Telomere Biology Disorders

Telomere Biology and Cancer Risk with Dr. Sharon Savage and NIH Study Participant

Telomeres cap the ends of chromosomes, which carry genetic information in cells. They function like the plastic tip on a shoelace and protect chromosomes. As we age, our telomeres shorten. Individuals with telomere biology disorders are born with abnormally short telomeres and may have various medical complications. Below is a list of telomere biology disorders studied as part of the IBMFS Cohort Study at the NCI.

Dyskeratosis Congenita (DC)

Individuals with DC have abnormal shape/texture of finger and toe nails, abnormal skin pigmentation and white patches in the mouth. DC is more common in males. About half of individuals with DC develop bone marrow failure. Onset may be in early childhood, but diagnoses are often made later, because the findings on physical examination often become more obvious with age and complications may increase with age. Over a dozen genes have been identified as causing DC, and there are more still to be discovered.

What are the major findings on physical examination?

The classic triad includes:

  • Abnormal shape/texture to fingernails and toenails (dysplastic)
  • Abnormal skin pigment (light and dark spots or lacy pattern)
  • White patches in the mouth (leukoplakia)

What is the age at diagnosis?

  • DC diagnoses have occurred from birth to more than 60 years of age
  • The diagnosis is usually made between the ages of 10 to 30 years
  • There is a range of severity for DC; more complicated cases are usually diagnosed at younger ages

What is the natural progression of bone marrow failure in individuals with DC?

  • Some individuals with DC can live for years without bone marrow failure while others develop symptoms earlier.
  • Bone marrow failure means the number of blood cells is too low because the bone marrow has stopped producing enough mature cells.
  • Individuals typically start with low blood count in one of these types of cells, and then progress to low counts in two or more types of blood cells (also known as aplastic anemia):
    • Low red blood cell count (anemia)
    • Low platelet count (thrombocytopenia)
    • Low white blood cell count (leukopenia)

What types of cancer are individuals with DC at higher risk of developing?

  • Tongue, mouth, and throat cancer ("head and neck" squamous cell carcinoma)
  • Leukemia (cancer of blood and bone marrow)
  • Non-Hodgkin lymphoma (cancer of lymphatic system)
  • Cancer of the esophagus, stomach, colon, and rectum ("gastrointestinal")

How is DC diagnosed?

  • Presence of at least 2 out of 3 classic triad (abnormal nails, skin pigmentation, and/or white spots in the mouth) or other classical findings
  • Telomere length testing
  • Genetic Testing


  • Over a dozen DC susceptibility genes have been identified. Different genes affect risk in different ways, depending upon how they were inherited—one copy, two-copies, or X-chromosome linked.
  • DC susceptibility genes with autosomal dominant inheritance patterns (only one copy of the gene variant is needed to cause the disease): RTEL1, TINF2, TERC, TERT, NAF1
  • DC susceptibility genes with autosomal recessive pattern (both copies of the gene variant need to be inherited to cause the disease): RTEL1, PARN, TERT, WRAP53, ACD, NHP2, NOP10, CTC1, STN1, POT1
  • X-linked recessive patterns (males only need one copy of the gene variant to cause the disease; females would need two): DKC1
  • TINF2 is also known to occur de novo (spontaneous disease causing genetic variant; not inherited).
  • 70-80% of individuals with DC have a known disease-causing gene variant.

Hoyeraal-Hreidarsson (HH) Syndrome

HH Syndrome has findings consistent with DC, plus low birth weight, developmental delay, small heads, small cerebellums, immunodeficiency, and bone marrow failure. Some people with HH have abnormal genetic variants in DKC1, TINF2, TERT, or RTEL1; other genes may be identified in the future.

Revesz Syndrome (RS)

Findings in Revesz Syndrome may be similar to DC, plus a specific finding in both eyes, called "exudative retinopathy", and calcifications in the brain. So far, these individuals have had disease-causing gene variants in TINF2; other genes may be identified in the future.

Coats Plus (CP) Syndrome

Some findings in CP Syndrome are similar to RS, plus weak bones (osteopenia), and gastrointestinal bleeding due to abnormal blood vessel formation Disease-causing gene variants for CP individuals are found in CTC1, STN1, and POT1.

Idiopathic Pulmonary Fibrosis (IPF)

Idiopathic pulmonary fibrosis is a lung disease that results in the scarring (fibrosis) of the lungs that often has an unknown reason (idiopathic). While IPF can be an isolated disease indicative of an underlying telomere biology disorder, it can also be one of the more severe complications in individuals with DC.

What are the major findings on physical examination?

  • Shortness of breath worsened by physical activity
  • Chronic cough
  • Inspiratory crackles (abnormal noises on lung exam with stethoscope)
  • Nail clubbing (nails of fingers and toes take on an upside-down spoon appearance)

What is the age at diagnosis?

  • In DC individuals, IPF manifests in one of two patterns:
    • IPF can occur early in life following the onset of bone marrow failure.
    • IPF might also be the first life-threatening complication in people with DC.
  • IPF in the absence of DC symptoms and/or bone marrow failure, may be the first feature of a telomere-biology disorder in those over the age of 40.

What is the natural progression of bone marrow failure in individuals with IPF?

  • Individuals with isolated IPF may not develop bone marrow failure but their blood counts should be closely monitored.
  • In young individuals with DC, the onset of bone marrow failure is typically seen prior to developing IPF.

What types of cancer are individuals with IPF at higher risk of developing?

  • Individuals with IPF due to a telomere biology disorder may be at risk for DC-associated cancers.

How is IPF specifically diagnosed?

  • Pulmonary function tests
  • Chest imaging (CT or x-ray)
  • Viewing the lung airways using a camera (bronchoscopy)


Pathogenic variants in five different genes are associated with the development of IPF: TERT, TERC, RTEL1, PARN, and NAF1. All five of these genes are inherited in an autosomal dominant pattern, meaning individuals need one abnormal gene variant in order to have IPF. About 8-15% of familial IPF cases are associated with variants in TERT or TERC.

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How can I join?

Individuals with one of the inherited bone marrow failure syndromes and their family members are encouraged to participate.

Phone: 1-800-518-8474 to speak with a member of our research team