Congenital dyskeratosis: causes, symptoms, diagnosis, treatment

The first description of congenital (congenital) dyskeratosis (Dyskeratosis congenita) was performed by a dermatologist Zinsser in 1906, and in the 30s. It was also supplemented by dermatologists Kohl and Engman, therefore another name for this rare form of hereditary pathology is the "Zinsser-Kohl-Engman syndrome".

Dyskeratosis is congenital (synovial syndrome of Zinsser-Engman-Cole) - a rare disease. Inherited in most cases X-linked recessively, the pathological gene is localized in Xq28.

Symptoms of congenital (congenital) dyskeratosis

The main clinical symptoms are poikiloderma, dystrophic nail changes, leukoplakia on the mucous membranes of the oral cavity and genital organs. Often observed keratosis of the palms and soles, defects in hair, teeth, bone and muscle tissue, eyes and other organs. There are blood changes, similar to Fanconi anemia and associated with bone marrow hypoplasia. Increased propensity to develop malignant tumors, including in the leukoplak zone. More often the faces of a male heart attack. The cause of the disease is unknown. There are data on the violation of the processes of cell division, chromosomal instability with increased exchange of sister chromatids, there are discontinuities in loci 2q33 and 8q22, which suggests the localization of the oncogene at these points.

There are data on the defects of stem cells in the bone marrow, an inferior immune response.

The classic diagnostic triad of congenital dyskeratosis consists of the following symptoms: reticular hyperpigmentation of the facial, neck and shoulder pads, nail dystrophy and mucosal leukoplakia. A total of about 200 cases of congenital dyskeratosis have been described. Three-fourths of cases are inherited by the X-linked recessive type, the rest are autosomal recessive or autosomal dominant. According to the types of inheritance, the ratio of men and women is 4.7: 1. Interestingly, cases of autosomal recessive and autosomal dominant inheritance can in fact be cases of X-linked inheritance with asymmetric inactivation of the X chromosome in female carriers, when only the X chromosome that carries the mutation of the inherent dyskeratosis gene is active. One of the genes of congenital dyskeratosis is mapped in the region of Xq28 and is called the diskurin. The role of diskurin in the inhibition of apoptosis of the cells expressing it has been postulated.

It is necessary to note an astonishing scatter in the age of diagnosis. In general, it seems that the autosomal dominant variant of congenital dyskeratosis proceeds milder than X-linked and autosomal recessive.

Approximately 85% of patients develop aplastic anemia - thus, congenital dyskeratosis is the second most frequent form of bone marrow failure after Fanconi anemia. Changes in the skin and its appendages are most often found in the first 10 years of life, especially the changes in the nails are particularly typical: first they become brittle, acquire longitudinal striation and become like fingernails affected by a fungus. With age, changes in nails progress and often in the second decade of life, individual nail plates completely disappear, especially this is characteristic of the V toes of the feet. Reticular depigmentation is variable in nature - from the ephemeral grayish net pattern of the skin to large, about 4-8 mm in diameter, the areas of depigmentation on a dark hyperpigmented background. Especially bright is the reticular depigmentation in the neck and chest. Leukoplakia of the oral mucosa often appears in the second decade of life. A characteristic feature of all skin manifestations of congenital dyskeratosis is their aggravation with age. As a rule, the signs of ectodermal dysplasia appear several years before the development of cytopenia, sometimes the diagnosis of congenital dyskeratosis is established after the appearance of hematologic changes, although retrospective analysis often reveals an earlier manifestation of other characteristic features. It should be noted that cases of the appearance of characteristic skin changes have been described even after the development of aplastic anemia. In addition to the classical diagnostic triad, in patients with congenital dyskeratosis, a variety of anomalies of ectoderm derivatives are described, sometimes giving very bizarre clinical combinations leading patients to physicians of various specialties.

The average age of establishing a diagnosis of hematopoiesis with congenital discreet dyskeratosis is about 8 years, roughly coinciding with the age of the manifestation of pancytopenia in Fanconi anemia. The most frequent first clinical symptoms are repeated nasal bleeding due to progressive thrombocytopenia, which precedes the appearance of anemia and neutropenia often for several years. Hematologic characteristics of aplastic anemia in congenital dyskeratosis do not have any specific features - along with pancytopenia, macrocytosis and an increase in Hb F concentration are revealed. If bone marrow examination is performed in the early phase of the disease, its cellularity can be increased, but later, with the increase of cytopenia, the cellularity of the bone marrow inevitably falls.

With congenital dyskeratosis, the derivatives of all three embryonic leaves are affected: ento-, meso-, and ectoderm. Among the abnormalities described with congenital discreet dysarthatosis, it is interesting to note the severe progressive immunodeficiency, sometimes combined with cerebellar hypoplasia ( Hoyeraall-Hreidarsson syndrome), the tendency to develop cirrhosis and fibrosis of the liver and lungs, and a predisposition to malignant neoplasms. Malignant tumors were recorded in more than 20 patients with congenital dyskeratosis, the oral cavity of the oropharynx and gastrointestinal tract was most often affected, the histological type was dominated by adenocarcinomas and squamous cell carcinomas.

Unlike Fanconi anemia, studies of sensitivity to bifunctional clastogens in cells of congenital dyskeratosis of all types of inheritance (diepoxybutane, mitomycin, or nitrogen-mustard) do not reveal an increased number of chromosomal abnormalities, which makes it possible to clearly differentiate these 2 diseases, sometimes phenotypically similar. Conservative treatment of bone marrow failure in congenital dyskeratosis is very difficult and to date has little prospects. In some patients transient improvement of hematopoiesis can be achieved with the help of androgens.

Pathomorphology. There is a slight thinning of the epidermis, poorly expressed hyperkeratosis, uneven pigmentation of the basal layer, in the dermis - an increase in the number of melanophages that are more often localized perivascular in the papillate and upper part of the mesh layer, sometimes found in the subcutaneous tissue.

In the upper part of the dermis, there are banded or focal infiltrates of lymphogistocyte character. V.G. Kolyadenko et al. (1979) noted a violation of the structure of collagen fibers in the form of their homogenization, the fragmentation of elastic fibers.

Treatment of congenital dyskeratosis

The experience of allogeneic bone marrow transplantation with congenital dyskeratosis is contradictory: transplant engraftment can be achieved in the vast majority of patients, but abnormally high mortality from GVHD, veno-occlusive disease of the liver, kidneys and lungs limits the application of this method. In all likelihood, high-dose radiochemotherapy and the "graft-versus-host" reaction accelerate the natural evolution of the affected meso and endoderm derivatives, since cases of veno-occlusive disease and idiopathic cirrhosis, as well as idiopathic interstitial pneumonia, in patients with congenital dyskeratosis are described as variants of the natural evolution of the disease and outside the context of allogeneic BMT. Another obstacle to successful bone marrow transplantation lies in the possible use as a donor of sibling, also suffering from congenital dyskeratosis, in which the symptoms of the disease are not yet detectable.

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