Dyskeratosis congenita is a general term for genetic disorders that lead to excess skin pigmentation, nail dystrophy and mucosal leukoplakia. Patients suffer and may die from distinct grades of bone marrow failure.
To date, mutations affecting ten different genes have been identified as possible DC triggers. However, each one of these genes may show a variety of different mutations that may yield distinct degrees of protein dysfunction. In this context, more than 50 mutations have been described for the DKC1 gene. Also, environmental factors seem to influence symptom onset and severity and even members of the same family, parents that inherited a determined genetic disorder to their children, may not necessarily present the same clinical picture. Even though the exact mechanisms behind such phenomena are not completely understood, these are the reasons for the heterogeneity in age of DC symptom onset, symptom progress, affected tissues and severity of pathological conditions.
Early symptom onset is generally associated with rapid and severe disease progress. Indeed, symptoms do usually not manifest until childhood or adolescence except in cases of the very severe Hoyeraal-Hreidarsson syndrome and Revesz syndrome. Mild cases may even progress asymptomatically until well into adulthood and manifest in form of one single symptom then [10]. These patients may, however, develop malignant neoplasms. TERC, TERT and TINF2 mutations tend to cause these less severe forms of the disease.
The classical symptom triad for DC is often triggered by DKC1 mutations and is characterized by excess skin pigmentation, nail dystrophy and mucosal leukoplakia. These symptoms usually manifest before the age of ten and are most likely followed by bone marrow failure in between ten more years. About 90% of these patients develop bone marrow failure before becoming 30 years old. Malignant neoplasms are less frequently observed here than in those patients suffering from mild forms of DC.
In detail, the following symptoms may be observed:
While the classical symptom triad of excess skin pigmentation, nail dystrophy and mucosal leukoplakia may directly prompt the tentative diagnosis of DC, symptoms resulting from bone marrow failure require a more thorough workup. Blood samples need to be analyzed and will typically show pancytopenia, but in many cases only one or two of anemia, thrombocytopenia and leukopenia will be detected. Bone marrow biopsies may reveal aplastic anemia.
Spirometric tests and diagnostic imaging of the lungs is indicated to assess lung function and to detect possible lung cancer. Further images may be helpful to confirm or rule out the presence of malignant neoplasms in other tissues.
Additional diagnostic measures need to be adjusted to the individual case. If mucosal leukoplakia is present but hyperpigmentation and nail dystrophy are not, histopathologic analysis of a corresponding biopsy provide information regarding the nature of mucosal alterations. This applies similarly to dermatological findings. Ophthalmologic, urological and neuropsychiatric symptoms require their own workup.
Genetic testing and confirmation of known mutations may be diagnostic, but about one in three patients does not present any of the aforementioned gene disorders. Thus, failure to detect any genetic defect does not rule out DC [13]. Flow fluorescence in situ hybridization may be used on subsets of leukocytes, particularly on lymphocytes, to measure telomere length and to detect abnormally short telomeres [14].
DC therapy consists in delay of bone marrow failure, palliative treatment of present symptoms and life style adaptions to avoid disease progress. There is no cure for DC.
Bone marrow failure may initially be treated with androgens like oxymetholone [15]. Such treatment may improve anemia and possibly thrombocytopenia. However, long-term effects are not to be expected.
Because androgen therapy in pediatric patients may accelerate growth, corticosteroids may supplement the former. Not only do corticosteroids reduce growth acceleration, they may also serve to counteract the hemorrhagic diathesis caused by thrombocytopenia.
Hematopoietic growth hormones such as granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor may be administered to stimulate proliferation of neutrophil precursors. As is the case for androgen therapy, effects are usually transient.
Bone marrow or stem cell transplantation may eventually cure aplastic anemia but not premature cell aging in other tissues [16]. Success of transplantations may depend on immunosuppressive therapy, but DC patients are very sensitive towards chemotherapy and irradiation. Busulfan and melphalan should be avoided. Potentially lethal pulmonary complications may occur after stem cell transplantation which is why this therapeutic measure should be reserved for patients mainly suffering from bone marrow failure.
If DC patients develop malignant neoplasms, they should be surgically removed if at all possible. As has been mentioned above, chemotherapy and irradiation are not suitable therapeutic options.
Additionally, any habits that accelerate aging should strictly be avoided. Tobacco and alcohol are not to be consumed by DC patients. Skin care and an adequate oral hygiene are very important measures to prevent skin lesions, tooth loss and even certain malignancies.
The prognosis associated with DC is poor and life expectancy is less than 30 years. Only palliative therapy may be provided, although bone marrow and stem cell transplantations may cure aplastic anemia. Nevertheless, about 70% of DC patients eventually die from bone marrow failure and consequences. Gene mutations triggering DC affect all organ systems and predispose for infections, hemorrhages and malignant degeneration of rapidly dividing cell types.
It has been suggested that prognosis is somewhat better in DC forms triggered by mutations that are inherited with an autosomal dominant traits.
X-linked inheritance has been shown for mutations in DKC1, a gene encoding for the nucleolar protein dyskerin. Such mutations account for about half of all DC cases [1].
Less frequently observed are gene defects affecting TERC (telomerase RNA component), TERT (telomerase reverse transcriptase) and TINF2 whose gene products are required for telomere replication, catalytic activity of telomerases and telomere protection, respectively, and that are inherited with an autosomal dominant trait.
TERT mutations may also be inherited in an autosomal recessive manner and this applies for additional proteins, too [4].
While DKC1 mutations account for the majority of DC cases, there are several other genes whose gene products interfere with telomerase function and telomere replication. Penetrance varies and environmental factors significantly affect symptom onset and severity. Thus, DC is a very heterogenous disease that is diagnosed if characteristic symptoms such as excess skin pigmentation, nail dystrophy and leukoplakia are detected. Indeed, bone marrow failure is of utmost clinical importance but less obvious than the aforementioned symptoms and is therefore not part of the original definition of DC. And although this generic term comprises several genetic disorders, DC is a rare disease and incidence rates have been estimated to be less than 1 per 1,000,000 individuals [5].
Because the majority of mutations that account for DC is X-linked, males are affected more frequently than females [6]. Symptoms often manifest during childhood, but due to the above mentioned heterogeneity, age at symptom onset, symptoms themselves and severity may vary widely.
Chromosomes consist of DNA strands whose ends are formed by non-coding sequence repeats called telomeres. In humans, they may measure several thousand base pairs. However, during DNA replication after successful mitosis, telomeres are shortened. At one point, telomeres are too short for further cell division, chromosomal stability can no longer be guaranteed and cells either remain in a senescent state of indivisibility or undergo apoptosis to avoid malignant degeneration. Indeed, telomere shortening seems to be the molecular basis of aging.
Telomerase is an enzyme capable of adding telomeric sequence repeats to shortened telomeres. It thus prolongs the life cycle of cells, particularly of stem cells and germ cells, and contributes to cellular cancer prevention. Telomerase dysfunctions will mainly affect tissues with fast rates of cell division, e.g., skin, skin appendages, mucosa and bone marrow - those tissues showing symptoms of DC. So far, all gene mutations that have been identified as possible triggers of DC could be linked to telomerase function, telomere protection and replication [7] [8]. DKC1, TERC and TERT gene products are part of the telomerase complex, while other affected proteins fulfill additional functions, e.g., telomere protection. Consequently, dysfunction of proteins defective in DC patients leads to reduced telomerase activity, premature telomere shortening and cellular senescence [9]. In fact, telomeric DNA in DC patients is significantly shorter than in healthy controls of the same age.
In detail, DKC1 encodes for dyskerin, a protein involved in ribosomal RNA metabolism that forms part of the telomerase complex. More than 50 DKC1 mutations have been described so far. Mutations in TERC affect the telomerase RNA component and this molecule serves as the template for telomere replication. TERT, telomerase reverse transcriptase, forms the catalytic subunit of the telomerase complex.
No preventive measures can be recommended.
Families with known problems of DC may benefit from genetic counseling.
Dyskeratosis congenita (DC) is a general term utilized for a variety of genetic disorders whose most characteristic symptoms are excess skin pigmentation, nail dystrophy and mucosal leukoplakia. Disease progress often consists in malignant degeneration of precancerous mucosal lesions, development of squamous cell carcinoma, pulmonary fibrosis or lung cancer [1]. Also, the majority of DC patients eventually suffers from bone marrow failure and possibly subsequent hematologic malignancies.
Because DC may be triggered by different gene mutations, it may be inherited with an X-linked or autosomal trait, in form of a dominant or recessive allele. To date, ten mutations affecting function and activity of telomerase or associated proteins have been described as potential causes of DC. Presumably, additional mutations may also account for DC since there is a considerable share of DC patients who does not display any of the known gene defects. These mutations lead to premature telomere shortening, tissue and stem cell senescence and predisposition for cancer [2].
The main cause of death in DC patients is bone marrow failure. Only a hematopoietic stem cell transplantation may be effective in avoiding it and in improving the patient's prognosis [3]. Otherwise, there is no causative treatment for DC and only palliative therapy can be provided.
Dyskeratosis congenita (DC) is a general term for genetic disorders associated with premature aging of cells.
Causes
Distinct gene mutations may trigger DC. All these mutations interfere with telomere protection and replication, whereby telomeres are non-coding DNA sequences that confer stability to chromosomes. Each time a cell divides, these telomeres are shortened a little bit. After a determined number of divisions, a cell cannot divide any longer without an increased risk for malignant degeneration and cancer development. Thus, the cell initiates what is called a programmed cell death. However, there are certain cell types that need to maintain their ability to divide, particularly stem cells located in the bone marrow. These cells dispose of an enzyme called telomerase whose function is to re-extend shortened telomeres. Telomerase activity is reduced in DC patients, telomeres are shortened prematurely and cells tend to age much faster than in healthy individuals.
Symptoms
The above explained mechanisms of reduced telomerase activity and accelerated telomere shortening mainly affect tissues characterized by a rapid turn over, e.g. skin, skin appendages, mucosa and bone marrow. Therefore, DC may manifest in form of excess skin pigmentation, nail dystrophy and mucosal leukoplakia, i.e., white patches that become visible on the oral mucosa, as well as bone marrow failure. The latter, in turn, leads to anemia, thrombocytopenia and leukopenia which manifest in fatigue, breathing difficulties, bluish discoloration of the skin, a tendency to bleed, bleeding gums and nosebleed and recurrent infections with any type of pathogen. DC patients also have a high risk of developing cancer.
Diagnosis
A tentative diagnosis may be based on the presence of several of the above mentioned symptoms. Laboratory analyses of blood and bone marrow samples confirm low cell counts of virtually all cell types. If the patient presents alterations that cannot be clearly identified, tissue biopsies may be taken and histopathologically examined. Diagnostic imaging may be applied to evaluate the condition of the patient's lungs and to detect possible tumors. A new diagnostic technique allows for measuring the length of telomeres. Abnormally short telomeres support the diagnosis of DC.
Positive testing for gene mutations known to trigger DC may confirm the diagnosis. However, about one in three DC patients suffers from other, as of yet unknown mutations that cannot be easily detected with genetic analysis.
Treatment
There is no cure for DC. Therapy with androgens or growth hormones may stimulate production of red and white blood cells in the bone marrow. The tendency to bleed may be somewhat counteracted with corticosteroids. However, these drugs only mediate short- to mid-term effects. Patients who suffer mainly from bone marrow failure may benefit from bone marrow or stem cell transplantation. Otherwise, only supportive therapy can be provided.
DC patients should avoid consumption of tobacco and alcohol. Skin care and good oral hygiene are also important and may delay the onset of certain symptoms.