Fcps style questions on leukocytes adhesion defect and chediak higashi syndrome and chronic granulomatous disease. Key with explanation at the end

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FCPS-Style MCQs: Leukocyte Adhesion Defect (LAD), Chédiak-Higashi Syndrome (CHS), and Chronic Granulomatous Disease (CGD)

QUESTIONS

Q1. A 3-month-old boy presents with his third episode of bacterial skin infection (Staphylococcus aureus). His mother also noticed that his umbilical cord stump did not separate until he was 5 weeks old. His CBC shows a WBC of 28,000/μL even when he is not acutely infected. Peripheral blood smear shows normal-appearing neutrophils. Which of the following is the most likely underlying molecular defect?

A. Deficiency of NADPH oxidase membrane component (gp91phox)
B. Mutation in the β2 chain of CD11/CD18 integrins
C. Defect in LYST protein causing lysosomal trafficking abnormality
D. Deficiency of fucosyl transferase required for sialyl-Lewis X synthesis
E. Mutation in WASP gene affecting cytoskeletal signaling

Q2. A child with leukocyte adhesion deficiency type 1 (LAD-1) is evaluated. Which of the following laboratory or clinical findings is MOST characteristic of this condition?

A. Giant cytoplasmic granules on peripheral blood smear
B. Defective oxidative burst on nitroblue tetrazolium (NBT) test
C. Persistent leukocytosis even in the absence of acute infection
D. Silvery hair and partial oculocutaneous albinism
E. Thrombocytopenia with eczema

Q3. The integrins LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) share a common chain that is mutated in LAD-1. This shared chain is:

A. α1 chain
B. α2 chain
C. β2 chain
D. β1 chain
E. γ chain

Q4. A 2-year-old child is brought with recurrent pyogenic infections since infancy. Physical examination reveals partial albinism (silvery hair, light skin), and peripheral blood smear shows giant azurophilic granules in neutrophils. Which of the following best explains the pathogenesis of recurrent infections in this child?

A. Absent oxidative burst due to NADPH oxidase deficiency
B. Failure of leukocyte adhesion to endothelium due to absent CD18
C. Defective lysosomal fusion causing impaired phagocytic killing
D. Absent sialyl-Lewis X preventing rolling on selectins
D. Complement C3 deficiency preventing opsonization

Q5. In Chédiak-Higashi syndrome, the characteristic giant granules in leukocytes are best described as resulting from:

A. Excessive reactive oxygen species production
B. Failure of phagosome-lysosome fusion causing granule accumulation
C. Aberrant phagolysosome fusion leading to giant organelles
D. Defective neutrophil degranulation due to NADPH oxidase mutation
E. Excessive NFκB activation causing cytokine release

Q6. A child with Chédiak-Higashi syndrome suddenly develops high fever, hepatosplenomegaly, lymphadenopathy, and pancytopenia. This feared complication is best described as:

A. Transformation to acute leukemia
B. Hemophagocytic lymphohistiocytosis (accelerated phase)
C. Secondary amyloidosis
D. Graft-versus-host disease
E. Septic shock from Aspergillus infection

Q7. The gene mutated in Chédiak-Higashi syndrome encodes which protein?

A. gp91phox (NOX2)
B. Rac2 GTPase
C. LYST (lysosomal trafficking regulator)
D. MyD88 adaptor protein
E. CalDAG-GEF1

Q8. A 4-year-old boy presents with recurrent deep-seated infections with catalase-positive organisms (Staphylococcus aureus, Aspergillus, Klebsiella, Serratia, Nocardia). His mother is unaffected. NBT test shows no color change (negative). Which is the MOST likely inheritance pattern for this condition?

A. Autosomal dominant
B. X-linked dominant
C. X-linked recessive (defect in gp91phox)
D. Autosomal recessive (defect in cytoplasmic p47phox)
E. Mitochondrial inheritance

Q9. In chronic granulomatous disease (CGD), why are patients specifically susceptible to catalase-positive organisms rather than catalase-negative organisms (like Streptococcus)?

A. Catalase-negative organisms cannot survive inside phagolysosomes
B. Catalase-negative organisms generate their own hydrogen peroxide, which CGD phagocytes can still use for killing
C. Catalase-positive organisms have thicker capsules that resist complement
D. CGD patients lack IgG antibodies against catalase-negative organisms
E. Catalase-negative organisms are cleared by eosinophils

Q10. A child with CGD undergoes the dihydrorhodamine (DHR) flow cytometry test. What result is expected?

A. Normal oxidative burst with increased baseline fluorescence
B. Absent or markedly reduced shift to fluorescent rhodamine 123
C. Hyperactivation of neutrophil NADPH oxidase on stimulation
D. Increased neutrophil count with giant granules
E. Absent CD18 expression on flow cytometry

Q11. The granuloma formation seen in CGD occurs because:

A. Patients mount excessive IgE-mediated allergic responses
B. The neutrophil oxidative burst is hyperactivated
C. Macrophages attempt to wall off organisms the neutrophils failed to kill, forming chronic inflammatory collections
D. Complement activation leads to membrane attack complex deposition
E. T regulatory cells fail to suppress CD4+ T cell responses

Q12. Prophylactic itraconazole and trimethoprim-sulfamethoxazole are commonly used in CGD. Additionally, which immunomodulatory agent reduces the frequency of serious infections in CGD?

A. Intravenous immunoglobulin (IVIG)
B. Interferon-gamma (IFN-γ)
C. Anti-IL-17 therapy
D. Granulocyte colony stimulating factor (G-CSF)
E. Rituximab

Q13. LAD-2 differs from LAD-1 in that:

A. LAD-2 affects Mac-1 expression; LAD-1 affects LFA-1 only
B. LAD-2 results from a defect in fucosyl transferase, impairing synthesis of sialyl-Lewis X (ligand for selectins)
C. LAD-2 causes a defect in the oxidative burst rather than adhesion
D. LAD-2 is X-linked; LAD-1 is autosomal recessive
E. LAD-2 causes giant granules whereas LAD-1 causes absent CD18

Q14. Which of the following conditions presents with delayed umbilical cord separation, severe periodontitis, and recurrent skin and mucosal infections WITHOUT pus formation?

A. Chronic granulomatous disease
B. Chédiak-Higashi syndrome
C. Leukocyte adhesion deficiency type 1
D. Wiskott-Aldrich syndrome
E. Hyper-IgE (Job) syndrome

Q15. A peripheral blood smear from a child with partial albinism shows the finding illustrated below. This finding is MOST consistent with which condition?

(Giant azurophilic granules in neutrophils and other leukocytes)

A. LAD-1
B. Chronic granulomatous disease
C. Chédiak-Higashi syndrome
D. Myeloperoxidase deficiency
E. G6PD deficiency

ANSWER KEY WITH EXPLANATIONS

Answer 1: B - Mutation in the β2 chain of CD11/CD18 integrins

LAD-1 is caused by mutations in the gene encoding the β2 integrin chain (CD18), which is shared by LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18). Without functional integrins, neutrophils cannot adhere to and migrate through the vascular endothelium to sites of infection. Classic findings include:

Delayed umbilical cord separation (often >4 weeks; requires neutrophil-mediated inflammation for normal cord detachment)
Persistent leukocytosis (even between infections) because neutrophils cannot leave the circulation
Recurrent bacterial infections without pus
Normal neutrophil morphology on smear

Option A (gp91phox deficiency) is CGD. Option C (LYST defect) is Chédiak-Higashi. Option D (fucosyl transferase deficiency) is LAD-2.

(Robbins Basic Pathology; Goldman-Cecil Medicine)

Answer 2: C - Persistent leukocytosis even in the absence of acute infection

Because LAD-1 neutrophils cannot adhere to endothelium and marginate, they accumulate in the blood even when no acute infection is present, causing persistent leukocytosis. This is a hallmark distinguishing feature.

Giant granules (A) = Chédiak-Higashi
Defective NBT test (B) = CGD
Silvery hair/albinism (D) = Chédiak-Higashi
Thrombocytopenia + eczema (E) = Wiskott-Aldrich syndrome

Answer 3: C - β2 chain

LFA-1 = CD11a/CD18 and Mac-1 = CD11b/CD18. CD18 is the β2 chain shared by both integrins. A mutation in this single gene therefore eliminates function of both integrins simultaneously. CD11a and CD11b are the distinct α chains. LAD-1 is autosomal recessive.

Answer 4: C - Defective lysosomal fusion causing impaired phagocytic killing

The hallmark of Chédiak-Higashi syndrome is a mutation in LYST, a lysosomal trafficking regulator protein. This causes aberrant phagolysosome fusion, resulting in formation of giant granules and impaired delivery of lysosomal enzymes to phagosomes. Consequently, intracellular killing of bacteria is defective. The clinical triad is: (1) partial oculocutaneous albinism with silvery hair, (2) recurrent pyogenic infections, and (3) peripheral blood giant granules.

Answer 5: C - Aberrant phagolysosome fusion leading to giant organelles

In CHS, the LYST protein normally regulates lysosomal membrane trafficking. When LYST is defective, lysosomes fuse with each other abnormally and grow into giant granules (megagranules). These are seen in neutrophils, eosinophils, monocytes, and even melanocytes (causing enlarged melanosomes with pigment dilution). The neutrophil degranulation is impaired because these giant granules cannot properly fuse with phagosomes.

Answer 6: B - Hemophagocytic lymphohistiocytosis (accelerated phase)

The "accelerated phase" of CHS is a life-threatening hemophagocytic lymphohistiocytosis (HLH)-like episode driven by lymphohistiocytic infiltration of organs. It manifests as:

Pancytopenia
Hepatosplenomegaly
Lymphadenopathy
Fever

This complication is fatal without hematopoietic stem cell transplantation (HSCT), which is the definitive treatment. Survivors who are not transplanted develop progressive neurologic deterioration.

(Dermatology 2-Volume Set 5e; Robbins Basic Pathology)

Answer 7: C - LYST (lysosomal trafficking regulator)

The CHS gene encodes LYST (also called CHS1), a large cytosolic protein that regulates lysosomal trafficking. Its exact mechanism remains incompletely understood, but it is required for normal granule size regulation. Mutations in LYST cause the characteristic giant granules and defective organelle morphology in all granule-containing cells (leukocytes, melanocytes, neurons, platelets).

gp91phox (NOX2) = CGD (X-linked)
CalDAG-GEF1 = LAD-3
MyD88 = TLR signaling defect

Answer 8: C - X-linked recessive (defect in gp91phox)

CGD is X-linked in approximately 66% of cases, due to mutations in gp91phox (the membrane component of NADPH oxidase, encoded by the CYBB gene on the X chromosome). The affected boy, unaffected mother (carrier) pattern fits X-linked recessive. The remaining ~33% are autosomal recessive (mutations in p47phox, p67phox, p22phox, or p40phox - cytoplasmic components).

Key organisms in CGD: catalase-positive bacteria and fungi - S. aureus, Klebsiella, Serratia marcescens, Burkholderia cepacia, Nocardia, and Aspergillus.

Answer 9: B - Catalase-negative organisms generate their own hydrogen peroxide, which CGD phagocytes can still use for killing

This is a classic and high-yield concept. In normal phagocytes, NADPH oxidase generates superoxide → H₂O₂ → hypochlorous acid (via myeloperoxidase) to kill bacteria. In CGD, this oxidative burst is absent.

Catalase-negative organisms (e.g., Streptococcus, Pneumococcus) produce their own H₂O₂ as a metabolic byproduct and cannot neutralize it - so the residual H₂O₂ from the bacteria itself can still be used by CGD phagocytes (via MPO) to generate killing products.

Catalase-positive organisms produce catalase enzyme that destroys H₂O₂, so CGD phagocytes have no H₂O₂ available for killing and are defenseless against these organisms.

Answer 10: B - Absent or markedly reduced shift to fluorescent rhodamine 123

The dihydrorhodamine (DHR) assay is the standard diagnostic test for CGD. DHR 123 is a non-fluorescent dye that is oxidized to bright green fluorescent rhodamine 123 by the NADPH oxidase-derived reactive oxygen species. In CGD:

No/minimal oxidative burst → no DHR oxidation → no fluorescent shift on flow cytometry

The older NBT (nitroblue tetrazolium) test is also used: normal neutrophils reduce yellow NBT to purple formazan; CGD neutrophils cannot reduce it (test remains yellow/colorless).

Answer 11: C - Macrophages attempt to wall off organisms the neutrophils failed to kill

In CGD, neutrophils ingest organisms but cannot kill them due to the absent oxidative burst. The organisms persist inside phagolysosomes, triggering a persistent inflammatory signal. Macrophages are recruited and attempt to contain the infection, but since they too have defective killing, they form granulomas - collections of activated macrophages attempting to wall off the microbes. This is how the disease got its name: "chronic granulomatous disease."

Answer 12: B - Interferon-gamma (IFN-γ)

A landmark controlled trial showed that recombinant IFN-γ reduces the frequency of serious infections in CGD by approximately 70%. The mechanism is thought to involve upregulation of residual NADPH oxidase activity and enhancement of non-oxidative killing pathways.

Standard prophylaxis in CGD includes:

Trimethoprim-sulfamethoxazole (bacterial prophylaxis)
Itraconazole (fungal prophylaxis, especially against Aspergillus)
IFN-γ (immunomodulation)
HSCT is curative but reserved for severe cases

Answer 13: B - LAD-2 results from a defect in fucosyl transferase, impairing synthesis of sialyl-Lewis X

Leukocyte recruitment to sites of infection involves two steps:

Rolling - mediated by selectins binding sialyl-Lewis X (on leukocyte surface)
Firm adhesion - mediated by integrins (LFA-1/Mac-1) binding ICAM-1

LAD-1: defect in β2 integrin (CD18) → impaired firm adhesion
LAD-2: defect in fucosyl transferase → absent sialyl-Lewis X → impaired rolling on selectins

LAD-2 is therefore a defect in the earlier step (rolling), while LAD-1 is a defect in firm adhesion. Both are autosomal recessive.

(Robbins Basic Pathology; Cellular & Molecular Immunology)

Answer 14: C - Leukocyte adhesion deficiency type 1

The triad of:

Delayed umbilical cord separation (>3-4 weeks)
Recurrent bacterial infections without pus formation (neutrophils cannot leave the blood to form pus)
Severe periodontitis

...is pathognomonic for LAD-1. The absence of pus is a cardinal distinguishing feature - even when there is tissue infection, no neutrophil infiltrate can form because neutrophils are stuck in the bloodstream.

Answer 15: C - Chédiak-Higashi syndrome

Giant azurophilic (bluish) granules in neutrophils, eosinophils, and other granule-containing leukocytes on peripheral blood smear are the hallmark of Chédiak-Higashi syndrome, resulting from aberrant fusion of lysosomes into giant organelles due to LYST protein deficiency. This finding, combined with silvery hair and partial albinism, is diagnostic.

Quick Summary Table

Feature	LAD-1	Chédiak-Higashi	CGD
Gene/protein	β2 integrin (CD18)	LYST	gp91phox (X-linked), p47phox (AR)
Mechanism	Defective firm adhesion	Defective lysosomal trafficking	Defective oxidative burst (NADPH oxidase)
Organisms	Bacteria (extracellular)	Catalase+ bacteria, fungi	Catalase+ (S. aureus, Aspergillus, Serratia, Nocardia)
Key finding	Persistent leukocytosis, no pus	Giant granules + albinism + silvery hair	Granuloma formation
Cord separation	Delayed	Normal	Normal
Diagnostic test	CD18 flow cytometry	Peripheral smear	NBT test / DHR assay
Smear	Normal	Giant granules	Normal
Feared complication	Overwhelming sepsis	Accelerated phase (HLH)	Invasive Aspergillosis
Treatment	HSC transplant	HSCT (curative)	IFN-γ, TMP-SMX, itraconazole; HSCT curative

And MPO deficiency

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FCPS-Style MCQs: Myeloperoxidase (MPO) Deficiency

QUESTIONS

Q1. A 35-year-old man with poorly controlled type 2 diabetes mellitus presents with recurrent Candida infections of the skin and mucous membranes. His peripheral blood smear shows normal neutrophil morphology. NBT (nitroblue tetrazolium) test is normal. A special peroxidase stain of his neutrophils shows absent staining. Which of the following is the most likely diagnosis?

A. Chronic granulomatous disease
B. Leukocyte adhesion deficiency type 1
C. Myeloperoxidase deficiency
D. Chédiak-Higashi syndrome
E. Specific granule deficiency

Q2. Myeloperoxidase (MPO) deficiency is inherited as which pattern, and what is its approximate incidence?

A. X-linked recessive; 1 in 100,000
B. Autosomal recessive; 1 in 2,000
C. Autosomal dominant; 1 in 50,000
D. X-linked dominant; 1 in 5,000
E. Mitochondrial; 1 in 10,000

Q3. Myeloperoxidase normally converts hydrogen peroxide (H₂O₂) into which potent microbicidal agent?

A. Superoxide (O₂•⁻)
B. Hydroxyl radical (OH•)
C. Hypochlorous acid (HOCl)
D. Nitric oxide (NO)
E. Hydrogen peroxide (H₂O₂) itself

Q4. In which of the following clinical scenarios is MPO deficiency most likely to become symptomatic?

A. A healthy 10-year-old child with recurrent Staphylococcal skin abscesses
B. A 45-year-old HIV-positive patient on antiretrovirals
C. A 50-year-old patient with uncontrolled diabetes mellitus who develops disseminated candidiasis
D. A neonate with delayed umbilical cord separation
E. A teenager with partial albinism and silvery hair

Q5. A blood sample from a patient with suspected MPO deficiency is run through an automated CBC analyzer. Which of the following instrument artefacts may be observed?

A. Falsely elevated platelet count due to platelet clumping
B. Neutrophils classified as "large unstained cells" (LUC), falsely lowering the monocyte count
C. Falsely decreased WBC count due to cell lysis
D. Giant granules falsely elevating the eosinophil count
E. Elevated immature granulocyte count

Q6. In MPO deficiency, the NBT (nitroblue tetrazolium) test result is:

A. Negative (no color change) - same as CGD
B. Positive (normal purple formazan formation)
C. Weakly positive only with PMA stimulation
D. Negative only with bacterial challenge
E. Indeterminate due to giant granules

Q7. Which of the following best distinguishes MPO deficiency from chronic granulomatous disease (CGD)?

A. Both conditions have absent NBT test
B. MPO deficiency has normal NADPH oxidase function with absent MPO staining; CGD has defective NADPH oxidase with absent oxidative burst
C. MPO deficiency causes granuloma formation; CGD does not
D. MPO deficiency is X-linked; CGD is autosomal recessive
E. MPO deficiency presents with delayed cord separation; CGD does not

Q8. The role of myeloperoxidase in the neutrophil killing cascade is best described as:

A. First step - generates superoxide from NADPH
B. Second step - converts superoxide to H₂O₂ via superoxide dismutase
C. Third step - uses H₂O₂ and Cl⁻ to generate HOCl (bleach), the most potent microbicidal molecule in the cascade
D. Final step - activates complement to opsonize bacteria
E. Initiates neutrophil rolling on the endothelium

Q9. Most patients with MPO deficiency are asymptomatic because:

A. They have compensatory upregulation of the alternative complement pathway
B. They have enhanced T-cell cytotoxicity
C. Their NADPH oxidase remains intact, generating sufficient H₂O₂ and other ROS to kill most organisms even without MPO
D. They have higher baseline IgG levels
E. Their macrophages compensate entirely for neutrophil dysfunction

Q10. Which of the following organisms is particularly problematic in symptomatic MPO deficiency?

A. Pseudomonas aeruginosa
B. Candida species and Staphylococcus aureus
C. Neisseria meningitidis
D. Streptococcus pneumoniae
E. Mycobacterium tuberculosis

ANSWER KEY WITH EXPLANATIONS

Answer 1: C - Myeloperoxidase deficiency

The key clues here are:

Recurrent Candida infections in a diabetic patient - diabetes unmasks latent MPO deficiency
Normal NBT test - rules out CGD (CGD has a negative/absent NBT)
Normal neutrophil morphology on smear - rules out Chédiak-Higashi (which has giant granules)
Absent peroxidase staining of neutrophils - diagnostic of MPO deficiency

MPO deficiency is the most common inherited neutrophil defect, occurring in approximately 1 in 2,000 persons. The vast majority are clinically silent. Symptoms emerge mainly when another immunocompromising condition (especially diabetes mellitus) is present.

(Harrison's Principles of Internal Medicine 22E)

Answer 2: B - Autosomal recessive; 1 in 2,000

MPO deficiency is inherited as autosomal recessive due to mutations in the MPO gene. It is the most common inherited phagocyte defect with an incidence of approximately 1 in 2,000 persons - far more common than CGD or Chédiak-Higashi syndrome. Despite its relatively high prevalence, it is usually clinically silent, which is why it is often an incidental finding on automated CBC analyzers.

Answer 3: C - Hypochlorous acid (HOCl)

The MPO-halide system is the most potent arm of neutrophil killing:

H₂O₂ + Cl⁻ → HOCl (hypochlorous acid) + OH⁻

HOCl is essentially bleach - it is bactericidal, fungicidal, and virucidal. It denatures proteins, destroys membranes, and inactivates enzymes of pathogens. Without MPO, this step is absent, though upstream H₂O₂ production (via NADPH oxidase → superoxide → H₂O₂) remains intact.

The sequence of the oxidative burst:

NADPH oxidase → superoxide (O₂•⁻)
Superoxide dismutase → H₂O₂
MPO + Cl⁻ → HOCl (most microbicidal)

Answer 4: C - A 50-year-old patient with uncontrolled diabetes mellitus who develops disseminated candidiasis

MPO deficiency is normally clinically silent because the rest of the NADPH oxidase pathway remains intact and is sufficient for killing most organisms. However, when a second immunodeficiency is added - particularly diabetes mellitus - the combination results in serious fungal infections, especially disseminated Candida infections.

Diabetes impairs multiple arms of immunity (T-cell function, complement, neutrophil function). When superimposed on MPO deficiency, the already-compromised anti-Candida defense fails completely.

(Tietz Textbook of Laboratory Medicine; Harrison's)

Answer 5: B - Neutrophils classified as "large unstained cells" (LUC), falsely lowering the monocyte count

Automated CBC analyzers use peroxidase staining to classify leukocytes. In MPO-deficient patients, neutrophils lack peroxidase activity and therefore fail to stain - the analyzer misclassifies them as "large unstained cells" (LUC) rather than neutrophils, which can artificially lower the monocyte count (since LUC and monocytes occupy similar channels). This is a well-recognized laboratory artefact and can actually be one of the first clues that leads to the diagnosis of MPO deficiency.

(Tietz Textbook of Laboratory Medicine)

Answer 6: B - Positive (normal purple formazan formation)

This is a high-yield distinction:

Test	MPO Deficiency	CGD
NBT test	Normal (positive - purple formazan)	Absent (yellow - no color change)
Oxidative burst	Intact (NADPH oxidase works)	Absent
MPO staining	Absent	Normal
DHR assay	Normal fluorescent shift	No/minimal shift

In MPO deficiency, NADPH oxidase generates superoxide and H₂O₂ normally. The NBT test depends on superoxide production (not MPO), so the NBT is normal. The defect is only in the downstream HOCl generation step.

Answer 7: B - MPO deficiency has normal NADPH oxidase; CGD has defective NADPH oxidase

This comparison is essential:

MPO deficiency: NADPH oxidase intact → normal superoxide and H₂O₂ production → NBT normal → MPO absent → no HOCl generation. Usually asymptomatic; Candida/S. aureus infections when diabetic.
CGD: NADPH oxidase absent/defective → no superoxide, no H₂O₂ → NBT negative → susceptible to all catalase-positive organisms; granuloma formation.

MPO deficiency does NOT cause granulomas (that is CGD's hallmark). MPO deficiency is NOT X-linked (it is AR; CGD is 66% X-linked). Delayed cord separation is LAD, not MPO deficiency.

Answer 8: C - Third step - uses H₂O₂ and Cl⁻ to generate HOCl

The full neutrophil killing cascade:

NADPH oxidase (membrane gp91phox + cytoplasmic p47phox/p67phox) → reduces O₂ to superoxide (O₂•⁻)
Superoxide dismutase (SOD) → converts O₂•⁻ to H₂O₂
Myeloperoxidase (MPO) + Cl⁻ → converts H₂O₂ to HOCl (most potent microbicidal product)

MPO is located in the primary (azurophilic) granules of neutrophils. When phagolysosomes form, MPO is delivered into the phagosome where it catalyzes the HOCl reaction, directly killing ingested microbes.

Answer 9: C - NADPH oxidase remains intact, generating sufficient H₂O₂ and other ROS

Although HOCl production is absent in MPO deficiency, the upstream pathway (NADPH oxidase → superoxide → H₂O₂) is fully functional. H₂O₂ itself and other reactive oxygen species can still kill most common bacteria directly. Additionally, non-oxidative killing mechanisms (defensins, elastase, lactoferrin, cathepsins in secondary granules) remain intact. This multi-layered redundancy explains why most MPO-deficient individuals live completely normal lives and are never diagnosed unless an automated CBC reveals the peroxidase-staining anomaly.

Answer 10: B - Candida species and Staphylococcus aureus

When MPO deficiency becomes symptomatic (usually in the context of diabetes), the organisms responsible are Candida spp. (especially C. albicans) and Staphylococcus aureus. Candida killing is particularly MPO-dependent - HOCl is especially important against fungi. S. aureus is also a classic target.

This contrasts with:

CGD: catalase-positive organisms (S. aureus, Aspergillus, Serratia, Klebsiella, Nocardia, Burkholderia cepacia)
LAD: extracellular bacteria (S. aureus, gram-negatives)
CHS: pyogenic bacteria (S. aureus, Streptococcus)
Terminal complement deficiency (C5-C9): Neisseria species

Updated Summary Table (All Four Conditions)

Feature	LAD-1	Chédiak-Higashi	CGD	MPO Deficiency
Gene/protein	CD18 (β2 integrin)	LYST	gp91phox (XLR) / p47phox (AR)	MPO gene
Inheritance	AR	AR	X-linked (66%), AR (33%)	AR
Incidence	Rare	Very rare (~300 worldwide)	Rare	1 in 2,000 (most common)
Mechanism	No firm adhesion	Defective lysosomal trafficking → giant granules	No oxidative burst (no NADPH oxidase)	No HOCl generation (NADPH oxidase intact)
NBT/DHR test	Normal	Normal	Abnormal (negative)	Normal
MPO staining	Normal	Normal	Normal	Absent
Blood smear	Normal	Giant granules	Normal	Normal
Cord separation	Delayed	Normal	Normal	Normal
Key organisms	Bacteria (no pus)	S. aureus, fungi	S. aureus, Aspergillus, Serratia, Nocardia	Candida, S. aureus (only if diabetic)
Clinical course	Severe	Severe + HLH	Moderate-severe	Usually asymptomatic
Granulomas	No	No	Yes	No
Albinism	No	Yes (silvery hair)	No	No
Treatment	HSCT	HSCT (curative)	IFN-γ, TMP-SMX, itraconazole; HSCT	Treat underlying disease (e.g. diabetes)

The single most testable fact about MPO deficiency: It is the most common inherited neutrophil defect, usually asymptomatic, with a normal NBT test (unlike CGD), and becomes clinically apparent mainly in diabetic patients who develop Candida infections.

FCPS style questions on Digeorge syndrome, SCID, X linked agammaglobulinemia, CVID, IgA deficiency, Hyper IgM syndrome, Wiskott Aldrich syndrome and complement deficiencies

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FCPS-Style MCQs: Primary Immunodeficiencies

DiGeorge Syndrome | SCID | XLA | CVID | IgA Deficiency | Hyper-IgM | Wiskott-Aldrich | Complement Deficiencies

QUESTIONS

SECTION A: DiGeorge Syndrome

Q1. A neonate presents on day 2 of life with hypocalcaemic tetany. Chest X-ray shows absence of thymic shadow. Echocardiography reveals a truncus arteriosus. Which chromosomal deletion is responsible?

A. 11q23 deletion
B. 22q11.2 deletion
C. 17p13 deletion
D. 7q11 deletion
E. 5p deletion

Q2. In DiGeorge syndrome, the immunological defect results from failure of development of which embryological structure?

A. Bone marrow stem cells
B. 3rd and 4th pharyngeal pouches
C. Bursa of Fabricius equivalent
D. Common lymphoid progenitor in fetal liver
E. 1st and 2nd branchial arches

Q3. A 3-month-old with DiGeorge syndrome develops severe oral candidiasis and Pneumocystis jirovecii pneumonia. Which of the following best explains the susceptibility to these organisms?

A. Absent B cells with normal T cells
B. Absent antibodies due to BTK mutation
C. Absent thymus leading to T cell deficiency with preserved B cells
D. Absent NADPH oxidase
E. Complement C3 deficiency

Q4. A child with complete DiGeorge syndrome has which of the following immunological profile?

A. Low T cells, normal/elevated B cells, low immunoglobulins
B. Low T cells, low B cells, normal NK cells
C. Normal T cells, absent B cells, absent immunoglobulins
D. Low T cells, low B cells, low NK cells (T-B-NK-)
E. Normal T and B cells, absent NK cells

Q5. The treatment of choice for complete DiGeorge syndrome (total athymia) is:

A. Monthly IVIG infusions
B. Hematopoietic stem cell transplantation
C. Thymic transplantation
D. Prophylactic co-trimoxazole alone
E. Gene therapy targeting TBX1

SECTION B: Severe Combined Immunodeficiency (SCID)

Q6. A 4-month-old male infant presents with failure to thrive, recurrent oral candidiasis, Pneumocystis jirovecii pneumonia, and persistent diarrhea. A lymphocyte count is severely reduced. This presentation is most consistent with which diagnosis?

A. X-linked agammaglobulinemia
B. Severe combined immunodeficiency
C. DiGeorge syndrome
D. Wiskott-Aldrich syndrome
E. Common variable immunodeficiency

Q7. The most common form of X-linked SCID is caused by a mutation in the gene encoding:

A. RAG1/RAG2 recombinase
B. Adenosine deaminase (ADA)
C. Common gamma chain (γc) of cytokine receptors (IL2RG)
D. JAK3 kinase
E. ZAP-70

Q8. X-linked SCID has which lymphocyte profile?

A. T- B- NK-
B. T- B+ NK-
C. T- B+ NK+
D. T+ B- NK+
E. T+ B+ NK-

Q9. A child with SCID from adenosine deaminase (ADA) deficiency has which of the following as the primary mechanism of lymphocyte death?

A. Failure of VDJ recombination in lymphocyte precursors
B. Accumulation of deoxyadenosine and dATP which is toxic to lymphocytes (especially T cells)
C. Absent common gamma chain causing failure of IL-7 signaling
D. Failure of calcium-mediated T cell activation
E. Loss of RAG1 preventing TCR gene rearrangement

Q10. A 6-month-old infant with SCID receives a live attenuated rotavirus vaccine. What is the expected consequence?

A. Normal vaccine response with protective immunity
B. Mild transient diarrhea only
C. Disseminated vaccine-strain infection (vaccine-derived disease)
D. Anaphylaxis due to absent IgE
E. Autoimmune hepatitis

Q11. The definitive treatment for most forms of SCID is:

A. Monthly IVIG infusions
B. Bone marrow / hematopoietic stem cell transplantation
C. Thymic transplantation
D. Interferon-gamma therapy
E. Corticosteroid-sparing immunosuppression

SECTION C: X-Linked Agammaglobulinemia (XLA)

Q12. A 9-month-old male infant who was well in early infancy begins developing recurrent otitis media, sinusitis, and pneumonia caused by Streptococcus pneumoniae and Haemophilus influenzae. His tonsils are absent on examination. Serum immunoglobulins are undetectable. This is most consistent with:

A. SCID
B. X-linked agammaglobulinemia (XLA)
C. DiGeorge syndrome
D. Common variable immunodeficiency
E. IgA deficiency

Q13. The molecular defect in XLA (Bruton's agammaglobulinemia) results in arrest of B cell maturation at which stage?

A. Stem cell to pro-B cell
B. Pro-B cell to pre-B cell
C. Pre-B cell stage (failure to progress to immature B cell)
D. Immature B cell to naive B cell
E. Naive B cell to plasma cell

Q14. Which of the following is the affected gene/protein in XLA?

A. Common gamma chain (IL2RG)
B. RAG1/RAG2
C. Bruton's Tyrosine Kinase (BTK)
D. CD40 ligand (CD154)
E. WASP protein

Q15. Why are infants with XLA typically well during the first 6 months of life?

A. Maternal T cells cross the placenta and provide protection
B. Maternal IgG crosses the placenta and provides passive immunity
C. Fetal immunoglobulin production compensates until 6 months
D. NK cells provide sufficient immunity in early infancy
E. Complement system is fully functional from birth

Q16. Which of the following organisms causes a unique and disproportionately severe, often fatal, complication in XLA patients?

A. Candida albicans
B. Aspergillus fumigatus
C. Enterovirus (echovirus, coxsackievirus)
D. Mycobacterium tuberculosis
E. Pneumocystis jirovecii

SECTION D: Common Variable Immunodeficiency (CVID)

Q17. A 28-year-old woman presents with recurrent sinopulmonary infections since her teens, chronic diarrhea, and splenomegaly. Serum IgG, IgA, and IgM are all markedly reduced. She has normal numbers of B cells in the peripheral blood. Which is the most likely diagnosis?

A. X-linked agammaglobulinemia
B. Common variable immunodeficiency
C. Hyper-IgM syndrome
D. IgA deficiency
E. Wiskott-Aldrich syndrome

Q18. CVID differs from XLA in which of the following ways?

A. CVID affects only males; XLA affects both sexes equally
B. CVID presents in infancy; XLA presents in adulthood
C. CVID has normal or near-normal numbers of circulating B cells that fail to differentiate into plasma cells; XLA has absent B cells
D. CVID has absent T cells; XLA has normal T cells
E. CVID is caused by BTK mutation; XLA has an unknown genetic cause

Q19. A duodenal biopsy from a CVID patient shows which characteristic finding?

A. Villous atrophy with intraepithelial lymphocytes (celiac-like pattern) with absent plasma cells
B. Lymphoid follicular hyperplasia with abundant plasma cells
C. Non-caseating granulomas with normal plasma cell numbers
D. Crypt abscesses with neutrophilic infiltrate
E. Normal mucosa

Q20. Which malignancy is CVID patients at significantly increased risk for?

A. Acute myeloid leukemia
B. Hepatocellular carcinoma
C. B-cell lymphoma and gastric cancer
D. Squamous cell carcinoma of the skin
E. Neuroblastoma

SECTION E: Selective IgA Deficiency

Q21. The most common primary immunodeficiency in the general population is:

A. X-linked agammaglobulinemia
B. CVID
C. Selective IgA deficiency
D. Hyper-IgM syndrome
E. DiGeorge syndrome

Q22. A 25-year-old woman donates blood. During pre-transfusion testing, her serum IgA level is found to be undetectable. She has a history of mild recurrent respiratory infections. Which serious transfusion complication is she at risk of developing if she receives blood products containing IgA?

A. Hemolytic transfusion reaction
B. Transfusion-associated circulatory overload (TACO)
C. Anaphylactic reaction due to anti-IgA antibodies
D. Febrile non-hemolytic transfusion reaction
E. Graft-versus-host disease

Q23. Selective IgA deficiency is defined as a serum IgA level of:

A. Less than 50 mg/dL with normal IgG and IgM
B. Less than 7 mg/dL (or undetectable) with normal IgG and IgM in a patient over age 4 years
C. Absent IgA and IgM with normal IgG
D. Less than 100 mg/dL with reduced IgG
E. Undetectable IgA in a child under 2 years of age

Q24. IgA deficiency is associated with increased susceptibility to which of the following autoimmune conditions?

A. Rheumatoid arthritis and Type 1 diabetes mellitus only
B. Coeliac disease, SLE, and rheumatoid arthritis
C. Multiple sclerosis and Crohn's disease
D. Ankylosing spondylitis and Reiter's syndrome
E. Polymyositis and dermatomyositis

SECTION F: Hyper-IgM Syndrome

Q25. A 2-year-old boy presents with recurrent Pneumocystis jirovecii pneumonia and Cryptosporidium cholangitis. Serum immunoglobulins reveal markedly elevated IgM but absent IgG, IgA, and IgE. This presentation is most consistent with:

A. X-linked agammaglobulinemia
B. SCID
C. Hyper-IgM syndrome (X-linked, CD40L deficiency)
D. Common variable immunodeficiency
E. Selective IgA deficiency

Q26. X-linked Hyper-IgM syndrome is caused by a defect in which molecule?

A. Bruton's tyrosine kinase (BTK)
B. CD40 ligand (CD154) on T cells
C. CD40 on B cells
D. WASP protein
E. RAG2 recombinase

Q27. Why does Hyper-IgM syndrome cause susceptibility to Pneumocystis jirovecii and Cryptosporidium (typically opportunistic infections of T cell deficiency)?

A. CD40L deficiency prevents isotype switching only, leaving T cell function intact
B. CD40L is expressed on T cells; its deficiency impairs T cell activation of macrophages via CD40, resulting in defective cell-mediated immunity in addition to absent isotype switching
C. IgM cannot opsonize intracellular organisms
D. Elevated IgM blocks complement activation
E. BTK deficiency also impairs macrophage function

Q28. In Hyper-IgM syndrome, immunoglobulin class switching fails because:

A. B cells cannot produce RNA transcripts for IgG, IgA, or IgE
B. T cells cannot express CD40L, which is required to deliver the CD40 signal on B cells needed for germinal center reactions and class-switch recombination
C. AID (activation-induced cytidine deaminase) is absent
D. There is no IL-4 or IL-13 signaling
E. B cells cannot enter lymph node germinal centers due to absent CXCR5

SECTION G: Wiskott-Aldrich Syndrome

Q29. A 1-year-old male presents with the classic triad of eczema, thrombocytopenia, and recurrent infections. Platelets are small on blood smear. Which is the most likely diagnosis?

A. Hyper-IgM syndrome
B. Wiskott-Aldrich syndrome
C. DiGeorge syndrome
D. CVID
E. Chédiak-Higashi syndrome

Q30. The WASP (Wiskott-Aldrich Syndrome Protein) is expressed in which cells, and its primary role is:

A. All nucleated cells; transcription factor for immunoglobulin genes
B. Exclusively in bone marrow-derived hematopoietic cells; links antigen receptor signaling to cytoskeletal reorganization (actin polymerization)
C. T cells only; mediates VDJ recombination
D. B cells only; required for isotype class switching
E. Megakaryocytes only; mediates platelet production

Q31. In early Wiskott-Aldrich syndrome, what is the earliest antibody production defect?

A. Inability to produce any immunoglobulin class
B. Inability to produce antibodies against T cell-independent polysaccharide antigens (encapsulated bacteria)
C. Absent IgG with normal IgM
D. Inability to make IgE causing no allergic responses
E. Absent isotype class switching

Q32. The immunoglobulin profile in Wiskott-Aldrich syndrome typically shows:

A. Elevated IgM, absent IgG, IgA, IgE
B. Low IgM, normal or elevated IgA and IgE, variable IgG
C. Absent all immunoglobulin classes
D. Normal all immunoglobulin classes
E. Elevated IgE only

Q33. Patients with Wiskott-Aldrich syndrome have a significantly increased risk of developing which malignancy?

A. Neuroblastoma
B. EBV-associated lymphoma (B-cell lymphoma)
C. Wilms tumor
D. Acute myeloid leukemia
E. Rhabdomyosarcoma

SECTION H: Complement Deficiencies

Q34. A young adult presents with recurrent episodes of Neisseria meningitidis meningitis (third episode). There is no other immunodeficiency. Which complement deficiency is most likely?

A. C1q deficiency
B. C2 deficiency
C. C3 deficiency
D. Deficiency of terminal complement components (C5-C9)
E. Properdin deficiency

Q35. C2 deficiency is the most common complement deficiency. It is associated with:

A. Recurrent Neisseria infections only
B. Severe pyogenic infections and an SLE-like autoimmune disease
C. Angioedema due to uncontrolled C1 activation
D. Recurrent Staphylococcal infections
E. Hereditary hemolytic uremic syndrome

Q36. A child presents with recurrent life-threatening pyogenic infections with encapsulated bacteria (S. pneumoniae, H. influenzae, Klebsiella) from early infancy. Serum complement studies show very low CH50, very low AH50, and undetectable C3 levels. Which is the most likely diagnosis?

A. C2 deficiency
B. C3 deficiency
C. Terminal complement deficiency (C5-C9)
D. Mannose-binding lectin deficiency
E. C1 inhibitor deficiency

Q37. C1q deficiency is specifically associated with which autoimmune disease, and what is the mechanism?

A. Ankylosing spondylitis; C1q triggers HLA-B27 autoimmunity
B. SLE; C1q is required for clearance of apoptotic cell debris and immune complexes - its absence leads to accumulation triggering autoimmunity
C. Rheumatoid arthritis; C1q opsonizes joint synovium
D. Type 1 diabetes mellitus; C1q prevents molecular mimicry
E. Wegener's granulomatosis; C1q suppresses ANCA production

Q38. A 25-year-old man presents with recurrent episodes of non-pitting facial and laryngeal swelling without urticaria. C4 levels are consistently low. C1q levels are normal. C1 inhibitor level is low. Which is the most likely diagnosis?

A. Selective IgA deficiency
B. C2 deficiency
C. Hereditary angioedema (C1 inhibitor deficiency)
D. C3 deficiency
E. Properdin deficiency

Q39. The CH50 assay (total hemolytic complement) tests which complement pathway?

A. Alternate pathway only
B. Lectin pathway only
C. Classical pathway only
D. Classical pathway (C1 through C9 - all components needed for complete lysis)
E. Common terminal pathway (C5-C9) only

Q40. A child with frequent Streptococcus pneumoniae bacteremia is found to have very low C3 levels with normal C1q, C2, and C4. Normal factor B and factor D. This pattern is most consistent with:

A. Classical pathway deficiency
B. Isolated C3 deficiency
C. Alternative pathway deficiency
D. C1 inhibitor deficiency
E. Terminal pathway deficiency

ANSWER KEY WITH EXPLANATIONS

SECTION A: DiGeorge Syndrome

Answer 1: B - 22q11.2 deletion

DiGeorge syndrome is caused by a 22q11.2 deletion (most commonly a 3-Mb hemizygous deletion), which affects the TBX1 gene. It is part of the broader 22q11.2 deletion syndrome (velocardiofacial syndrome, conotruncal anomaly face syndrome). The classic triad is:

Hypoparathyroidism (hypocalcemia, tetany)
Thymic aplasia/hypoplasia (T cell immunodeficiency)
Conotruncal cardiac defects (truncus arteriosus, tetralogy of Fallot, interrupted aortic arch)

It is autosomal dominant but most cases arise as de novo mutations. Remember: CATCH-22 - Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia, 22q11.

(Goldman-Cecil Medicine)

Answer 2: B - 3rd and 4th pharyngeal pouches

The thymus and parathyroid glands both develop from the 3rd and 4th pharyngeal (branchial) pouches. In DiGeorge syndrome, failure of normal migration and development of these pouches results in thymic aplasia (no T cell maturation) and absent/hypoplastic parathyroids (hypocalcemia). The cardiac outflow tract defects arise from abnormal migration of neural crest cells from the same region.

Answer 3: C - Absent thymus leading to T cell deficiency with preserved B cells

DiGeorge syndrome is a primary T cell deficiency. Without the thymus, T cell precursors cannot mature into functional T cells. Since T cells are required for:

Cell-mediated immunity (Candida, PCP, intracellular pathogens)
T-dependent B cell activation (antibody class switching)

...patients are susceptible to both fungal/opportunistic infections and eventually humoral immune failure. B cells are present in the periphery (they mature in bone marrow, not thymus) but function is impaired due to absent T cell help.

Answer 4: A - Low T cells, normal/elevated B cells, low immunoglobulins

In DiGeorge syndrome: T cells are low/absent (no thymus for maturation), B cells are present (mature independently in bone marrow), but immunoglobulins are eventually low because B cells need T cell help (CD40L-CD40 interaction) for class switching and affinity maturation. NK cells are relatively preserved. Complete DiGeorge (T-B+NK+) is the typical immunophenotype.

(Compare to X-SCID: T-B+NK- ; ADA-SCID: T-B-NK-)

Answer 5: C - Thymic transplantation

The treatment of choice for complete DiGeorge syndrome (total athymia) is thymic transplantation (using cultured postnatal thymic tissue). This allows T cell precursors to migrate to the graft and mature into functional T cells. IVIG is used adjunctively for antibody replacement but does not correct the underlying T cell defect. HSCT does not reconstitute thymic function and is generally not the treatment for complete DiGeorge.

SECTION B: SCID

Answer 6: B - Severe combined immunodeficiency

The key features pointing to SCID are:

Age of onset ~4 months (after maternal IgG wanes)
Combined B and T cell failure - fungal (Candida, PCP) AND bacterial infections
Failure to thrive
Markedly reduced lymphocytes

XLA presents later (6-9 months), mainly with bacterial infections, without fungal/PCP infections. CVID presents in adulthood/teens. DiGeorge has cardiac and hypocalcemia features. WAS has the classic triad with thrombocytopenia.

Answer 7: C - Common gamma chain (γc) of cytokine receptors (IL2RG)

X-linked SCID (the most common form of SCID) is caused by mutations in IL2RG, encoding the common gamma chain (γc), which is shared by receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Loss of γc means:

No IL-7 signaling → no T cell development
No IL-15 signaling → no NK cell development
B cells develop but are non-functional without T cell help

This produces the T-B+NK- phenotype.

Answer 8: B - T- B+ NK-

X-linked SCID (γc chain deficiency) phenotype = T- B+ NK-

T cells absent: no IL-7 signaling via γc
B cells present: B cells develop in bone marrow independent of γc, but are non-functional
NK cells absent: IL-15 (which uses γc) is essential for NK development

Other SCID phenotypes:

Type	T	B	NK
X-linked (IL2RG)	-	+	-
JAK3 deficiency	-	+	-
ADA deficiency	-	-	-
RAG1/2 deficiency	-	-	+
IL-7Rα deficiency	-	+	+

Answer 9: B - Accumulation of deoxyadenosine and dATP toxic to lymphocytes

ADA (adenosine deaminase) is involved in purine salvage. In its absence, deoxyadenosine and its metabolite dATP accumulate. dATP is particularly toxic to lymphocytes (especially T cells) because it inhibits ribonucleotide reductase, blocks DNA synthesis, and induces apoptosis. T cells are most affected because they have high ADA requirements for proliferation. ADA-SCID produces a T-B-NK- phenotype. This is unique because all lymphocyte lineages are affected, unlike most SCID forms.

Answer 10: C - Disseminated vaccine-strain infection

SCID patients have an absolute contraindication to all live attenuated vaccines (oral rotavirus, BCG, varicella, MMR, live influenza). Without functional T and B cells, the vaccine strain cannot be cleared and causes progressive, disseminated, fatal infection. BCG vaccination in undiagnosed SCID causes disseminated BCG disease. This is why SCID is a pediatric emergency - if missed at birth, a routine vaccine can be fatal.

(Goldman-Cecil Medicine, SCID table)

Answer 11: B - Hematopoietic stem cell transplantation

HSCT (bone marrow/stem cell transplant) is the only curative treatment for most forms of SCID. The donor HSCs populate the bone marrow and reconstitute all lymphocyte lineages. Ideally done before 3.5 months of age (before serious infections). For ADA-SCID specifically, enzyme replacement therapy (PEG-ADA) and gene therapy are also options. IVIG provides passive protection temporarily but does not cure the disease.

SECTION C: X-Linked Agammaglobulinemia

Answer 12: B - X-linked agammaglobulinemia

Key diagnostic features of XLA:

Male infant, healthy in first 6 months (protected by maternal IgG)
Recurrent pyogenic bacterial infections after 6 months (S. pneumoniae, H. influenzae, Pseudomonas)
Absent tonsils and lymph nodes (no germinal centers, no B cells)
Undetectable all Ig classes (pan-agammaglobulinemia)
Infections are typically bacterial, NOT fungal/viral (T cells are intact)

SCID presents earlier (3-4 months) with fungal infections also. CVID presents in teens/adulthood. DiGeorge has cardiac/hypocalcemia. IgA deficiency is usually mild.

Answer 13: C - Pre-B cell stage (failure to progress to immature B cell)

BTK is essential for signal transduction from the pre-BCR (pre-B cell receptor), which tests whether a functional heavy chain has been produced. Without BTK, pre-B cells receive no survival/differentiation signal and cannot progress to immature B cells. The block is specifically at the pre-B cell to immature B cell transition.

B cell development: Pro-B → Pre-B → [BTK required] → Immature B → Mature naive B cell

Answer 14: C - Bruton's Tyrosine Kinase (BTK)

XLA is caused by mutations/deletions in the BTK gene (Xq21.3-22), encoding Bruton's tyrosine kinase. BTK is a cytoplasmic tyrosine kinase that transduces signals from the pre-BCR and BCR. It is also expressed in myeloid cells (monocytes, macrophages), which is why susceptibility to infection extends beyond just the absence of antibodies.

CD40L mutation → Hyper-IgM syndrome
WASP mutation → Wiskott-Aldrich syndrome
IL2RG mutation → X-linked SCID
RAG1/2 → AR-SCID (T-B-NK+)

Answer 15: B - Maternal IgG crosses the placenta

Maternal IgG crosses the placenta actively via the FcRn (neonatal Fc receptor) throughout gestation, reaching peak levels in the neonate at birth. This maternal IgG provides passive immunity for approximately 3-6 months. As maternal IgG is catabolized and the infant's own antibody production (absent in XLA) cannot compensate, infections begin at 6-9 months. This is also why maternal IgA and IgM do NOT cross the placenta (IgA is secretory; IgM is too large) - only IgG provides this protection.

Answer 16: C - Enterovirus (echovirus, coxsackievirus)

Enteroviral infections (particularly echovirus and coxsackievirus) are uniquely dangerous in XLA. Normally, humoral immunity (IgG, IgA) is the key defense against enteroviruses. In XLA, chronic or disseminated enteroviral infection causes progressive, fatal meningoencephalitis - a condition not seen in healthy individuals. Patients can also develop a dermatomyositis-like syndrome. This is a classic and frequently tested distinguishing feature of antibody deficiencies.

Candida/PCP = T cell deficiencies. Aspergillus = CGD/SCID. Neisseria = terminal complement deficiency.

SECTION D: Common Variable Immunodeficiency

Answer 17: B - Common variable immunodeficiency

CVID is the most common symptomatic primary immunodeficiency in adults. The distinguishing features from XLA:

Affects both males and females
Presents in teens or adulthood (not infancy)
Normal or near-normal B cell numbers in blood (the defect is in B cell terminal differentiation to plasma cells)
All Ig classes are low (IgG markedly, IgA and IgM also)
Recurrent sinopulmonary infections (encapsulated bacteria), chronic diarrhea (Giardia), splenomegaly, autoimmunity

(Cellular & Molecular Immunology; Goldman-Cecil)

Answer 18: C - CVID has B cells; XLA has absent B cells

Feature	XLA	CVID
Sex	Males only (X-linked)	Both sexes
Age of onset	Infancy (6-9 months)	Teens/adulthood
B cells	Absent	Present (normal numbers)
Mechanism	Arrest at pre-B stage (BTK)	B cells cannot differentiate to plasma cells
Gene	BTK (known)	Multiple genes (heterogeneous)
Ig	All absent	All low

CVID is called "common variable" because the genetic cause is variable and heterogeneous (no single gene identified in most cases), and it is the most common clinically significant antibody deficiency.

Answer 19: A - Villous atrophy with absent plasma cells

Duodenal biopsy in CVID shows a celiac-like pattern - villous atrophy, increased intraepithelial lymphocytes - but critically, plasma cells are absent (unlike true celiac disease where plasma cells are present and increased). Lymphoid follicular hyperplasia (lymphonodular hyperplasia) may also be seen. Giardia lamblia is commonly found on luminal surface. The absence of plasma cells in biopsy is diagnostically important and distinguishes CVID from other enteropathies.

(Quick Compendium of Clinical Pathology)

Answer 20: C - B-cell lymphoma and gastric cancer

CVID patients have a significantly elevated risk of:

B-cell non-Hodgkin lymphoma (~8% lifetime risk, ~5-10x increased)
Gastric cancer (increased due to Helicobacter pylori-related chronic atrophic gastritis from impaired mucosal immunity)
Autoimmune cytopenias (hemolytic anemia, ITP) are also common non-infectious complications

SECTION E: Selective IgA Deficiency

Answer 21: C - Selective IgA deficiency

Selective IgA deficiency is the most common primary immunodeficiency with an incidence of approximately 1 in 500-700 in Caucasian populations. The vast majority (~85%) are asymptomatic and discovered incidentally. XLA is rare, CVID is rare, Hyper-IgM is very rare. IgA deficiency's prevalence is orders of magnitude higher than any other primary immunodeficiency.

Answer 22: C - Anaphylactic reaction due to anti-IgA antibodies

IgA-deficient individuals may develop anti-IgA antibodies (IgG class). When they receive blood products containing IgA (whole blood, FFP, washed RBCs inadequately washed), the anti-IgA antibodies trigger a severe anaphylactic reaction. This is a classic transfusion medicine danger point. IgA-deficient patients who need transfusion should receive:

Washed red blood cells (to remove IgA-containing plasma)
Blood from other IgA-deficient donors
IgA-depleted IVIG if immunoglobulin replacement is needed

Answer 23: B - Less than 7 mg/dL (or undetectable) with normal IgG and IgM in a patient over 4 years

The definition of selective IgA deficiency is:

Serum IgA < 7 mg/dL (most labs report as undetectable or <0.07 g/L)
Normal serum IgG and IgM (distinguishes from CVID where all are low)
Age >4 years (because IgA normally takes time to mature - low IgA before age 4 may be physiological/transient)

If IgG and IgM are also low → consider CVID, not selective IgA deficiency.

Answer 24: B - Coeliac disease, SLE, and rheumatoid arthritis

IgA deficiency is associated with multiple autoimmune diseases:

Coeliac disease (IgA is the antibody used for screening - anti-tTG IgA - so testing is falsely negative in IgA-deficient patients with coeliac; always check total IgA first)
SLE and rheumatoid arthritis
Type 1 diabetes, Graves' disease, inflammatory bowel disease

The association with coeliac is clinically critical - IgA-deficient coeliac patients can be missed if only IgA-based tests are ordered.

SECTION F: Hyper-IgM Syndrome

Answer 25: C - Hyper-IgM syndrome (X-linked, CD40L deficiency)

The diagnostic clues here are:

PCP pneumonia (opportunistic, T cell-type infection)
Cryptosporidium cholangitis (sclerosing cholangitis in bile duct - classic for Hyper-IgM)
Elevated IgM, absent IgG/IgA/IgE (isotype switching failure)
Male infant (X-linked pattern)

Cryptosporidium sclerosing cholangitis is a pathognomonic complication of X-linked Hyper-IgM syndrome and is almost never seen in other antibody deficiencies.

Answer 26: B - CD40 ligand (CD154) on T cells

X-linked Hyper-IgM syndrome (the most common and classic form) is caused by mutations in CD40L (CD154), encoded on the X chromosome and expressed on activated T cells. CD40L on T cells binds CD40 on B cells, delivering the co-stimulatory signal required for:

Germinal center formation
Isotype class switch recombination (IgM → IgG, IgA, IgE)
Somatic hypermutation and affinity maturation

Without CD40L, B cells remain stuck producing only IgM. Note: Autosomal recessive forms exist due to mutations in CD40 (on B cells) or AID (activation-induced cytidine deaminase).

(Cellular & Molecular Immunology)

Answer 27: B - CD40L deficiency impairs macrophage activation via CD40, impairing cell-mediated immunity

This is the most important and most tested concept in Hyper-IgM syndrome. CD40L is not just used for B cell activation - activated T cells also express CD40L to signal CD40 on macrophages and dendritic cells, which is required for macrophage activation and killing of intracellular pathogens (including Pneumocystis and Cryptosporidium). Therefore, Hyper-IgM is not just a B cell/antibody disease - it also has a significant T cell effector arm defect, explaining susceptibility to typically T-cell-controlled organisms.

Answer 28: B - CD40L on T cells cannot signal CD40 on B cells

Class switch recombination requires the following steps:

BCR engagement by antigen
CD40L (on T helper cell) binds CD40 (on B cell) → essential co-stimulation
Cytokines (IL-4 for IgE, TGF-β for IgA, IFN-γ for IgG subclasses) direct the specific switch
AID (activation-induced cytidine deaminase) catalyzes the DNA switch recombination

Without the CD40-CD40L interaction, AID is not activated and no switching occurs. B cells can only produce IgM (which doesn't require class switching). Option C (AID absence) is the defect in the autosomal recessive form of Hyper-IgM, not the classic X-linked form.

SECTION G: Wiskott-Aldrich Syndrome

Answer 29: B - Wiskott-Aldrich syndrome

The classic WAS triad is:

Weird eczema
Antibody deficiency (recurrent bacterial infections)
Small platelets (thrombocytopenia + microplatelets on smear)

It is X-linked recessive, hence only males affected. Small platelet size (microthrombocytopenia) is a distinguishing feature - unlike ITP where platelets are large.

Answer 30: B - Exclusively in bone marrow-derived cells; links antigen receptor signaling to cytoskeletal reorganization

WASP is expressed exclusively in hematopoietic (bone marrow-derived) cells. It is an intracellular signaling molecule that links membrane receptors (BCR, TCR) to the actin cytoskeleton via the Arp2/3 complex, enabling actin polymerization. This is essential for:

T cell activation and immunological synapse formation
B cell activation
Platelet shape change and function
NK cell killing
Dendritic cell migration

The cytoskeletal defect explains why platelets are small (abnormal membrane architecture) and why T and B cell activation is impaired.

(Cellular & Molecular Immunology)

Answer 31: B - Inability to produce antibodies against T cell-independent polysaccharide antigens

In early WAS, the first immunological defect is impaired antibody response to T-cell-independent type 2 (TI-2) antigens, specifically polysaccharide antigens of encapsulated bacteria (S. pneumoniae, H. influenzae, meningococcus). This is because WASP is needed for the B cell cytoskeletal reorganization required to respond to TI-2 antigens (which signal through the BCR without T cell help). Later, T cell function also deteriorates.

Answer 32: B - Low IgM, normal or elevated IgA and IgE, variable IgG

WAS has a characteristic but unusual Ig pattern:

IgM: low (first to become abnormal)
IgA: normal to elevated
IgE: elevated (contributes to the eczema and allergic diathesis)
IgG: variable (may be low, normal, or elevated depending on stage)

This is distinct from XLA (all absent), CVID (all low), and Hyper-IgM (IgM high, rest absent). The elevated IgE explains why these patients have atopic eczema.

Answer 33: B - EBV-associated lymphoma

WAS patients have a markedly elevated risk of lymphoid malignancies, particularly EBV-associated B-cell lymphomas and T-cell lymphomas. The risk increases with age as immunodeficiency worsens. Autoimmune complications (hemolytic anemia, vasculitis, IBD-like disease) also occur. HSCT is curative if performed early and is the treatment of choice. Gene therapy is an emerging option.

SECTION H: Complement Deficiencies

Answer 34: D - Deficiency of terminal complement components (C5-C9)

Recurrent Neisseria meningitidis (and N. gonorrhoeae) infections are the hallmark of terminal complement (C5-C9, membrane attack complex - MAC) deficiency. Neisseria species have thin outer walls that are uniquely susceptible to killing by the MAC. Without C5-C9, the MAC cannot form and these organisms cannot be killed despite normal opsonization and phagocytosis. Patients may have ≥2-3 episodes of meningococcal disease - any recurrent Neisseria infection should trigger complement testing.

Properdin (alternative pathway stabilizer) deficiency also predisposes to Neisseria but is X-linked.

Answer 35: B - Severe pyogenic infections and an SLE-like autoimmune disease

C2 deficiency is the most common complement deficiency in Caucasians (~1 in 10,000). It is associated with:

Increased bacterial infections (particularly encapsulated organisms)
SLE-like autoimmune disease (the dominant manifestation in many patients)

The SLE association is explained by the role of classical pathway proteins (C1q, C4, C2) in clearing apoptotic cell debris and immune complexes. Without this clearance, self-antigens from apoptotic cells accumulate and trigger autoimmunity. C2 deficiency is the most common cause of complement-associated SLE.

(Robbins Basic Pathology)

Answer 36: B - C3 deficiency

C3 is the central molecule of complement - all three activation pathways (classical, alternative, lectin) converge on C3. C3 deficiency causes:

Severe recurrent pyogenic infections from birth (encapsulated bacteria)
Very low CH50 (classical pathway affected) AND very low AH50 (alternative pathway affected) - because both converge on C3
Susceptibility to both pyogenic bacteria AND immune complex diseases

C3 deficiency is more severe than C2 deficiency because C3b is the main opsonin and without it, phagocytosis is severely impaired. Neisseria (C5-C9 deficiency) would have normal C3 levels.

Answer 37: B - SLE; C1q is required for clearance of apoptotic debris

C1q deficiency has the strongest association with SLE among all complement deficiencies (~90% of C1q-deficient individuals develop SLE-like disease). The mechanism:

C1q normally binds to and tags apoptotic cell blebs for clearance by phagocytes
Without C1q, apoptotic debris accumulates
DNA, histones, and other nuclear antigens from apoptotic cells are exposed to the immune system
This drives anti-nuclear antibody (ANA) production and SLE

This is why SLE patients often have low complement during flares - complement is consumed by immune complex deposition.

Answer 38: C - Hereditary angioedema (C1 inhibitor deficiency)

The clinical triad of:

Recurrent non-pitting angioedema (face, lips, larynx, bowel wall)
No urticaria (distinguishes from allergic angioedema)
Low C4 (consistently low even between attacks)
Low C1 inhibitor (functional or quantitative)
Normal C1q (distinguishes from acquired C1-inhibitor deficiency from lymphoma/SLE)

...is diagnostic of Hereditary Angioedema (HAE). C1 inhibitor (C1-INH) normally inhibits activated C1r, C1s, kallikrein, and factor XIIa. Without it, bradykinin accumulates causing swelling. Treatment: C1-INH concentrate, icatibant (bradykinin B2 antagonist), or tranexamic acid prophylaxis.

Answer 39: D - Classical pathway (C1 through C9)

The CH50 assay (total hemolytic complement, 50% hemolysis endpoint) measures the ability of patient serum to lyse antibody-sensitized sheep red blood cells. This requires an intact classical pathway from C1 through C9. Any deficiency in C1q, C1r, C1s, C4, C2, C3, C5, C6, C7, C8, or C9 will give a low or zero CH50. The AH50 assay (alternative pathway hemolytic complement) tests the alternative pathway separately.

Answer 40: B - Isolated C3 deficiency

When:

CH50 is low (classical pathway affected)
AH50 is low (alternative pathway affected)
C1q, C2, C4 are normal (proximal classical pathway intact)
Factor B, Factor D normal (alternative pathway components intact)
C3 is undetectable

...the defect must be at C3, the convergence point of all pathways. Isolated C3 deficiency is rare but produces the most severe complement-associated immunodeficiency.

Master Summary Table

Condition	Inheritance	Defect	Immune cells affected	Key infections	Unique features
DiGeorge	AD (22q11.2 del)	TBX1; absent thymus	↓T, normal B	Fungi, PCP, viral	Hypocalcemia, cardiac defects, absent thymic shadow
SCID (X-linked)	X-linked	IL2RG (γc chain)	T-B+NK-	All organisms	Vaccine-strain dissemination
SCID (ADA)	AR	ADA; dATP toxicity	T-B-NK-	All organisms	Rib flaring, neurological signs
XLA	X-linked	BTK; pre-B arrest	Absent B cells	Encapsulated bacteria, Enterovirus	No tonsils/nodes; safe 1st 6 months
CVID	Sporadic/AD	B cell differentiation failure	Normal B, ↓ plasma cells	Encapsulated bacteria, Giardia	Adults; B-cell lymphoma risk; absent plasma cells on biopsy
IgA deficiency	Variable	Unknown; isolated IgA absent	Absent secretory IgA	Mild respiratory/GI	Anaphylaxis with blood products; coeliac association
Hyper-IgM	X-linked	CD40L (T cells)	↑IgM, absent IgG/A/E; macrophage defect	PCP, Cryptosporidium, encapsulated bacteria	Cryptosporidium cholangitis
Wiskott-Aldrich	X-linked	WASP; cytoskeletal defect	T & B dysfunction, microplatelets	Encapsulated bacteria, viral, fungal	Eczema + thrombocytopenia + infections triad; ↑IgE, ↓IgM
C2 deficiency	AR	C2	Opsonization impaired	Encapsulated bacteria	Most common complement deficiency; SLE
C3 deficiency	AR	C3	All complement pathways	Encapsulated bacteria (severe)	Low CH50 AND AH50
C5-C9 deficiency	AR	MAC	Bactericidal killing	Neisseria (recurrent)	Recurrent meningococcal disease
C1q deficiency	AR	C1q	Immune complex clearance	Mild infections	Strongest SLE association
HAE (C1-INH)	AD	C1 inhibitor	Bradykinin regulation	N/A	Angioedema without urticaria; low C4 always

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