Dyskeratosis Congenita Pathophysiology

Dyskeratosis congenita is a genetic condition that affects many parts of the body and in particular, the nails, skin and mucosal membranes. The condition is usually inherited in an X-linked recessive manner and therefore affects more men than women.

In around 50% of cases, the condition is known to arise from mutations in the TERT, TERC, DKC1 or TINF2 genes. These genes code for specialized proteins that help to maintain telomeres. Telomeres are regions of repetitive DNA sequences found at either end of a chromosome. They protect the chromosome from deteriorating or fusing with another chromosome and also induce apoptosis (programmed cell death) after a cell has divided a certain number of times and become “worn out.”

Mutations in the genes mentioned disrupt the maintenance of these telomeres, which become shortened. Groups of cells that undergo rapid cell division are particularly vulnerable to the effects of abnormally short telomeres and people with dyskeratosis congenita suffer from a range of problems affecting tissues such as the skin, hair follicles, nail beds, oral mucosa and bone marrow.

In the 50% of sufferers without these gene mutations, the cause of dyskeratosis congenita remains unknown, although researchers suspect that other genes involved in telomere maintenance may be involved.

Common features of dyskeratosis congenita

The three main characteristics of this condition include leukoplakia or whitish discoloration of the mucous membranes; dystrophy or abnormality of the nails and skin pigmentation.

A reticulated or patchy pattern to the pigmentation is seen in nearly 90% of sufferers. Sun exposed areas are more commonly affected, such as the upper trunk, face and neck. Nail changes are also seen in 90% of cases, with fingernails more commonly affected than toe nails. The nails become thin and distorted. In around 80% of patients, the inner lining of the cheeks, mouth, tongue and throat develop a whitish discolouration.

People with dyskeratosis congenita are prone to disorders that affect the bone marrow. These dangerous conditions cause bone marrow failure and death in nearly 70% of cases. The chromosomal instability that arises due to poor telomere maintenance can also lead to uncontrolled cell division, which raises the risk of cancer.