About DC

What is Dyskeratosis Congenita and Telomere Biology Disorder?

Dyskeratosis congenita (DC)  and Telomere Biology Disorder (TBD) is an extremely rare, genetically inherited multi-symptom disorder (it is estimated to occur in one out of one million people worldwide). It can be characterized by a variety of symptoms including skin abnormalities, abnormal nail growth, lesions in the mucous membranes (such a leukoplakia in the mouth: white patches of potentially precancerous tissue), and in approximately 90% of the cases, progressive bone marrow failure. A variety of other abnormalities can also occur; these, as well as further detail on those listed above, are itemized in the section titled “Symptoms” (below). DC patients come from all over the world and there seems to be no bias as to race or ethnicity. The disorder does, however, appear to be much more prevalent in men than women.
 
Most often, the first outward symptoms of DC appear by age 10. Skin and nail abnormalities tend to present first. Bone marrow failure and other serious complications tend not to appear until the patient reaches his/her 20’s and 30’s. However, the ages at which different patients manifest different symptoms can vary greatly. The database of cases is still so limited that making generalizations is difficult.
 
Summary:

Estimated to occur in one out of one million people, Dyskeratosis Congenita (DC) is a genetic disorder that can be inherited or develop spontaneously in utero. The progressive disease affects numerous systems, but primarily targets those with rapid cell replacement. A spectrum of variants and manifestations occur with symptoms ranging from mild to extremely severe. As of 2013, nine different gene mutations have been discovered. These genes are found on different chromosomes, but are similar in that each gene plays some role in the biology of telomeres, which are the molecular ends of each chromosome. This dysfunction of the telomere results in certain cells, especially those that more frequently reproduce, being unable to regenerate normally.

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, and bone marrow failure are among the most common symptoms, but a host of other complications are associated with the disease. Most commonly, serious symptoms such as bone marrow failure and pulmonary fibrosis do not appear until a patient’s 20’s or 30’s.

At present there is no cure for DC. However, several treatments help manage the disease. Anabolic steroids and bone marrow-stimulating drugs can encourage cell production in the marrow. Bone marrow, or stem cell, transplant (BMT) is the only long-term solution for the most serious disease complication, 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 for 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.

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. And 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. At present, DC Outreach is undertaking the creation of a universal medical treatment protocol, which, with the guidance of our medical advisory board and the help of expert clinicians from a range of specialties, will 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.

Genetics:
 
DC is a genetically inherited disease. It can be inherited in one of three types: autosomal dominant, autosomal recessive, or the most common form, X-linked recessive (where the gene responsible for DC is carried on the X-chromosome). The DKC1 gene was identified in 1998 and the gene (TERC-RNA component of telomerase) mutated in autosomal dominant DC was identified in 2001. Genetic analysis can test for these genes. Because of this, family members can be tested. An infant at risk can be tested either prenatally or immediately at birth. This would allow for early treatment. Early diagnosis would also allow a patient to harvest his own bone marrow for storage for possible use in the future.  Currently only 9 genes have been discovered so far: 
 
Diagnosis:
 
DC can be definitively diagnosed in most cases by genetic testing.
There are a couple of ways to test for it: the patient can either submit a blood sample or have his mouth swabbed for cells to be tested. Testing is available through the DKC registry (to contact them, click on this link for their e-mail address) and through a company called GeneDx. In certain 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.
 
Symptoms:
 
The most typical symptoms of DC include the combination of
  * skin and nail abnormalities,
  * leukoplakia of the mucous membranes, and
  * bone marrow failure.
 
Skin abnormalities can include:
  * Abnormal pigmentation with hyper- (too much) or hypo- (not enough) pigmented spots and patches. This occurs in some form in about 90% of patients. 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, hyperkeratosis (thickening and drying out) of the palms and soles, and loss of the ridges on the fingers and toes.
 
Nail abnormalities, which appear in approximately 90% of patients, can include:
  * Ridges and vertical splitting, and
  * Weakening and thinning…
     Usually beginning with the fingernails and then the toenails. Eventually this can lead to small or even absent nails.
 
Mucous Membrane Leukoplakia consist of potentially pre-cancerous white patches on the insides of the mouth and the upper throat, or possibly even other mucousal sites such as the esophagus, the genitor-urinary tract, the anus, the glans penis and the tear ducts. Patients can have an increased risk of malignancies such as squamous cell carcinomas particularly at the sites of the leuokoplakia.
 
Bone Marrow Failure: This most serious symptom of DC manifests in some manner in about 90% of all patients. It can first show up in any one of several ways depending on the patient: either…
  * Thrombocytopenia (low platelet count — the cells needed for clotting);
  * Neutropenia (low white count — the cells needed for immunity); and/or
  * Anemia (low red blood count — the cells needed to carry oxygen and iron).
Of the patients who die from some DC-related condition, bone marrow failure – or some resulting ailment – is the culprit about 70% of the time. Most of the remaining 30% is accounted for by pulmonary complications and malignancies.
 
Lung complications: Approximately 20% of patients develop pulmonary problems such as pulmonary fibrosis. It is suggested that DC patients avoid taking any drugs with lung toxicity and that they have their lungs shielded from any radiation. This is to help protect against lung failure post bone marrow transplant.
 
Eyes: patients with DC have shown increased incidence of conjunctivitis and either excessive tearing or excessive dryness.
 
Skeletal: patients may have osteoporosis, aseptic necrosis, scoliosis, and/or mandibular hypoplasia (small jaw).
 
Gastrointestinal: cirrhosis, simultaneous enlargement of the liver and the spleen.
 
Neurologic: some patients may show signs of learning issues and mental retardation.
 
Genitourinary: abnormalities of the genitals or urinary tract.
 
Treatment:
The most devastating symptom of DC is bone marrow failure. It is often treated with either anabolic steroids (eg, oxymetholone) or bone marrow stimulating drugs such as Epogen, which stimulates the production of red blood cells, and Neupogen, which stimulates white blood cell production.
The only long-term cure is a bone marrow transplant or a stem cell transplant. These transplants have not always been so successful due to the fact that many patients have complications resulting from the pulmonary symptoms. The best candidates for this are patients with sibling donors (i.e., perfect matches) and no history of pulmonary disease. Even for “ideal” transplant candidates, however, the procedure carries a high level of risk and is usually only performed as a last resort.
 
Although DC is a rare disease, there is research being done by several institutions. 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. In addition, the National Cancer Institute at the National Institute of Health (NIH) in Bethesda, MD is conducting a study on genetically inherited bone marrow failure diseases, including DC.
 
 
 
Bibliography:
 
Dyskeratosis Congenita: Contact a Family–for families with disabled children.
 
eMedicine–Dyskeratosis Congenita: Article by David T Robles, MD
 
Dyskeratosis Congenita–Rare/Orphan Diseases
 

 

What is a Telomere?

Telomeres are structures on the ends of chromosomes that protect the strands of DNA, much like the plastic aglets that protect the ends of your shoelaces. Telomeres shorten naturally in everyone as they age. However, persons with DC have telomeres that are much shorter than expected for their age. While the research is ongoing, scientists over the years have found that DC is caused by a mutation in one of six genes important in telomere biology However only about one-half of patients with DC have an identifiable mutation in one of these genes. Ongoing research aims to discover more DC-associated gene mutations, and to learn how telomere genes contribute to cancer development and aging.