Dyskeratosis Congenita

Dyskeratosis congenita is a rare genetic disorder characterized by nail dystrophy, skin pigmentation changes, and oral leukoplakia, which significantly increases the risk of bone marrow failure and cancer.

Overview

Dyskeratosis congenita is a disorder that can affect many parts of the body. It is defined by three characteristic features:

• Nail dystrophy: Fingernails and toenails that grow poorly or are abnormally shaped.
• Skin pigmentation changes: Alterations in skin coloring, especially on the neck and chest, often described as a "lacy" pattern.
• Oral leukoplakia: White patches inside the mouth.

The severity of the disorder varies widely among affected individuals. The least severely affected individuals have only a few mild physical features and normal bone marrow function. More severely affected individuals experience many characteristic physical features and may develop bone marrow failure, cancer, or pulmonary fibrosis by early adulthood.

Symptoms and Complications

People with dyskeratosis congenita have an increased risk of developing several life-threatening conditions, particularly those that impair bone marrow function. These disorders disrupt the ability of the bone marrow to produce new blood cells.

Bone Marrow and Cancer Risks

• Bone marrow failure: Occurs when the bone marrow does not produce enough new blood cells.
• Myelodysplastic syndrome: A condition in which immature blood cells fail to develop normally; this may progress to a form of blood cancer called leukemia.
• Leukemia: Individuals are at increased risk of developing leukemia even if they never develop myelodysplastic syndrome.
• Other cancers: Higher than average risk of developing cancers of the head, neck, anus, or genitals.

Other Signs and Symptoms

Additional signs and symptoms that occur in some people with dyskeratosis congenita include:

• Pulmonary fibrosis: A condition causing scar tissue to build up in the lungs, decreasing oxygen transport into the bloodstream.
• Eye abnormalities: Such as narrow tear ducts that may become blocked, preventing drainage of tears and leading to eyelid irritation.
• Dental problems.
• Hair loss or prematurely grey hair.
• Low bone mineral density (osteoporosis).
• Joint degeneration: Avascular necrosis of the hip and shoulder joints.
• Liver disease.
• Urethral stenosis: In some affected males, narrowing of the urethra may lead to difficult or painful urination and urinary tract infections.

Developmental Variants

While most people with dyskeratosis congenita have normal intelligence and motor skill development, developmental delay may occur in some severely affected individuals.

• Hoyeraal Hreidaarsson syndrome: A severe form where affected individuals have an unusually small and underdeveloped cerebellum, the part of the brain that coordinates movement.
• Revesz syndrome: A severe variant involving abnormalities in the retina (the light-sensitive tissue at the back of the eye) in addition to other symptoms of dyskeratosis congenita.

Causes and Genetics

In about half of people with dyskeratosis congenita, the disorder is caused by mutations in the TERT, TERC, DKC1, or TINF2 gene. These genes provide instructions for making proteins that help maintain structures known as telomeres, which are found at the ends of chromosomes.

Telomeres help protect chromosomes from abnormally sticking together or breaking down (degrading). 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 (undergo apoptosis).

Role of Telomerase and Shelterin

Telomeres are maintained by two important protein complexes called telomerase and shelterin.

• Telomerase: Helps maintain normal telomere length by adding small repeated segments of DNA to the ends of chromosomes each time the cell divides. The main components are hTR (an RNA molecule produced from the TERC gene) and hTERT (produced from the TERT gene). The DKC1 gene produces dyskerin, a protein that binds to hTR and helps stabilize the telomerase complex.
• Shelterin: Helps protect telomeres from the cell's DNA repair process. Without this protection, the repair mechanism would sense chromosome ends as abnormal breaks and either attempt to join them or initiate apoptosis. The TINF2 gene provides instructions for making a protein that is part of the shelterin complex.

Mutations in TERT, TERC, DKC1, or TINF2 result in dysfunction of these complexes, leading to impaired maintenance of telomeres and reduced telomere length. Cells that divide rapidly are especially vulnerable to the effects of shortened telomeres. As a result, people with dyskeratosis congenita may experience problems affecting quickly dividing cells in the body, such as cells of the nail beds, hair follicles, skin, oral mucosa, and bone marrow.

Breakage and instability of chromosomes resulting from inadequate telomere maintenance may lead to genetic changes that allow cells to divide in an uncontrolled way, resulting in the development of cancer.

Associated Genes

In a small number of individuals, mutations in other genes involved with telomere maintenance have been identified. Other affected individuals have no mutations in any of the genes currently associated with dyskeratosis congenita, though other unidentified genes related to telomere maintenance are likely involved.

• CTC1
• DKC1
• TERC
• TERT
• TINF2
• NHP2
• NOP10
• RTEL1
• WRAP53

Inheritance

Dyskeratosis congenita can have different inheritance patterns depending on the specific gene mutation involved.

• X-linked recessive: When caused by DKC1 gene mutations. The DKC1 gene is located on the X chromosome. In males (who have only one X chromosome), one altered copy of the gene is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies, males are affected much more frequently than females. Fathers cannot pass X-linked traits to their sons.
• Autosomal dominant: One copy of the altered gene in each cell is sufficient to cause the disorder.
• Autosomal recessive: Both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Frequency

The exact prevalence of dyskeratosis congenita is unknown. It is estimated to occur in approximately 1 in 1 million people.

Other Names

• Zinsser-Cole-Engman syndrome