Chédiak-Higashi syndrome

• Chédiak-Higashi syndrome is a rare autosomal recessive primary immunodeficiency disorder characterized by
  • oculocutaneous albinism,
  • recurrent pyogenic infections, and
  • progressive neurologic dysfunction.
• It is caused by mutations in the LYST gene (Lysosomal Trafficking Regulator), leading to impaired lysosomal exocytosis and the formation of characteristic giant granules in various cell types.

Pathophysiology

The LYST protein is essential for the normal trafficking of proteins into lysosomes and specialized organelles like melanosomes and lytic granules.

• Giant Granules: Pathognomonic finding on peripheral blood smears; these are enlarged lysosomes seen in neutrophils, monocytes, and lymphocytes.
• Immune Dysfunction: Impaired fusion of lysosomes with phagosomes prevents effective bacterial killing by neutrophils and impairs cytotoxic activity of Natural Killer (NK) cells and T-lymphocytes.

Clinical Features

• Oculocutaneous Albinism: Partial pigmentary dilution of hair, skin, and eyes; photophobia and nystagmus are common.
• Recurrent Infections: Recurrent skin, respiratory, and soft tissue infections (typically Staphylococcus aureus or Streptococcus pyogenes).
• Neurological Involvement: Progressive peripheral neuropathy, ataxia, and cognitive impairment, often worsening in the "accelerated phase."
• Accelerated Phase (Hemophagocytic Lymphohistiocytosis - HLH): A life-threatening complication characterized by systemic lymphohistiocytic infiltration, leading to pancytopenia, hepatosplenomegaly, and high-grade fevers.

Diagnosis

• Peripheral Blood Smear: Identification of large, peroxidase-positive azurophilic granules in leukocytes.
• Genetic Testing: Molecular confirmation of homozygous or compound heterozygous mutations in the LYST gene.
• Bone Marrow: Shows evidence of hemophagocytosis during the accelerated phase.

Management

• Definitive Therapy: Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) is the only curative treatment and must be performed as early as possible, ideally before the onset of the accelerated phase.
• Supportive Care: Prophylactic antibiotics, antifungals, and aggressive management of infections.
• Accelerated Phase: Managed with protocols similar to HLH (e.g., corticosteroids, etoposide, or cyclosporine).