Trait Document

Dyskeratosis Congenita (DC) is a rare genetic condition characterized by an increased risk for bone marrow failure (BMF) in addition to three classic features: skin abnormalities, fingernail and toenail abnormalities, and white patches inside the mouth.

Nearly all individuals with DC will develop BMF, with 90% of these cases occurring by age 30. Cancer also occurs more frequently in DC patients, especially cancers of the bone marrow, head, neck, and tongue. Not all individuals with DC have the same symptoms, even in the same family; some will have only BMF, while others may have cancers and other, more severe features. Some of these associated features can include very slow growth during pregnancy, small head size and genitals, underdevelopment of the brain, developmental delay, abnormalities of the eyes, teeth, and hair, and diseases of the lungs, liver, and bones (especially the hips and shoulders). The average age of diagnosis of DC is 15 years, but it can vary widely from presentation at birth to 75 years of age. There are two particularly severe forms of DC, Refesz syndrome and Hoyeraal-Hreidarsson syndrome, both of which tend to involve many systems in the body and occur in very young individuals.

DC is now known to be a disorder of shortened telomeres, the ends of chromosomes that are made of many repeats of the same DNA sequence. The length of telomeres is controlled by the enzyme telomerase. This enzyme plays an important role in the timing of cell growth and division. The most accurate method of testing for DC is called telomere flow FISH. This type of test studies the length of the telomeres in white blood cells.

Seven genes have been identified to cause DC: DKC1, TERT, TERC, WRAP53, NOP10, NHP2, and TINF2. Each of these genes makes a protein that plays a role in the telomere length pathway. Mutations or changes in any one of these genes are thought to interfere with this pathway, resulting in very short telomeres in affected individuals. Approximately 50% of individuals with DC have an identifiable mutation in one of these genes.

Management for DC often involves thorough skin and nail examinations, regular dental examinations, and regular clinical examinations by a head and neck specialist and hematologist. Additional screening may include special blood tests, bone marrow aspiration and biopsy (i.e., a sample of bone marrow removed with a needle), lung function tests, ultrasound imaging of the liver, and thorough skin and gynecologic examinations.

Individuals with DC that have BMF require special treatments for their BMF, thus it is very important to make a diagnosis of DC before making treatment plans. The only known cure for this condition is a bone marrow transplant (i.e., replacing unhealthy bone marrow cells with healthy bone marrow cells from a donor), although this can be risky in patients with DC who have other complicated medical issues. Anyone related to the affected individual who is considering donating bone marrow must first be tested for DC. Some other medications, such as certain hormones, have been shown to be effective in treating BMF due to DC, but must be used with caution because of side effects and interactions with other drugs.

DC may be inherited in one of three patterns of inheritance: X-linked recessive, autosomal dominant, and autosomal recessive pattern. They are explained below.

Mutations in the DKC1 gene cause X-linked DC. An X-linked recessive pattern means that in females, both copies of a gene (i.e., one on each X chromosome) must have a change or mutation, whereas in males, only one copy of a gene must have a mutation to be affected. A female with a mutation in one copy of a gene on the X chromosome is said to be a “carrier” for an X-linked condition, and is typically not affected.

Mutations in the TERC, TINF2, and TERT genes are inherited in an autosomal dominant pattern. This means inheriting one mutation is enough for an individual to be affected and show signs of DC. The mutation can be inherited from an affected parent or it can occur brand new (de novo) in an affected child.

Mutations in the WRAP53, NHP2, and NOP10 genes are inherited in an autosomal recessive pattern. This inheritance pattern means that an individual has to inherit two mutations (i.e., one from each parent) to be affected. If both parents are carriers of a mutation they have a 1 in 4 (25%) chance with each pregnancy of having a child with the condition.

The risk to family members depends on the pattern of inheritance.

If a father is affected with DC, his daughters will be carriers of DC and his sons will be unaffected. If a mother is a carrier of DC, each daughter has a 1 in 2 chance (i.e., 50%) of being a carrier and each son has a 1 in 2 chance (i.e., 50%) of being affected with DC.

The risk to family members depends on whether or not the individual with DC has a parent affected with DC. If a parent also has the condition, the risk of having a child with DC is 50% with each pregnancy. If a parent does not have DC, the risk of other siblings being affected is very low.

Parents of a child with DC are carriers of DC. If a sibling of a child with DC is unaffected, he/she has a 2 in 3 (66%) chance of being a carrier of DC.

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