Dyskeratosis Congenita

Estimated to occur in one out of one million people, Dyskeratosis Congenita (DC) is a genetic disorder that can be inherited from family members, or develop as a new mutation while inside the womb. DC can affect virtually any organ in the body, but primarily targets those organs that need continual regeneration to survive. The organs most commonly involved are the skin and nails, the bone marrow where blood cells are produced, the lung and the gastrointestinal tract, including the liver. Patients with DC are also more at risk of developing certain types of cancers, compared with other people in the general population.

Signs and symptoms of DC 

The symptoms and the age of presentation in DC varies considerably from patient to patient. Most often, symptoms of DC present by the age of 10, but some patients are adults before signs appear. Skin and nail abnormalities, irregular changes in mucus membranes (the lining of the mouth), and bone marrow failure (low blood cell counts) are among the most common symptoms, but a host of other complications are associated with the disease (see below). Most commonly, serious symptoms such as bone marrow failure and pulmonary fibrosis do not appear until a patient’s 20s or 30s, however there are more severe forms of DC which present in very young children.

The most typical symptoms of DC include the combination of:

Skin abnormalities

  • Abnormally light or dark patches of skin, usually seen on the face, neck and upper chest
  • Thickening of the skin on the palms and soles of the feet can also occur

Nail abnormalities

  • Thin, brittle nails often with ridges in them. Patients can often completely lose their nails, both on the hands and the feet.

White spots on the inside of the mouth (mucous membranes) known as leukoplakia

  • These spots are often the site of later development of cancers in patients with DC

Low blood cell counts due to bone marrow failure

  • Can present with bleeding, tiredness due to anaemia or infections
  • This is the most serious complication of DC, and is the cause of death in up to 70% of patients.

Other symptoms may include:

Hair

  • Alopecia (balding) of the scalp, eyebrows, and eyelashes, and premature greying

Lung complications

  • Approximately 20% of patients develop pulmonary problems such as pulmonary fibrosis
  • This is the second leading cause of death in patients with DC, accounting for 20% of deaths

Eyes

  • Patients with DC have shown increased incidence of conjunctivitis and either excessive tearing or excessive dryness

Bones

  • Patients may have osteoporosis (thinning of the bones), aseptic necrosis (bone death, usually involving the hip bone), scoliosis (curved spine), and/or mandibular hypoplasia (small jaw)

Gastrointestinal tract

  • Cirrhosis of the liver – scarring in the liver which can lead to liver failure
  • Difficulty swallowing due to narrowing of the oesophagus

Neurologic

  • Some patients may show signs of learning issues and mental retardation

Genitourinary

  • Abnormalities of the genitals or urinary tract.

Genetics of DC and diagnosis

It is known that DC is a disorder that effects the telomere. The telomere is DNA found at the very ends of the chromosomes, and they act to cap and protect the important genetic material found within the chromosome. When telomeres become extremely short, signals within the cell stop the cell from dividing, or lead to death of the cell. To date, there are 11 genes known to be mutated in DC. All of these genes are important in maintaining adequate telomere length, or in helping the telomere to function as a protective cap. In patients with DC, dysfunction of the telomere as a result of mutations in these genes results in certain cells, especially those that more frequently reproduce, being unable to regenerate normally. This ultimately leads to organ damage and dysfunction.

Diagnosis

The diagnosis of DC is difficult for many doctors. This is due to the rarity of the disorder, but also due to the many different combinations of symptoms patients with DC may present with. Patients who present with skin and nail changes along with low blood counts or pulmonary fibrosis, should be suspected of having DC, and testing should be arranged. All patients who have family members who also suffer from bone marrow failure, lung fibrosis or liver cirrhosis, should also consider having testing performed. A thorough family history also helps to identify patients who may have DC.

Testing for DC can take a number of forms. Initially, tests to identify organ damage and failure may need to be carried out. This includes blood tests looking at blood cell counts, liver and kidney function, but may also include bone marrow biopsies and scans of various organs, e.g. lung and liver scans. Most patients with DC have very short telomeres when tested, and telomere length testing can act as a screening test for DC.

Ultimately, finding a genetic mutation in one of the 11 known genes that causes DC will confirm the diagnosis. Once this is known, testing on other family members may be carried out in order identify other affected individuals.

Telomere length testing and genetic testing are now available in Australia. For further information, please contact a member of DCOP who can provide details of this testing to your treating clinician.

Treatment of DC

At present there is no cure for DC. Once a patient is diagnosed with DC, the aim of treatment is to monitor for known complications, and avoid medication or lifestyle choices which may trigger or worsen these complications. Regular surveillance for cancer is important, so that early surgical treatment can be successful before the cancer spreads. Monitoring bone marrow, lung, kidney and liver function are also important.

The most serious complication of the disease is bone marrow failure, and there are several management options for patients. Anabolic steroids and bone marrow-stimulating drugs can encourage cell production in the bone marrow. This can boost blood counts, leading to decreased bleeding, infection or anaemia. Some patients require blood transfusions if their bone marrow failure is severe.

Bone marrow, or stem cell, transplantation (BMT) is the only long-term solution for bone marrow failure.  However, BMT treats only the marrow failure.  It will not cure DC, and a patient who has undergone BMT is still at risk of all the other problems associated with the disease.  As researchers and doctors have advanced their understanding of DC and honed the transplant process, success rates for this therapy have improved. However, transplant continues to carry a high risk for even the most ideal candidate.

There is no cure for other manifestations of DC. When organ damage and dysfunction becomes life threatening, organ transplantation, such as lung transplantation, may be an option.

Future research

Around the world, researchers are studying the science behind DC, hoping to understand its causes, but more importantly to treat and possibly cure the illness. More accurate treatments are being developed as the subtleties that underlie the spectrum of symptoms of Dyskeratosis Congenita are uncovered. Discoveries about the faulty genetic mechanisms that underlie the condition have given rise to potential cellular therapies that might one day facilitate good health.

Within the past decade as diagnoses have improved, more and more patients with DC have been identified. However, the rarity of the condition has prevented broad understanding. As more physicians become aware of the disease and can recognize its manifestations, more will be learned.

In the USA, DC Outreach is undertaking the creation of a universal medical treatment protocol, which will help provide the first-ever comprehensive set of guidelines for the management and treatment of the disease.

With the internet’s ability to uncover information, patients around the world are finding others like them. As the DC community grows so does its support network. DC Outreach members’ lives are made easier knowing other people with so much in common. The strength gained through increased numbers and awareness will only bear positively on our futures.