An Overview of Chediak-Higashi Syndrome

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Chediak-Higashi syndrome is a rare autosomal recessive genetic disorder. It arises from an abnormality in the DNA that causes abnormalities within lysosomes, or elements within cells that are critical to many important aspects of the body's function.

The immune system is particularly affected by this disease, leaving the body less able to fight off viruses and bacteria, leading to recurrent infections that often prove fatal during childhood. Lysosomal dysfunction also causes various other problems, including neurologic abnormalities, albinism, and coagulation defects.

It is a very rare condition, with an incidence of less than one in 1,000,000. Less than 500 cases have been reported worldwide.

Symptoms

Albinism

Those with this genetic abnormality are usually identified in infancy and childhood. Melanocytes, which are melanin-forming cells, are not appropriately transported to where they need to go. (Melanin is the pigment in the eyes, skin, and hair.)

This causes those with Chediak-Higashi to present with oculocutaneous albinism (oculo, meaning "eyes," and cutaneous, meaning "skin"). Most patients have light skin with thin light hair that may be gray, white, or blond-appearing. Their eyes are also usually light-colored and they may have photophobia, nystagmus, strabismus, or decreased visual acuity.

The "cutaneous" manifestation of the oculocutaneous albinism may be present as either hyperpigmentation or hypopigmentation that are speckled appearing.

Progressive Neurologic Dysfunction

Neurologic defects, including the peripheral and central nervous system, are progressive and occur in about 10 to 15 percent of those who survive into early childhood and beyond. They include a wide range of problems including seizures, movement disorders, dementia, developmental delay, weakness, sensory deficit, tremor, ataxia, and cranial nerve palsies.

Immune Deficiency

Frequent infections caused by specific bacteria including staphylococcus aureus, streptococcus pyogenes, and pneumococcus species. Neutrophils, the infection-fighting cells in our body, are not functioning properly in this syndrome due to abnormal granules that affect the ability of the white blood cells to fight infection.

The infections are usually severe and are located on the skin, respiratory tract, and mucous membranes.

The infections are known as "pyogenic," which means they are pus-filled and usually foul-smelling. They range from being superficial to deep, which can cause ulcerations. These leave bad scars and heal slowly. Hemophagocytic lymphohistiocytosis (HLH) may also occur, causing a severe immunodeficiency. This is when there is a massive lymphohistiocytic infiltration into the organ systems causing fever, enlarged spleen and liver, and bleeding.

This can occur early on during infancy or early childhood, known as the "accelerated phase" of the disease, and is usually lethal.

Blood disorders

Patients are unable to clot due to a defect with platelets, which leads to abnormal bleeding and easy bruising.

Other diseases

Other organ systems may be impacted such as the kidneys, gastrointestinal tract, and periodontal diseases may occur.

Causes

Chediak-Higashi syndrome is a rare autosomal recessive genetic disorder caused by mutations in the LYST gene. This means that both parents carry a copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

The LYST gene provides instructions for making a protein known as the lysosomal trafficking regulator. Without this regulator, lysosomal function, size, and structure are disrupted and the body can't perform its regular maintenance and functions.

These functions include disposing of unwanted content within cells by using digestive enzymes to digest bacteria, breaking down toxic substances, and recycling cell components. The malfunctioning immune system cannot protect the body from infections.

Diagnosis

The diagnosis of Chediak-Higashi is usually suspected in those patients with partial oculocutaneous albinism and recurrent pyogenic infections. The first step is to make a blood smear. This is examined for classic signs of the disease, which include giant azurophilic granules in neutrophils, eosinophils, and other granulocytes. They are found in many locations including the bone marrow, melanocytes, gastric mucosa, fibroblasts renal tubular epithelium, and the peripheral and central nerve tissue.

There are several disorders that appear similarly to Chediak-Higashi. In order to differentiate between some of those (including Griscelli Syndrome, Hermansky Pudlak Syndromes), genetic testing must be performed. These look for mutations in the CHS1/LYST gene.

There is then diagnostic criteria in the accelerated phase of the disease, of which the patient needs five out of the eight criteria which include fever, enlarged spleen, decrease of at least two peripheral blood lines, low or absent natural killer cell activity, hyperferritinemia, and, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis in bone marrow, spleen or lymph nodes, and high levels of interleukin 2 receptor. This criteria is the same for hemophagocytic lymphohistiocytosis.

If there is a suspicion of a fetus in utero having this disease due to a positive family history, it is possible to diagnosis it prenatally with chorionic villus sampling, fetal blood, or hair sampling.

Treatment

Initial treatment upon diagnosis involves the use of antibiotics prophylactically to prevent bacterial infections. If infections do occur, aggressive treatment is warranted. In order to prevent infection, granulocyte colony stimulating factor (known as G-CSF) is used to try and decrease infection by increasing neutrophils that will fight off bacteria.

Glucocorticoids and removal of the spleen have proved to be somewhat successful to delay the onset of the accelerated phase and other therapies used include intravenous gammaglobulin, antivirals, and chemotherapy. None of these therapies are curative, however.

In order to correct the immune and hematologic impact of Chediak-Higashi an allogenic hematopoietic cell transplantation (HCT), including cord blood transplantation, is the treatment of choice. Even if this is successful, it does not prevent oculocutaneous albinism or the progressive neurologic disabilities that inevitably cause neurologic deterioration.

HCT is thought to be more successful if fewer infections have occurred in the patient, especially HLH. Therefore, early HCT is ideal and can lower the risk of HLH and the accelerated phase of the disease from occurring.

Successfully transplanted patients have no significant infections and do not progress to (or have a recurrence of) the accelerated phase.

If not transplanted, most patients with Chediak-Higashi die from pyogenic infection before they are seven years old. In a review of 35 children with Chediak-Higashi syndrome, the five-year probability of survival posttransplantation was 62 percent.

However, the few patients who survive to early adulthood, whether they were transplanted or not, develop neurologic deficits by the time they reach their early twenties.

Be sure to discuss with your doctor if you have a family history of the disease.

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