The immune system is particularly affected by this disease, leaving the body less able to fight off viruses and bacteria. This leads 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 in appearance. 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 in appearance.
Progressive Neurologic Dysfunction
Neurologic defects, including the peripheral and central nervous system, are progressive and occur in about 10% to 15% 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 include 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 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.
If the disease is not successfully treated, most children reach the accelerated phase of the disease, which involves hemophagocytic lymphohistiocytosis (HLH), causing severe immunodeficiency.
HLH results 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, and it is usually lethal.
Blood Disorders and Other Diseases
Patients are unable to clot due to a defect with platelets, which leads to abnormal bleeding and easy bruising.
Additionally, other organ systems may be impacted, such as the kidneys and gastrointestinal tract. Periodontal diseases may also 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.
Several disorders appear similar to Chediak-Higashi. In order to differentiate between some of those—including Griscelli syndrome and Hermansky-Pudlak syndrome—genetic testing must be performed. These look for mutations in the CHS1/LYST gene.
Diagnostic criteria in the accelerated phase of the disease, of which the patient needs five out of the eight criteria, include:
FeverEnlarged spleenDecrease of at least two peripheral bloodlinesLow or absent natural killer cell activityHyperferritinemiaHypertriglyceridemia and/or hypofibrinogenemiaHemophagocytosis in bone marrow, spleen, or lymph nodesHigh 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 diagnose 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 in delaying the onset of the accelerated phase, and other therapies used include intravenous gamma globulin, 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.
If not transplanted, most patients with Chediak-Higashi die from pyogenic infection before they are 7 years old. In a review of 35 children with Chediak-Higashi syndrome, the five-year probability of survival post transplantation was 62%.
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 talk with your healthcare provider if you have a family history of the disease.
