Chediak Higashi Syndrome

 Chediak Higashi Syndrome

Chediak Higashi syndrome (CHS) is an autosomal recessive disorder that is characterized by easy bruising, oculocutaneous albinism and recurrent pyogenic infections.

The defect is caused by a mutation in the lysosomal trafficking regulator protein that leads to decreased phagocytosis and predisposition to recurrent bacterial infection. This activity reviews the evaluation and management of Chediak Higashi syndrome and explains the role of the interprofessional team in managing patients with this condition.

Objectives:

Identify the mutations in LYST or CHS1 gene as the underlying defect in the etiology of Chediak Higashi syndrome.

Describe the pathophysiology of Chediak Higashi syndrome.

Summarize the use of allogeneic hematopoietic stem cell transplantation (HSCT) as the only cure of Chediak Higashi syndrome.

Review the importance of improving care coordination among the interprofessional team members to educate the caregiver on methods to prevent complications, remain compliant with medications and undergo the recommended immunization

Signs & Symptoms

The symptoms of CHS may be apparent during early infancy. Hair is typically blond or light brown with a silvery tint. Affected children may be abnormally sensitive to light (photosensitivity) because of the reduced pigment in the eyes and skin, and may exhibit rapid, involuntary, eye movements (nystagmus). More important and more serious are the effects of CHS on the patient’s immune and nervous systems.

In CHS, white blood cells contain abnormal granules that are markedly enlarged. These granules can be seen by looking at the blood cells under the microscope, and if present, are diagnostic of CHS. These abnormal granules affect the ability of the white blood cells to fight infection. Children are susceptible to frequent bacterial, viral, and fungal infections, particularly of the skin and respiratory tract. Children with CHS can also have abnormally low levels of white blood cells. Children with this disorder may bruise easily or bleed excessively when injured. Platelet numbers are usually normal, but the platelets do not function properly causing easy bruising or prolonged bleeding.

The disease can be categorized into classic and atypical (mild) forms. Individuals with the atypical form may have fewer or less severe, infections and milder symptoms. Children with the classic form of the disease are at risk for developing the accelerated phase. The accelerated phase occurs in up to 85% of patients and can occur at any age. The accelerated phase is caused by an excess production of lymphocytes by the immune system. Patients can develop symptoms such as fever, swollen lymph nodes, enlargement of the liver and spleen, anemia, low WBC count, and low blood platelet count. This is a serious condition and needs to be treated right away.

Neurological symptoms occur in early adulthood. Symptoms involving the nervous system include an unsteady posture and walk (ataxia) and loss of sensation in the arms and legs (peripheral neuropathy).This can progress to physical weakness and disability. Some patients can have symptoms that resemble Parkinson’s disease.

Causes

Chediak-Higashi syndrome is inherited as an autosomal recessive genetic trait. The responsible gene has been mapped to chromosomal locus 1q42.1-q42.2 and is known as LYST gene.

The abnormal gene affects the “traffic patterns” or movement of proteins within the cells. Proteins (or enzymes) that are meant to go from one part of the cell to another may be misdirected or fail to be transported.

For example, a granule in which the skin pigment (melanin) is made is interfered with so that the pigment cannot be transported to the appropriate skin cell. Similarly, a defect in the transport within a white blood cell (WBC) renders the cell helpless in killing infective agents like viruses or bacteria and causing the immune problems.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 1q42.1” refers to band 42.1 on the long arm of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait, which are on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits an abnormal gene for the same trait from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of Chediak- Higashi syndrome. Comparisons may be useful for a differential diagnosis:

Griscelli syndrome, also known as Chediak-Higashi-like syndrome, is a rare inherited disorder characterized by partial albinism and abnormalities of platelets and white blood cells. The symptoms are similar to those of CHS.  There are 3 different types of Griscelli syndrome. Type 2 is very similar to CHS as patients have reduced pigment and immune abnormalities. These patients are also at risk for the accelerated phase. On laboratory analysis, the white blood cells do not have the giant granules like those seen in Chediak- Higashi syndrome; therefore, the diagnoses are made differentially based on these WBC granules.

Hermansky-Pudlak syndrome is a rare inherited disorder characterized by reduced skin, hair, and/or eye pigmentation (albinism), abnormal platelets, and the excessive storage of a fatty substance (ceroid) in various parts of the body. The symptoms of Hermansky-Pudlak syndrome include reduced color in the skin, hair, and eyes, impaired vision, and excessive bleeding. Fatty deposits of ceroid in the lungs, intestines, heart, and/or kidneys may cause impaired function in many organs of the body. One type of Hermansky-Pudlak syndrome can also have immune abnormalities. Frequently the first symptoms of Hermansky-Pudlak syndrome in a child include easy bruising, bleeding gums, nosebleeds, and excessive bleeding after surgery or injury. (For more information on this disorder, choose “Hermansky-Pudlak” as your search term in the Rare Disease Database.)

Oculocutaneous albinism is a disease that results in visual impairment and iris/retinal depigmentation. Depigmentation can range from reduced to complete loss. This can be diagnosed independent of CHS due to the lack of infectious history or neurologic abnormalities.

Familial hemophagocytic lymphohistiocytosis (FLH) is characterized by highly active macrophages and T-lymphocytes that act as acute illnesses with fevers, reduction in blood cell count, and enlarged spleens and livers. There is variable age of onset. Neurological symptoms also may present in the form of pressure in the brain, irritability, stiff neck, low muscle tone, spastic muscles, convulsions, cranial nerve palsies, loss of muscle control (ataxia), hemi/quadriplegia, blindness, and coma. Liver dysfunction and immune cell destruction are also symptoms. Median survival for children is less than two months usually due to infection. This disease is autosomal recessive and caused by a mutation in one of the FHL1-FHL5 genes.

Vici syndrome is characterized by a lack of pigment, immunodeficiency, lack of development of the corpus callosum, cataracts of both eyes, and cleft lip and palate. Cognitive impairment, seizures, and severe respiratory infections have also been observed with this syndrome.

Diagnosis of Chédiak-Higashi Syndrome

Genetic testing

Neutropenia, decreased natural killer–cell cytotoxicity, and hypergammaglobulinemia are common.

A peripheral blood smear is examined for giant granules in neutrophils and other cells; a bone marrow smear is examined for giant inclusion bodies in leukocyte precursor cells.

The diagnosis of Chédiak-Higashi syndrome can be confirmed with genetic testing for LYST mutations.

Because this disorder is extremely rare, there is no need to screen relatives unless clinical suspicion is high. Even if a sibling is a carrier, the likelihood of them encountering another carrier and having children is extremely low.

Treatment

Supportive care using antibiotics, interferon gamma, and sometimes corticosteroids

Hematopoietic stem cell transplantation

Prophylactic antibiotics can help prevent infections, and interferon gamma can help restore some immune system function. Pulse doses of corticosteroids and splenectomy sometimes induce transient remission of Chédiak-Higashi syndrome.

However, unless hematopoietic stem cell transplantation is done, most patients with Chédiak-Higashi syndrome die of infections by age 7 years. Transplantation of unfractionated human leukocyte antigen (HLA)-identical bone marrow after pretransplantation cytoreductive chemotherapy may be curative. Five-year posttransplantation survival rate is about 60%.