General Pathology & Immunology

Defect in BTK (Bruton tyrosine kinase) gene on X chromosome → arrest of pre-B cell maturation into naive B cells.

Absence of mature B cells (CD19, CD20, CD21 negative); markedly decreased or undetectable all immunoglobulin classes (IgG, IgA, IgM, IgE). Normal T cell counts.

Male infant, asymptomatic until 6 months of age (maternal IgG wanes). Recurrent pyogenic sinopulmonary infections (S. pneumoniae, H. influenzae) and enteroviral infections (coxsackie, echovirus, polio vaccine). Hypoplastic or ABSENT tonsils and peripheral lymph nodes (no germinal centers).

Failure of B cells to isotype-switch to IgA. Most common primary immunodeficiency (~1 in 600).

Severely decreased serum IgA (<7 mg/dL) with normal IgG and IgM levels. Normal B and T cell counts.

Most patients are asymptomatic. Can present with the 5 As: Asymptomatic, Airway infections (recurrent sinopulmonary), Atopy (asthma/eczema), Autoimmune disease (celiac, vitiligo, SLE), and Anaphylaxis on blood transfusion (recipient has anti-IgA antibodies against donor IgA).

Defect in B-cell differentiation into plasma cells; polygenic etiology. Usually diagnosed in adulthood (20s–30s).

Normal number of circulating B cells, but severe deficiency of plasma cells and markedly reduced serum IgG, IgA, and IgM. Poor antibody response to vaccination.

Recurrent bacterial respiratory infections (bronchiectasis), chronic giardiasis, enteropathy. High risk of autoimmune disorders (rheumatoid arthritis, immune thrombocytopenia) and malignancies (lymphoma, gastric adenocarcinoma).

Microdeletion of chromosome 22q11.2 resulting in failure of development of 3rd and 4th pharyngeal pouches.

Marked lymphopenia with severely decreased CD3+ T cells; normal B-cell counts but impaired antibody responses. Hypocalcemia (low serum PTH and Ca2+).

Classic CATCH-22 Mnemonic: Conotruncal cardiac anomalies (Tetralogy of Fallot, Truncus arteriosus), Abnormal facies (low-set ears, micrognathia, hypertelorism), Thymic hypoplasia/aplasia (absent thymic shadow on infant chest X-ray), Cleft palate, Hypocalcemia/tetany secondary to parathyroid hypoplasia.

Autosomal dominant STAT3 mutation leading to deficiency of Th17 helper T cells and impaired recruitment of neutrophils to epithelial surfaces.

Extremely elevated serum IgE (>2,000 IU/mL); marked peripheral eosinophilia; decreased Th17 cell frequency.

Mnemonic FATED: coarse Facies (broad nose, deep-set eyes), cold staphylococcal Abscesses (lack classic warmth/erythema due to defective neutrophil recruitment), retained primary Teeth (two rows of teeth), elevated IgE, Dermatologic eczema (severe pruriginous dermatitis). Also prone to pneumatoceles from S. aureus pneumonia.

Most common: X-linked recessive mutation in IL-2R gamma chain (IL2RG) causing defective cytokine signaling (IL-2, 4, 7, 9, 15, 21). Autosomal recessive: Adenosine Deaminase (ADA) deficiency causing toxic dATP buildup in lymphocytes.

Severe absolute lymphopenia; absence of T cells (CD3+); absent or non-functional B and NK cells; absence of thymic shadow on chest X-ray; absent T-cell receptor excision circles (TRECs) on newborn screening.

Presents in first months of life with severe recurrent opportunistic infections (Candida thrush, Pneumocystis jirovecii pneumonia, CMV, Pseudomonas), chronic intractable diarrhea, and profound failure to thrive.

Autosomal recessive defect in ATM gene on chromosome 11q22, which encodes a serine/threonine kinase that senses DNA double-strand breaks and halts cell cycle for non-homologous end-joining (NHEJ).

Markedly elevated alpha-fetoprotein (AFP); lymphopenia with decreased IgA, IgG2, and IgE; radiation sensitivity and chromosomal breakage.

Triad: Progressive cerebellar Ataxia (wheelchair-bound by early teens), spider Telangiectasias (oculocutaneous, appearing at age 3–5 on bulbar conjunctiva and ears), and severe Immunodeficiency with recurrent sinopulmonary infections. Extremely high risk of leukemia and lymphoma. Extreme sensitivity to ionizing radiation (X-rays/CT scans must be minimized!).

X-linked recessive mutation in WAS gene, encoding Wiskott-Aldrich syndrome protein (WASp). Impairs actin cytoskeleton remodeling in leukocytes and megakaryocytes.

Microthrombocytopenia (small platelets with decreased count); elevated IgA and IgE; decreased IgM; normal or slightly reduced IgG.

Mnemonic WATER: Wiskott-Aldrich, Thrombocytopenia (petechiae, purpura, bloody diarrhea in infancy), Eczema (flexural atopic dermatitis), Recurrent pyogenic infections (encapsulated bacteria). Platelet size is SMALL (differentiates from ITP where platelets are large).

Autosomal recessive defect in LFA-1 integrin (CD18 subunit / ITGB2 gene), preventing neutrophil adhesion to ICAM-1 on inflamed vascular endothelium and migration out of vessels into tissues.

Extreme peripheral leukocytosis (>50,000/μL with neutrophilia) during active infections, yet biopsies of infected sites reveal ABSENCE OF NEUTROPHILS (pus is absent).

Classic triad: (1) Delayed detachment/separation of the umbilical cord (>30 days; normal is 1–2 weeks), (2) Recurrent non-purulent skin and mucosal bacterial and fungal infections with impaired wound healing (necrotic ulcers), and (3) Absence of pus formation.

Autosomal recessive mutation in LYST gene (lysosomal trafficking regulator), causing defective microtubule polymerization and failure of phagosome-lysosome fusion in phagocytes and melanocytes.

Pancytopenia; giant azurophilic granules in granulocytes, platelets, and melanocytes on peripheral blood smear.

Mnemonic PLAIN: Progressive neurodegeneration (ataxia, peripheral neuropathy), Lymphohistiocytosis / accelerated hemophagocytic phase, Albinism (partial oculocutaneous with silvery hair and pale skin), recurrent pyogenic Infections (staph/strep), Neuropathy (sensory and motor).

Deficiency of NADPH oxidase (gp91phox most common, X-linked recessive; or p47phox, AR), preventing the respiratory burst that converts molecular oxygen into superoxide radicals ($O_2^{\bullet-}$).

Abnormal Dihydrorhodamine (DHR) flow cytometry assay (absence of green rhodamine 123 fluorescence); Nitroblue Tetrazolium (NBT) dye reduction test fails to turn dark blue (remains yellow/colorless).

Recurrent infections and abscesses by Catalase-Positive organisms (which break down their own endogenous $H_2O_2$, leaving phagocytes unable to kill them). Catalase-positive pathogens: S. aureus, Pseudomonas (Burkholderia) cepacia, Serratia marcescens, Nocardia, Aspergillus ("Cats Need PLACESS to Belch Hairballs"). Granuloma formation in bowel and urinary tract causing obstruction.

Autosomal dominant defect in SERPING1 gene encoding C1 esterase inhibitor. Unregulated activation of kallikrein leads to excessive production of BRADYKININ.

Decreased C4 level (best screening test); decreased C1 esterase inhibitor level or function; normal C1q in hereditary form (decreased in acquired).

Recurrent episodes of painless, non-pitting subcutaneous and mucosal edema involving the face, lips, larynx (airway obstruction danger), and GI tract (severe colicky abdominal pain mimicking acute abdomen). CRITICAL: Pruritus and urticaria are ABSENT (distinguishing it from histamine-mediated angioedema!). ACE inhibitors are STRICTLY CONTRAINDICATED (prevent bradykinin breakdown).

Inherited deficiency of complement components C5, C6, C7, C8, or C9, preventing formation of the Membrane Attack Complex (MAC).

Low or undetectable CH50 (total hemolytic complement) activity with normal AH50; normal individual early complement levels.

Recurrent invasive infections by Neisseria species: Neisseria meningitidis (meningococcemia, meningitis) and Neisseria gonorrhoeae (disseminated gonococcal infection).

Acquired somatic mutation in PIGA gene in hematopoietic stem cells, leading to deficiency of glycosylphosphatidylinositol (GPI) anchors. Cells lack CD55 (Decay-Accelerating Factor / DAF) and CD59 (MAC Inhibitory Protein / MIRL).

Flow cytometry demonstrating absence of CD55 and CD59 on RBCs and granulocytes; negative direct antiglobulin (Coombs) test; elevated LDH, indirect bilirubin, reticulocytosis, and low haptoglobin.

Classic triad: (1) Coombs-negative hemolytic anemia with nocturnal hemoglobinuria (dark morning urine due to slight nocturnal respiratory acidosis enhancing complement lysis), (2) Pancytopenia / aplastic anemia, and (3) Venous thrombosis at unusual sites (Budd-Chiari hepatic vein thrombosis, portal vein, cerebral sagittal sinus).