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

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