Chédiak-Higashi syndrome

Chédiak-Higashi syndrome is a rare childhood autosomal recessive disorder that affects multiple systems of the body, and arises from a mutation in the lysosomal trafficking regulator gene, LYST. It arises from a microtubule polymerization defect which leads to a decrease in phagocytosis. The decrease in phagocytosis results in recurrent pyogenic infections, partial albinism, and peripheral neuropathy.

It is named for the Cuban physician and serologist Alejandro Moisés Chédiak (1903-1993) and the Japanese pediatrician Otokata Higashi (1902-1981).^[1] It is often spelled without the accent as Chediak–Higashi syndrome.

Chediak-Higashi syndrome is a disease with impaired bacteriolysis due to failure of phagolysosome formation. As a result of disordered intracellular trafficking there is impaired lysosome degranulation with phagosomes, so phagocytosed bacteria are not destroyed by the lysosome‘s enzymes.

In addition, secretion of lytic secretory granules by cytotoxic T cells is also affected.

The disease is characterised by large lysosome vesicles in phagocytes (neutrophils), which thus have poor bactericidal function, leading to susceptibility to infections, abnormalities in nuclear structure of leukocytes, anaemia, and hepatomegaly.

Most children with Chédiak–Higashi syndrome ultimately reach a stage known as the accelerated phase — the lymphoma-like-syndrome. This severe phase of the disease is thought to be triggered by a viral infection (usually the Epstein-Barr virus, EBV). In the accelerated phase, defective white blood cells divide uncontrollably and invade many of the body’s organs. The accelerated phase is associated with fever, episodes of abnormal bleeding, overwhelming infections, and organ failure. These medical problems are usually life-threatening in childhood.

Associated features:

• Abnormalities in melanocytes (albinism)
• Nerve defects
• Bleeding disorders
• Periodontal disease of deciduous dentition

Chediak-Higashi syndrome is inherited in a autosomal recessive pattern.

Chédiak–Higashi syndrome is caused by mutations in the LYST gene. This gene provides instructions for making a protein known as the lysosomal trafficking regulator. Researchers believe that this protein plays a role in the transport (trafficking) of materials into structures called lysosomes. Lysosomes act as recycling centers within cells. They use digestive enzymes to break down toxic substances, digest bacteria that invade the cell, and recycle worn-out cell components. Although the lysosomal trafficking regulator protein is involved in the normal function of lysosomes, its exact role is unknown.^[2]

• Life threatening infections
• Pyodermas and deep abscesses
• Neuropathy – begins in the teenage years
• Life threatening bleeding
• Loss of vision
• Renal failure
• Frequent infections especially with Epstein-Barr virus
• Lymphoma-like cancer
• Early death

Death often occurs in the first 10 years of life, from chronic infections or accelerated disease that results in lymphoma-like illness. However, some affected children have survived longer.

Patients with Chediak-Higashi syndrome usually present with thefollowing symptoms:

• Dizziness
• Weakness
• Photophobia
• Tremor
• Photosensitive skin
• Neuropathy
• Frequent infections – Staphylococcus aureus
• Numbness
• Seizures
• Unsteady walking (ataxia)
• Nosebleeds or easy bruising
• Intellectual disability (mental retardation)

• Hypopigmentation skin (albinism) – partial
• Silvery hair

• Nystagmus

• Hepatomegaly
• Splenomegaly

• Neuropathy

• Complete blood count and differential count – reveal neutropenia, thrombocytopenia
• Hypergammaglobulinemia
• Bleeding time – prolonged
• Liver function tests – elevated bilirubin
• Peripheral blood smear – giant granules in neutrophils, eosinophils, and granulocytes are seen when examined using light microscopy.
• Bone marrow smear – peroxidase positive giant inclusion bodies in leukocyte precursor cells. The inclusion bodies contain lysosomal enzymes.
• Fluorescence cytometric analysis of leukocyte granules

• Brain and spinal cord atrophy

• Brain and spinal cord atrophy

• Delayed nerve conduction

• May reveal seizure activity

There is no specific treatment for Chédiak–Higashi syndrome. Bone marrow transplants appear to have been successful in several patients. Infections are treated with antibiotics and abscesses are surgically drained when appropriate. Antiviral drugs such as acyclovir have been tried during the terminal phase of the disease. Cyclophosphamide and prednisone have been tried. Vitamin C therapy has improved immune function and clotting in some patients.

Genetic counseling is recommended before becoming pregnant if you have a family history of Chediak-Higashi.

• Griscelli syndrome (also known as “Chédiak-Higashi like syndrome”)

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