Dyskeratosis Congenita

What goes wrong

Telomeres are repeated DNA sequences at the ends of chromosomes that shorten each time a cell divides. An enzyme complex called telomerase, and related proteins, normally maintain them in stem cells. In DC, genetic variants in genes such as DKC1, TERT, TERC, TINF2, RTEL1 and others impair telomere maintenance. Telomeres become critically short, and stem cells stop dividing or die.

Tissues that need constant renewal are most affected: bone marrow, skin, nails, the lining of the mouth and gut, hair follicles, lungs and liver.

Inheritance

DC can be inherited in X-linked (DKC1, affecting mainly boys), autosomal dominant (TERT, TERC, TINF2) or autosomal recessive patterns. In dominant families, symptoms can appear earlier and more severely in each new generation, because shorter telomeres are passed on. Severe early forms include Hoyeraal-Hreidarsson syndrome and Revesz syndrome.

Signs and symptoms

The classic triad

Not everyone has all three, and some people have none, particularly in adult-onset forms.

Other features

• Bone marrow failure: low blood counts causing tiredness, infections and bleeding; affects most people by adulthood. See aplastic anemia.
• Lungs: pulmonary fibrosis and, less often, abnormal blood vessels in the lungs.
• Liver: fibrosis and cirrhosis.
• Eyes: blocked tear ducts with constant watering, and retinal changes.
• Hair: early graying and hair loss.
• Teeth: early tooth loss and gum disease.
• Bones: low bone density and avascular necrosis of the hips.
• Gut: narrowing of the esophagus and bowel problems.
• Short stature and developmental delay in severe forms.

Cancer risk

People with DC have a much higher risk of myelodysplastic syndrome, acute myeloid leukemia and squamous cell cancers of the head, neck and anogenital area, often at young ages.

Diagnosis

1. Clinical suspicion: the triad, unexplained marrow failure, early pulmonary fibrosis or liver disease, or a strong family history.
2. Telomere length testing: flow-FISH testing of white blood cells; telomeres below the 1st percentile for age strongly suggest DC.
3. Genetic testing: confirms the gene variant and allows family testing.
4. Baseline organ assessment: blood counts, bone marrow biopsy, lung function and CT, liver tests and imaging, eye and dental examination.

DC must be distinguished from other inherited marrow failure syndromes such as Fanconi anemia and Shwachman-Diamond syndrome, and from acquired aplastic anemia, because treatment differs.

Treatment

Bone marrow failure

• Hematopoietic stem cell transplant is the only curative treatment for marrow failure. People with DC are very sensitive to chemotherapy and radiation, so specialized reduced-intensity regimens without radiation are used at experienced centers. Transplant does not prevent lung or liver disease.
• Androgens such as danazol or oxymetholone can improve blood counts and may slow telomere shortening; they need monitoring for liver effects.
• Transfusions and growth factors as supportive care.

Immunosuppressive therapy used for acquired aplastic anemia does not work in DC.

Lungs and liver

Avoid smoking and lung irritants. Lung transplant may be considered for advanced pulmonary fibrosis, and liver transplant for liver failure.

Surveillance

Regular monitoring is central:

• blood counts at least yearly, often more frequently
• yearly bone marrow examination in some cases
• lung function tests
• liver tests and ultrasound
• head and neck cancer screening by a dentist or ENT specialist every 6 to 12 months
• skin and gynecological cancer checks
• eye and dental care

Avoid alcohol, tobacco and excess sun exposure, and keep vaccinations up to date.

Outlook

The course varies widely, from severe childhood illness to mild disease first noticed in adulthood. Bone marrow failure, lung disease and cancer are the main causes of death. Median survival has historically been in the 40s, but earlier diagnosis, better transplant approaches and surveillance are improving outcomes. Care at a center experienced in telomere biology disorders is recommended.

Frequently asked questions

What is dyskeratosis congenita?

It is a rare inherited disorder in which telomeres, the protective ends of chromosomes, are very short. This causes early failure of rapidly dividing tissues, especially the bone marrow, and typical nail, skin and mouth changes. It also raises the risk of lung disease, liver disease and cancer.

What is the triad of dyskeratosis congenita?

The classic triad is abnormal nails (nail dystrophy), lacy net-like skin pigmentation on the neck and chest, and white patches inside the mouth (oral leukoplakia). Many people do not have all three, so blood telomere testing is used for diagnosis.

How is dyskeratosis congenita inherited?

It can be X-linked, autosomal dominant or autosomal recessive, depending on the gene involved. Genetic counseling helps families understand the risk to children and relatives. Relatives considering bone marrow donation should be tested, because a carrier may not be a suitable donor.

What is the life expectancy with dyskeratosis congenita?

It varies widely. Severe forms can be life-threatening in childhood, while milder forms may first appear in adulthood. Historically, median survival was in the 40s, but specialized transplant care, surveillance and early treatment of complications are improving outlook.