Dyskeratosis congenita represents a hereditary disorder affecting multiple organ systems. The syndrome is characterized by abnormal pigmentation of the skin and mucous membranes and growth disturbances of fingernails and toenails. Causative treatment is often only possible with stem cell transplantation.
What is dyskeratosis congenita?
Dyskeratosis congenita is a collective term for various hereditary telomeropathies. Telomeropathies are diseases that result from a disruption of telomerase activity. Particularly in cells that are subject to strong cell division, such as immune or blood cells, telomerase has a high activity. In other cells, however, telomerase activity is not detectable. If the telomerase activity is disturbed, the new formation of 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. This is when the symptoms of dyskeratosis congenita, among others, develop. Telomerase is an enzyme that stops or even reverses the shortening of telomeres during cell divisions. As a result, the cell division activity of these cells is maintained. Telomeres are located at the ends of chromosomes and consist of constantly repeating nucleotide sequences of DNA in association with certain proteins. Each time a cell divides, the telomeres shorten by about 100 nucleotides. At a length of 4-6 kb, cell division stops. The cells then either undergo targeted apoptosis (targeted cell death) or enter a resting stage. Telomeres are responsible for the stability of chromosomes. The enzyme telomerase can now lengthen telomeres again by attaching chains of repetitive nucleic acid sequences. Among other things, the aging process of the organism is also attributed to the slow shortening of telomeres. The shorter telomeres become, the slower cell division becomes.
Causes
When the activity of telomerase is disturbed, cell division comes to a halt very quickly. This has a particularly fatal effect on hematopoietic cells and immune cells. The clinical picture of dyskeratosis congenita develops. There are genetically very heterogeneous forms of dyskeratosis congenita. Thus, the corresponding mutations can be autosomal dominant, autosomal recessive or x-linked recessive. The enzyme telomerase is embedded in a whole telomerase complex with different proteins. Each protein is involved in the function of telomerase. Thus, in addition to mutations that directly affect telomerase, mutations of other proteins in the complex can also affect telomerase activity. Thus, at least ten genes are known whose mutations can lead to dyskeratosis congenita. Mutations of the TERC and DKC1 genes directly affect telomerase. Together with mutations of TERT and TINF2, they account for about 50 percent of all cases of dyskeratosis congenita. The mutations of TERC and DKF1 can be detected prenatally.
Symptoms, complaints, and signs
The clinical picture of dyskeratosis congenita is highly variable. There are very mild forms with minor external changes in which normal bone marrow function is noted. In more severe forms of the disease, psychological abnormalities come to the fore. Sometimes bone marrow depressions, pulmonary fibrosis or even carcinomas develop already in childhood. However, there are three typical symptoms of the disease. These are abnormally shaped finger and toe nails, changes in skin pigmentation on the chest and neck, and leukoplakia (white patches on the oral mucosa). Life-threatening symptoms of the disease are bone marrow depression, myodysplastic syndrome or aplastic anemia. In bone marrow depression, normal blood formation stops. Too few red blood cells, white blood cells and platelets are produced. The consequences are anemia, a severe weakening of the immune system with increased susceptibility to infection, and increased risk of bleeding due to the lack of platelets. In myodysplastic syndrome, blood formation originates from genetically altered stem cells. As a result, more and more immature blood cells are produced, which may develop into acute myeloid leukemia (AML).The likelihood of the occurrence of other cancers such as anal carcinomas, head and neck carcinomas or carcinomas of the reproductive organs is also greatly increased. Furthermore, potentially fatal pulmonary fibrosis may also develop. Abnormalities of the digestive tract, liver, genitourinary system, and dental abnormalities have also been observed. In addition to neurologic disorders, hair loss, pulmonary abnormalities, skeletal abnormalities, or narrowing of the lacrimal ducts may also occur. In most cases, there is normal mental and motor development. However, in severe cases, developmental disorders may occur due to a severely underdeveloped cerebellum. Sometimes the retina of the eye is also disturbed.
Diagnosis
Diagnosis of dyskeratosis congenita is made by interpretation of the presenting symptoms, history of the patient’s own and family medical history, and possibly by human genetic testing for mutations in the TERC or DKC1 genes.
Complications
In most cases, dyskeratosis congenita results in various malformations on the body, and the patient’s internal organs may also be affected. Pigmentary abnormalities also usually occur. The patient also suffers from a severely weakened immune system and becomes ill more often as a result. Likewise, various inflammations on the body can occur in a simplified manner. The risk of cancer is also increased due to dyskeratosis congenita, so that the compilations of cancer may result. Hair loss and skeletal disorders often occur. Also the mental development is disturbed and limited in severe cases, so that the affected person suffers from retardation. The daily life of the affected person becomes extremely limited due to the disease and the quality of life is reduced. In some cases, the affected person is then dependent on the help of other people in everyday life. Unfortunately, a causal treatment of dyskeratosis congenita is 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 complete blindness. In many cases, the parents also suffer from psychological distress and depression.
When should one go to the doctor?
At best, dyskeratosis congenita can be diagnosed in childhood. Parents who notice signs of pulmonary fibrosis, carcinoma, or bone marrow depression in their child should notify the pediatrician immediately. Other warning signs that require clarification include: abnormally shaped finger and toe nails, altered skin pigmentation around the chest and neck, and white patches on the oral mucosa (leukoplakia). In case of signs such as bone marrow depression or aplastic anemia mentioned above, the emergency physician must be called immediately. At the latest when an increasing weakening of the immune system is noticed, a doctor must be consulted. Otherwise, a wide variety of diseases such as cancer, lung anomalies, developmental disorders or skeletal disorders may develop. These diseases, which predominantly occur in adulthood, require immediate clarification by the general practitioner. Other contacts include various specialists such as gastroenterologists, pulmonary specialists, or dermatologists, depending on the symptom and condition. Because dyskeratosis congenita usually takes a severe course, close monitoring by the physician is indicated in all cases after initial treatment.
Treatment and therapy
The therapy of dyskeratosis congenita depends on the severity of the disease. In many cases, symptomatic treatment of the disease is initially sufficient. Causative treatment is only possible by bone marrow stem cell transplantation. This method is used when conventional therapy is no longer possible. For stem cell transplantation, a suitable donor must be found in whom as many tissue characteristics as possible match the recipient. Furthermore, there are studies with the synthetic androgen danazol. Thereby the prolongation of telomeres and hematological improvements were observed. However, no therapy recommendations can yet be made here because the risks cannot yet be assessed.
Prospects and prognosis
The prognosis of dyskeratosis congenita depends on the extent and intensity of the individual symptoms.In each patient, the disease presents with individual manifestations. These are evaluated individually and taken into account in the creation of a personal treatment plan. Since it is a hereditary disease, there is no cure. Without medical care, the symptoms increase as life progresses. In most patients, significant relief of symptoms is achieved in stem cell therapy. For this purpose, a transplantation of the bone marrow is performed. This procedure is risky and associated with numerous side effects. However, it is often the only way to achieve an improvement in health. If the treatment is successful, the patient experiences a significant improvement in his well-being within the next weeks and months. If the bone marrow is rejected by the organism, the prognosis is further worsened. The existing malformations on the body are treated in surgical interventions. In this process, an attempt is made to establish the best possible functional capability. The results are good thanks to modern possibilities, but the status of natural health is not reached despite all efforts. Since patients often suffer from a weakened immune system, a healthy lifestyle and a balanced diet can do much to improve one’s health.
Prevention
Because dyskeratosis congenita is hereditary, no general recommendations can be made for its prevention. However, prenatal diagnosis is possible by human genetic testing for mutations in the TERC and DKC1 genes.
Follow-up
The measures or options for aftercare are very limited in the disease dyskeratosis congenita. In this case, the affected person is usually primarily dependent on comprehensive examination and treatment to prevent further discomfort or complications. An independent cure is not to be expected. The earlier the dyskeratosis congenita is detected, the better the further course of this disease usually is. In most cases, the symptoms of dyskeratosis congenita can only be alleviated by stem cell transplantation. There is no other possibility of treatment available to the affected person, so that the measures of aftercare are also very limited in this case. Since the transplantation of stem cells is usually a serious operation, the affected person should take care of himself after such an operation and usually also rest. Regular examinations of the body are also necessary in order to detect further complaints at an early stage. Individual deformities can be alleviated with the help of surgical interventions. Whether dyskeratosis congenita will result in a reduced life expectancy for the affected individual cannot be universally predicted.
Here’s what you can do yourself
Children suffering from dyskeratosis congenita require the support of parents and physicians. Parents should always keep an eye on their child and watch for any changes in behavior. If any unusual symptoms then appear, 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 tendency to infection. However, should further complaints develop, a medical examination is indicated in any case. Any malformations are best treated surgically at an early stage. If this is done in early childhood, no major consequential damage usually occurs later in life. Nevertheless, those affected should have regular examinations by a physician even in adulthood. If dyskeratosis congenita is associated with carcinoma or pulmonary fibrosis, daily habits may also have to be changed. For example, scarring of the lungs is often associated with shortness of breath and other breathing difficulties that should be treated with asthma medications or inhalers. If a carcinoma has already been detected and removed, regular check-ups with a specialist are indicated.
