Bit · Rheum/Immuno
DiGeorge vs Bruton vs CVID vs Hyper-IgM vs SCID
Five primary immunodeficiencies that all give recurrent infection in childhood, but split on which arm of immunity is broken. The pivot is which cell line is missing.
Mechanism
The immune system has four major effector pathways: B cells (antibodies), T cells (cellular immunity), phagocytes, and complement. Each of these five disorders is a different lesion in B/T cells:
- DiGeorge syndrome — 22q11.2 deletion → failure of 3rd and 4th pharyngeal pouches → absent thymus and parathyroids. Triad: thymic aplasia (T-cell deficiency, recurrent viral/fungal/protozoal infections), hypocalcemia (parathyroid absence → tetany), conotruncal cardiac defects (truncus arteriosus, tetralogy of Fallot). 'CATCH-22': Cardiac, Abnormal facies, Thymic aplasia, Cleft palate, Hypocalcemia, chromosome 22.
- Bruton (X-linked) agammaglobulinemia — defect in BTK (Bruton tyrosine kinase) → B cells can't mature beyond pre-B. No B cells, no immunoglobulins, no lymph nodes/tonsils. Boys (X-linked) present after 6 months (maternal IgG gone) with recurrent bacterial sinopulmonary infections, especially encapsulated organisms (S. pneumo, H. flu, N. meningitidis).
- Common Variable Immunodeficiency (CVID) — multiple genetic causes, but common phenotype: defective B-cell differentiation into plasma cells → low IgG ± IgA ± IgM. Onset typically late (adolescence/adulthood). Recurrent sinopulmonary infections, increased autoimmunity, increased risk of lymphoma and gastric cancer.
- Hyper-IgM syndrome — most common form is X-linked defect in CD40 ligand on T cells (less commonly CD40 on B cells, or AID). Class-switching can't happen → high IgM, low IgG/A/E. Recurrent pyogenic infections, opportunistic infections (Pneumocystis, Cryptosporidium), failure to thrive.
- Severe Combined Immunodeficiency (SCID) — multiple causes (X-linked common γ-chain mutation; autosomal ADA deficiency; others) → defective T-cell AND B-cell function. The most severe primary immunodeficiency. Failure to thrive, chronic diarrhea, oral candidiasis, opportunistic infections, no thymic shadow on CXR. Treat: bone marrow transplant or gene therapy. Fatal if untreated.
Differentiator Table
| DiGeorge | Bruton | CVID | Hyper-IgM | SCID | |
| Defective cell | T cells (thymic aplasia) | B cells (BTK) | B cells → plasma cells | T-cell CD40L (class switching) | T AND B cells |
| Genetics | 22q11.2 deletion (sporadic mostly) | X-linked recessive (BTK) | Variable, often sporadic | X-linked (CD40L) most common | X-linked γ-chain; AR ADA deficiency |
| Age of onset | Neonatal (cardiac defects, tetany) | After 6 months (maternal IgG wanes) | Adolescence / adulthood | Infancy | Within first months of life |
| Immunoglobulins | Normal-ish (T cell problem) | All very low | Low IgG ± IgA ± IgM | ↑ IgM, ↓ IgG/A/E | All very low |
| B cells | Normal number | ABSENT (or very low) | Normal number, defective function | Normal | Often absent or non-functional |
| T cells | ↓ (thymic aplasia) | Normal | Variable | Normal number | Absent or non-functional |
| Classic infections | Viral, fungal, PCP | Encapsulated bacteria (sinopulmonary) | Sinopulmonary, GI infections, giardia | Pyogenic + opportunistic (PCP, Crypto) | Everything (bacterial, viral, fungal, opportunistic) |
| Distinctive feature | Hypocalcemia + truncus / TOF + cleft palate + chr 22 del | No tonsils, no LN; absent B cells; boys after 6 mo | Adult-onset low Ig; ↑ autoimmunity; ↑ lymphoma | ↑↑ IgM, no class switching | No thymic shadow on CXR; chronic diarrhea + thrush + FTT |
| Treatment | Calcium, thymus transplant in severe; PCP prophylaxis | Monthly IVIG | Monthly IVIG | Monthly IVIG; HSCT | HSCT, gene therapy, IVIG bridge |
The Pivot
Two questions usually settle it:
- Are the cardiac defect, hypocalcemia, and cleft palate present? → DiGeorge. (CATCH-22)
- If it's an antibody-only problem: infant boy with no B cells → Bruton. Older child/adult with low IgG → CVID. ↑ IgM with everything else low → Hyper-IgM.
- If T and B cells are both gone → SCID.
NBME-Style Stem
A 9-month-old boy is brought in for the fourth episode of acute otitis media in 4 months, along with two pneumonias. Examination shows no palpable tonsils or cervical lymph nodes. Flow cytometry shows B cells < 1% of lymphocytes; T cells are normal. Serum IgG, IgA, and IgM are all profoundly low. Which of the following is the most likely diagnosis?
Concept Anchor
Five primary immunodeficiencies, five different broken parts: T cells gone (DiGeorge), B cells gone (Bruton), plasma cells fail late (CVID), class switching fails (Hyper-IgM), both gone (SCID). Find the missing cell line and the diagnosis follows.