Chediak-Higashi syndrome

Definition

Chediak-Higashi syndrome (CHS) is a very rare disease that affects almost every organ in the body. It is an autosomal recessive disease that results from an abnormality in lysosomes (a sac-like container of enzymes) that travel within cells. The problems that occur with this disease are quite varied and present in two stages.

Description

Chediak-Higashi syndrome was named for the two scientists who, in 1957, further detailed the disorder first described by a Cuban doctor in 1943. The disease progresses through two different stages: the "stable phase" and the "accelerated phase." This rare disease has both classic external signs and distinct cellular problems that always result in a fatal outcome.

Affected individuals have many kinds of immune system problems, making them more likely to get infections and cell proliferation problems. People with CHS have a lowered ability to target infectious organisms, and once their immune cells do become involved, they have a harder time killing the infectious organisms.

Affected individuals also have problems with their melanocytes, the cells that produce melanin, the compound that gives skin, hair, and eyes their color. Often, this can result in signs of albinism (lack of color in the skin, hair, and eyes).

Genetic profile

Chediak-Higashi is an autosomal recessive disease, which requires both parents to be carriers of altered, or mutated, genes. CHS often occurs in families with a history of marrying close relatives. Based on genetic mapping that was first done in a mouse model of Chediak-Higashi syndrome, a mutated gene found on chromosome 1q is thought to be the cause of the disease. This gene is called LYST.

Genetic tests of many different affected people with the disease have revealed strong signs of allelic variability (different mutations in the same gene). Some evidence suggests that the allelic variability accounts for the many different presentations of the disease, such as differing age of presentation, differences in the severity of symptoms, and different progression into the second stage of the disease.

Demographics

About 200 cases of CHS have been described in the world's literature. It is seen in the same number of males and females. Often there is a history of intermarriage.

Signs and symptoms

People with Chediak-Higashi syndrome will often have many different clinical problems such as recurrent bacterial infections without clear causes, fevers that cannot be explained, severe gingivitis (gum disease), peripheral and cranial neuropathies, vision problems, lack of coordination, weakness, easy bruising, and loss of coloring (hypopigmentation) of the hair, skin and eyes.

During the accelerated phase, affected people may show signs of enlargement of the liver and spleen (hepatosplenomegaly), low blood platelet counts (thrombocytopenia), low counts of a certain white blood cell group (neutropenia), and low red blood cell counts (anemia). Abnormal cells can cause bone marrow infiltration and suppression, and this may lower blood counts further, making affected individuals even more susceptible to get infections. The transformation to the accelerated phase of this disease tends to occur in the first or second decade of life.

Diagnosis

Diagnosis of CHS is based on microscopic examination of an affected person's blood, and possibly their bone marrow. Examiners look for giant lysosomal granules, which are abnormal groups of cellular sections inside certain white blood cells. At present, the carrier state of Chediak-Higashi syndrome cannot be diagnosed. Prenatal testing has been done using fetal blood samples and cells taken from the amniotic fluid around the fetus. Genetic testing is not yet available.

Since this disorder is passed on in an autosomal recessive fashion, parents who have one affected child should have genetic counseling before future pregnancies. With each pregnancy, these parents will have a 25% chance of having another affected child.

Treatment and management

The treatment of Chediak-Higashi syndrome differs based on the stage of the illness. During the stable phase, treatment is aimed at controlling infectious problems. Prophylactic antibiotics can be given to affected individuals to reduce the risk of contracting the more common infections. Some evidence suggests that treatment with high doses of ascorbic acid (vitamin C) can help improve people clinically as well as improve immune system cell functions in laboratory tests.

During the accelerated phase of this disease, treatment is very difficult. Some affected people have done well with chemotherapy that is aimed at the abnormally growing cells. Some literature has claimed benefits from bone marrow transplants. Also, some literature has indicated that the vaccination of affected individuals against specific viruses may help prevent transformation of the disease from the stable phase into the accelerated phase.

Prognosis

Most affected people described in the medical literature died of infections during the accelerated phase of CHS. This occurred during their youth or teenage years. There are some reports of affected people living into their 30s.

Resources

BOOKS

Nathan, David, et al. "Disorders of Degranulation: Chediak-Higashi Syndrome." Nathan and Oski's Hematology of Infancy and Childhood Philadelphia, Pennsylvania: W. B. Saunders Company, 1998.

WEBSITES

Lo, Wilson, et al. "Entry 214500: Chediak-Higashi Syndrome; CHS1." OMIM—Online Mendelian Inheritance In Man <http://www3.ncbi.nlm.nih.gov/Omim/searchomim.html.>

Benjamin M. Greenberg