Random Dermatology MCQ - Chediak Higashi syndrome

A 3-year-old child with a history of recurrent pyogenic infections and partial oculocutaneous albinism presents with fever, hepatosplenomegaly, and pancytopenia. On examination, the hair has a characteristic silvery-metallic sheen. A peripheral blood smear reveals large, abnormal granules within the neutrophils. What is the most likely underlying cellular defect and the dreaded complication that this patient is now developing?

A. Defect in neutrophil adhesion (LAD); complication is severe periodontal disease.
B. Defect in the lysosomal trafficking regulator (LYST) gene leading to giant granules; complication is the accelerated phase (hemophagocytic lymphohistiocytosis).
C. Defect in NADPH oxidase (chronic granulomatous disease); complication is deep-seated infections with catalase-positive organisms.
D. Defect in antibody production (Bruton's agammaglobulinemia); complication is enteroviral meningoencephalitis.
E. Defect in the WAS protein (Wiskott-Aldrich syndrome); complication is bleeding from thrombocytopenia.

Correct Answer: B. Defect in the lysosomal trafficking regulator (LYST) gene leading to giant granules; complication is the accelerated phase (hemophagocytic lymphohistiocytosis).

Answer and Explanation

The correct answer is B. This question describes the classic presentation of Chediak-Higashi syndrome (CHS). The key clues are the triad of partial oculocutaneous albinism (silvery hair, nystagmus, photophobia), recurrent pyogenic infections, and the finding of giant granules in leukocytes on blood smear. The underlying defect is a mutation in the LYST gene, which regulates lysosomal trafficking, leading to the formation of giant dysfunctional granules in multiple cell types. The development of fever, hepatosplenomegaly, and pancytopenia in a patient with CHS signals the onset of the "accelerated phase", which is a life-threatening hemophagocytic lymphohistiocytosis (HLH)-like condition.

Why the Other Options are Incorrect:

• A. Defect in neutrophil adhesion (LAD): This presents with delayed separation of the umbilical cord, severe gingivitis/periodontitis, and impaired pus formation, but not albinism or giant granules.

• C. Defect in NADPH oxidase (CGD): This presents with recurrent infections with catalase-positive organisms (e.g., S. aureus, Aspergillus) and granuloma formation. The nitroblue tetrazolium (NBT) test is diagnostic. Albinism and giant granules are not features.

• D. Defect in antibody production (XLA): This is an X-linked disorder presenting after 6 months of age with recurrent bacterial infections, very low B-cells, and agammaglobulinemia. It does not involve albinism or cellular granules.

• E. Defect in the WAS protein (WAS): This X-linked disorder presents with the triad of eczema, thrombocytopenia (with small platelets), and recurrent infections. It does not cause albinism or giant granules.

Additional High-Yield Information for Exams:

• Pathogenesis: The LYST gene mutation leads to defective lysosome and granule formation and trafficking. This causes:

  • Immune Deficiency: Giant granules in neutrophils cannot properly fuse with phagosomes, impairing microbial killing. NK-cell and cytotoxic T-cell function is also defective.

  • Albinism: Giant melanosomes in melanocytes cannot be properly transferred to keratinocytes, leading to dilution of pigmentation.

  • Bleeding Diathesis: Platelet dense granules are abnormal, leading to mild bleeding tendencies.

• Clinical Features:

  • Partial Albinism: Silvery-gray hair, iris translucency, photophobia, nystagmus.

  • Infections: Recurrent sinopulmonary and skin infections, often with Staphylococcus aureus.

  • Neurologic: Progressive neuropathy, ataxia, and cognitive decline may develop, even in patients who survive the accelerated phase.

• The Accelerated Phase: This is a fatal complication occurring in ~85% of patients, often triggered by viral infection (especially EBV). It is characterized by a hemophagocytic lymphohistiocytosis (HLH) picture: uncontrolled T-cell and macrophage activation leading to fever, hepatosplenomegaly, lymphadenopathy, pancytopenia, coagulopathy, and hemophagocytosis in the bone marrow.

• Differential Diagnosis: Other causes of albinism with immunodeficiency include Griscelli syndrome (types 1 & 2) and Hermansky-Pudlak syndrome (type 2). These lack the pathognomonic giant cytoplasmic granules.

• Prognosis: Without treatment, most children die from infection or the accelerated phase in the first decade. Survival into adulthood often involves severe neurologic sequelae.

• Management & Rationale:

  • Rationale: The only curative therapy is hematopoietic stem cell transplantation (HSCT), which corrects the immune defect and prevents the accelerated phase. It must be performed before the onset of the accelerated phase for optimal outcomes.

  • First-line Curative Therapy: Allogeneic HSCT is the treatment of choice. It resolves the immunodeficiency and prevents HLH but does not correct the neurologic degeneration.

  • Management of Accelerated Phase: Treated with HLH protocols (e.g., etoposide, dexamethasone, cyclosporine) as a bridge to urgent HSCT, though outcomes are poor once this phase has begun.

  • Supportive Care: Prophylactic antibiotics, antiviral therapy (acyclovir), and aggressive treatment of infections.