Chediak-Higashi-like (LYST)

Overview

Chediak-Higashi syndrome (OMIM: 214500) is a very rare inherited disorder. It is characterised by issues with the immune system, leading to a higher risk of severe and recurrent infections [PMID:30177726]. Beyond immune problems, the condition can also affect hair colour, skin, and the nervous system. It is present from birth, although the severity and specific signs can vary between individuals. This condition is universally caused by pathogenic changes in the LYST gene.

Symptoms & clinical features

Individuals with Chediak-Higashi syndrome often experience recurrent, severe bacterial infections, particularly affecting the lungs, skin, and gut. These infections can become life-threatening without appropriate clinical management [PMID:30177726]. Another common feature is hypopigmentation, which means reduced colouration of the skin and hair, often resulting in silvery-grey hair and paler skin compared to other family members. Affected individuals may also have problems with blood clotting and bruising easily, due to issues with platelet function [PMID:30177726]. Neurological symptoms can also develop, potentially including developmental delays or difficulties with movement and coordination, though these can vary in onset and severity.

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Affected organs

The primary organs affected in Chediak-Higashi syndrome are those involved in the immune system, such as the bone marrow, where immune cells are produced, and lymph nodes. These issues lead to a reduced ability to fight off infections. The skin and hair are also commonly affected due to problems with melanin production, which determines colour. In some cases, the nervous system can be impacted, which may lead to a range of neurological signs. Blood cells, particularly platelets, can also be affected, leading to clotting issues.

Immune cells

Immune system dysfunction

Cellular impact

Mechanism at cellular level

Risks & severity

Chediak-Higashi syndrome is typically a serious condition, with immune deficiency being a significant concern. The risk of severe, persistent infections is high and can lead to life-threatening complications. The severity of the condition can vary, even within the same family, with some individuals experiencing more pronounced symptoms than others. Neurological complications can also progress over time in some cases. The exact prevalence of Chediak-Higashi syndrome is not well established due to its rarity.

Genetic causes

Chediak-Higashi syndrome is caused by pathogenic changes in the LYST gene (lysosomal trafficking regulator). The LYST gene provides instructions for making a protein that is crucial for the proper formation and function of lysosomes within cells. Lysosomes are compartments within cells that digest and recycle waste materials; they are particularly important for immune cells and pigment-producing cells. Pathogenic variants in LYST disrupt this process, leading to abnormally large lysosomes and problems with their function [PMID:35073998]. This affects how immune cells can kill invading pathogens and how melanin is produced, explaining the immune deficiencies and hypopigmentation seen in the syndrome. It also impacts other cell types, leading to the broader range of signs.

• LYST
  lysosomal trafficking regulator
  The LYST gene provides instructions for producing the lysosomal trafficking regulator protein, which is critical for the proper function and movement of lysosomes within cells.

Inheritance pattern

Chediak-Higashi syndrome follows an autosomal recessive inheritance pattern. This means that an individual must inherit two copies of the altered LYST gene - one from each parent - to develop the condition. If a person inherits only one altered copy of the gene, they are typically a 'carrier' and usually do not show any signs or symptoms of the condition. When both parents are carriers, there is a 1 in 4 (25%) chance with each pregnancy that their child will inherit two altered copies and develop the syndrome. There is a 2 in 4 (50%) chance the child will be a carrier, and a 1 in 4 (25%) chance the child will inherit two working copies of the gene and not be affected or a carrier.

Diagnosis & testing

Diagnosis of Chediak-Higashi syndrome typically begins with recognising the characteristic clinical signs, such as recurrent infections, hypopigmentation, and abnormal bleeding or bruising. Blood tests may show specific immune cell abnormalities, such as the presence of abnormally large granules within white blood cells, which can be a key indicator. The diagnosis is confirmed through genetic testing, which identifies pathogenic changes in the LYST gene. In the UK, such genetic testing usually falls under the NHS Genomic Medicine Service (GMS) pathways, often initiated by a clinical geneticist, immunologist, or paediatrician. Relevant R-codes for genetic testing may include those for primary immunodeficiencies or syndromic conditions, depending on the specific clinical presentation and local laboratory offerings.

Management & lifestyle

Management of Chediak-Higashi syndrome focuses on addressing the specific symptoms and preventing complications. This often involves regular monitoring of immune function and prompt, aggressive treatment of infections with antibiotics or antifungal medications. Prophylactic antibiotics may be used to reduce the frequency of infections. Genetic counsellors can provide essential information and support to affected individuals and their families, helping them understand the condition and its inheritance pattern. Management is typically coordinated through specialist centres within the NHS, often involving multidisciplinary teams including immunologists, haematologists, neurologists, and dermatologists. There is no specific cure, so treatment aims to manage symptoms and improve quality of life.

UK care pathway

In the UK, individuals suspected of having Chediak-Higashi syndrome would typically be referred to a clinical genetics service or a specialist immunology or paediatric team within the NHS. These teams can assess symptoms, arrange appropriate investigations, and coordinate genetic testing through the NHS Genomic Medicine Service (GMS). Genetic counsellors are an integral part of this pathway, offering information, support, and discussions about the implications of a genetic diagnosis for the individual and family. The GMS uses a national test directory, which includes R-codes for various genetic tests; specific R-codes for primary immunodeficiencies or related syndromic conditions would be considered.

Related conditions

Chediak-Higashi syndrome is an autosomal recessive condition causing immune deficiency and hypopigmentation. Other conditions that cause immune deficiency or hypopigmentation, such as Griscelli syndrome or Hermansky-Pudlak syndrome, might also present with overlapping features. These conditions are typically differentiated through genetic testing, as they are caused by pathogenic variants in different genes.

Frequently asked questions