Dyskeratosis congenita

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:

• Autosomal dominant dyskeratosis congenita (the gene comes from one parent): MIM* #127550
• Autosomal recessive dyskeratosis congenita (a gene comes from each parent): MIM #224230
• Dyskeratosis congenita linked to the X-chromosome (only affect males) MIM #305000
• Sporadic forms of dyskeratosis congenita.

*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:

1. item one
   1. item 2
   2. item 3

• Nail dystrophy
  • Longitudinal ridging
  • Loss of nails
  • Koilonychia (thin spoon-shaped nails)
• Abnormal skin pigmentation
  • Reticulate (lace-like) hyperpigmentation of skin creases, described as 'dirty neck' (>90%)
• Oral leukoplakia
  • Appears later in childhood
  • White patches in the mouth

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

Other skin changes can include:

• Early hair greying or hair loss
• Sparse eyelashes
• Nail ridging
• Hyperhidrosis (excessive sweating)
• Squamous cell carcinomas (SCC), often arising in teens or twenties (50% by 40 years). SCC is often found in mucosal sites including oral cancer

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:

• Mouth – oral cancer especially SCC of the tongue
• Airways – carcinomas of larynx or bronchus
• Digestive tract – carcinomas of oesophagus, colon, pancreas and anorectal
• Bone marrow – leukaemias, in particular, acute myeloid leukaemia is 200 times more common than in the general population.
• Lymphomas

The 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:

• One or more features of the classic mucocutaneous triad
• Bone marrow failure, such as aplastic anaemia
• Two or more of the other internal changes known to occur in dyskeratosis congenita:
  • eyes – excessive tears
  • nervous system – learning difficulties, developmental/intellectual disability, ataxia (unsteadiness), underdeveloped cerebellum, microcephaly (small brain), deafness
  • lungs – pulmonary fibrosis (scarring), abnormal blood vessels
  • bones – osteoporosis (thin bones), aseptic necrosis (bone death), scoliosis (twisted spine), short stature
  • teeth – extensive dental loss and decay, decreased root/crown ratios, mild taurodontism (enlarged tooth and pulp chamber)
  • digestive system – liver fibrosis/failure, oesophageal stricture (narrowing), peptic ulcer
  • genitourinary system – hypogonadism (small testes), undescended testes, phimosis (tight foreskin), urethral stricture (narrowing)

The combinations of clinical features, the 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:

• Hoyeraal–Hreidarsson syndrome – very short stature, bone marrow failure, immunodeficiency, underdeveloped cerebellum
• idiopathic aplastic anaemia (anaemia due to bone marrow failure)
• myelodysplasia (bone marrow failure)
• idiopathic pulmonary fibrosis
• paroxysmal nocturnal haemoglobinuria
• Revesz syndrome – bilateral exudative retinopathy (eye disease), bone marrow hypoplasia (failure), nail dystrophy, fine hair, cerebellar hypoplasia, growth retardation

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:

• Oxymetholone – an anabolic steroid that helps bone marrow function in two-thirds of patients for several years.
• Haematopoietic growth factors – erythropoietin, granulocyte macrophage colony-stimulating factor and granulocyte colony-stimulating factor.
• Bone marrow transplant – this was invariably fatal in dyskeratosis congenita due to the rapid development of liver failure or lung fibrosis post-transplant. It has now been recognised that this was due to intolerance to the pretransplant chemotherapy and/or radiotherapy. Bone marrow transplants have now been performed successfully in a small number of dyskeratosis congenita patients with less aggressive pretransplant therapy.

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.

• Most mutations affect telomerase. Without effective telomerase, the telomere length gets shorter with each cell division and quickly becomes so short the cell dies much sooner than normal. This is most important in cells that divide a lot, such as in the bone marrow and skin.
• Other mutations affect the protein ‘shelterin’ which shelters the telomeres from damage by DNA repair mechanisms.