Dyskeratosis congenita is a disorder that can affect many parts of the body. There are three features that are characteristic of this disorder: fingernails and toenails that grow poorly or are abnormally shaped (nail dystrophy); changes in skin coloring (pigmentation), especially on the neck and chest, in a pattern often described as "lacy"; and white patches inside the mouth (oral leukoplakia).

People with dyskeratosis congenita have an increased risk of developing several life-threatening conditions. They are especially vulnerable to disorders that impair bone marrow function. These disorders disrupt the ability of the bone marrow to produce new blood cells. Affected individuals may develop aplastic anemia, also known as bone marrow failure, which occurs when the bone marrow does not produce enough new blood cells. They are also at higher than average risk for myelodysplastic syndrome, a condition in which immature blood cells fail to develop normally; this condition may progress to a form of blood cancer called leukemia. People with dyskeratosis congenita are also at increased risk of developing leukemia even if they never develop myelodysplastic syndrome. In addition, they have a higher than average risk of developing other cancers, especially cancers of the head, neck, anus, or genitals.

People with dyskeratosis congenita may also develop pulmonary fibrosis, a condition that causes scar tissue (fibrosis) to build up in the lungs, decreasing the transport of oxygen into the bloodstream. Additional signs and symptoms that occur in some people with dyskeratosis congenita include 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); degeneration (avascular necrosis) of the hip and shoulder joints; or liver disease. Some affected males may have narrowing (stenosis) of the urethra, which is the tube that carries urine out of the body from the bladder. Urethral stenosis may lead to difficult or painful urination and urinary tract infections.

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

While most people with dyskeratosis congenita have normal intelligence and development of motor skills such as standing and walking, developmental delay may occur in some severely affected individuals. In one severe form of the disorder called Hoyeraal Hreidaarsson syndrome, affected individuals have an unusually small and underdeveloped cerebellum, which is the part of the brain that coordinates movement. Another severe variant called Revesz syndrome involves abnormalities in the light-sensitive tissue at the back of the eye (retina) in addition to the other symptoms of dyskeratosis congenita.

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. In a small number of individuals with dyskeratosis congenita, 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. In these cases, the cause of the disorder is unknown, but other unidentified genes related to telomere maintenance are likely involved.

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).

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 of telomerase, called hTR and hTERT, are produced from the TERC and TERT genes, respectively. The hTR component is an RNA molecule, a chemical cousin of DNA. It provides a template for creating the repeated sequence of DNA that telomerase adds to the ends of chromosomes. The function of the hTERT component is to add the new DNA segment to chromosome ends. The DKC1 gene provides instructions for making another protein that is important in telomerase function. This protein, called dyskerin, attaches (binds) to hTR and helps stabilize the telomerase complex.

The shelterin complex helps protect telomeres from the cell's DNA repair process. Without the protection of shelterin, the repair mechanism would sense the chromosome ends as abnormal breaks in the DNA sequence and either attempt to join the ends together or initiate apoptosis. The TINF2 gene provides instructions for making a protein that is part of the shelterin complex.

TERT, TERC, DKC1, or TINF2 gene mutations result in dysfunction of the telomerase or shelterin 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 a variety of problems affecting quickly dividing cells in the body such as cells of the nail beds, hair follicles, skin, lining of the mouth (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 in people with dyskeratosis congenita.

Normal Function

The CTC1 gene provides instructions for making a protein that plays an important role in structures known as telomeres, which are found at the ends of chromosomes. Telomeres are short, repetitive segments of DNA that 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).

The CTC1 protein works as part of a group of proteins known as the CST complex, which is involved in the maintenance of telomeres. This complex is part of the special machinery that some cells use to copy (replicate) telomeres so they do not become too short as cells divide. Studies suggest that the CTC1 protein may also have roles in DNA replication unrelated to telomeres, but these functions are not well understood.

Health Conditions Related to Genetic Changes

Coats plus syndrome

At least 20 mutations in the CTC1 gene have been identified in people with Coats plus syndrome. This disorder is characterized by an eye condition called Coats disease plus abnormalities of the brain, bones, gastrointestinal system, and other parts of the body.

Most people with Coats plus syndrome have a mutation in one copy of the CTC1 gene in each cell that eliminates the function of the CTC1 protein and a mutation in the other copy of the gene that reduces but does not eliminate the protein's function. This combination of mutations leaves only a small amount of functional CTC1 protein available to work as part of the CST complex. The resulting impairment of this complex affects the replication of telomeres, although the effect on telomere structure and function is unclear. Some studies have found that people with CTC1 gene mutations have abnormally short telomeres, while other studies have found no change in telomere length. Researchers are working to determine how telomeres are different in people with CTC1 gene mutations and how these changes could underlie the varied signs and symptoms of Coats plus syndrome.

Dyskeratosis congenita

MedlinePlus Genetics provides information about Dyskeratosis congenita

Other Names for This Gene

• AAF-132
• AAF132
• alpha accessory factor 132
• C17orf68
• conserved telomere capping protein 1
• CRMCC
• CST complex subunit CTC1
• CTS telomere maintenance complex component 1
• FLJ22170
• HBV DNAPTP1-transactivated protein B
• RP11-849F2.8
• tmp494178

Genomic Location

Normal Function

The DKC1 gene provides instructions for making a protein called dyskerin. This protein is involved in maintaining structures called 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).

Telomeres are maintained by two important protein complexes, telomerase and shelterin. Telomerase counteracts the shortening of telomeres by adding small repeated segments of DNA to the ends of chromosomes each time the cell divides. One component of telomerase, called hTR, provides a template for creating the repeated sequence of DNA that telomerase adds to the ends of chromosomes. The dyskerin protein attaches (binds) to hTR and helps stabilize the telomerase complex.

In most types of cells, telomerase is either undetectable or active at very low levels. However, telomerase is highly active in cells that divide rapidly, such as cells that line the lungs and gastrointestinal tract, cells in bone marrow, and cells of the developing fetus. Telomerase allows these cells to divide many times without becoming damaged or undergoing apoptosis. Telomerase is also abnormally active in most cancer cells, which grow and divide without control or order.

Dyskerin is also involved in the production of ribosomal RNA (rRNA), a chemical cousin of DNA. Ribosomal RNA is required for assembling protein building blocks (amino acids) into functioning proteins.

Health Conditions Related to Genetic Changes

Dyskeratosis congenita

More than 40 mutations in the DKC1 gene have been identified in people with dyskeratosis congenita. This disorder is characterized by changes in skin coloring (pigmentation), white patches inside the mouth (oral leukoplakia), and abnormally formed fingernails and toenails (nail dystrophy). People with dyskeratosis congenita have an increased risk of developing several life-threatening conditions, including cancer and a progressive lung disease called pulmonary fibrosis. Many affected individuals also develop a serious condition called aplastic anemia, also known as bone marrow failure, which occurs when the bone marrow does not produce enough new blood cells.

Most of the DKC1 gene mutations that cause dyskeratosis congenita change single amino acids in the dyskerin protein. Researchers believe that these changes probably interfere with the dyskerin protein's ability to bind to hTR, resulting in dysfunction of the telomerase complex.

Impaired telomerase function prevents the normal maintenance of telomeres and leads to 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 a variety of problems affecting quickly dividing cells in the body, such as cells of the nail beds, hair follicles, skin, lining of the mouth (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 in some people with dyskeratosis congenita.

Idiopathic pulmonary fibrosis

MedlinePlus Genetics provides information about Idiopathic pulmonary fibrosis

Other Names for This Gene

• CBF5
• CBF5 homolog
• cbf5p homolog
• DKC
• DKC1_HUMAN
• dyskeratosis congenita 1, dyskerin
• dyskerin
• FLJ97620
• H/ACA ribonucleoprotein complex subunit 4
• H/ACA ribonucleoprotein complex subunit 4 isoform 1
• H/ACA ribonucleoprotein complex subunit 4 isoform 2
• NAP57
• NOLA4
• nopp140-associated protein of 57 kDa
• nucleolar protein family A member 4
• nucleolar protein NAP57
• snoRNP protein DKC1
• XAP101

Genomic Location

Normal Function

The TERC gene provides instructions for making one component of an enzyme called telomerase. Telomerase maintains structures called telomeres, which are composed of repeated segments of DNA found at the ends of chromosomes. Telomeres 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). Telomerase counteracts the shortening of telomeres by adding small repeated segments of DNA to the ends of chromosomes each time the cell divides.

In most types of cells, telomerase is either undetectable or active at very low levels. However, telomerase is highly active in cells that divide rapidly, such as cells that line the lungs and gastrointestinal tract, cells in bone marrow, and cells of the developing fetus. Telomerase allows these cells to divide many times without becoming damaged or undergoing apoptosis. Telomerase is also abnormally active in cancer cells, which grow and divide without control or order.

The telomerase enzyme consists of two major components that work together. The component produced from the TERC gene is known as hTR. The hTR component is an RNA molecule, a chemical cousin of DNA. It provides a template for creating the repeated sequence of DNA that telomerase adds to the ends of chromosomes. The other major component of telomerase, which is produced from a gene called TERT, is known as hTERT. The function of hTERT is to add the new DNA segment to chromosome ends.

Health Conditions Related to Genetic Changes

Dyskeratosis congenita

At least 20 mutations in the TERC gene have been identified in people with dyskeratosis congenita. This disorder is characterized by changes in skin coloring (pigmentation), white patches inside the mouth (oral leukoplakia), and abnormally formed fingernails and toenails (nail dystrophy). People with dyskeratosis congenita have an increased risk of developing several life-threatening conditions, including cancer and a progressive lung disease called pulmonary fibrosis. Many affected individuals also develop a serious condition called aplastic anemia, also known as bone marrow failure, which occurs when the bone marrow does not produce enough new blood cells.

Some of the TERC gene mutations that cause dyskeratosis congenita result in an absent or unstable hTR molecule; others change the way hTR interacts with hTERT or other components of the telomerase enzyme.

TERC gene mutations lead to telomerase dysfunction, 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 a variety of problems affecting quickly dividing cells in the body such as cells of the nail beds, hair follicles, skin, lining of the mouth (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 in some people with dyskeratosis congenita.

Idiopathic pulmonary fibrosis

Several mutations in the TERC gene have been identified in people with the progressive lung disease idiopathic pulmonary fibrosis. This condition causes scar tissue (fibrosis) to build up in the lungs, which makes the lungs unable to transport oxygen into the bloodstream effectively. Mutations in the TERC gene have been found in cases that run in families (familial pulmonary fibrosis) and, less commonly, in isolated (sporadic) cases. Some individuals with idiopathic pulmonary fibrosis due to TERC gene mutations have family members with other features of dyskeratosis congenita (described above), such as aplastic anemia or cancer.

Mutations in the TERC gene reduce or eliminate the function of telomerase, which allows telomeres to become abnormally short as cells divide. The shortened telomeres likely trigger cells that divide rapidly, such as cells that line the inside of the lungs, to stop dividing or to die prematurely. In people with idiopathic pulmonary fibrosis, shorter telomeres are associated with a more severe disease and a quicker decline in lung function. Additional research is needed to confirm how shortened telomeres contribute to the progressive scarring and lung damage characteristic of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis is a complex disease that is probably caused by a combination of genetic and environmental factors. Studies suggest that many affected people with TERC gene mutations may have also been exposed to environmental risk factors, such as cigarette smoke or certain kinds of dust or fumes. It is possible that mutations in the TERC gene increase a person's risk of developing idiopathic pulmonary fibrosis, and then exposure to certain environmental factors can trigger the disease.

Other disorders

TERC gene mutations have also been found in people with isolated aplastic anemia, a form of bone marrow failure that occurs without the other physical features of dyskeratosis congenita (described above). Researchers suggest that mutations affecting different parts of the telomerase enzyme may account for the absence of these features. Some believe that isolated aplastic anemia caused by TERC gene mutations may actually represent a late-onset form of dyskeratosis congenita in which physical features such as nail dystrophy are mild and may not be noticeable.

Other Names for This Gene

• hTERC
• hTR
• SCARNA19
• small Cajal body-specific RNA 19
• telomerase RNA
• telomerase RNA component gene
• TR
• TRC3

Genomic Location

Normal Function

The TERT gene provides instructions for making one component of an enzyme called telomerase. Telomerase maintains structures called telomeres, which are composed of repeated segments of DNA found at the ends of chromosomes. Telomeres 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). Telomerase counteracts the shortening of telomeres by adding small repeated segments of DNA to the ends of chromosomes each time the cell divides.

In most types of cells, telomerase is either undetectable or active at very low levels. However, telomerase is highly active in cells that divide rapidly, such as cells that line the lungs and gastrointestinal tract, cells in bone marrow, and cells of the developing fetus. Telomerase allows these cells to divide many times without becoming damaged or undergoing apoptosis. Telomerase is also abnormally active in most cancer cells, which grow and divide without control or order.

The telomerase enzyme consists of two major components that work together. The component produced from the TERT gene is known as hTERT. The other component is produced from a gene called TERC and is known as hTR. The hTR component provides a template for creating the repeated sequence of DNA that telomerase adds to the ends of chromosomes. The hTERT component then adds the new DNA segment to chromosome ends.

Health Conditions Related to Genetic Changes

Dyskeratosis congenita

At least 40 mutations in the TERT gene have been identified in people with dyskeratosis congenita. This disorder is characterized by changes in skin coloring (pigmentation), white patches inside the mouth (oral leukoplakia), and abnormally formed fingernails and toenails (nail dystrophy). People with dyskeratosis congenita have an increased risk of developing several life-threatening conditions, including cancer and a progressive lung disease called pulmonary fibrosis. Many affected individuals also develop a serious condition called aplastic anemia, also known as bone marrow failure, which occurs when the bone marrow does not produce enough new blood cells.

Most of the TERT gene mutations that cause dyskeratosis congenita change single protein building blocks (amino acids) in the hTERT protein, causing it to be unstable or dysfunctional. The mutations interfere with telomerase function, 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 a variety of problems affecting quickly dividing cells in the body such as cells of the nail beds, hair follicles, skin, lining of the mouth (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 in some people with dyskeratosis congenita.

Idiopathic pulmonary fibrosis

At least 70 mutations in the TERT gene have been identified in people with the progressive lung disease idiopathic pulmonary fibrosis. This condition causes scar tissue (fibrosis) to build up in the lungs, which makes the lungs unable to transport oxygen into the bloodstream effectively. Mutations in the TERT gene have been found in cases that run in families (familial pulmonary fibrosis) and, less commonly, in isolated (sporadic) cases. Some individuals with idiopathic pulmonary fibrosis due to TERT gene mutations have family members with other features of dyskeratosis congenita (described above), such as aplastic anemia or cancer.

Mutations in the TERT gene reduce or eliminate the function of telomerase, which allows telomeres to become abnormally short as cells divide. The shortened telomeres likely trigger cells that divide rapidly, such as cells that line the inside of the lungs, to stop dividing or to die prematurely. In people with idiopathic pulmonary fibrosis, shorter telomeres are associated with a more severe disease and a quicker decline in lung function. Additional research is needed to confirm how shortened telomeres contribute to the progressive scarring and lung damage characteristic of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis is a complex disease that is probably caused by a combination of genetic and environmental factors. Studies suggest that many affected people with TERT gene mutations may have also been exposed to environmental risk factors, such as cigarette smoke or certain kinds of dust or fumes. It is possible that mutations in the TERT gene increase a person's risk of developing idiopathic pulmonary fibrosis, and then exposure to certain environmental factors can trigger the disease.

Breast cancer

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Cholangiocarcinoma

MedlinePlus Genetics provides information about Cholangiocarcinoma

Melanoma

Mutations in the TERT gene have been associated with an increased risk of a type of skin cancer called melanoma. Researchers suggest that these mutations may impair telomere maintenance and result in DNA damage. Damage to genes that help control the growth and development of cells can cause uncontrolled cell growth and lead to development of cancer.

Cancers

Mutations in the TERT gene have also been associated with an increased risk of a form of blood cancer called acute myeloid leukemia. As in melanoma (described above), researchers think changes in the TERT gene may impair telomere maintenance, which leads to DNA damage. Damage to genes that help control the growth and development of blood cells can cause uncontrolled cell growth and promote the development of leukemia.

Other disorders

TERT gene mutations have also been found in people with isolated aplastic anemia, a form of bone marrow failure that occurs without the other physical features of dyskeratosis congenita (described above). Researchers suggest that mutations affecting different parts of the telomerase enzyme may account for the absence of these features. Some believe that isolated aplastic anemia caused by TERT gene mutations may actually represent a late-onset form of dyskeratosis congenita in which physical features such as nail dystrophy are mild and may not be noticeable.

Other Names for This Gene

• EST2
• hEST2
• TCS1
• telomerase catalytic subunit
• telomerase-associated protein 2
• TERT_HUMAN
• TP2
• TRT

Genomic Location

Normal Function

The TINF2 gene provides instructions for making part of the shelterin protein complex. This complex consists of a group of proteins that work together to 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).

The shelterin complex helps protect telomeres from the cell's DNA repair process. Without the protection of shelterin, the repair mechanism would sense the chromosome ends as abnormal breaks in the DNA sequence and either attempt to join the ends together or initiate cellular self-destruction (apoptosis).

Health Conditions Related to Genetic Changes

Dyskeratosis congenita

At least 15 mutations in the TINF2 gene have been identified in people with dyskeratosis congenita, including a severe form of this disorder called Revesz syndrome. Dyskeratosis congenita is characterized by changes in skin coloring (pigmentation), white patches inside the mouth (oral leukoplakia), and abnormally formed fingernails and toenails (nail dystrophy). People with dyskeratosis congenita have an increased risk of developing several life-threatening conditions, including cancer and a progressive lung disease called pulmonary fibrosis. Many affected individuals also develop a serious condition called aplastic anemia, also known as bone marrow failure, which occurs when the bone marrow does not produce enough new blood cells.

Most of the TINF2 gene mutations that cause dyskeratosis congenita change single protein building blocks (amino acids) in the TINF2 protein, likely disrupting the function of the protein. The mutations result in dysfunction of the shelterin complex, interfering with its protection of telomeres and leading to reduced telomere length. Shortened telomeres can result in damage to genetic material, causing the cell to stop dividing or to undergo apoptosis.

Cells that divide rapidly are especially vulnerable to the effects of shortened telomeres. As a result, people with dyskeratosis congenita may experience a variety of problems affecting quickly dividing cells in the body such as cells of the nail beds, hair follicles, skin, lining of the mouth (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 in some people with dyskeratosis congenita.

Idiopathic pulmonary fibrosis

MedlinePlus Genetics provides information about Idiopathic pulmonary fibrosis

Other Names for This Gene

• (TRF1)-interacting nuclear factor 2 variant 1
• TERF1 (TRF1)-interacting nuclear factor 2
• TERF1-interacting nuclear factor 2
• TERF1-interacting nuclear factor 2 isoform 1
• TERF1-interacting nuclear factor 2 isoform 2
• TIN2
• TINF2_HUMAN
• TRF1-interacting nuclear protein 2

Genomic Location

Dyskeratosis congenita can have different inheritance patterns.

When dyskeratosis congenita is caused by DKC1 gene mutations, it is inherited in an X-linked recessive pattern. The DKC1 gene is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell 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 of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

When dyskeratosis congenita is caused by mutations in other genes, it can be inherited in an autosomal dominant or autosomal recessive pattern. Autosomal dominant means one copy of the altered gene in each cell is sufficient to cause the disorder. Autosomal recessive means 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.

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