Fanconi anemia: causes, symptoms, diagnosis, treatment

Fanconi anemia was first described in 1927 by the Swiss pediatrician Guido Fanconi, who reported three brothers with pancytopenia and physical defects. The term Fanconi anemia was proposed by Naegeli in 1931 to describe the combination of familial Fanconi anemia and congenital physical defects. Today, the diagnosis of Fanconi anemia does not require the presence of congenital malformations or Fanconi anemia per se. Fanconi anemia is a rare autosomal recessive disorder with an incidence of 1 in 360,000 births, with a 1.1:1 ratio in favor of boys.

To date, more than 1,200 cases of Fanconi anemia are known, and their number is rapidly increasing as a result of the introduction of laboratory diagnostic methods that make it possible to establish a diagnosis of the disease in siblings of a patient with Fanconi anemia even before the manifestation of aplastic anemia, as well as in patients with characteristic malformations, but without hematological anomalies.

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

Causes of Fanconi Anemia

Fanconi anemia is an autosomal recessive disease with variable penetrance and genetic heterogeneity. Heterozygous carriage occurs with a frequency of 1:300. Karyotyping of lymphocytes and fibroblasts of patients with Fanconi anemia reveals chromosomal abnormalities in a large percentage of cases. It is believed that the defective genes responsible for the reduction of the body's reparative properties are located in chromosomes 22 and 20.

[ 5 ], [ 6 ]

Pathogenesis of Fanconi anemia

In the bone marrow, decreased cellularity, suppression of all hematopoietic germs (erythroid, myeloid, megakaryocytic), and proliferation of adipose tissue are detected. The defect of hematopoiesis in Fanconi anemia is localized at the level of the stem cell. Hematopoietic cells have an increased maturation time. The life span of erythrocytes in children with Fanconi anemia is significantly reduced (by 2.5-3 times).

Symptoms of Fanconi Anemia

The average age at diagnosis of Fanconi anemia is 7.9 years for boys and 9 years for girls, with 75% of cases of Fanconi anemia being diagnosed between 3 and 14 years of age. Concern for Fanconi anemia should in no way be limited by age: the age at diagnosis varies remarkably widely, from birth to 48 years and from birth to 32 years for females and males, respectively.

The classic appearance of a patient with Fanconi anemia is short stature, microcephaly, microphthalmia, dark skin tone ("permanent tan"), areas of hyper- and hypopigmentation of the skin and mucous membranes, and malformed 1st fingers. In Fanconi anemia, various organs and systems are affected by congenital defects and developmental anomalies to an unequal degree. About 6% of patients have no anomalies at all. Such cases were previously described in the literature under the name of Estren-Dameshek anemia - after the authors who in 1947 described 2 families with constitutional hypoplastic anemia without developmental defects. The diagnosis of Fanconi anemia must be confirmed by tests for chromosome hypersensitivity, especially since developmental anomalies can be common to Fanconi anemia and other hereditary aplastic anemias, such as congenital dyskeratosis. The severity of malformations can vary greatly even within a single family: there are many known cases of Fanconi anemia among siblings, one of whom had no malformations, while the other did.

Laboratory signs of Fanconi anemia

Three-line aplasia is the most typical manifestation of Fanconi anemia, but observations of initially hematologically intact homozygotes have shown that thrombocyto- or leukopenia often precede the development of pancytopenia. The first hematological abnormalities in Fanconi anemia are regularly detected after respiratory viral infections, vaccinations, and sometimes hepatitis, as is typical for idiopathic aplastic anemias. Even in the preanemic phase, Fanconi anemia is characterized by pronounced macrocytosis, accompanied by a significant increase in the level of fetal hemoglobin. Bone marrow puncture is usually depleted of hematopoietic cellular elements, lymphocytes predominate, plasma cells, mast cells, and stromal elements are found - a clinical picture indistinguishable from idiopathic aplastic anemia. Bone marrow aspirates often reveal dysmyelopoiesis and dyserythropoiesis, particularly megaloblastoidism, which led Fanconi to call this anemia "perniciosiform." Bone marrow biopsies in the early stages of the disease reveal hypercellular areas of active residual hematopoiesis, which disappear as the disease progresses.

One of the fundamental phenomena characteristic of blood cells of patients with Fanconi anemia is their tendency to form specific chromosomal abnormalities - breaks, sister exchanges, endoreduplications during cell culturing in vitro. Incubation of PHA-stimulated lymphocytes of patients with Fanconi anemia with bifunctional alkylating agents that cause DNA cross-linking 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 modern diagnostics and differential diagnostics of Fanconi anemia, since spontaneous aberrations may be either absent in patients with Fanconi anemia or 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 patients with Fanconi anemia stop in the G2 phase of the mitotic cycle, which served as the basis for the development of another diagnostic test for Fanconi anemia using the flow fluorimetry method.

The age of first appearance of Fanconi anemia in one family is often concordant, but it can also 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 steadily progressed: 80% of patients died from complications of pancytopenia within 2 years after the diagnosis of aplastic anemia and almost all patients died after 4 years. It should be mentioned that several cases of spontaneous improvement and even complete recovery of hematological parameters have been recorded.

The second most common hematological presentations of Fanconi anemia are acute leukemia and myelodysplastic syndromes. Approximately 10% of patients with Fanconi anemia, clinical cases of which are described in the literature, subsequently developed acute leukemia. In all cases, with the exception of 2, leukemia was myeloid. There are even cases of Fanconi anemia diagnosis in a patient with residual cytopenia many years after successful chemotherapy for AML. The frequency of myelodysplastic syndromes is somewhat lower - about 5%, and only in 1/5 of these patients was further evolution of MDS into AML traced, and several patients with MDS survived for more than 10 years. According to studies of the International Fanconi Anemia Registry, the risk of developing AML or MDS in patients with Fanconi anemia is 52% by the age of 40. Karyotypic abnormalities (monosomy 7, trisomy 21, deletion 1) are often detected, which allow AML and MDS in patients with Fanconi anemia to be classified as secondary. Interestingly, although the risk of developing MDS/AML in patients with chromosomal abnormalities is approximately 10 times higher than without them, the presence of chromosomal aberrations does not necessarily mean the development of MDS. Clones carrying abnormalities may spontaneously disappear or replace each other.

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

Treatment of Fanconi anemia

As already mentioned, symptomatic treatment of aplastic anemia in Fanconi anemia is not able to radically change the prognosis of the disease. The first and only group of drugs to date that can improve the short- and medium-term prognosis in Fanconi anemia are androgens. They were first successfully used to treat Fanconi anemia by Shahidi and Diamond in 1959. In the West, the most popular androgen with relatively acceptable side effects is oxymetholone (dose 2-5 mg/kg), in Ukraine methandrostenolone is still used (dose 0.2-0.4 mg/kg). When treated with androgens, a hematological response of varying quality is achieved in approximately 50% of patients. The effect of androgens is manifested after 1-2 months, then there is an increase in the level of leukocytes, and last of all, the number of platelets increases, and it often takes 6-12 months to achieve a plateau in the platelet response. When androgens are discontinued, the disease relapses in almost all patients; the absence of relapse of pancytopenia after androgen discontinuation has been described only in a small number of patients and, as a rule, was associated with the onset of puberty. That is why, after achieving maximum hematological improvement, the dose of androgens should be carefully reduced, without canceling it completely. The use of androgens significantly increases life expectancy in patients who responded to treatment: the median life expectancy is 9 years after diagnosis versus 2.5 years, respectively, for those patients for whom androgen treatment was ineffective. Previously, in order to prevent untimely closure of growth zones, prednisolone was prescribed in a dose of 5-10 mg every other day together with androgens; however, glucocorticosteroids have no independent value in the treatment of Fanconi anemia.

At present, the only method of final cure of hematological syndrome in Fanconi anemia is allogeneic hematopoietic stem cell transplantation (HSCT). In total, more than 250 hematopoietic cell transplantations have been performed worldwide for Fanconi anemia.

The problem of treating leukemia and myelodysplastic syndromes in patients with Fanconi anemia is particularly difficult, since the increased sensitivity of the tissues of these patients to many chemotherapeutic agents and 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 cases of diagnosis of Fanconi anemia many years after successful treatment of acute leukemia indicate at least the theoretical possibility of successful chemotherapy. A more optimistic prognosis is in patients with AML and MDS who underwent allogeneic HSCT without previous chemotherapy.

What is the prognosis for Fanconi anemia?

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