Fanconi Anemia: Causes, Symptoms, Diagnosis, Treatment

Fanconi anemia was first described in 1927 by the Swiss pediatrician Guido Fanconi, who reported on 3 brothers with pancytopenia and physical vices. The term "Fanconi anemia" was proposed by Negeli in 1931 to refer to the combination of Fanconi's family anemia and congenital physical malformations. Today, in order to establish the diagnosis of Fanconi anemia, it is not necessary that there are neither malformations nor Fanconi anemia per se. Fanconi anemia is a rare autosomal recessive disease, its frequency is 1 for 360,000 children born with a ratio of 1.1: 1 in favor of boys.

To date, more than 1200 cases of Fanconi anemia are known and their number is rapidly increasing as a result of the introduction of laboratory diagnostic methods that allow the diagnosis of the disease in siblings of the Fanconi anemia before the manifestation of aplastic anemia, as well as in patients with characteristic developmental malformations, but without hematological anomalies.

[1], [2], [3], [4]

Causes of Anemia Fanconi

Fanconi anemia is an autosomal recessive disease with variable penetrance and genetic heterogeneity. Heterozygous carriage occurs at a frequency of 1: 300. When karyotyping lymphocytes and fibroblasts of Fanconi anemia patients, chromosome abnormalities are detected in a large percentage of cases. It is believed that the defective genes responsible for reducing the reparative properties of the organism are located in the 22nd and 20th chromosomes.

[5], [6]

Pathogenesis of Fanconi Anemia

In the bone marrow, reduced cellularity, oppression of all germs of the hemopoiesis (erythroid, myeloid, megakaryocytic), fatty tissue proliferation are revealed. Defect hemopoiesis in Fanconi anemia is localized at the level of the stem cell. Hemopoietic cells have an increased ripening time. The lifespan of erythrocytes in children with Fanconi anemia is significantly reduced (by 2.5-3 times).

Symptoms of Anemia Fanconi

The average age of diagnosis of Fanconi anemia is 7.9 years for boys and 9 for girls, with 75% of Fanconi anemia diagnosed between 3 and 14 years of age. Alertness for Fanconi anemia should in no case be limited to the age range: variations in the age of the patients in whom the diagnosis was made are unusually broad - from birth to 48 years and from birth to 32 years for females and males, respectively.

The classic appearance of the patient with Fanconi anemia is low growth, microcephaly, microphthalmia, a swarthy skin tint ("permanent tanning"), areas of hyper and hypopigmentation of the skin and mucous membranes and ugly fingers. With Fanconi anemia, various organs and systems are affected by congenital malformations and developmental anomalies in an unequal degree. About 6% of patients do not have any anomalies at all. Earlier, such cases were described in the literature under the name of anemia of Estrena-Dameshek - by the name of the authors, who in 1947 described 2 families with a constitutional hypoplastic anemia without developmental defects. The diagnosis of Fanconi anemia should be necessarily confirmed by tests for chromosome hypersensitivity, especially since developmental abnormalities may be common for Fanconi anemia and other hereditary aplastic anemia, for example, congenital dyskeratosis. The severity of developmental defects can vary greatly even within the same family: many cases of Fanconi anemia among siblings are known, one of which had no developmental defects, and the other had.

Laboratory signs of anemia Fanconi

Three-arousal aplasia is the most typical manifestation of Fanconi anemia, but observations of initially hematologically intact homozygotes have shown that often thrombocytopenic or leukopenia precedes the development of pancytopenia. The first hematological abnormalities in Fanconi anemia are naturally detected after respiratory viral infections, inoculations, sometimes hepatitis - as it is typical for idiopathic aplastic anemia. For Fanconi anemia, even pronounced macrocytosis is typical even in the pre-anemic phase, accompanied by a significant increase in the level of fetal hemoglobin. Bone marrow is usually depleted of hematopoietic cellular elements, lymphocytes predominate, plasma cells, mast cells and stromal cells are found - a clinical picture indistinguishable from idiopathic aplastic anemia. Often in the aspirate of the bone marrow, dismyelopoiesis and dyserothyroposis, in particular, megaloblasticity, are discovered, due to which Fanconi called this anemia "pernicious". In bone marrow biopsy specimens, early stages of the disease reveal hypercellular areas of active residual hemopoiesis that disappear as the disease progresses.

One of the fundamental phenomena characteristic for blood cells of patients with Fanconi anemia is their tendency to form specific chromosomal abnormalities - ruptures, sister exchanges, endoreduplications in the cultivation of cells in vitro. Incubation of PHA-stimulated lymphocytes in patients with Fanconi anemia with bifunctional alkylating agents that cause DNA crosslinking between guanidine bases located on both one and two complementary chains - nitrogen-mustard, platinum preparations, mitomycin and especially diepoxybutane - sharply increases the number of aberrations. This phenomenon, called the clastogenic effect, underlies the modern diagnosis and differential diagnostics of Fanconi anemia, as spontaneous aberrations may both be absent in patients with Fanconi anemia and may be present in patients with other syndromes, in particular, with Nijmegen syndrome. Under the influence of bifunctional alkylating agents, the cell cycle slows down: the cells of Fanconi anemia stop in the G2 phase of the mitotic cycle, which served as the basis for the development of yet another diagnostic test for Fanconi anemia using the flow fluorometry method.

The age of the first appearance of Fanconi anemia in one family is often concordant, but may vary significantly, including in identical twins. In the past, in the absence of specific treatment (androgens or bone marrow transplantation) and only blood transfusions, the disease progressed steadily: 80% of patients died of complications of pancytopenia within 2 years after the diagnosis of aplastic anemia and almost all patients died 4 years later. It should be mentioned that there have been several cases of spontaneous improvement and even complete restoration of hematological parameters.

The second most frequent development of the hematological presentation of Fanconi anemia is acute leukemia and myelodysplastic syndromes. Approximately 10% of patients with Fanconi anemia, whose clinical cases are described in the literature, later developed acute leukemia. In all cases, except for 2, leukemias were myeloid. There are even cases of the diagnosis of Fanconi anemia in a patient with residual cytopenia many years after successful AML chemotherapy. Somewhat lower the incidence of myelodysplastic syndromes is about 5%, and only a fifth of these patients have followed the evolution of MDS in AML and several patients with IBS have lived more than 10 years. According to the studies of the International Fanconi Anemia Register, the risk of developing AML or MDS in patients with Fanconi anemia is 52% to 40 years. Often, karyotypic anomalies (monosomy 7, trisomy 21, deletion 1) are identified that allow us to classify AML and MDS in patients with Fanconi anemia as secondary. Interestingly, although the risk of developing MDS / AML in patients with chromosomal abnormalities is about 10 times higher than without them, the presence of chromosomal aberrations does not necessarily mean the development of MDS. Clones bearing anomalies can spontaneously disappear or alternate.

In addition to hematological abnormalities, Fanconi anemia is characterized by a tendency to develop tumors. The risk of developing malignant tumors in patients with Fanconi anemia is 10%, of which 5% falls on liver tumors and 5% on other tumors. Tumors are less common in children - the average age of diagnosis of liver tumors is 16 years, and the remaining tumors - 23 years. Tumors of the liver (hepatocellular carcinoma, hepatoma, adenoma, etc.), as well as peliosis ("blood lakes") are more common in men (1.6: 1 ratio), and the use of androgens increases the risk of their occurrence. At the same time, extrahepatic tumors are more common in women (3: 1 ratio) even after exclusion of gynecological tumors. The most frequent forms of cancer in Fanconi anemia are flaky cell carcinomas of the tongue and esophageal cancer, which account for more than 30% of all extrahepatic tumors in Fanconi anemia, the remaining tumors are 5-7 times less common.

Treatment of Fanconi Anemia

As already mentioned, the symptomatic treatment of aplastic anemia with Fanconi anemia is not able to radically change the prognosis of the disease. The first and only to date group of drugs that can improve the short- and medium-term prognosis for Fanconi anemia are androgens. For the first time, they were successfully used to treat the anemia of Fanconi Shahidi and Diamond in 1959. In the West, the most popular androgen with relatively acceptable side effects is oxymetalone (a dose of 2-5 mg / kg), in Ukraine, methandrostenolone (dose 0, 2-0.4 mg / kg). In the treatment of androgens, a hematologic response of varying quality is achieved in approximately 50% of patients. The effect of androgens is manifested after 1-2 months, then the level of leukocytes rises, and the number of platelets increases, and in order to reach a platelet plateau plateau it is often required 6-12 months. With androgen cancellation, almost all patients experience a relapse of the disease, the absence of recurrence of pancytopenia after androgen cancellation is described only in a small number of patients and, as a rule, was associated with the onset of puberty. That is why after reaching the maximum of hematologic improvement, the dose of androgens should be carefully reduced, not abolishing it altogether. The use of androgens significantly increases the life expectancy of responding patients: the median of life expectancy is 9 years after diagnosis, versus 2.5 years, respectively, for those patients in whom androgen treatment was not effective. Previously, in order to prevent untimely closure of growth zones, prednisolone was administered together with androgens at a dose of 5-10 mg every other day, however, glucocorticosteroids have no independent value in the treatment of Fanconi anemia.

At the moment, the only method for the final cure of the hematologic syndrome in Fanconi anemia is the allogeneic transplantation of hematopoietic stem cells (TSCC). In total, more than 250 hemopoietic cell transplantations have been performed for Fanconi anemia.

The problem of treatment of leukemias and myelodysplastic syndromes in patients with Fanconi anemia is of particular complexity, since the increased sensitivity of the tissues of these patients to many chemotherapeutic agents and the reduced bone marrow reserve predispose to the development of severe visceral and hematological toxicity. To date, the vast majority of more than 100 patients with Fanconi anemia with leukemia and myelodysplastic syndromes have died. As a rule, death occurs within 2 months after the diagnosis of leukemia, although the cases of diagnosis of Fanconi anemia many years after the successful treatment of acute leukemia speak at least of the theoretical possibility of successful chemotherapy. More optimistic is the prognosis in patients with AML and MDS, who underwent allogeneic TSCT without previous chemotherapy.

What is the prognosis of Fanconi anemia?

Without successful bone marrow transplantation, Fanconi anemia has a serious prognosis. At the same time, patients suffer more and die more often not from anemia, but from opportunistic infections due to neutropenia and a defect of immunity or increased bleeding due to thrombocytopenia. Children with Fanconi anemia have an increased risk of developing non-lymphoid leukemia (5-10%).