Congenital neutropenias

Neutropenia is defined as a decrease in the number of circulating neutrophils in peripheral blood below 1500/mcl (in children aged 2 weeks to 1 year, the lower limit of the norm is 1000/mcl). A decrease in neutrophils to less than 1000/mcl is considered mild neutropenia, 500-1,000/mL - moderate, less than 500 - severe neutropenia (agranulocytosis).

Congenital and acquired neutropenia are distinguished.

The main forms of congenital neutropenia include two rare diseases associated with a primary defect in neutrophil production - severe congenital neutropenia (SCN) and cyclic neutropenia (CN). The results of molecular genetic studies over the past decade indicate a common genetic defect underlying both diseases.

Severe congenital neutropenia

Pathogenesis

Severe congenital neutropenia is a genetically heterogeneous syndrome with an autosomal dominant inheritance pattern. Representatives of both sexes are affected with equal frequency. The most common genetic defect in patients with SCN is a mutation in the ELA2 gene (localized on chromosome 19 p13.3), encoding neutrophil elastase ELA-2. Mutations in this gene are also detected in cyclic neutropenia. In SCN, mutations occur along the entire length of the BLA2 gene. Molecular screening of the ELA2 gene in patients has revealed about 30 different mutations. Neutrophil elastase, a xerine protease, is contained in the primary granules of neutrophils and is synthesized at the promyelocyte stage. The exact role of this enzyme remains unclear, but it is suggested that promyelocytes with mutant neutrophil elastase undergo accelerated apoptosis in the bone marrow.

In addition, in rare cases of SCN, mutations in the GFII (neutrophil elastase activating factor) and 6-CSFR genes encoding the G-CSF receptor are detected. Kostmann syndrome

Kostmann syndrome is a variant of SCN that is inherited in an autosomal recessive manner.

In 1956, R. Kostmann was one of the first to describe a case of congenital agranulocytosis in six children from a consanguineous marriage, in a Swedish family with traceable autosomal recessive inheritance of the disease. In all patients, neutropenia was associated with a block of myelopoiesis at the promyelocyte stage. In 1975, a description of 10 more cases in Sweden was published. To date, only one surviving representative of the "Kostmann family" is known, in which 5 more children were born after 1975.

X-linked neutropenia (XLN)

Several cases of X-linked neutropenia have been described in the literature. Two of these patients had a mutation in the WASP gene, a gene affected in patients with Wiskott-Aldrich syndrome. Interestingly, despite mutations in the same gene, patients with XLN do not have thrombocytopenia or other features of Wiskott-Aldrich syndrome. It is assumed that the mutation in XLIM leads to permanent activation of the WASP protein. However, the pathogenesis of neutropenia itself is unknown.

Symptoms of X-linked neutropenia

The first signs of severe congenital neutropenia appear in the first months of life. In the neonatal period, episodes of unmotivated fever, local foci of bacterial infection of the skin, subcutaneous tissue, prolonged healing of the umbilical wound, and purulent omphalitis may be observed. Lymphadenitis and hepatosplenomegaly are noted. A typical manifestation of the disease is recurrent severe ulcerative stomatitis and gingivitis. Patients suffer from purulent otitis, severe respiratory tract infections, recurrent pneumonia, lung abscesses, urinary tract infections, and gastrointestinal tract infections. Without adequate therapy, severe septic processes, septicemia, liver abscesses, and peritonitis develop. Typical pathogens include various strains of Staphylococcus, pseudomonas, E. coli, and Clostridia. In addition to infectious manifestations, growth retardation and physical development are possible.

Blood tests from the first months of life show profound neutronepia, in most cases the neutrophil count does not exceed 200/mL, even in the case of severe infection. Monocytosis, increased platelet count, and mild anemia are usually observed. The total leukocyte count is often normal due to monocytosis. The proteinogram shows hypergammaglobulinemia, the complement level is normal in most cases. Antineutrophil antibodies are not detected. When studying the phagocytic function of neutrophils, the superoxide metabolism indices are close to normal, the absorption and digestion capacity are not impaired. Unlike healthy donors, neutrophils of patients express CD64+ (FcyR1 receptor), the expression of CD16+ FcyIII receptor is reduced. The response to IL-8 is also reduced.

When examining the bone marrow against the background of myeloid hyperplasia, an increased number of myeloblasts, a maturation interruption is detected at the level of promyelocytes, eosinophilia is often encountered. Cytogenetic examination reveals a normal karyotype of bone marrow cells.

All patients with SCN are at high risk for developing myelodysplastic syndrome and acute myeloid leukemia, but the relationship between these complications and G-CSF therapy remains unclear. According to the French registry, which includes more than 350 patients with congenital severe neutropenia, the rate of transformation to acute myeloid leukemia is approximately 2% per year. In this group of patients, no relationship was observed between malignant transformation of the disease and age, gender, duration of treatment, or G-CSF dose.

These data indicate the need for continuous monitoring of patients, including regular clinical examination, monitoring of laboratory parameters, and myelograms at least once a year.

Treatment of X-linked neutropenia

Results of clinical trials using glucocorticosteroids, androgens, lithium preparations, intravenous immunoglobulin showed their ineffectiveness. Granulocyte colony-stimulating factor (G-CSF) preparations, used since the late 80s, have significantly improved the course of the disease in most patients. The initial daily dose is usually 3-5 mcg / kg, then an effective dose and frequency of administration of the drug are selected. In some cases, a significant increase in dosage is necessary, reaching 100 mcg / kg per day or more. Long-term observations of patients receiving G-CSF therapy show that they do not experience a decrease in the effectiveness of treatment associated with the formation of antibodies, bone marrow depletion. Among the side effects, the most common is flu-like syndrome, about 5% of patients develop mild or moderate thrombocytopenia. However, in some cases, G-CSF therapy is ineffective. Such cases are an indication for bone marrow and peripheral stem cell transplantation.

An important component of patient treatment is adequate antibacterial therapy, prescribed, among other things, prophylactically.

Forecast

The course of the disease is severe; without adequate therapy, most patients die at a young age, the mortality rate reaches 70%.

Cyclic neutropenia

Cyclic neutropenia is also a rare disease and is characterized by a significant (less than 200/mL) decrease in the number of neutrophils in the peripheral blood, occurring with a periodicity of about 3 weeks. The frequency in the population is approximately 1-2 cases per 1 million. Representatives of both sexes are affected with equal frequency.

Pathogenesis of cyclic neutropenia

The disease occurs sporadically or has an autosomal dominant inheritance pattern. As mentioned above, it is based on a mutation of the ELA2 gene. In sporadic cases of cyclic neutropenia, mutations are usually localized in intron 4 of the gene. Accelerated apoptosis of neutrophil precursors, more pronounced in SCN, is a common feature of these diseases.

Many aspects of the pathophysiology of these diseases remain unclear, in particular, there is no precise explanation for the cyclicity of neutropenia. It is possible that cyclicity may be observed in cases of moderate acceleration of apoptosis, in which there is no loss of significant numbers of precursors, as is observed in SCN. Thus, the different phenotypes of the diseases may depend on specific mutations that determine the rate of apoptosis of myeloid precursors.

It is not entirely clear why transformation to AML occurs only in severe congenital neutropenia. Perhaps, in response to the significant loss of myelocytes in the bone marrow of patients with SCN, there is a more intense release of stem cells, which are more susceptible to leukemic transformation.

Symptoms of cyclic neutropenia

Compared with severe congenital neutropenia, cyclic neutropenia has a more favorable course. The first signs of the disease appear in the first year of life. The clinical picture is characterized by recurrent bacterial infections of various localizations with a certain periodicity. The periodicity is from 14 to 36 days, in 70% of patients - 21 days. Episodes of neutropenia usually last from 3 to 10 days, after which the number of neutrophils returns to normal or subnormal values. During neutropenia, the number of monocytes increases. Infectious and inflammatory lesions of the skin, deep tissue, lymphadenitis, paraproctitis occur in patients with febrile fever. Severe ulcerative lesions of the periodontium, aphthous stomatitis, glossitis, gingivitis develop. Various parts of the respiratory tract are also involved, otitis recur. Among the etiologically significant ones are: pyogenic flora, pathogens of opportunistic infections, fungi, The greatest threat to life is anaerobic bacteremia caused by Clostridium spp., which is the cause of destructive enterocolitis and peritonitis.

Treatment of cyclic neutropenia

Most cases of cyclic neutropenia respond to G-CSF therapy, administered at a dose of 2-3 mcg/kg per day, daily or every other day (in some patients - 2 times a week). G-CSF administration does not affect the cyclicity of the disease, but can reduce the duration of neutralizing episodes and the severity of neutropenia.

Unlike patients with severe congenital neutropenia, transformation of the disease into AML was not observed.

In addition to the described forms of congenital severe neutropenia, there are a large number of congenital syndromes, one of the manifestations of which is neutropenia.

Selected congenital syndromes associated with neutropenia

Syndrome	Type of inheritance	Gene	Clinical picture
Giler IgM syndrome (HIGM1)	HS	Gр39	Combined immunodeficiency, neutropenia of varying severity (cyclic forms are known)
Reticular DNA genesis		Unknown	Combined immunodeficiency, neutropenia, anemia
WHIM syndrome	AR	CXCR4	Hypogammaglobupineemia, neutropenia, warts, recurrent bacterial infections
Chediak-Higashi syndrome	AR	LYST	Neutropenia, albinism, giant cytoplasmic granules, lymphohistiocytic infiltration, thrombocytopagia, NK cell dysfunction
Shwachman-Damond syndrome (Schwachmann - Diamond)	AR		Neutropenia, aplastic anemia, skeletal abnormalities, growth retardation, pancreatic insufficiency
Barth syndrome	HS	TAZ	Neutropenia, often cyclical, cardiomyopathy, ammoniac aciduria
Cohen syndrome dysmorphia	AR	COH1	Neutropenia, mental retardation,

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