Telomere Syndromes and Dyskeratosis Congenita
Telomere syndromes are inherited conditions that can cause bone marrow failure and lung disease. These syndromes vary in severity and can affect children and adults. In rare cases, a patient’s telomere syndrome may appear as a condition called dyskeratosis congenita. The condition, which makes up about 1 percent of all telomere syndromes, is characterized by abnormal findings in the skin, mouth and nails. Advances in understanding the basis of these conditions have helped physicians identify patients with dyskeratosis congenita and telomere syndromes.
Telomere syndromes, including dyskeratosis congenita, are caused by abnormally short telomeres, which are the protective ends of chromosomes. When telomeres become abnormally short, cells can no longer divide effectively. An inherited mutation (change in the DNA code) in the gene that produces the telomere-lengthening enzyme called telomerase disables the enzyme and causes telomeres to shorten at a faster rate.
The most commonly mutated genes in telomere syndromes are TERT (which stands for telomerase reverse transcriptase) and TR (also known as TERC). Mutations in the DKC1 gene, located on the sex-linked X chromosome, and TINF2 can also cause dyskeratosis congenita and its related disorders. In some cases, inherited mutations in an affected family cannot be found, even though short telomeres are identified in family members. Because inherited mutations are not always found among patients’ families, telomere syndromes are diagnosed in patients who have a combination of abnormally short telomeres along with specific clinical features. Johns Hopkins investigators are conducting research to identify additional genetic causes of telomere syndromes.
Symptoms of telomere syndromes vary and depend on each patient’s telomere length. Some patients have few or no symptoms. The conditions include:
- Bone Marrow Failure – a serious symptom of dyskeratosis congenita, bone marrow failure occurs in many children with the condition. Bone marrow failure commonly occurs when patients experience thrombocytopenia, a low number of blood-clotting cells called platelets, or neutropenia, a low number of white blood cells that play a role in the body’s immune system.
- Pulmonary fibrosis – Pulmonary fibrosis, or scarring of the lung, is the most common symptom of telomere syndromes, and usually affects adults who may not have bone marrow failure. It also occurs in children who have undergone bone marrow transplantation.
- Liver disease – Scarring of the liver (cirrhosis) can also be a complication of telomere syndromes, and patients who experience this often have an enlarged spleen.
- Gastrointestinal disease— In severe cases among young children, telomere disorders can cause isolated problems in the gut, including bloody diarrhea and insufficient weight gain and physical growth called failure to thrive.These symptoms often appear in patients with a rare telomere disorder known as Hoyeraal-Hreidarsson syndrome.
- Skin and mucosal abnormalities – In dyskeratosis congenita, patients’ skin may have abnormal pigmentation, with a lack or overabundance of spots and patches. The pigmentation pattern typically appears on sun-exposed areas of the face, neck and upper trunk. A condition called leukoplakia, which can appear as white patches on the insides of the mouth can also occur.Other symptoms can include hair graying at a young age and nail weakness or splitting along with ridging
Other symptoms include eye problems (such as excessive tearing), skeletal problems (such as osteoporosis or weakness of bone tissue in the hips or elsewhere), or narrowing of the esophagus, called stenosis.
- Cancer risk -- In a small subset of patients, telomere syndromes may be associated with increased cancer risk. These cancers may appear on the skin or in the mucosal membranes in the mouth and elsewhere. Cancers of the bone marrow such as myelodysplastic syndrome or acute leukemia, can also occur.
- Hoyeraal-Hreidarsson syndrome is very rare and is usually diagnosed in the first years of life and represents a severe form of telomere syndromes. It is characterized by small weight, failure to thrive, and cerebellar and immune abnormalities.
Telomere syndromes are diagnosed in patients who have symptoms associated with the condition and abnormally short telomeres length. In 20 – 60 percent of patients, a genetic change (mutation) in a gene associated with telomere syndromes may be identified.
Timing of treatment –In many mild cases where the rate of progression is slow, patients may not require treatment for many years. Treatment decisions are individualized to each patient and discussed with clinicians who are experienced in treating this condition.
Medications – Anecdotal reports of using steroid drugs (known as androgens) in patients with bone marrow failure have been shown to improve blood cell counts.
Stem cell transplant/Bone marrow transplant – Treatment for severe bone marrow failure disorders due to telomere shortening is bone marrow/stem cell transplantation, in which a patient’s bone marrow or peripheral blood stem cells are replaced with those from a healthy donor. Telomere syndrome patients are prone to side effects from certain drugs used in standard transplants and should undergo a modified transplant regiment in a center with experience in this particular condition. At Johns Hopkins, we have successfully performed bone marrow transplants for this condition.
Lung and liver disease– Lung or liver transplantation may also be appropriate for some patients whose pulmonary fibrosis or liver cirrhosis are the primary complications.
For more information on bone marrow transplants.
The Telomere Clinic at Johns Hopkins
The Telomere Clinic at 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 dyskeratosis congenita, 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, hepatology, and otolaryngology. For the past 10 years, our team has pioneered the management of these disorders and are expert in individualizing care for patients and their families. To schedule appointments, call 410-955-8964.
Telomere Length Measurement for Clinical
In 2016, a clinically-certified test to determine telomere length in patients suspected to have telomere syndromes has become available to clinicians around the world through the Johns Hopkins Hospital. Pathology Laboratories. For questions related to this testing, please contact Mary Armanios, M.D. at firstname.lastname@example.org or email@example.com.
Opportunities to Advance Care through Research
At Johns Hopkins, there is a thriving research effort to advance the care of patients with telomere syndromes. Over the past decade, clinical and basic science researchers have been working together to define new criteria for defining symptoms for these conditions to facilitate their recognition and to understand their genetic basis.
Among research efforts led by Mary Armanios, M.D., is a long-term study to understand the natural history, genetics and spectrum of short telomere syndromes. More than 300 patients have enrolled in the Johns Hopkins-based Telomere Syndrome Registry which gathers information provided by patients in order to advance this area.
In addition, Johns Hopkins clinicians and scientists are studying how telomere disorders cause stem cell failure and pulmonary fibrosis with the goal of advancing the treatment of these conditions. The distinguished scientific team is led by Dr. Carol W. Greider, Professor and Director of the Department of Molecular Biology and Genetics and the recipient of the 2009 Nobel Prize in Medicine for the co-discovery of telomerase.
Links to literature
Syndromes of Telomere Shortening
The Telomere Syndromes
Lung Transplantation In Telomerase Mutation Carriers with Pulmonary Fibrosis
Recent discoveries and news releases
The Nobel Prize in Physiology or Medicine 2009
"Telomere" Expert Carol Greider Shares 2009 Nobel Prize in Physiology or Medicine
Linking telomerase genetics to idiopathic pulmonary fibrosis genetics
Linking telomere biology to emphysema genetics
Read a press release on Dr. Armanios’ finding that shortened telomeres may place patients with DC, and others, at higher risk for diabetes.
Read a press release on Dr. Armanios' research on the link between shortened telomeres and emphysema in smokers.