What are the other Names for this Condition? (Also known as/Synonyms)

• Dyskeratosis Congenita Syndrome
• Dysfunctional Telomere Maintenance
• Zinsser-Engman-Cole Syndrome

What is Dyskeratosis Congenita? (Definition/Background Information)

• Dyskeratosis Congenita (DKC) is a rare genetic condition that affects the bone marrow. The condition prevents the bone marrow from creating a sufficient amount of blood cells. This can result in bone marrow failure causing other conditions such as anemia
• Dyskeratosis Congenita is caused by genetic mutation(s) and at least 6 genes, namely, DKC1, TERC, TERT, TINF2, NOP10, and NHP2, are known to be involved. Due to this, a family history of the disorder is considered to be a key risk factor
• Even though Dyskeratosis Congenita is a congenital disorder, the manifestation of signs and symptoms mostly occur during childhood and adolescence that progresses into adulthood. A male prevalence is generally observed
• The presentations of the disorder also include abnormally-shaped fingernails and toenails, changes in skin pigmentation (specifically around the neck and chest region), and white patches inside the mouth (termed oral leukoplakia)
• These symptoms form the basis of diagnosis of Dyskeratosis Congenita along with blood tests for specific gene mutations. The treatment is symptomatic and may include skin therapy, hormone therapy, and stem cell transplantation, if necessary
• The prognosis varies depending on the severity of the signs and symptoms and may be assessed on a case-by-case basis. Nevertheless, most individuals with Dyskeratosis Congenita have shortened life-spans

Who gets Dyskeratosis Congenita? (Age and Sex Distribution)

• Characteristics of Dyskeratosis Congenita develop between the ages of 5-15, with the average age being 10 years
• Males have a higher rate of incidence than females, with the male-female ratio being 3:1
• All races and ethnic groups can be affected

What are the Risk Factors for Dyskeratosis Congenita? (Predisposing Factors)

• A family history of Dyskeratosis Congenita is an important risk factor, since it is a genetic condition

It is important to note that having a risk factor does not mean that one will get the condition, A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Dyskeratosis Congenita? (Etiology)

According to current scientific research, mutations associated with six genes have been linked to Dyskeratosis Congenita. However, as these mutations only explain half of the cases of Dyskeratosis Congenita, there is a possibility that there may be additional unknown genes causing DKC.

Dyskeratosis Congenita can be inherited in an X-linked, autosomal dominant, or autosomal recessive manner.

The X-linked Dyskeratosis Congenita is known to be caused by:

• Mutations in the DKC1 gene
• The DKC1 gene contains instructions for synthesis of the protein dyskerin
• The protein dyskerin plays a role in the creation of small structures within ribosomes (cells structures that are in charge of assembling proteins) and in telomeres (structures found at the end of chromosomes that aid in replication and stability)

The autosomal dominant form of Dyskeratosis Congenita is caused by:

• Mutations in three different genes:
  • The first gene is the telomerase RNA gene TERC. It is located on the long arm of chromosome 3
  • The second gene is the telomerase TERT gene. It is located on the short arm of chromosome 5
  • The third gene is the TINF2 gene. This gene is located on the long arm of chromosome 14. It encodes the telomere-associated protein TIN2
• Individuals, who carry the TERC or TERT gene mutation, often exhibit a milder form of the disorder compared to those with the X-linked form
• Individuals with certain TINF2 gene mutations exhibit early onset of the disorder; also, in such cases, the disorder is known to be more severe

Mutations in three different genes are responsible for autosomal recessive Dyskeratosis Congenita.

• The first gene is the NOP10 (NOLA3) gene located on the long arm of chromosome 15
• The second gene is the NHP2 (NOLA2) gene located on the long arm of chromosome 5
• The third gene is the TERT gene on chromosome 5

In addition to the three forms of inheritance, Dyskeratosis Congenita can occur sporadically.

• Sporadic Dyskeratosis Congenita results when a de novo (new) mutation takes place. A de novo mutation either arises within the germ cells (egg or sperm) of an individual, or shortly after conception
• Patients with de novo mutation usually have a moderate to severe form of Dyskeratosis Congenita
• De novo mutations in the DKC1 gene and TINF2 gene are responsible for many cases of spontaneous Dyskeratosis Congenita. Although, de novo mutations in the TERT gene causing the condition are very rare
• Mutations in the DKC1 gene accounts for approximately 20-25% of all sporadic cases

Autosomal dominant: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children, born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Dyskeratosis Congenita?

The signs and symptoms of Dyskeratosis Congenita vary among those affected, due to the specific genetic mutation present/involved. Some have mild signs and symptoms, while others have severe presentations.

In many cases, the symptoms do not typically present themselves until childhood/early adolescence. In some rare cases, the symptoms may appear later in one’s life. It is generally observed that the earlier the symptoms present themselves, the more severe is the condition.

• Skin abnormalities, most commonly involving the skin on the face, neck and shoulders:
  • Abnormal discoloration of the skin with a net-like pattern (called reticulated hyperpigmentation)
  • Gray, flat spots (macules)
• Nail abnormalities may include:
  • Cracking or splitting of nails (fissures)
  • Underdevelopment of nails (hypoplasia)
  • Distortion and degeneration of the nails
• Oral lesions include thick, white patches on the mucus membranes of the mouth (oral leukoplakia). In rare cases, patches can develop on the mucus membranes of the anus and the urethra

Bone marrow abnormalities can lead to bone marrow failure. Bone marrow failure results in a deficiency in red cells, white cells, and platelets (pancytopenia).

• Low red blood cell count can cause the following symptoms - tiredness/weakness, lightheadedness/dizziness, shortness of breath, and pale skin
• Low white blood cell count reduces the capacity of the body in fighting infections
• Low platelet count can cause the following symptoms - easy/excessive bruising, prolonged bleeding from cuts, bleeding from gums or nose, and blood in urine or stool

How is Dyskeratosis Congenita Diagnosed?

Dyskeratosis Congenita is diagnosed in the following manner:

• Complete medical history and a thorough physical examination
• Assessment of signs and symptoms
• Blood tests for specific genetic mutations that cause Dyskeratosis Congenita. The specific mutations include:
  • DKC1 gene
  • Telomerase RNA gene TERC on the long arm of chromosome 3
  • Telomerase TERT on the short arm of chromosome 5
  • TINF2 gene on the long arm of chromosome 14
  • NOP10 (NOLA3) gene on the long arm of chromosome 15
  • NHP2 (NOLA2) gene on the long arm of chromosome 5
• Bone marrow biopsy to determine the cause of low blood count

In most cases, healthcare providers can suspect if an individual has Dyskeratosis Congenita through the presenting signs and symptoms. However, the sole method of diagnosing DKC is through genetic testing.

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis. 

What are the possible Complications of Dyskeratosis Congenita?

Dyskeratosis Congenita affects many systems of the body and the potential complications may include:

• Abnormal nails, reticular skin pigmentation, and thickened, white patches inside of the mouth (oral leukoplakia) can cause emotional stress
• Bone marrow failure causing low blood count that can result in severe bleeding and infection
• Thickening of lung tissue (pulmonary fibrosis) causing difficulty in breathing
• Liver disease
• Brain (neurological) and eye (ophthalmic) abnormalities
• Increased risk for cancer

How is Dyskeratosis Congenita Treated?

There is no consensus among medical professionals on how to treat Dyskeratosis Congenita, as it is a rare condition. Most treatment plans are established based on the specific set of symptoms noted in the individual.

The treatments measures may include the following:

• Use of moisturizing creams to prevent damage to the skin
• Good dental hygiene to help prevent early tooth loss. It can also help delay the development of malignancy (cancer) of the tongue
• Synthetic male hormones or androgens (such as oxymetholone) may be administered to increase red blood cell count as well as platelet production in some individuals
• In conjunction with artificial male hormones, corticosteroid (e.g., prednisone) therapy may be added as a supplemental treatment
• Individuals with bone marrow failure may have to undergo hematopoietic stem cell transplantation, which can potentially cure blood abnormalities associated with Dyskeratosis Congenita
• Avoiding smoking to preserve the lungs (in adults)
• Avoiding alcohol to preserve the liver (in adults)

In case of cancer, the healthcare provider will consider treatment options that are appropriate for the specific cancer present. Treatments can include chemotherapy, surgery, and/or radiation therapy.

How can Dyskeratosis Congenita be Prevented?

Currently, there are no specific methods or guidelines to prevent Dyskeratosis Congenita, since it is a genetic condition.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders such as DKC

Regular medical screening at periodic intervals with tests, scans, and physical examinations are mandatory.

What is the Prognosis of Dyskeratosis Congenita? (Outcomes/Resolutions)

• The prognosis of Dyskeratosis Congenita depends on the severity of the signs and symptoms. Individuals with mild signs and symptoms have a better prognosis than individuals with severe signs and symptoms
• It is reported that life expectancy ranges from infancy to late adulthood. Morbidity is typically caused by bone marrow failure, cancer, and/or lung complications
• Around 40% of the individuals are known to have bone marrow failure by the age of 40 years, which can be fatal

Additional and Relevant Useful Information for Dyskeratosis Congenita:

• The TERT gene can cause Hoyeraal-Hreidarsson syndrome which is considered to be a severe form of Dyskeratosis Congenita
• The TERT gene mutation has also been found in individuals with Revesz syndrome, a variant of Dyskeratosis Congenita