Dyskeratosis congenita (DC) is a very rare, inherited bone marrow disorder. It can be characterized by a variety of symptoms including skin abnormalities, abnormal nail growth, and lesions in the mouth and other mucous membranes. In approximately 90 percent of cases, patients develop progressive bone marrow failure. People with DC also are at higher risk of developing leukemia or myelodysplastic syndrome, a condition in which immature blood cells fail to develop normally.
DC is caused by a change/mutation in genes. Usually the genes that are not working correctly are passed to children by their parents, though sometimes this change can happen in a child without DC being passed on by his or her parents.
In about half of cases, DC is caused by mutations in the class="genesymbol"TERT, class="genesymbol"TERC, class="genesymbol"DKC1 or class="genesymbol"TINF2 genes, which provide instructions for making proteins that help maintain telomeres, structures located at the ends of chromosomes. Telomeres help protect chromosomes from abnormally sticking together or breaking down. In most cells, telomeres become progressively shorter as the cell divides. After a certain number of cell divisions, the telomeres become so short that they trigger the cell to stop dividing or to self-destruct. Telomeres are maintained by two important complexes called telomerase and shelterin. Telomerase adds small repeated segments of DNA to the ends of chromosomes each time the cell divides. Shelterin protects telomeres from the cell’s DNA repair process. Mutations in the TINF2 genes result in dysfunction of the telomerase or shelterin complexes, leading to impaired maintenance of telomeres and reduced telomere length.
The most typical symptoms of DC include the combination of skin and nail abnormalities, lesions in mucous membranes and bone marrow failure.
Skin abnormalities can include:
- Abnormal pigmentation with too much or not enough pigmented spots and patches. The pattern typically appears on the face, neck and upper trunk and involves sun-exposed areas.
- Alopecia (balding) of the scalp, eyebrows, and eyelashes, and premature graying, thickening and drying out of the palms and soles, and loss of the ridges on the fingers and toes.
Nail abnormalities usually begin with the fingernails and then toenails. They include:
- Ridges and vertical splitting
- Weakening and thinning
Mucous Membrane abnormalities – a condition called leukoplakia, or potentially pre-cancerous white patches on the insides of the mouth and the upper throat, or other sites such as the esophagus, the genitourinary tract, the anus, the glans penis and the tear ducts.
Bone Marrow Failure -- this most serious symptom of DC occurs in about 90 percent of patients. It can first show up in any of the following ways:
- Thrombocytopenia (low platelet count — the cells needed for clotting)
- Neutropenia (low white count — the cells needed for immunity)
- Anemia (low red blood count — the cells needed to carry oxygen and iron)
Other symptoms include:
- Lung complications – About 20 percent of patients develop pulmonary problems such as pulmonary fibrosis.
- Eye complications -- Patients with DC have shown increased incidence of conjunctivitis (pink eye) and either excessive tearing or excessive dryness.
- Skeletal problems -- Patients may have osteoporosis, scoliosis, death of bone tissue, and/or a small jaw.
- Gastrointestinal problems – including cirrhosis, or simultaneous enlargement of the liver and the spleen.
- Neurologic problems -- Some patients may show signs of learning issues and mental retardation.
- Genitourinary problems -- abnormalities of the genitals or urinary tract
Most people with DC are born with it, though symptoms may not appear for years. Some babies are diagnosed with DC shortly after being born, while others may not be diagnosed until reaching adulthood. Most people are diagnosed between the ages of 10 and 30.
DC can be definitively diagnosed in most cases by genetic testing. Patients can either submit a blood sample or have their mouths swabbed for cells for testing. In some cases the results of this testing have been negative even when the disease is present; in these cases, diagnosis must be made via identification of symptoms.
Doctors also may do blood tests to check the level of each kind of blood cell, or to look for shortened telomeres.
Medications – Drugs to help build up levels of blood cells may be given, such as steroids, neupogen or epogen.
Stem cell transplant/Bone marrow transplant – The only curative treatment for bone marrow failure disorders is stem cell transplantation, in which a patient’s bone marrow/stem cells are replaced with those from a healthy, matching donor. The most successful outcomes are among patients who have an unaffected, tissue-compatible sibling to serve as a donor.
At Johns Hopkins
Researchers at Johns Hopkins have been studying mice and how the lack of the protein telomerase contributes to the aging process and stem cell death. This research has major implications for DC patients.
The Telomere Clinic in the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins provides multidisciplinary care to patients who are suspected to have or who carry the diagnosis of telomere-related disorders, including DC, cancer, bone marrow failure/aplastic anemia, and lung disease including idiopathic pulmonary fibrosis and liver cirrhosis. Our clinic brings together geneticists and genetic counselors working closely with expert physicians in adult and pediatric hematology, bone marrow transplant, pulmonary medicine, lung transplant medicine, hepatology, and otolaryngology. Together, our team has established expertise in the management of these disorders, and is at the forefront of leading the effort to individualize care for affected patients and their families.
In addition, a group directed by Mary Yousry Armanios, M.D., has ongoing research efforts including a long-term study to understand the genetics and spectrum of telomere disorders through a registry that has been based at Johns Hopkins since 2005.
Read apress release on Dr. Armanios’ finding that shortened telomeres place patients with DC, and others, at higher risk for diabetes.