What is Chediak-Higashi Syndrome?
Chediak Higashi syndrome (CHS) is a rare genetic disorder that was first detailed back in 1943 and then further explored in 1952 and 1954 when researchers found an issue with certain parts of the white blood cells in affected patients.
This condition causes various symptoms such as lighter skin and eye color (oculocutaneous albinism), bruising easily, a weakened immune system (abnormal functions of the natural killer cells), and frequent skin infections. These are all caused by a change or ‘mutation’ in a specific gene known as the lysosomal trafficking regulator (LYST) gene. Some people with CHS also experience neurological symptoms such as problems with movement and coordination (ataxia) and nerve-related issues (neuropathies) which can be a leading symptom in some less typical forms of the disease.
One of the telltale signs of CHS is the presence of unusually large granules, especially in white blood cells and bone marrow – this helps in diagnosing the condition.
Health problems can occur due to frequent infections or due to a stage called ‘accelerated phase’ where there is excessive growth of white blood cells into major organs. Sadly, 80% of deaths related to CHS occur in the first ten years of life. However, those who live into adulthood usually experience worsening neurological symptoms.
One potential treatment is allogeneic hematopoietic stem cell transplantation, which is a type of stem cell transplant that uses cells from a donor. This can help with blood-related and immune system issues, but it doesn’t halt the progression of the neurological damage that also occurs in CHS.
What Causes Chediak-Higashi Syndrome?
The root cause of this genetic condition is a mutation, or a change, in a specific gene called LYST or CHS1. This gene plays a key role in the functioning of lysosomes, which are specialized compartments within cells. It helps regulate the movement of lysosomes as well as the creation, merging, and transport of particles inside the cell. The gene in question is found in a particular part of your body’s 1st chromosome.
Scientists have found around 40 different types of changes or ‘mutations’ in this gene. They include what are known as ‘nonsense and missense mutations’, which are basically mistakes in the gene, along with ‘deletions and insertions’, which involve parts of the gene being removed or added.
Risk Factors and Frequency for Chediak-Higashi Syndrome
The exact number of how frequently this condition occurs is uncertain. Only about 500 cases have been reported around the world. It’s tricky to find a precise number because some people with the condition might have been reported more than once. Additionally, individuals who only have mild symptoms often go unnoticed or unreported.
- The condition affects a diverse range of races.
- People of all ages can get it. However, it usually starts after birth and is found often in children under the age of five.
Signs and Symptoms of Chediak-Higashi Syndrome
The disease in question affects patients from a young age, causing recurring infections, partial albinism (particularly affecting the eyes and skin), and issues with blood clotting. The severity of the disease largely depends on the particular type of mutation, with mutations that result in a loss of function typically leading to a severe form of the disease beginning in childhood. Conversely, a missense mutation is linked to a milder form of the disease that starts in adolescence or later in life. Cell phenotype also plays a role in the severity of the disease.
Clinical signs of this disease include the following:
- Partial albinism: This is a key trait, though the level of pigment dilution can vary. It affects the skin, hair, and eyes and can give the hair a metallic or “silvery” appearance. Under a microscope, you can see the clump of pigment within the hair shaft. Decreased pigmentation in the iris can lead to decreased pigmentation of the retina, which can potentially affect vision. Other eye-related symptoms can include sensitivity to light, increased red reflex, and involuntary eye movement.
- Immunodeficiency: Those affected have a tendency toward recurrent, often severe, infections that typically start in infancy. These are usually bacterial or fungal infections. Skin infections and upper respiratory tract infections are particularly common. Recently, periodontitis has been recognized as an important sign of immune dysfunction and can help in diagnosing the disease.
- Bleeding tendency: Patients exhibit mild symptoms like nosebleeds, mucous or gum bleeding, and easy bruising. These symptoms are usually unobtrusive and do not require medical intervention.
- Accelerated phase: This is a serious progression of the disease experienced by 85% of patients that can occur at any age. It often leads to fever, enlarged liver and spleen, swollen lymph nodes, low white blood cell count, anemia, and sometimes low platelet count. It was originally thought to be triggered by a certain type of cancer, but it’s now known to be caused by excessive activation of certain immune cells in the bone marrow and lymphoid organs. This leads to the consumption of blood cells and the production of many pro-inflammatory cytokines.
- Neurological issues: These may manifest by early adulthood, even after successful stem cell transplant. This is due to the long-term progression of the disease and it may involve stroke, coma, lack of coordination, tremors, sensory and motor neuropathies, and absent tendon reflexes.
- Atypical phenotype: A few patients may have a less typical or mild form of the disease. It may include subtle or no albinism, a decrease in blood platelet-dense bodies with subtle bleeding symptoms, severe childhood infections which reduce with age, and progressive neurological symptoms. The neurological symptoms are inconsistent and non-specific and could be the most predominant symptom with only subtle changes in pigmentation, immune functions, and bleeding abnormalities. All individuals, however, have abnormal granules within the white blood cell.
It is important to note that the patient’s lifespan tends to be considerably shortened — about 90% of patients unfortunately pass away within the first 10 years of life.
Testing for Chediak-Higashi Syndrome
Anyone with signs of a weakened immune system, lighter skin, hair, or eye color than their family, a temporary or permanent low number of white blood cells, or unexplained neurological symptoms should consider being checked for a condition called Chediak-Higashi syndrome.
How is Chediak-Higashi syndrome diagnosed?
Diagnosis of the disease can be determined through testing. A key indication of this condition is the presence of unusually large granules or particles in certain cells, such as skin color cells (melanocytes), white blood cells (leukocytes), and bone marrow cells where these white blood cells are produced (their precursors). These granules can also be found in connective tissue cells (fibroblasts), nerve tissue, and hair.
Molecular genetic testing can also be done to identify changes in the LYST gene. This gene is responsible for the condition, so any variations in it can confirm a diagnosis of Chediak-Higashi syndrome.
If Chediak-Higashi syndrome is confirmed, your doctor will perform additional tests to understand the extent of the disease. These can include:
(a) Checking to see if the disease has entered an ‘accelerated phase’. Signs of this include:
* An enlarged spleen (splenomegaly).
* Recurring or unexplained fever.
* A reduction in at least two types of blood cells (cytopenia).
* Increased levels of a protein involved in inflammation (ferritin).
* Increased levels of a marker of immune system activity (soluble interleukin-2 receptor levels).
* Evidence of increased breakdown and consumption of blood cells (hemophagocytosis) in either the bone marrow or in the fluid that surrounds the brain and spinal cord.
* Sign of liver dysfunction like increased triglyceride levels or decreased fibrinogen levels.
(b) A thorough neurological examination will be conducted to check for any signs of brain or nerve disorder.
(c) Screening for a type of cancer called lymphoma, as the symptoms can appear similar to those seen in an accelerated phase of Chediak-Higashi syndrome.
(d) A genetic consultation to understand how the condition may have been inherited and the risks to other family members.
Treatment Options for Chediak-Higashi Syndrome
The treatment for certain blood disorders and immune deficiencies involves a procedure known as allogeneic hematopoietic stem cell transplantation (HSCT) – a transplant using stem cells (cells that can become any type of cell in the body). It’s best to carry out this procedure soon after diagnosis and before the disease progresses to a more severe phase. If the severe phase has been reached, efforts should be made to control the disease before proceeding with transplant. To manage this severe phase, a combination of drugs – dexamethasone, cyclosporine A, and etoposide – have proven effective, though relapses can occur. The overall survival rate after 5 years is around 62%, but this can vary based on the match of the donor’s and recipient’s immune cell markers (HLA) and the disease stage at the time of transplant.
For vision issues, correcting irregularities in the eye’s shape (refractive defects) might improve sight. Wearing sunglasses can also protect eyes sensitive to UV light. Regarding skin lightening (hypopigmentation), regular use of sunscreen can prevent sun damage and skin cancers. The level of protection needed depends on how severe the skin lightening is.
Neurological symptoms may progressively worsen, so it’s important for older patients to start rehabilitation early in the disease course.
Efforts should be made to limit exposure to infectious agents. Certain anti-inflammatory drugs (NSAIDs) should be avoided as they can increase bleeding risks. Antibiotics should be used promptly to manage bacterial infections. The use of preventive antibiotics prior to dental or invasive procedures is debated, but could be necessary in certain cases. Immunizations are important. For those undergoing invasive procedures, a medication named desmopressin can be given intravenously to control bleeding. A platelet transfusion might be required in serious trauma cases or extensive bleeding scenarios.
In terms of monitoring, there are no specific guidelines that apply to everyone. It is generally recommended, however, that patients are evaluated for HSCT as soon as possible after diagnosis and that eye exams are carried out. For the atypical or adult-onset form of the disease, yearly screenings are recommended which include an abdominal ultrasound, a complete blood count and tests to check for signs of liver disease, high blood fat levels (hypertriglyceridemia), levels of an iron-storing protein (serum ferritin), and levels of a specific immune system protein (interleukin-2 receptor). If there is a suspicion of involvement of the brain or spinal cord or the disease is progressing rapidly, further tests might be needed. Finally, in the case of pregnancy, there isn’t much data available, but it seems the disease doesn’t impact pregnancy, labor, or affect mothers who have been diagnosed with the disease.
What else can Chediak-Higashi Syndrome be?
When diagnosing genetic conditions that affect the color of the skin, hair, and eyes (oculocutaneous albinism), doctors should consider other similar conditions. These may include:
- Griscelli Syndrome: This rare disorder has features in common with Chediak Higashi including partial albinism, low counts of all blood cells (pancytopenia), the eating away of blood cells by certain white blood cells (hemophagocytosis), and problems with both the antibody-mediated and cell-mediated parts of the immune system.
- Hermansky-Pudlak Syndrome: This is identified by eye and skin color problems, bleeding issues, and unwanted matter (ceroid lipofuscin) accumulating in different organs. However, these syndromes don’t show abnormal particles in a specific type of white blood cell (neutrophil), which is typical for Chediak Higashi.
- Pseudo-Chediak-Higashi Anomaly: Large particles like those in Chediak Higashi can also be observed in types of blood cancer, namely acute and chronic myeloid leukemia. When this happens, it’s referred to as the Pseudo-Chediak-Higashi anomaly.
Other conditions worth considering are:
- Cross Syndrome: This is identified by less pigmentation, involvement of the central nervous system including developmental delay, and eye abnormalities.
- Deficiency of Endosomal Adaptor P14: Identified in 2007, this syndrome includes short height, partial albinism, innate low neutrophil levels, and lymph deficiency. In this case, the neutrophils show heavy particles and unusual functions around the ingestion and neutralization of bacteria (phagosome functions). This is different from the giant particles seen in neutrophils in Chediak Higashi.
- Familial Hemophagocytic Lymphohistiocytosis: A disorder inherited in a manner where both parents must pass the gene to the child (autosomal recessive). It’s caused by a mutation in one of five genes, leading to five subtypes of the condition. Symptoms include prolonged fever, enlarged liver and spleen, and abnormalities in the nervous system including lack of coordination, coma, paralysis on one side, fits, and increased pressure within the skull. This may start early within the first few months of life or even in the womb. However, symptoms can also appear later in childhood or adulthood.
What to expect with Chediak-Higashi Syndrome
Chediak Higashi syndrome is a condition that is primarily dangerous due to recurrent infections or a rapid progression phase where there is an excessive growth of lymphatic cells into important organs. The majority of deaths, around 80%, happen within the first 10 years of the patient’s life. If a person with Chediak Higashi syndrome lives into their adult years, they typically start to experience worsening neurological symptoms.
Preventing Chediak-Higashi Syndrome
This is a disease that is passed down through families, meaning that both parents must carry one abnormal LYST gene, even though they themselves do not show symptoms of the disease. Doctors often recommend a type of testing called molecular genetic testing to determine if the parents are carriers of this gene.
If both parents carry the gene, there is a 25% chance their child will develop the disease. There is also a 50% chance the child could carry the abnormal gene but not show signs of the disease and finally, a 25% chance the child will not have the disease or carry the gene.
It’s important that brothers and sisters of a child with the disease also get tested. This is critical because, if they are also at risk, the quicker they start treatment, the better the outcome. In this case, HSCT is a treatment that could be carried out before more severe symptoms develop.
There are different types of testing. If we know the exact abnormal gene in your family, we can look for it directly. If we don’t know the exact abnormal gene, we can look at a blood sample under a microscope to check for signs of the disease.
The best time to check someone for this gene or for their likelihood to develop the disease is before they plan on having a child. It’s important for adults who carry the gene or might carry the gene, or who have the disease, to understand the risks and complications. They should consider genetic counseling to help them understand these risks. There is also a method called preimplantation genetic diagnosis. This is an option for couples where the abnormal gene is known, and it can help them prevent passing it on to their children.
Doctors can also suggest a process called DNA banking for people with the disease. This involves storing the DNA, usually from white blood cells, for future use. As our understanding of genes continues to improve, this could potentially be helpful in the future.