The dyskeratosis congenita is an inherited disease that affects multiple organ systems. The syndrome is characterized by abnormal pigmentation of the skin and mucous membranes, as well as stunted growth of fingernails and toenails. A causal treatment is often only possible through a stem cell transplant.

What is congenital dyskeratosis?

According to Ezhoushan, dyskeratosis congenita is a collective term for various hereditary telomeropathies. Telomeropathies are diseases that result from a disruption of telomerase activity. Telomerase is particularly active in cells that are subject to strong cell division, such as immune or blood cells.

However, telomerase activity cannot be detected in the other cells. If the telomerase activity is disturbed, the formation of new important blood and immune cells can no longer take place effectively because the telomeres become shorter with each cell division and thus endanger the stability of the chromosome. Among other things, the symptoms of dyskeratosis congenita develop.

Telomerase is an enzyme that stops or even reverses the shortening of telomeres when cells divide. As a result, the cell division activity of these cells is retained. The telomeres are located at the ends of the chromosomes and consist of repeating nucleotide sequences of DNA combined with certain proteins.

Each time a cell divides, the telomeres shorten by around 100 nucleotides. Cell division stops at a length of 4–6 kb. The cells then either undergo targeted apoptosis (targeted cell death) or go into a dormant state. Telomeres are responsible for the stability of the chromosomes.

The enzyme telomerase can now lengthen the telomeres again by adding chains of repetitive nucleic acid sequences. Among other things, the aging process of the organism is attributed to the slow shortening of the telomeres. The shorter the telomeres, the slower cell division becomes.

Causes

If the activity of telomerase is disturbed, cell division comes to a standstill very quickly. This has a particularly fatal effect on the blood-forming cells and immune cells. The clinical picture of dyskeratosis congenita arises. There are genetically very heterogeneous forms of dyskeratosis congenita.

The corresponding mutations can be autosomal dominant, autosomal recessive or x-linked recessive. The enzyme telomerase is embedded in a whole telomerase complex with various proteins. Every protein is involved in the function of telomerase.

In addition to mutations that directly affect telomerase, mutations of other proteins in the complex can also affect telomerase activity. At least ten genes are known whose mutations can lead to dyskeratosis congenita. The mutations in the TERC and DKC1 genes directly affect telomerase.

Together with mutations of TERT and TINF2, they account for around 50 percent of all cases of congenital dyskeratosis. The mutations of TERC and DKF1 can already be detected prenatally.

Symptoms, ailments & signs

The clinical picture of dyskeratosis congenita is very variable. There are very mild forms with minor external changes in which normal function of the bone marrow can be noted. In more severe forms of the disease, psychological abnormalities come to the fore.

Sometimes bone marrow depression, pulmonary fibrosis or even carcinoma develop in childhood. However, there are three typical symptoms of the condition. These are abnormally shaped fingernails and toenails, changes in skin pigmentation on the chest and neck, and leukoplakia (white spots on the lining of the mouth).

Life-threatening symptoms are bone marrow depression, myodysplastic syndrome and aplastic anemia. In the case of bone marrow depression, normal blood formation ceases. Too few red blood cells, white blood cells and platelets are produced.

The consequences are anemia, a severe weakening of the immune system with an increased susceptibility to infection and an increased risk of bleeding due to the lack of blood platelets. In myodysplastic syndrome, blood formation is based on genetically modified stem cells. In the process, more and more immature blood cells are produced, from which acute myeloid leukemia (AML) can develop.

The likelihood of developing other types of cancer such as anal cancer, head and neck cancer, or cancer of the genital organs is also greatly increased. Potentially fatal pulmonary fibrosis can also develop. Anomalies in the digestive tract, liver, genitourinary system, and dental anomalies were also observed.

In addition to neurological disorders, hair loss, lung abnormalities, skeletal disorders or narrowing of the tear ducts can also occur. Usually there is normal mental and motor development. In severe cases, however, developmental disorders can occur due to a severely underdeveloped cerebellum. Sometimes the retina of the eye is also disturbed.

Diagnosis

The diagnosis of dyskeratosis congenita is made by interpreting the symptoms, the anamnesis of the own and family medical history and possibly by genetic tests for mutations in the TERC or DKC1 gene.

Complications

In most cases, congenital dyskeratosis leads to various malformations on the body, which can also affect the patient’s internal organs. Most of the time, pigment disorders also occur. The patient also suffers from a severely weakened immune system and becomes ill more often as a result.

Likewise, in simplified terms, various types of inflammation can occur on the body. The risk of cancer is also increased by the dyskeratosis congenita, so that the compilations of cancer can result. Hair loss and skeletal disorders often occur. In severe cases, mental development is also disturbed and restricted, so that the person concerned suffers from retardation.

The everyday life of the person affected is extremely restricted due to the illness and the quality of life is reduced. In some cases, the person concerned is then dependent on the help of other people in everyday life. A causal treatment of dyskeratosis congenita is unfortunately not possible. However, many symptoms can be treated with the help of a stem cell donation, so that the symptoms are limited.

However, life expectancy is still reduced due to the disease. The eyes can also be affected by dyskeratosis congenita, so that the patient suffers from visual disturbances or from complete blindness. In many cases, the parents also suffer from psychological complaints and depression.

When should you go to the doctor?

In the best case scenario, congenital dyskeratosis can be diagnosed in childhood. Parents who notice signs of pulmonary fibrosis, carcinoma or bone marrow depression in their child should inform their pediatrician immediately. Other warning signs that require clarification are: abnormally shaped fingernails and toenails, changes in skin pigmentation in the area of ​​the chest and neck, and white spots on the oral mucosa (leukoplakia).

An emergency doctor must be called immediately if there are signs such as the aforementioned bone marrow depression or aplastic anemia. A doctor must be consulted at the latest when an increasing weakening of the immune system is noticed. Otherwise, a wide variety of diseases such as cancer, lung abnormalities, developmental disorders or skeletal disorders can develop. These diseases, which mainly occur in adulthood, require immediate clarification by the general practitioner.

Other contact persons are various specialists such as gastroenterologists, lung specialists or dermatologists, depending on the symptom and condition. Since congenital dyskeratosis usually takes a severe course, close monitoring by the doctor is indicated in any case after the initial treatment.

Treatment & Therapy

The therapy of dyskeratosis congenita depends on the severity of the disease. In many cases, symptomatic treatment of the disease is initially sufficient. A causal treatment is only possible through a stem cell transplant in the bone marrow.

This method is used when conventional therapy is no longer possible. A suitable donor must be found for the stem cell transplant, in which as many tissue characteristics as possible match the recipient. There are also studies with the synthetic androgen danazol.

The elongation of telomeres and haematological improvements were observed. However, no therapy recommendations can be made here because the risks cannot yet be assessed.

Outlook & forecast

The prognosis of congenital dyskeratosis depends on the extent and intensity of the individual symptoms. The disease manifests itself with individual characteristics in each patient. These are assessed individually and taken into account when creating a personal treatment plan. Since it is a hereditary disease, there is no cure. Without medical care, the symptoms worsen later in life.

In most patients, a significant alleviation of the symptoms is achieved with stem cell therapy. A bone marrow transplant is carried out for this. This procedure is risky and has numerous side effects. However, it is often the only way to improve your health. If the treatment is successful, the patient will experience a significant improvement in their wellbeing within the next few weeks and months.

If the bone marrow is rejected by the body, the prognosis worsens even further. The existing malformations on the body are treated in surgical interventions. An attempt is made to achieve the best possible functionality. Thanks to modern possibilities, the results are good; the status of natural health is not achieved despite all efforts. Since the patients often suffer from a weakened immune system, a healthy lifestyle and a balanced diet can do a lot to improve your own health.

Prevention

Since congenital dyskeratosis is hereditary, no general recommendations for its prevention can be given. A prenatal diagnosis, however, is possible through human genetic tests for mutations in the TERC and DKC1 genes.

Aftercare

The measures or options for follow-up care are very limited in the case of dyskeratosis congenita. As a rule, the person concerned is primarily dependent on a comprehensive examination and treatment so that there are no further complaints or complications. Independent healing is not to be expected. The earlier the dyskeratosis congenita is detected, the better the further course of this disease is usually.

In most cases, the symptoms of congenital dyskeratosis can only be relieved by transplanting stem cells. There is no other possibility of treatment available to the person affected, so that the follow-up measures are very limited. Since the transplantation of stem cells is usually a difficult procedure, those affected should take it easy and usually rest after such an procedure.

Regular examinations of the body are also necessary in order to identify further complaints at an early stage. Individual malformations can be alleviated with the help of surgical interventions. It cannot be universally predicted whether congenital dyskeratosis will result in a reduced life expectancy for the person affected.

You can do that yourself

Children who suffer from congenital dyskeratotis require the support of their parents and doctors. Parents should always keep an eye on their child and watch out for any changes in behavior. Should any unusual symptoms develop, these can be clarified quickly and treated if necessary.

In addition, the physical symptoms of the disease must be counteracted. In addition to regular exercise and a healthy diet, hygienic measures are also recommended. This counteracts the weakening of the immune system, but also the increased susceptibility to infection. If there are any further complaints, a medical examination is definitely indicated.

Any malformations are best treated surgically at an early stage. If this happens in early childhood, there is usually no major consequential damage later in life. Nevertheless, those affected should have themselves regularly examined by a doctor even in adulthood.

If congenital dyskeratosis is associated with carcinoma or pulmonary fibrosis, daily habits may also need to be changed. Scarring of the lungs is often associated with shortness of breath and other breathing difficulties that should be treated with asthma medication or inhalers. If a carcinoma has already been found and removed, regular preventive examinations by a specialist are indicated.