Chédiak–Higashi syndrome

Overview

Chédiak–Higashi syndrome (CHS) is a rare, autosomal recessive genetic disorder that affects multiple systems in the body, especially the immune and nervous systems. It is characterized by partial albinism, increased susceptibility to infections, bleeding tendencies, and progressive neurological decline. The disease is caused by a defect in intracellular transport, leading to the formation of giant lysosomal granules in white blood cells, which impairs their function. CHS typically presents in infancy or early childhood and often progresses to a life-threatening accelerated phase resembling lymphoma.

Causes

CHS is caused by mutations in the LYST gene (also known as CHS1), located on chromosome 1q42.1–q42.2. The LYST gene encodes a protein involved in the regulation of lysosomal trafficking within cells. When this gene is mutated, lysosomes and other cell organelles cannot move or function properly, especially in immune cells such as neutrophils and cytotoxic T-cells. This dysfunction leads to impaired immune responses, abnormal pigmentation, and damage to the nervous system. The condition follows an autosomal recessive inheritance pattern, meaning both copies of the gene must be mutated for the disease to manifest.

Symptoms

Symptoms of Chédiak–Higashi syndrome vary by disease phase and severity but generally include:

• Partial oculocutaneous albinism: Pale skin, silvery hair, and light-colored eyes due to abnormal melanin distribution

• Recurrent infections: Especially respiratory and skin infections due to defective white blood cell function

• Bleeding disorders: Easy bruising or prolonged bleeding from minor injuries due to platelet dysfunction

• Photophobia and nystagmus: Due to abnormal ocular pigmentation

• Neurological symptoms: Peripheral neuropathy, muscle weakness, ataxia, and progressive intellectual decline

• Accelerated phase: A severe, potentially fatal episode marked by fever, lymphadenopathy, hepatosplenomegaly, pancytopenia, and organ failure; resembles hemophagocytic lymphohistiocytosis (HLH)

Diagnosis

CHS is diagnosed through a combination of clinical signs, blood tests, and genetic analysis. Diagnostic steps include:

• Peripheral blood smear: Reveals giant granules in neutrophils and other white blood cells—a hallmark of CHS

• Hair microscopy: May show irregular melanin clumps in hair shafts

• Platelet function tests: To assess clotting abnormalities

• Immunological testing: Evaluates the function of neutrophils and cytotoxic T-cells

• Genetic testing: Confirms mutations in the LYST gene

• Bone marrow biopsy: May show evidence of hemophagocytosis during the accelerated phase

Treatment

There is no cure for CHS, but treatment focuses on managing symptoms, preventing infections, and addressing the accelerated phase. Treatment strategies include:

• Antibiotics: Prophylactic and therapeutic antibiotics to treat or prevent infections

• Antiviral and antifungal medications: In cases of viral or fungal complications

• High-dose steroids and immunosuppressants: To manage the accelerated phase and reduce inflammation

• Hematopoietic stem cell transplantation (HSCT): The only potentially curative treatment, especially effective when performed before the accelerated phase; it restores immune function but does not prevent neurological decline

• Supportive care: For bleeding, vision issues, and neurological complications

Prognosis

The prognosis for individuals with Chédiak–Higashi syndrome is generally poor without stem cell transplantation. Most patients enter the accelerated phase within the first decade of life, which is often fatal if not promptly treated. With early HSCT, survival rates improve significantly, though neurological symptoms may continue to progress. Supportive care, early diagnosis, and genetic counseling for families are essential components of long-term management and care planning.