Dyskeratosis congenita

Author: Dr Delwyn Dyall-Smith FACD, Dermatologist, 2010.

What is dyskeratosis congenita?

Dyskeratosis congenita is also known as Zinsser–Engman–Cole syndrome. It is a group of genetic diseases that most commonly manifest with mucocutaneous signs, bone marrow failure and/or lung or liver fibrosis.

There is considerable variability in the severity, age at onset and organ involvement, even within individual families. The various clinical features are now known to be due to ‘telomere shortening’ (unstable chromosomes), one of the causes of premature ageing. Since identifying the genetic changes, it has been discovered that a number of other conditions are due to changes in the same genes.

Who gets dyskeratosis congenita?

Dyskeratosis congenita is inherited and usually presents in childhood. Variants include:

*MIM is an abbreviation for Mendelian Inheritance in Man

Autosomal dominant forms of dyskeratosis congenita show ‘genetic anticipation’ where the parent of an affected child carries the mutation but shows no signs of the condition and each subsequent generation develops signs of disease earlier.

The severity of the disease depends on telomere length – the shorter the telomeres the more severe the disease, and this can often be linked to the type of inheritance. Generally the X-linked form is the most severe, the autosomal dominant form the mildest and the autosomal recessive type can be anywhere in between the two extremes.

Clinical features of dyskeratosis congenita

The classical mucocutaneous triad of dyskeratosis congenita was originally defined by the following three mucocutaneous features:

The first two features usually appear by the age of 10 years.

Other skin changes can include:

Bone marrow failure develops by the age of 30 years in 80-90%.

In addition to skin cancer, many other forms of cancer occur commonly in this syndrome, usually developing in the twenties:

New classification of dyskeratosis congenita

With the identification of the genetic mutations of dyskeratosis congenita, other previously unconnected manifestations have now been linked. A proposed modification of the definition is:

The combinations of clinical features, age of onset and severity vary with different mutations and within families.

A number of other conditions have now been shown to have the same genetic mutations as classic dyskeratosis congenita. These include:

How is dyskeratosis congenita diagnosed?

The diagnosis of dyskeratosis congenita is based on the definition above.

Gene mutations have so far only been identified in approximately 50% of cases.

It may be possible to distinguish dyskeratosis congenita by flow-FISH analysis due to the very short telomeres compared to age-matched controls.

It is important to consider the diagnosis in cases of bone marrow failure or lung fibrosis where no other cause has been identified, oral leukoplakia in a young person with no history of tobacco use and in early onset cancers.

What is the treatment of dyskeratosis congenita?

There is no cure at this time for dyskeratosis congenita. Treatment is aimed at maintaining bone marrow function as this is the major cause of death:

Although dyskeratosis congenita would seem to be an ideal condition for gene therapy, no progress has been made in this direction yet.

Genetic counselling is important for the planning of future pregnancies. Ante-natal diagnosis has been achieved successfully.

What is the outcome for dyskeratosis congenita?

The degree of severity and age at death is quite variable. Some forms are milder with survival into the forties; others are fatal in infancy. The main causes of death are bone marrow failure in 75-80% (due to increased susceptibility to infection or haemorrhage), lung fibrosis in 10-15% or cancer in 10%.

How does dyskeratosis congenita arise?  

The telomere is a region of repetitive DNA that forms a cap over the end of a chromosome in normal cells. It protects the end of the chromosome and ensures its stability. The normal cell divides about 50 times in its lifetime. The telomere gets shorter with every cell division. Eventually telomere shortening results in damaged DNA that can't divide any more; hence telomere shortening is associated with cellular ageing.

An enzyme called telomerase prevents telomere shortening. It is secreted by some stem cells and nearly all cancer cells, allowing them to keep on dividing.

Mutations have currently been identified in six genes coding for proteins involved in the maintenance of telomeres.

Type of dyskeratosis congenitaGene mutation
Autosomal dominant
  • TERT and TERC mutations affect telomerase.
  • TINF2 gene mutations affect shelterin.
  • DKC1 mutations affect dyskerin protein, a component of telomerase.
Autosomal recessive
  • NHP2, NOP10,TERT, TERC, TINF2 mutations.
Hoyeraal–Hreidarsson syndrome
Revesz syndrome
Some cases of idiopathic aplastic anaemia
  • TINF2 mutations

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