Chédiak-Higashi Syndrome

Chédiak-Higashi syndrome (CHS) is an autosomal recessive disorder caused by mutations affecting a lysosomal trafficking regulator protein. This protein plays a crucial role in the inability of neutrophils to kill phagocytosed microbes. Patients with CHS exhibit recurrent pyogenic infections, easy bleeding and bruising, and neurologic manifestations. The syndrome is also associated with oculocutaneous albinism. The diagnosis is made based on analysis of the patient’s blood or bone marrow smear and genetic testing. The treatment of choice is allogeneic hematopoietic cell transplantation.

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Overview

Epidemiology

  • Incidence: < 1 in 1 million people
  • < 500 cases reported worldwide
  • Most patients die before 10 years of age.

Etiology

  • Mode of inheritance: autosomal recessive
  • Gene: mutations in CHS1 (or LYST) gene
    • Encodes for a lysosomal trafficking regulator, which plays a role in trafficking materials into lysosomes
    • The exact role lysosomal trafficking regulator proteins play in killing off microbes in lysosomes is unknown.

Pathophysiology

  • Disruption in lysosomal function, maintenance, and trafficking → failure in phagolysosome formation → phagocytosed bacteria are not destroyed by lysosomal enzymes
  • Additional effects:
    • Impaired chemotaxis
    • Melanocytes are unable to transfer melanin to keratinocytes → albinism
    • ↓ Platelet storage granules → impaired platelet aggregation → bleeding

Clinical Presentation

General signs and symptoms

Signs and symptoms that usually appear soon after birth include the following:

  • Oculocutaneous albinism (nonpigmented skin, eyes, and hair)
  • Lymphadenopathy
  • Gingivitis and periodontal disease
  • Oral ulcers
  • Bleeding:
    • Mucosal bleeding (e.g., gingival, epistaxis)
    • Easy bruising
  • Immunodeficiency: 
    • Severe and recurrent pyogenic sinopulmonary infections
    • Common organisms:
      • Staphylococcus aureus (most common)
      • Streptococcus
      • Fungi
  • Late-onset neurological manifestations:
    • Central and peripheral neuropathies
    • Sensory loss
    • Muscle weakness
    • Parkinsonism
    • Cerebellar ataxia
    • Cognitive impairment
Hypopigmented eyes Chediak-Higashi syndrome

Hypopigmented eyes and eyelashes in a patient with oculocutaneous albinism:
This may be seen in Chédiak-Higashi syndrome.

Image: “Eyes from a patient with OCA1A” by Karen G et al. License: CC BY 2.0

Accelerated phase

Chédiak-Higashi syndrome (CHS) can progress to the accelerated phase or lymphoma-like syndrome, where defective WBCs divide uncontrollably and undergo metastasis. Signs and symptoms include:

  • Fever
  • Jaundice
  • Hepatosplenomegaly
  • Lymphadenopathy
  • Pancytopenia
  • Abnormal bleeding
  • Profound immunodeficiency
  • Organ failure

Diagnosis

  • Peripheral blood smear: giant azurophilic granules can be seen in 
    • Neutrophils
    • Eosinophils
    • Granulocytes
  • Bone marrow smear:
    • Shows “giant inclusion bodies” in leukocyte precursor cells 
    • Granules are peroxidase positive and contain lysosomal enzymes.
  • Microscopic examination of hair:
    • Clumped melanin granules that are larger than those found in normal hairs 
    • Bright and polychromatic refringence pattern
  • Genetic testing for mutations in the LYST gene
  • Supporting laboratory evaluation:
    • Neutropenia 
    • Hypergammaglobulinemia

Management

  • Treatment of choice: allogeneic hematopoietic cell transplantation
  • Supportive management:
    • Treat infections with appropriate antibiotics
    • Routine immunizations
    • Platelet transfusions for serious bleeding
    • Management of the accelerated phase:
      • Corticosteroids
      • intravenous immunoglobulin (IVIG)
      • Chemotherapy (e.g., etoposide, methotrexate)
      • Splenectomy

Differential Diagnosis

  • Leukocyte adhesion deficiency type 1: an inherited condition resulting in a lack of CD18 expression on neutrophils leading to a decrease in the ability of neutrophils to migrate from the blood vessels. Patients with this condition will have recurrent infections, delayed wound healing, and an elevated neutrophil count. The deficiency is not associated with oculocutaneous albinism. The diagnosis is confirmed with flow cytometry demonstrating a deficiency in CD18. Hematopoietic stem cell transplant is the treatment of choice.
  • Chronic granulomatous disease: a consequence of defective phagocytic cells. Patients will have recurrent infections, abscesses, and granulomatous lesions of multiple organs. Hypergammaglobulinemia may be seen. The diagnosis is made with neutrophil function testing for superoxide production. Antimicrobial prophylaxis, interferon gamma, granulocyte transfusion, and hematopoietic stem cell transplantation are potential management options.
  • Severe congenital neutropenia: a rare disease resulting from genetic mutations that affect myelopoiesis. The condition manifests in infancy with life-threatening bacterial infections. Neutropenia is found on laboratory evaluation, often with an elevated monocyte count. A bone marrow biopsy will also aid in the diagnosis. Management includes granulocyte colony-stimulating factor and hematopoietic stem cell transplantation..
  • Myeloperoxidase deficiency: an autosomal recessive disorder that causes impaired microbial killing by phagocytes. The majority of patients are asymptomatic, while others can have recurrent, severe fungal infections. The diagnosis is made with histochemical staining for myeloperoxidase in neutrophils. There is no specific management for this condition, but patients should be treated for any infections.

References

  1. Nowicki, R.J. (2018). Chediak-Higashi syndrome. In Elston, D.M. (Ed.), Medscape. Retrieved March 23, 2021, from  https://emedicine.medscape.com/article/1114607-overview
  2. Boztug, K. (2021). Chediak-Higashi syndrome. In TePas, E. (Ed.), UpToDate. Retrieved May 3, 2021, from https://www.uptodate.com/contents/chediak-higashi-syndrome
  3. Fernandez, J. (2021). Chediak-Higashi syndrome. [online] MSD Manual Professional Version. Retrieved May 3, 2021, from https://www.msdmanuals.com/professional/immunology-allergic-disorders/immunodeficiency-disorders/ch%C3%A9diak-higashi-syndrome
  4. Ajitkumar, A., Yarrarapu, S.N.S., and Ramphul, K. (2021). Chediak Higashi syndrome. [online] StatPearls. Retrieved May 3, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK507881/

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