STEPTRACKERIMMUNOLOGY + PEDIATRICS + GENETICS | IMMUNODEFICIENCY | HIGH-YIELD REVIEW

T-Cell & Combined Deficiencies

T-cell defects bring viruses, fungi and intracellular bacteria from early infancy; because B cells need T-cell help, most are effectively combined.

FOCUS ON
DiGeorge (22q11.2 deletion): 3rd/4th pharyngeal pouch failure → absent thymus (↓ T cells) + absent parathyroids (hypocalcemic tetany) + conotruncal heart defects (truncus, tetralogy) + abnormal face, cleft palate. SCID: X-linked common γ chain (IL-2RG) or JAK3 (T⁻B⁺NK⁻), ADA deficiency (toxic dATP), RAG1/2, IL-7Rα → failure to thrive, chronic diarrhea, thrush, Pneumocystis, absent thymic shadow, low TRECs on newborn screen → no live vaccines, irradiated blood, stem cell transplant. Wiskott-Aldrich (WAS, X-linked): eczema, thrombocytopenia with small platelets, infections; ↑ IgE/IgA, ↓ IgM. Ataxia-telangiectasia (ATM): ataxia, telangiectasias, IgA deficiency, ↑ AFP, radiosensitivity, lymphoma. Hyper-IgE (Job, STAT3): cold staphylococcal abscesses, retained primary teeth, eczema, ↑ IgE, coarse face. IL-12R / IFN-γR: disseminated mycobacteria. Chronic mucocutaneous candidiasis: Th17/AIRE.
DISORDER
DEFECT
FINDINGS
CLUE · TREATMENT
DiGeorge syndrome
22q11.2 microdeletion (TBX1) → 3rd/4th pouch maldevelopment
Thymic aplasia (↓ T cells), hypoparathyroidism (↓ Ca²⁺), conotruncal defects, cleft palate, facial dysmorphism
Neonatal tetany or seizures · absent thymic shadow · psychiatric risk later
X-linked SCID
Common γ chain (IL-2RG) of IL-2, 4, 7, 9, 15, 21 receptors
T⁻ B⁺ NK⁻; nonfunctional B cells
Most common SCID · boys
ADA deficiency
Adenosine deaminase (AR) → dATP accumulates → toxic to lymphocytes
T⁻ B⁻ NK⁻; skeletal anomalies
Enzyme replacement, gene therapy
RAG1/2 · Artemis SCID
No VDJ recombination
T⁻ B⁻ NK⁺
Omenn (partial): erythroderma, eosinophilia, ↑ IgE
SCID — presentation
No functional T cells (± B)
Failure to thrive, chronic diarrhea, thrush, Pneumocystis, severe viral infections in first months
Low TRECs on newborn screen · no live vaccines (rotavirus, BCG) · irradiated blood · HSCT
MHC class II deficiency
Transcription factor defects (CIITA, RFX)
↓ CD4⁺ cells, hypogammaglobulinemia
Bare lymphocyte syndrome
Wiskott-Aldrich syndrome
WAS gene (X-linked) → cytoskeleton defect
Eczema, thrombocytopenia with small platelets, recurrent infections; ↓ IgM, ↑ IgA/IgE
Bleeding in a boy · autoimmunity, lymphoma · HSCT
Ataxia-telangiectasia
ATM (DNA double-strand break repair), AR
Cerebellar ataxia (toddler), oculocutaneous telangiectasias, IgA/IgG2 deficiency, ↑ AFP
Radiosensitive · lymphoma, leukemia · avoid X-rays
Hyper-IgE syndrome (Job)
STAT3 (AD) → ↓ Th17 → poor neutrophil recruitment
Cold (non-inflamed) S aureus abscesses, retained primary teeth, eczema, coarse face, fractures, very high IgE, eosinophilia
Pneumatoceles · DOCK8 (AR) adds viral skin infections
IL-12 / IFN-γ receptor defects
Th1 axis broken
Disseminated mycobacteria (incl. BCG, NTM), Salmonella
IFN-γ therapy (if receptor present)
Chronic mucocutaneous candidiasis
Th17 defects, AIRE (APS-1), STAT1 gain of function
Persistent Candida of skin, nails, mucosa
Endocrine autoimmunity with AIRE
X-linked lymphoproliferative disease
SAP (SH2D1A) → abnormal NK/T responses to EBV
Fulminant mono, HLH, lymphoma in boys
—

Mechanism — DiGeorge as an embryology defect

22q11.2 deletion
→
3rd pouchThymus, inferior parathyroids
4th pouchSuperior parathyroids
Neural crestOutflow tract, face
→
T-cell deficiency, hypocalcemia, truncus / TOF

SCID types

DEFECT
T
B
NK
γc (X-linked), JAK3
−
+ (nonfunctional)
−
ADA
−
−
−
RAG1/2, Artemis
−
−
+
IL-7Rα
−
+
+

How it's tested

COMMON CONFUSIONWiskott-Aldrich (small platelets, eczema, boys) vs ITP (large platelets, no eczema) vs hyper-IgE (eczema, abscesses, normal platelets).
THE TRAPA SCID infant given rotavirus or BCG vaccine can develop disseminated vaccine-strain infection — newborn TREC screening exists to catch them first.
YOUR APPROACHAge + infection type (viral, fungal, opportunist) + extra-immune clue (tetany, eczema, bleeding, ataxia, teeth) → syndrome → gene → test.

If you see… think…

Newborn with tetany, truncus arteriosus and absent thymus → DiGeorge (22q11.2)
Absent thymic shadow, thrush, Pneumocystis at 3 months → SCID
Newborn screening test for SCID → TRECs
SCID from toxic dATP → ADA deficiency
Most common SCID gene → IL-2RG (common γ chain)
Boy with eczema, petechiae and tiny platelets → Wiskott-Aldrich
Toddler with unsteady gait, eye telangiectasias, ↑ AFP → ataxia-telangiectasia
Cold abscesses, retained baby teeth, IgE 5000 → hyper-IgE (STAT3)
Disseminated BCG after vaccination, normal T counts → IL-12/IFN-γ receptor defect
Fatal mononucleosis in a boy → X-linked lymphoproliferative disease