Congenital neutropenia

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

Allocate congenital and acquired neutropenia.

The main forms of congenital neutropenia are two rare diseases associated with the primary defect in the production of neutrophils - severe congenital neutropenia (severe congenital neutropenia - SCN) and cyclic neutropenia (cyclic neutropenia - CN). The results of molecular genetic studies of the last 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 their poloi fall ill with the same frequency. The most common genetic defect in patients with SCN is a mutation in the ELA2 gene (localized on chromosome 19 p13.3), which codes for elastase of neutrophils ELA-2. Mutations of the same gene are detected with cyclic neutropenia. When SCN mutations occur throughout the length of the BLA2 gene. As a result of molecular screening of the ELA2 gene, about 30 different mutations were detected in patients. Neutrophil elastase, related to xerin proteases, is contained in the primary granules of neutrophils and is synthesized at the stage of promyelocyte. The exact role of this enzyme remains unclear, but it is assumed 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 activation factor) and 6-CSFR, which encodes the G-CSF receptor, are detected. Kostmann syndrome (Kostmann syndrome)

Costman's syndrome is a type of SCN that has an autosomal recessive type of inheritance.

In 1956, R. Kostmann was one of the first to describe the case of congenital agranulocytosis in six children from a closely related marriage, to a Swedish family with a traced autosomal recessive inheritance of the disease. In all patients, neutropenia was associated with the myelopoiesis block in the promyelocyte stage. In 1975, a further 10 cases were published in Sweden. By now only the only surviving representative of the "Costman family" is known, in which after 1975 another five children were born.

X-linked neutropenia (XLN)

Several cases of X-linked neutropenia have been described in the literature. In two of these patients, a mutation in the WASP gene was found in patients with Wiskott-Aldrich syndrome. Interestingly, despite the mutations of the same gene, patients with XLN do not have thrombocytopenia and other signs of Wiskott-Aldrich syndrome. It is assumed that the mutation at XLIM leads to a constant activation of the WASP protein. However, the pathogenesis of neutropenia is not known.

Symptoms of X-linked neutropenia

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

In blood tests from the first months of life there is deep neutronopia, in most cases the amount of neutrophils does not exceed 200 / mL, even in the case of the course of a severe infection. As a rule, there is monocytosis, an increase in the number of platelets, mild anemia. The total number of leukocytes is often normal due to monocytosis. In the proteinogram, there is hypergammaglobulinemia, the level of complement in most cases is normal. Antineutrophil antibodies are not detected. In the study of the phagocytic function of neutrophils, the parameters of superoxide metabolism are close to normal, the absorbing and digesting ability is not violated. Unlike healthy donors, neutrophils of patients express CD64 + (FcyR1 receptor), expression of CD16 + FcyIII receptor is reduced. The response to IL-8 is also decreased.

When studying the bone marrow against the background of myeloid hyperplasia, an increased number of myeloblasts, a rupture of ripening at the level of promyelocytes is detected, eosinophilia is often found. Cytogenetic examination reveals a normal karyotype of bone marrow cells.

All patients with SCN are at high risk for the development of myelodysplastic syndrome and acute myeloblastic leukemia, but the relationship of these complications to G-CSF therapy remains unclear. Given to the French registry, which includes more than 350 patients with congenital severe neutropenia, the level of transformation into acute myelogenous leukemia is approximately 2% per year. In this group of patients there was no association of malignant transformation of the disease with age, sex, duration of treatment, dose of G-CSF.

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

Treatment of X-linked neutropenia

Results of clinical trials using glucocorticosteroids, androgens, lithium preparations, intravenous immunoglobulin showed their inefficiency Granulocyte colony-stimulating factor (G-CSF) drugs, used since the late 1980s, and significantly improved the course of the disease in most patients. The initial daily dose is usually 3-5 μg / kg, then the effective dose and the frequency of administration of the drug are selected. In some cases, a significant increase in dosage is required, reaching 100 μg / kg per day or more. Long-term follow-up of patients receiving G-CSF therapy shows that they do not experience a decrease in the effectiveness of antibodies-mediated treatment or bone marrow depletion. Among the side effects, flu-like syndrome is most common, about 5% of patients develop mild to moderate thrombocytopenia. However, in some cases, G-CSF therapy is ineffective. Such cases are an indication for bone marrow transplantation, peripheral stem cells.

An important component of the treatment of patients is adequate antibiotic therapy, prescribing, 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 also refers to rare diseases and is characterized by a significant (less than 200 / mL) decrease in the number of peripheral blood neutrophils, occurring at a frequency of about 3 weeks. The frequency in the population is approximately 1-2 cases per 1 million. Representatives of both sexes fall ill with the same frequency.

Pathogenesis of cyclic neutropenia

The disease occurs sporadically or has an autosomal dominant inheritance pattern. It is based, as mentioned above, on the mutation of the ELA2 gene. In sporadic cases of cyclic neutropenia, mutations are usually localized in the 4 intron of the gene. Accelerated apoptosis of neutrophil precursors, more pronounced with 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 of the neutropenic cycle. It can be assumed that cyclicity can be observed in cases of moderate acceleration of apoptosis, in which there is no loss of a significant number of precursors, as is observed with SCN. Thus, a different phenotype of diseases can depend on specific mutations that cause the rate of apoptosis of myeloid progenitors.

It is not entirely clear why the transformation into AML occurs only with severe congenital neutropenia. Perhaps in response to a significant loss of myelocytes in the bone marrow of SCN patients, a more intensive ejection of stem cells that are more susceptible to leukemia transformation occurs.

Symptoms of cyclic neutropenia

In comparison 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 recurring with a certain periodicity of bacterial infections of different localization. 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 parameters. During the neutropenia, the number of monocytes increases. In patients with febrile fever, there are infectious and inflammatory skin lesions, deep cellular tissue, lymphadenitis, paraproctitis. Heavy ulcerative periodontal lesions develop, aphthous stomatitis, glossitis, and gingivitis. Also involved are various departments of the respiratory tract, otitis recur. Among the etiologically significant there are: piogenic flora, pathogens of opportunistic infections, fungi. Anaerobic bacteremia caused by Clostridium spp., Which is the cause of destructive enterocolitis, peritonitis, is the greatest threat to life.

Treatment of cyclic neutropenia

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

Unlike patients with severe congenital neutropenia, no transformation of the disease into AML was noted.

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

Individual congenital syndromes accompanied by neutropenia

Syndrome	Inheritance type	Gene	Clinical picture
Giler IgM syndrome (HIGM1)	HS	Gp39	Combined immunodeficiency, neutropenia of varying severity (cyclic forms are oocysts)
Reticular dnaenogenesis		Unknown	Combined immunodeficiency, neutropenia, anemia
WHIM syndrome	AR	CXCR4	Hypogammaglobulinemia, neutropenia, warts, repeated bacterial infections
Chediak-Higashi syndrome (Chiidiak-Higashi)	AR	LYST	Neutropenia, albinism, giant cytoplasmic granules, lymphohistiocytic infiltration, thrombocytopagia, abnormal NK cell function
Syndrome Schwamman-Damond (Schwachmann - Diamond)	AR		Neurotropenia, aplastic anemia, skeletal anomalies, growth retardation, pancreatic insufficiency
The syndrome of Bart (Barlh)	HS	TAZ	Neutropenia, often cyclic, cardiomyopathy, amnociduria
Cohen syndrome dysmorphic	AR	COH1	Neutropenia. Mental retardation,

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