Congenital dyskeratosis: causes, symptoms, diagnosis, treatment

The first description of congenital (congenital) dyskeratosis (Dyskeratosis congenita) was made by the dermatologist Zinsser in 1906, and in the 1930s it was supplemented by dermatologists Kohl and Engman, therefore another name for this rare form of hereditary pathology is “Zinsser-Kohl-Engman syndrome”.

Dyskeratosis congenita (syn. Zinsser-Engmann-Cole syndrome) is a rare disease inherited in most cases in an X-linked recessive manner, the pathological gene is localized in Xq28.

Symptoms of congenital (congenital) dyskeratosis

The main clinical symptoms are poikiloderma, dystrophic changes in the nails, leukoplakia on the mucous membranes of the oral cavity and genitals. Keratosis of the palms and soles, defects of the hair, teeth, bone and muscle tissue, eyes and other organs are often observed. There are blood changes similar to Fanconi anemia and associated with bone marrow hypoplasia. There is an increased tendency to develop malignant tumors, including in the leukoplakia zone. Males are more often affected. The cause of the disease is unknown. There is evidence of disruption of cell division processes, chromosomal instability with increased sister chromatid exchange, breaks in loci 2q33 and 8q22 occur, which suggests the localization of the oncogene at these points.

There is evidence of defects in stem cells in the bone marrow and an inadequate immune response.

The classic diagnostic triad of dyskeratosis congenita consists of the following symptoms: reticular hyperpigmentation of the skin of the face, neck and shoulders, dystrophy of the nails and leukoplakia of the mucous membranes. In total, about 200 cases of congenital dyskeratosis have been described. Three quarters of cases are inherited in an X-linked recessive manner, the rest are autosomal recessive or autosomal dominant. According to the types of inheritance, the ratio of males to females is 4.7:1. Interestingly, cases of autosomal recessive and autosomal dominant inheritance may actually represent cases of X-linked inheritance with asymmetric inactivation of the X chromosome in female carriers, when only the X chromosome carrying the mutation of the gene for congenital dyskeratosis is active. One of the genes for congenital dyskeratosis is mapped to the Xq28 region and is called dyskerin. A role of dyskerin in inhibiting apoptosis of cells expressing it has been postulated.

It is important to note the striking variation in age at diagnosis. Overall, it seems that the autosomal dominant variant of congenital dyskeratosis is milder than the X-linked and autosomal recessive variants.

Approximately 85% of patients develop aplastic anemia, making congenital dyskeratosis the second most common constitutional form of bone marrow failure after Fanconi anemia. Skin and skin appendage changes are most often detected in the first 10 years of life, with nail changes being particularly typical: at first they become brittle, acquire longitudinal striations and resemble nails affected by a fungus. With age, nail changes progress and often in the second decade of life individual nail plates completely disappear, this is especially typical for the fifth toes. Reticular depigmentation is variable - from an ephemeral grayish mesh pattern of the skin to large, about 4-8 mm in diameter, areas of depigmentation on a dark hyperpigmented background. Reticular depigmentation is especially pronounced in the neck and chest area. Leukoplakia of the oral mucosa most 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, signs of ectodermal dysplasia appear several years earlier than the development of cytopenia, sometimes the diagnosis of congenital dyskeratosis is established after the appearance of hematological changes, although retrospective analysis most often allows us to identify an earlier manifestation of other characteristic signs. It should be noted that cases of the appearance of characteristic skin changes after the development of aplastic anemia have also been described. In addition to the classic diagnostic triad, many anomalies of ectoderm derivatives have been described in patients with congenital dyskeratosis, sometimes giving very bizarre clinical combinations that lead patients to doctors of various specialties.

The average age of diagnosis of hematopoietic aplasia in congenital dyskeratosis is about 8 years, approximately coinciding with the age of manifestation of pancytopenia in Fanconi anemia. The most common first clinical symptoms are repeated nosebleeds due to progressive thrombocytopenia, which often precedes the appearance of anemia and neutropenia by several years. Hematological characteristics of aplastic anemia in congenital dyskeratosis do not have any specific features - along with pancytopenia, macrocytosis and an increase in the concentration of Hb F are detected. If the bone marrow examination is performed in the early phase of the disease, its cellularity may be increased, but later, with an increase in cytopenia, the cellularity of the bone marrow inevitably decreases.

In congenital dyskeratosis, the derivatives of all three germ layers are affected - the ento-, meso- and ectoderm. Among the anomalies described in congenital dyskeratosis, it is interesting to note severe progressive immunodeficiency, sometimes combined with cerebellar hypoplasia ( Hoyeraall-Hreidarsson syndrome), a tendency to develop cirrhosis and fibrosis of the liver and lungs, as well as a predisposition to malignant neoplasms. Malignant tumors were registered in more than 20 patients with congenital dyskeratosis, most often the oropharynx and gastrointestinal tract were affected, adenocarcinomas and squamous cell carcinomas predominated according to the histological type.

Unlike Fanconi anemia, studies of sensitivity to bifunctional clastogens of cells of patients with congenital dyskeratosis of all types of inheritance (diepoxybutane, mitomycin or nitrogen mustard) do not reveal an increased number of chromosomal abnormalities, which allows for a clear differentiation of these two diseases, sometimes phenotypically similar. Conservative treatment of bone marrow failure in congenital dyskeratosis is very difficult and has not been promising to date. In some patients, transient improvement in hematopoiesis can be achieved with androgens.

Pathomorphology. They reveal a slight thinning of the epidermis, mild hyperkeratosis, uneven pigmentation of the basal layer, in the dermis - an increase in the number of melanophages, which are often localized perivascularly in the papillary and upper part of the reticular layer, sometimes they are also found in the subcutaneous tissue.

In the upper part of the dermis, strip-like or focal infiltrates of lymphohistiocytic nature are observed. V.G. Kolyadenko et al. (1979) noted a disruption in the structure of collagen fibers in the form of their homogenization and fragmentation of elastic fibers.

Treatment of congenital dyskeratosis

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

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