Chediak-Higashi Syndrome

Snapshot | Chediak-Higashi Syndrome

• A 3-year-old boy is brought to his pediatrician with scraped knees. He had been playing and slipped, scraping his knees on the asphalt. His knees are severely infected, with visible pus. He has a history of bleeding gums and easy bruisability. On physical exam, he is febrile, his retina is noted to be pale, and his hair is very blonde. In fact, some parts of his hair are noted to be silver. He is started on broad-spectrum antibiotics.

Introduction

• Primary immunodeficiency from problems with phagocytosis
• Genetics
  • autosomal recessive
  • defect in lysosomal trafficking regulator gene LYST 
• Pathogenesis
  • microtubule dysfunction with failure of phagolysosome formation 
  • defective secretions
  • defective melanization of melanosomes
• Symptoms arise in childhood

Presentation

• Symptoms
  • recurrent pyogenic infections, especially of the skin and soft tissue
    • Staphylococcus spp.
    • Streptococcus spp.
  • dermatologic symptoms
    • partial albinism
      • hypopigmentation of skin, eyes, and hair
    • photosensitivity
  • infiltrative lymphohistiocytosis
  • neurological symptoms
    • progressive neurodegeneration
    • peripheral neuropathy
  • pancytopenia
    • easy bruising
    • recurrent infections
• bleeding

Evaluation

• Diagnosis with light microscopy of peripheral blood smear
  • eosinophilic peroxidase-positive giant granules in neutrophils and platelets 
• Bone marrow smear
  • giant lysosomes in leukocyte precursor cells
• CBC showing pancytopenia
• Mild coagulation defects
• prolonged bleeding time

Differential Diagnosis

• Leukocyte adhesion deficiency 
• Hyper IgM syndrome 

Treatment

• Early treatment is important
• Bone marrow transplant
• Treat infections as needed

Prognosis, Prevention, and Complications

• Prognosis
  • fatal in childhood, usually before age 10
  • mortality due to lymphoproliferative syndrome
  • if the affected individual lives to adulthood, progressive neurologic dysfunction is a dominant feature
• Complications
• 50-85% develop accelerated phase called hemophagocytic lymphohistiocytosis

Chediak-Higashi Syndrome (CHS) is a rare genetic disorder characterized by abnormal cellular vesicles, leading to a range of clinical manifestations affecting various systems. This syndrome primarily affects the immune and nervous systems, leading to immune dysfunction and neurological abnormalities.

Understanding Chediak-Higashi Syndrome is essential for medical professionals, particularly those in immunology, hematology, and genetics. This article provides a comprehensive overview of Chediak-Higashi Syndrome, including its types, function, related studies, treatment considerations, and clinical significance.

Types of Chediak-Higashi Syndrome:

Chediak-Higashi Syndrome can be classified into different types based on its genetic inheritance pattern:

1. Autosomal Recessive Type: This is the most common form of CHS and is inherited when an individual receives two mutated copies of the CHS1/LYST gene, one from each parent.
2. Atypical Type: Some individuals may exhibit milder or atypical forms of the syndrome due to variations in the genetic mutations.

Function of the CHS1/LYST Gene:

CHS1/LYST gene encodes a protein involved in vesicle trafficking and lysosomal function. Defective CHS1/LYST protein leads to abnormal vesicle formation and trafficking within cells.

Clinical Manifestations:

Chediak-Higashi Syndrome presents with a range of clinical features:

1. Albinism: Individuals with CHS often have partial albinism or hypopigmentation due to impaired melanosome function.
2. Neurological Abnormalities: Neurological manifestations include progressive neuropathy, muscle weakness, and cognitive impairment.
3. Giant Intracellular Inclusions: Cells in CHS patients contain large, abnormal vesicles, known as “giant granules,” which affect cellular function.
4. Immune Dysfunction: CHS patients have compromised immune function, leading to susceptibility to recurrent infections, particularly bacterial infections.

Chediak-Higashi Syndrome Studies:

1. Genetic Studies: Research focuses on identifying genetic mutations in the CHS1/LYST gene and their impact on cellular function.
2. Cellular Pathways: Studies investigate how abnormal vesicles and lysosomal dysfunction contribute to the clinical features of CHS.

Clinical Significance:

1. Immune Impairment: CHS leads to impaired immune function, increasing the risk of recurrent bacterial infections.
2. Neurological Complications: Progressive neurological symptoms can significantly impact a patient’s quality of life.

Conclusion:

Chediak-Higashi Syndrome is a rare genetic disorder characterized by abnormal vesicle trafficking and lysosomal function due to mutations in the CHS1/LYST gene. This leads to a range of clinical manifestations, including albinism, neurological abnormalities, giant intracellular inclusions, and immune dysfunction. The syndrome primarily affects the immune and nervous systems, leading to increased susceptibility to infections and progressive neurological symptoms.

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