What Is Chediak Higashi Syndrome?

Overview

Chediak-Higashi syndrome is a very rare disorder that affects several different parts of the body, most notably the immune system. This condition destroys immune system cells, making them less capable of fighting off invaders like viruses and bacteria. As a result, the majority of people with Chediak-Higashi syndrome experience recurring and chronic infections beginning in infancy or early childhood. These infections are often fatal or life-threatening.

Chediak-Higashi syndrome is further distinguished by albinism, a disorder characterised by unusually light colouring (pigmentation) of the skin, hair, and eyes. Affected people usually have fair skin and light-coloured hair with a metallic sheen. It also affects vision, causing issues such as blurred vision, fast, involuntary eye movements (nystagmus), and increased light sensitivity (photophobia).

Blood clotting (coagulation) problems in people with Chediak-Higashi syndrome cause easy bruising and erratic bleeding. Chediak-Higashi syndrome can also cause nervous system impairment in adults, resulting in weakness, clumsiness, difficulty walking, and seizures.

The majority of children with Chediak-Higashi syndrome move to the disorder's accelerated phase if the disease is not effectively managed. A viral infection is thought to be the cause of this severe stage of the disease. During the accelerated phase, white blood cells (which normally help fight infection) divide fast and invade many of the body's organs. The accelerated phase is distinguished by fever, unusual bleeding, overwhelming infections, and organ failure. In most cases, these medical disorders are fatal in youngsters.¹

Pathophysiology (Mechanism of disease formation)

The Chediak-Higashi syndrome (CHS1) gene (aka lysosomal trafficking regulator gene LYST) mutation disrupts protein synthesis and affects the storage and secretory functions of lysosomal granules (organs in cells that contain enzymes) of white blood cells like (leukocytes, fibroblasts, platelets, azurophilic granules of neutrophils, and melanosomes of melanocytes). Larger vesicles and inactive lysosomes are the result of the abnormalities.

These lysosomes are found in lymphocytes (white blood cells), which aid in the battle against infection. As a result, lymphocytes become dysfunctional. Natural killer cell activities were also observed to be decreased. Platelet aggregation was hampered and bleeding duration was extended due to a paucity of granules holding serotonin and adenosine phosphate (chemicals essential in the coagulation process).

CHS has a phase called the accelerated phase, which arises in 85% of the individuals affected. It is associated with a poor prognosis. In this phase, these lymphocytes spread all over the body and in huge numbers. It is believed that these lymphocytes help in the breakdown and consumption of red blood cells with the help of phagocytes (another white blood cell). This phase presents with liver, spleen, and lymph node enlargement and bone marrow failure.^{2 3}

Clinical presentation 

Patients with symptoms present at a young age. The severity of the condition has been found to correspond with genetics. In general, gene mutations that result in a loss of function cause the illness to manifest severely in childhood. Certain other forms of mutations, on the other hand, are linked to a milder teenage or adult-onset illness. 

The severity of the disease is linked not only to heredity but also to its biological expression. For example, investigations of individuals with various clinical presentations revealed a variety of intracellular granule expansions in distinct cell types.

The manifestations include:^{1 3}

• Partial oculo-cutaneous albinism (eye albinism):  This is a noticeable trait. However, the amount of colour dilution varies. It can affect the skin, hair, and eyes. The hair has a "silvery" look in the typical stages of the condition. The pigmentation of the retina is decreasing. As a result, visual acuity may be compromised, and individuals may have normal vision or some significant impairment.
• Immunodeficiency (weak immune system): Affected people suffer recurring infections that are generally severe and start in infancy. Bacterial and fungal infections are more common in patients. Some of the most frequent illnesses are skin infections and upper respiratory tract infections. 
• Bleeding tendency: Nasal bleeding, mucosal or mouth bleeding, and easy bruising are common symptoms. Symptoms are modest and usually do not necessitate medical attention.
• Neurologic manifestations: Despite successful stem cell transplantation, neurological symptoms appear by early adulthood. These alterations are caused by the disease's long-term development and include stroke, coma, ataxia, tremors, motor and sensory neuropathies, and the absence of deep tendon reflexes.

Diagnosis & management 

Some of the signs and symptoms are quite similar to cancer; therefore, it is critical that your healthcare practitioner takes a complete history to rule out cancer. Otherwise, diagnosis is made clinically, using diagnostics such as peripheral blood smear microscopy and/or molecular genetic testing.

Treatment of Clinical Symptoms:¹

1. Weak immune system
   • Hematopoietic stem cell transplantation (HSCT) is the sole treatment. As a result, HSCT should be performed as soon as the diagnosis is established.
   • When HSCT is performed prior to the establishment of the accelerated phase, the outcomes are the best. As a result, before HSCT can be performed, the accelerated phase must be ruled out or in remission.
   • If there is evidence of an accelerated phase, hemophagocytosis should be brought into remission before undergoing HSCT.
   • The treatment guidelines for the accelerated phase include a combination of medications (dexamethasone, cyclosporine, and etoposide). By eight weeks, around 75% of people have achieved remission. Relapses are common, and treatment responsiveness deteriorates over time.
2. Ocular symptoms
   • Correcting refractive problems may enhance visual acuity.
   • Sunglasses should be used to protect the eyes from UV radiation.
3. Hypopigmentation: To avoid skin cancer and UV damage, people should apply sunscreen. The level of protection is determined by the severity of hypopigmentation.
4. Neurological manifestation: Because the symptoms are progressive, elderly individuals should begin rehabilitation as soon as feasible during the course of the disease.

Avoiding secondary complications:

• As much as possible, protect yourself from infectious agents.
• NSAIDs (pain medications) should be avoided as well since they might increase bleeding tendencies.
• Antibiotics should be used promptly and aggressively to treat bacterial infections.
• The widespread use of antibiotic prophylaxis before dental or invasive treatments is debatable. It should, however, be considered in patients with a weakened immune system.
• Immunisations should be given.
• Intravenous desmopressin should be administered for 30 minutes before any invasive operations to assist in reducing bleeding. Platelet transfusion may be required in cases of severe trauma or substantial bleeding.

Monitoring

1. Classical chediak higashi
   • There are no specific guidelines for surveillance. 
   • Once a diagnosis has been established, the current norm is to assess for HSCT as soon as feasible.  
   • An ophthalmologic examination is also necessary.

There is little information accessible for those who have Chediak Higashi. However, there is no known effect on pregnancy or labour. The disease's progression had no influence on moms who were diagnosed with it.

Prognosis and complications

Recurrent infections or the development of an accelerated phase with lymphoproliferation into major organs are the most prevalent causes of mortality in people with Chediak Higashi syndrome. Eighty per cent of fatalities occur within the first decade of life, and those who survive into maturity acquire increasing neurological problems.¹

FAQs

What causes chediak higashi syndrome (CHS)? 

CHS is caused by a gene mutation in the CHS1 gene, which in turn leads to the process of lysosomal formation becoming dysfunctional. This leads to the lysosomes becoming too big or too small. Along with this, the white cells also get reprogrammed to attack the body's own cells.

Is CHS hereditary, and how is it inherited? 

CHS is a hereditary disease; it is inherited in the autosomal recessive pattern, which means that the affected individual will need a gene from each parent to be a person that manifests the disease. 

What are the key symptoms of CHS? 

Key symptoms of CHS are albinism, weak immune system - multiple infections, bleeding tendency and neurological manifestations like tremors, ataxia and reflex problems.

How is CHS diagnosed, and what tests are involved?

In CHS a blood test will show decreased neutrophils. A peripheral blood smear under a microscope will show giant granules in white cells.  A bone marrow sample can also be taken to see under a microscope, which will show more bodies in white cell precursors. Finally, a genetic test can be done for CHS1 mutations.

Summary 

Chédiak-Higashi syndrome (CHS) is a rare autosomal recessive lysosomal condition marked by recurrent infections, oculocutaneous albinism (OCA), bleeding complications, and gradual neurologic deterioration. CHS patients experience the accelerated phase in 85% of cases, which is characterised by infections, exhaustion, bruising, high fever, and white cell infiltration of the liver, spleen, and lymph nodes. Treatment for accelerated-phase CHS is complicated, and the outlook is bleak. All afflicted people, including adolescents and adults with atypical CHS and children with classic CHS, acquire neurologic symptoms during early adulthood after undergoing allogeneic hematopoietic stem cell transplantation (HSCT).

Routine infection prevention measures include educating the kids and carers about proper hygiene and paying close attention to oral and dental care. Sunscreen and skin protection should be worn to avoid sunburn and to protect delicate eyes from UV rays. While all dead or inactivated vaccinations are safe for these people, live vaccines are not.