Introduction

Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disorder which is caused by mutations in the lysosomal trafficking regulator (LYST) gene, meaning that an individual receives a copy of the faulty gene from each parent. It primarily affects the body’s immune system, nervous system and can affect pigmentation of the hair and skin, leading to an easily identifiable silver hair colour. Most cases occur during childhood, with patients experiencing an overwhelming number of infections, or they go through an accelerated phase in which the body cannot cope, resulting in most affected individuals passing away before they reach the age of 10.

Atypical or late-onset CHS is a type of the syndrome that generally has less-noticeable symptoms and typically has a later onset than the normal form of Chediak-Higashi syndrome. In some cases, the disorder may initially be considered as a different condition, leading to delays in treatment and misdiagnosis. Individuals may also have a slower or more subtle progression in symptoms, such as a less damaging impact on the immune system or nervous system, which complicates clinical diagnosis and assessment.

Early detection of atypical or late-onset Chediak-Higashi Syndrome is crucial for both diagnosis and treatment. The sooner that the individual is diagnosed, the more effective the treatment course can be, improving quality of life and reducing the risks associated with the condition. In this article, we will be delving further into the diagnostic challenges associated with atypical or late-onset CHS and the problems that occur during treatment.

Classic features of chediak-higashi syndrome

Caused by a genetic mutation in the LYST gene, Chediak-Higashi Syndrome is an autosomal recessive condition that affects the immune system, although it can affect other parts of the body. It mainly damages and harms the cells in the immune system, leaving them vulnerable to infections from bacteria and viruses. Therefore, individuals suffering from this condition have repeated infections that start from early childhood, which can be very dangerous and life-threatening.¹

There are several key clinical features present in children with CHS. One of the most important features is partial oculocutaneous albinism, which is when there is a reduction in melanin in the skin, hair and eyes, rather than a complete absence. In CHS, this is evident with the presence of silver-coloured hair and very light skin colour due to the change in melanin levels. Immunodeficiency is another prominent feature, with one of the important immune cells affected being cytotoxic T-lymphocytes, which release their granules and thus cytotoxic molecules to the outside of the cell in a process known as degranulation.² Since the immune system is compromised, this leads to the individual developing numerous recurrent infections, which are mainly bacterial. These infections tend to affect the skin region, the upper and lower respiratory tract and also the oral mucosa.

The accelerated phase happens in around 85% of cases and is the most common cause of mortality in individuals since it can happen at any age. Symptoms during this phase can be fever, anaemia, jaundice, enlarged liver and spleen (hepatosplenomegaly) and swollen lymph nodes (lymphadenopathy). The lack of Natural Killer (NK) cells and the impact of certain infections are thought to hasten this phase; more research is needed to confirm this.³

Atypical or late-onset CHS

Atypical or late-onset CHS differs from normal Chediak-Higashi Syndrome in the sense that, rather than having most of the symptoms such as partial oculocutaneous albinism, recurrent infections and an accelerated phase occurring during infancy or childhood, individuals with atypical CHS tend to see symptoms when they are teenagers or going into adulthood. Since it is possible that no significant symptoms are present until the second or third decade of an individual’s life, it is possible that atypical CHS can be misdiagnosed or detected with a delay due to the fact that the presentation of the condition may overlap with other neurodegenerative disorders.

Partial oculocutaneous albinism is another factor that is seen either very mildly or not at all. Not being able to see the distinct silver hair or hypopigmented skin that normally occurs during childhood means that diagnosing atypical CHS can be more difficult. Other neurodegenerative disorders, such as Parkinson’s, peripheral neuropathy and cerebellar deficits.⁴ These neurological symptoms are generally progressive and can make the person become very weak and dependent, having a huge effect on their quality of life.

Atypical CHS is an extremely rare condition, with only a few reported cases being documented. Its under-recognition is due to a combination of a generally subtle clinical presentation along with the absence of obvious immunodeficiency and pigmentation changes. As a result of this, many individuals go through multiple neurological and genetic tests before a confident diagnosis can be achieved, often years after symptoms appear.

Diagnostic challenges

Diagnosing atypical CHS has many diagnostic challenges due to its variable clinical features that are often nonspecific. Individuals often have progressive neurological symptoms such as peripheral neuropathy and cytopenia. Since other neurodegenerative and autoimmune diseases have similar symptoms, these signs can be mistakenly assigned to a different disorder, leading to misdiagnosis or even a delayed diagnosis. The overlapping of syndromes with conditions such as Hemophagocytic Lymphohistiocytosis (HLH) creates further confusion during diagnosis, especially in adults, where atypical presentations of CHS are less recognised.

One of the main reasons why a timely diagnosis is often not performed is due to the limited awareness of CHS amongst adult healthcare professionals. Since most reported cases happen in children, late-onset or atypical CHS may not be one of the conditions being considered for diagnosis. As a result, many individuals may go for years of testing and evaluations before the underlying cause is detected. A family history check can provide useful information, especially in cases where siblings or other relatives show similar symptoms. Genetic testing is crucial for diagnosis, particularly focusing on the mutations in the LYST gene. Peripheral blood tests are an important tool, as they can reveal characteristic granules in leukocytes, which are a distinct finding in CHS. Early diagnosis is essential for being able to provide support and manage symptoms, especially given the progressive nature of the neurological symptoms present in atypical CHS.

Therapeutic challenges

Atypical or late-onset CHS also has therapeutic challenges, as it is a progressive disease, meaning it gets worse over time. At the moment, Hematopoietic Stem Cell Transplantation (HSCT) is the only potentially curative treatment, showing signs at addressing the immunological defects and also preventing Hemophagocytic Lymphohistiocytosis (HLH).⁵ The problems lie in the fact that it does not work on all individuals, and it can be difficult to find donors in time, since the majority of patients die by the age of 10 due to the accelerated phase. This delay can lead to irreversible changes, such as progressive peripheral neuropathy, which don’t show any changes with current therapies. HSCT also does not reverse neurological damage that has already occurred.

Individuals get severe and recurrent infections, which can complicate the treatment procedure since many antibiotics, antifungal and antiviral medications will need to be prescribed to help keep the infections under control, which can be quite aggressive on the immune system. Patients will need constant care and support, symptomatic treatment and often physical rehabilitation, so they are under constant evaluation. If an individual develops HLH, treatment in the form of corticosteroids and medications such as cyclosporine may need to be given.⁶ The difficulty is managing and balancing immunosuppression whilst also preventing future infections from happening, which is a delicate and difficult task, which is why it poses a therapeutic challenge.

Summary

Atypical or late-onset CHS has many different diagnostic and therapeutic challenges, which can be hard to overcome. Unlike the normal paediatric form of CHS, the atypical version often has less subtle symptoms that can be hard to identify and diagnose, which leads to a delayed diagnosis. This delayed diagnosis can lead to irreversible damage and complications such as progressive neurodegeneration, which shows no significant improvement with current therapeutic treatments. Managing HLH episodes, recurrent chronic infections and immunological problems in patients adds complexity to treatment options, requiring a lot of time and effort to overcome.

As late-onset CHS is extremely rare and subtle, increased clinical observation is required and essential. Medical professionals need to consider every option during diagnosis and not overlook the possibility of CHS, even if it’s regarding an adult. Symptoms such as recurrent infections, unexplained immunodeficiency and even a progressive neurological symptom such as giant lysosomal granules in leukocytes (white blood cells) will need to be examined on the off chance that atypical CHS is present.

While there is no definitive cure for late-onset CHS, early detection can help control conditions, manage HLH episodes effectively and also potentially slow down neurological decline. As more time and research are spent on CHS and there is a greater understanding, hopefully, more effective treatment will be discovered, offering better solutions for this debilitating condition.