On this page
Dyskeratosis congenita (autosomal dominant)
This rare genetic disorder can lead to bone marrow failure, distinctive skin and nail changes, and an increased risk of certain cancers. It affects individuals from childhood and requires lifelong medical management.
Available at Jeen Health
Clinical tests that include this
Overview
Dyskeratosis congenita (DC) is a rare genetic disorder recognised by its characteristic triad of symptoms: abnormalities of the skin pigmentation, nail dystrophy, and white patches inside the mouth (oral leucoplakia) [PMID:33675402]. However, the condition can also affect many other parts of the body, including the bone marrow, lungs, and immune system. DC is part of a group of disorders called 'telomere biology disorders', which are caused by problems with the body's telomeres, protective caps at the ends of chromosomes.
Individuals with DC often experience a gradual decline in the ability of their bone marrow to produce blood cells, known as bone marrow failure. This can lead to serious complications such as anaemia, bleeding, and infections. The condition typically manifests in childhood, but the severity and age of onset can vary significantly between affected individuals, even within the same family [PMID:33675402].
Autosomal dominant DC means that inheriting just one copy of an altered gene is enough to cause the condition. Understanding this inheritance pattern is important for family planning and involves offering genetic counselling to discuss risks for relatives.
Symptoms & clinical features
The classic presentation of dyskeratosis congenita involves skin, nail, and oral features. Skin changes often include a lace-like or reticular pattern of hyperpigmentation (darkening), particularly on the neck, chest, and upper arms [PMID:33675402]. Nails can become thin, brittle, ridged, or grow poorly (nail dystrophy).
Oral leucoplakia, white patches in the mouth, is another key sign and carries a risk of transforming into oral cancer. Beyond these features, individuals may develop bone marrow failure, leading to anaemia (low red blood cells), thrombocytopaenia (low platelets causing bruising and bleeding), and leucopenia (low white blood cells making infections more likely). Lung fibrosis (scarring of the lungs), liver problems, and an increased risk of certain cancers, particularly head and neck cancers and acute myeloid leukaemia, are also associated with DC [PMID:33675402].
Other symptoms can include tooth abnormalities, eye issues, and gastrointestinal problems. The range and severity of these symptoms can differ greatly among individuals with DC, meaning some individuals may have only mild features, while others experience more severe, life-threatening complications.
Video: Genetics 101
Affected organs
Dyskeratosis congenita can affect multiple organ systems throughout the body. The primary systems involved are the bone marrow, leading to its failure to produce blood cells; the skin, manifesting as characteristic pigment changes; and the nails, showing dystrophy or abnormal growth. The mucous membranes of the mouth are also commonly affected, with white patches.
Less commonly, other organs can be involved, including the lungs (pulmonary fibrosis), liver (cirrhosis), and tear ducts (narrowing). The condition can also impact the immune system, making individuals more susceptible to infections. There is an increased risk of various cancers, reflecting the widespread impact of telomere dysfunction on cell health.
Risks & severity
The severity of dyskeratosis congenita is highly variable, ranging from mild symptoms that may be overlooked to severe, life-threatening complications occurring early in life. The most significant complication is bone marrow failure, which affects many individuals and is a leading cause of mortality [PMID:33675402]. The median age of onset for bone marrow failure can vary, but it often develops during childhood or early adulthood.
Individuals with DC also have a substantially increased lifetime risk of developing certain cancers, including squamous cell carcinomas of the head and neck, skin, and anogenital region, as well as acute myeloid leukaemia [PMID:33675402]. The risk of these cancers typically increases with age. Pulmonary fibrosis is another serious complication that can develop, particularly in adulthood.
Due to the variable nature of DC, predicting the exact course for any individual is challenging. Regular monitoring and proactive management are crucial to address potential complications as they arise.
Genetic causes
Dyskeratosis congenita (autosomal dominant) is caused by pathogenic variants in genes involved in maintaining telomeres. Telomeres are protective caps at the ends of our chromosomes that prevent genetic information from being lost during cell division, similar to the plastic tips on shoelaces [PMID:36574971]. They shorten with each cell division, and telomerase, an enzyme, helps to replenish their length.
Key genes associated with autosomal dominant DC include TERC (telomerase RNA component) and TERT (telomerase reverse transcriptase). TERC provides the RNA template for telomerase, while TERT is the catalytic protein component that synthesises new telomere DNA. Pathogenic variants in these genes disrupt the normal function of telomerase, leading to abnormally short telomeres [PMID:36574971].
When telomeres become too short, cells may stop dividing, leading to tissue damage and organ dysfunction. This explains the wide range of symptoms seen in DC, as many different cell types rely on healthy telomeres for proper function and maintenance.
- TERC telomerase RNA component
- TERT telomerase reverse transcriptase
Inheritance pattern
Autosomal dominant inheritance means that a person will develop the condition if they inherit just one copy of the altered gene. This altered gene can be inherited from either parent. If one parent has an autosomal dominant form of dyskeratosis congenita, there is a 50% chance that each child they have will also inherit the altered gene and therefore potentially develop the condition, regardless of the child's sex.
It is also possible for an individual to develop autosomal dominant DC without having an affected parent. This occurs due to a 'de novo' (new) pathogenic variant in the TERC or TERT gene, which arises for the first time in that individual. In such cases, the individual would be the first in their family to have the condition.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosing dyskeratosis congenita typically begins with a clinical suspicion based on the characteristic symptoms, such as skin pigmentation changes, nail dystrophy, and oral leucoplakia, especially when experienced by a younger individual [PMID:36574971]. Bone marrow failure or unexplained cytopenias (low blood cell counts) can also prompt investigation.
Confirmation of a DC diagnosis usually involves genetic testing to identify pathogenic variants in genes like TERC or TERT. Genetic testing can be accessed through the NHS Genomic Medicine Service, often following a referral from a specialist clinic, such as haematology, dermatology, or clinical genetics. The relevant NHS National Genomic Test Directory R-codes cover tests related to inherited bone marrow failure, or telomere biology disorders, which include DC. Measurements of telomere length may also provide supportive evidence for the diagnosis.
Management & lifestyle
Management of dyskeratosis congenita requires a multidisciplinary approach, involving specialists such as haematologists, dermatologists, respiratory specialists, and geneticists. The focus is on monitoring for potential complications and addressing symptoms as they arise. Regular full blood counts are essential to monitor for the development of bone marrow failure.
Bone marrow failure can be treated with therapies such as androgens to stimulate blood cell production, or in some cases, a bone marrow transplant (also known as a haematopoietic stem cell transplant) may be considered. Surveillance for cancer is also crucial, particularly for squamous cell carcinomas, and may involve regular physical examinations and endoscopic checks. Lung function tests can help monitor for pulmonary fibrosis.
Individuals with DC should avoid exposure to certain environmental factors that could worsen their condition, such as radiation and some chemotherapeutic agents. Genetic counselling is an important part of the management, offering support and information to individuals and families regarding the inheritance pattern and implications for family members.
UK care pathway
In the UK, individuals suspected of having dyskeratosis congenita would typically be referred to specialist clinics within the NHS. This could be a haematology service for blood-related issues, or clinical genetics for an assessment and consideration of genetic testing. Genetic testing for DC falls under the NHS National Genomic Test Directory R-codes for inherited bone marrow failure syndromes or telomere biology disorders. If a genetic diagnosis is confirmed, individuals and their families will have access to genetic counsellors. These professionals can provide information, support, and help families understand the condition, its inheritance, and implications for future planning.
Frequently asked questions
Is dyskeratosis congenita always severe?
No, the severity of dyskeratosis congenita can vary widely. Some individuals may experience mild symptoms that develop later in life, while others can have severe, life-threatening complications, such as bone marrow failure, early in childhood. Regular monitoring helps manage symptoms as they arise.
What is bone marrow failure?
Bone marrow failure occurs when the bone marrow, the soft tissue inside your bones, stops producing enough healthy blood cells. This can lead to anaemia (too few red blood cells), needing blood transfusions, increased risk of infections due to low white blood cells, and easy bruising or bleeding from low platelets.
Is there a cure for dyskeratosis congenita?
Currently, there is no cure for the underlying genetic cause of dyskeratosis congenita. Management focuses on treating symptoms and preventing complications. For severe bone marrow failure, a bone marrow transplant may be an option, but this carries its own risks and is not suitable for everyone.
Can dyskeratosis congenita be inherited if neither parent has the condition?
Yes, in some cases. While autosomal dominant means one affected parent can pass it on, it can also occur if a new (de novo) genetic alteration happens for the first time in an individual. In such situations, the individual would be the first in their family to have dyskeratosis congenita.
How often should someone with DC be monitored for cancer?
Individuals with dyskeratosis congenita have an increased risk of certain cancers. Therefore, regular cancer surveillance is typically recommended, with the frequency and type of screening tailored to the individual's age and specific risk factors. Your specialist team will provide guidance on appropriate monitoring schedules.