Dyskeratosis congenita and telomere biology disorders

A rare condition that begins at the ends of chromosomes

Dyskeratosis congenita is a rare inherited disorder that can affect the nails, skin, mouth, bone marrow, lungs and liver. It belongs to a wider group called telomere biology disorders, which share one thread: the protective caps on chromosomes are shorter than they should be. MedlinePlus estimates that it occurs in about 1 in 1 million people.

This page explains what telomeres do, how the condition shows up in the body, and how it is diagnosed. For the wider picture of marrow failure, see our overview of acquired vs inherited bone marrow failure.

What telomeres do, in plain words

Telomeres are the caps at the ends of chromosomes, the long strands of DNA that carry our genetic information. The National Cancer Institute (NCI) compares them to the plastic tip on a shoelace, which stops the end from fraying.

Telomeres get a little shorter each time a cell divides. An enzyme complex called telomerase helps maintain their length by adding short repeated segments of DNA to the chromosome ends. When telomeres become too short, the cell stops dividing or dies. Fast-dividing cells, such as those in the bone marrow, skin, hair follicles and nail beds, feel the effects first.

The classic triad, and why not everyone shows it

The traditional picture has three features. The first is nails that grow poorly or take an abnormal shape. The second is a lacy pattern of skin colour changes, usually on the neck and upper chest. The third is white patches inside the mouth, called oral leukoplakia.

Not everyone develops all three, and they can appear at different ages. GeneReviews notes that the triad may be absent in some people, and that features can arrive later or develop over time. That variability can make proper diagnosis challenging.

Bone marrow failure, lungs and liver

Marrow failure

Around half of people with dyskeratosis congenita develop bone marrow failure, according to the NCI. Marrow failure usually begins with a low count of one blood cell type and progresses to low counts in two or more types, which is the pattern called aplastic anaemia. Dyskeratosis congenita also raises the risk of myelodysplastic syndrome. For a related inherited marrow failure condition, see Shwachman-Diamond syndrome. Diagnosis is usually made between the ages of 10 and 30, because the physical signs tend to become more obvious with age.

Lungs and liver

Pulmonary fibrosis, scarring of the lungs that makes it harder for oxygen to pass into the blood, may be the first sign or may develop over time. GeneReviews says it may be more common after a stem cell transplant. Abnormal connections between blood vessels in the lungs, called pulmonary arteriovenous malformations, have also been reported.

Liver disease is increasingly recognised as a serious complication. Reported problems include nodular regenerative hyperplasia, fibrosis, cirrhosis and portal hypertension, and some people need a liver transplant. GeneReviews advises annual liver function tests whether or not androgen therapy is used, and close monitoring after transplant.

Cancer risk and what it means for monitoring

People with dyskeratosis congenita have a raised risk of several cancers, most notably leukaemia and squamous cell cancers of the head, neck and anogenital region. In an NCI cohort of 197 people followed for 15 years, cited in GeneReviews, the median age of cancer onset was 38. Head and neck squamous cell carcinomas were the most frequent solid tumours in that group.

Because these cancers can appear at unusually young ages, GeneReviews advises that a head or neck cancer in a person under 40 should prompt consideration of a telomere biology disorder. It also describes annual screening by an ear, nose and throat specialist and a dermatologist as part of surveillance.

Is dyskeratosis congenita inherited?

It can be, but the pattern depends on the gene involved. The NCI notes that more than a dozen genes have been linked to the condition. MedlinePlus reports that changes in TERT, TERC, DKC1 or TINF2 account for about half of cases. Some TINF2 variants arise spontaneously rather than being passed down, and in some people no changed gene is found.

The main patterns are:

• X-linked recessive, mostly through changes in DKC1, which affects males more often than females.
• Autosomal dominant, where one altered copy of a gene is enough to cause the condition.
• Autosomal recessive, where both copies of the gene must be altered.

Diagnosis: physical signs, telomere length and genes

Diagnosis brings together physical signs, family history and laboratory results. The NCI suggests that at least two of the three classic features, or other classical findings, should prompt testing. The key laboratory test measures telomere length in lymphocytes, a type of white blood cell. GeneReviews describes the standard method as flow-FISH, which compares the result with values for age. A result below the first centile for age was 97 percent sensitive and 91 percent specific for the condition in the reported data.

A short telomere result points towards a telomere biology disorder but does not name the cause. Genetic testing then looks for changes in the known genes. Clinicians choose a gene-targeted test when the features suggest particular genes, and a broader genomic test when they do not. The wider workup is covered in diagnosing bone marrow failure, and your haematology team can advise which route suits you.

When it appears as aplastic anaemia in adults

Some people first come to attention in adulthood with what is often called aplastic anaemia (aplastic anemia in US usage). Acquired aplastic anaemia is often progressive and can occur at any age. It has other known causes, including immune processes, infections and drug reactions, and in many people the cause is never found.

Telomere length testing helps identify the subset of later-onset cases that are in fact a telomere biology disorder. These people may have few or none of the other features, so the test may be the route to an accurate diagnosis. Someone with Fanconi anaemia, another inherited cause of marrow failure, may need a different set of tests, which is one reason the distinction matters.

Transplant considerations

Haematopoietic cell transplantation, usually called a stem cell transplant, is the only curative treatment for severe marrow failure or leukaemia in these disorders, according to GeneReviews. Outcomes have historically been poor, largely because of treatment toxicity, so transplant should take place at a centre experienced in these conditions. The donor matters too. Relatives who might donate should have telomere length or genetic testing, because family members can be mildly affected or show no features at all.

If no matched related donor is available, an unrelated donor transplant can be considered. GeneReviews notes that a trial of androgen therapy, such as oxymetholone or danazol, may be considered first. People with these disorders can be more sensitive to androgens, so the dose needs careful adjustment, with liver monitoring throughout. Haematopoietic growth factors should not be combined with androgens because of a rare risk of splenic rupture.

Living with a rare diagnosis

Questions about energy, work and family deserve their own answers. GeneReviews reports a clinically significant psychiatric diagnosis in 27 percent of 44 people in one recent retrospective study, so emotional health is worth raising early.

Community groups can help. Team Telomere describes itself as a community for people affected by telomere biology disorders, offering information and support to affected individuals, caregivers and families.

The clearest route runs through telomere length, not a single sign

No single feature settles the question. Telomere length testing, followed by genetic testing, turns a set of clues into a diagnosis, and that answer also shapes advice for relatives and transplant planning.