Congenital neutropenia

Definition

Congenital neutropenias are a group of genetically determined diseases characterized by a decrease in neutrophil leukocyte levels below 1500/μL and in children under one year of age – below 1000/μL. Clinically, it is manifested by private bacterial infections and delays in psychophysical development. The most common signs of congenital neutropenia are frequent gingivitis and stomatitis. Diagnosis is based on anamnesis, examination data, general blood count, and myelogram. Treatment tactics depend on the form of pathology. To stimulate the synthesis of neutrophil granulocytes, a granulocyte colony-stimulating factor is used.

General information

Congenital neutropenias are a group of inherited pathologies transmitted by autosomal dominant or autosomal recessive type. They are manifested by a decrease in the number of neutrophils in the peripheral blood. 

These pathologies are rare. The prevalence ranges from 1-2:100000 to 1 case per 1 million infants. Congenital neutropenia affects both boys and girls. The prognosis depends on the form of the disease; in Kostmann syndrome, the lethality reaches 97-100%, while in familial benign neutropenia, the outcome is usually favorable.

Causes of congenital neutropenia

Congenital neutropenias are genetically determined diseases inherited in an autosomal dominant or autosomal recessive pattern. 

The “lazy leukocyte” syndrome occurs against the background of impaired release of granulocytes from the bone marrow into the systemic bloodstream. The pathogenesis of this form of congenital neutropenia is based on mutation of the protein encoding the cell membrane of neutrophils and their accelerated apoptosis. In familial benign neutropenia in children, the process of differentiation of granulocytes in the bone marrow is disturbed – neutrophils remain at the metamyelocyte stage. 

Classification

In pediatrics, neutropenias are divided into congenital and acquired forms. Congenital forms include:

• Kostmann syndrome. The disease is based on early apoptosis and the absence of mature forms of neutrophilic leukocytes in the peripheral blood. In the bone marrow, proliferating cells to myelocytes are determined. It is characterized by a severe clinical picture already in the first months of life.
• Cyclic neutropenia. This form of congenital neutropenia is manifested by insufficient granulocytopoiesis, which has a recurrent character. Clinical symptoms occur simultaneously with episodes of agranulocytosis.
• Familial benign neutropenia. This form of congenital neutropenia is based on impaired maturation of neutrophil granulocytes. Clinically it is manifested rarely, so it does not require specific treatment.
• Syndrome of “lazy leukocytes.” The essence of the disease is a violation of the chemotaxis of neutrophils. It is manifested by frequent inflammatory diseases since infancy.

Symptoms of congenital neutropenia

The clinical pictures of different forms of congenital neutropenia have both common aspects and certain differences. In all types, inflammatory diseases often occur in organs that are in close contact with the external environment and are most sensitive to a weakened immune system. These include the skin, oral mucosa, tracheobronchial tree, lungs, and external and middle ear. Asthenic and intoxication syndromes are also almost always present. However, the age at which congenital neutropenia manifests and the frequency and severity of exacerbations can vary considerably.

Kostmann syndrome is characterized by pronounced symptoms already in the first months of a child’s life. The primary signs are fever of unclear etiology, frequent bacterial diseases of the skin, and subcutaneous fatty tissue (furuncles, phlegmons). In such children, they slowly heal umbilical wounds, poorly treatable omphalitis. There may be a delay in mental and physical development. Gradually join hepatosplenomegaly and lymphadenopathy. A characteristic sign of congenital neutropenia is lesions of the mucous membranes of the mouth and gums (gingivitis and stomatitis). In Kostmann syndrome, recurrent pneumonia, lung abscesses, cystitis, otitis media, urethritis, pyelonephritis, gastroduodenitis, paraproctitis, peritonitis, etc. are also noted. All of these pathologies are prone to generalization, which, without early treatment, leads to the development of sepsis and death.

Cyclic neutropenia manifests before the age of 1 year. It is also characterized by skin lesions, external ear, mucous membranes of the mouth and gums. A typical feature of this form of congenital neutropenia is the periodicity of relapses. Exacerbations can occur every 14-49 days, often every three weeks. In severe cases, especially when infected with anaerobic microflora, they develop severe complications in the form of peritonitis and sepsis, but their probability is much lower than in Kostmann syndrome. With age, the frequency and severity of recurrences decrease.

Familial benign neutropenia manifests between 2-3 months and one year of age. The clinical picture of this congenital neutropenia is dominated by rare gingivitis, stomatitis, and furunculosis. Otitis media and pulmonary lesions are even rarer. The listed diseases, as a rule, proceed in a mild form, the general condition of the child is disturbed little. The clinical picture of the “lazy leukocytes” syndrome is already observed in the first months of life. Most often, patients are diagnosed with upper respiratory tract bacterial lesions (laryngitis, pharyngitis, tracheitis), pneumonia, gingivitis, and stomatitis.

Diagnosis

Diagnosis of congenital neutropenia is based on collecting anamnestic data, performing a physical examination, and obtaining laboratory and instrumental study results. From the anamnesis, a pediatrician or neonatologist necessarily establishes the presence of similar hereditary diseases in parents or other relatives. Physical examination can reveal a moderate lag in physical development, lymphadenopathy, and hepatosplenomegaly. If bacterial complications develop, other specific changes will be detected.

The basis for the diagnosis of congenital neutropenia is a general blood count and myelogram. The OAC shows a decrease in leukocyte count below 4.5×109/L and neutrophil granulocytes to 1000/μL or lower in infants and 1500/μL or lower in children over one year of age. Congenital neutropenias are almost always accompanied by monocytosis and eosinophilia. Depending on the form, neutrophil levels can vary, as can changes in the bone marrow on bone marrow puncture. The myelogram in Kostmann syndrome reveals only neutrophil precursor cells – myeloblasts, promyelocytes, and myelocytes.

The absence of mature forms also manifests cyclic neutropenia, but repeated tests may reveal leukocytosis. Myelogram in familial benign neutropenia is characterized by a large number of metamyelocytes and a deficiency of mature neutrophils. The syndrome of “lazy leukocytes” is manifested by excessive saturation of the bone marrow with cells of all stages of differentiation, including mature cells. Other changes in laboratory or instrumental tests correspond to the resulting complications of congenital neutropenia. If necessary, a genetic diagnosis is performed.

Treatment of congenital neutropenia

Treatment of congenital neutropenia depends on the form of pathology. The basis of therapy is granulocyte colony-stimulating factor (G-CSF). This hormonal drug stimulates the synthesis and differentiation of neutrophil granulocytes in the bone marrow. Bone marrow transplantation may also be performed in this form of congenital neutropenia. In cyclic neutropenia, G-CSF is administered 2-3 days before the development of agranulocytosis. Benign familial neutropenia and “lazy leukocyte” syndrome usually do not require the use of G-CSF except in severe forms.

If bacterial complications develop against the background of congenital neutropenia, massive antibiotic therapy is carried out. Broad-spectrum antibiotics—III-IV generation cephalosporins and macrolides—are generally prescribed. In severe cases, intravenous immunoglobulins may be used. If necessary, detoxification therapy is carried out; symptomatic agents are used if indicated.

All these treatment options are available in more than 240 hospitals worldwide (https://doctor.global/results/diseases/congenital-neutropenia). For example, Autologous bone marrow transplantation (BMT) can be done in 10 clinics across Germany (https://doctor.global/results/europe/germany/all-cities/all-specializations/procedures/autologous-bone-marrow-transplantation-bmt).

Prognosis and prevention

The prognosis varies between the different forms of congenital neutropenia. In Kostmann syndrome, most children die of severe, treatment-resistant bacterial complications within the first few months of life. Cyclic neutropenia and the syndrome of “lazy leukocytes” have a more favorable prognosis – a lethal outcome is possible only in severe variants of the course and lack of timely diagnosis. In most cases, familial benign neutropenia does not lead to the death of the child – with age, the number of neutrophils increases, and immunity stabilizes.

There is no specific prevention of congenital neutropenia. Non-specific preventive measures include assessing the risk of genetic mutations in the child before birth through medical and genetic counseling. This examination can be performed by a geneticist at specialized centers. Pregnant women already undergo cordocentesis, amniocentesis, placenta, or choriocentesis followed by karyotyping. To prevent spontaneous mutations, which can also be accompanied by congenital neutropenia, the period of pregnancy should be excluded entirely from exposure to all teratogenic factors in the fetus. These include alcohol, drugs, tobacco products, chemicals, ionizing radiation, certain medications, etc., which can be used to prevent spontaneous mutations, which can also be accompanied by congenital neutropenia.