymphoid depletion
Lineage Assessment
Lymphopoiesis: severely reduced. Erythropoiesis: normal. Granulopoiesis: normal. Megakaryopoiesis: normal
Morphological Features
Shows severe lymphocyte depletion with preserved other hematopoietic lineages
Special Studies
Flow cytometry: recommend T/B/NK enumeration
Genetic testing: urgent SCID gene panel
Functional studies: lymphocyte proliferation
Clinical Correlation
URGENT: Findings consistent with SCID. Immediate isolation and treatment required
Final Diagnosis
Bone marrow consistent with severe combined immunodeficiency (SCID)