Infantile agranulocytosis

ALSO KNOWN AS: Agranulocytosis; granulocytopenia; granulopenia; neutropenia

DEFINITION Agranulocytosis is a condition that results from failure of an individual’s bone marrow to produce a sufficient quantity of white blood cells or from increased destruction of the white blood cells. As a result, the white blood cell count will be low. Acquired agranulocytosis occurs most often as a result of medications or treatments. A congenital agranulocytosis is a condition with which someone is born. Agranulocytosis usually responds well to treatment, so patients should contact their doctors if they think they may have this condition.

Risk Factors

Individuals should tell their doctors if they have any of the factors that increase their chances of developing agranulocytosis. Risk factors include undergoing chemotherapy treatment for cancer, taking certain drugs, infection, exposure to certain chemical toxins or radiation, autoimmune diseases, enlargement of the spleen, Vitamin B₁₂ or folate deficiency, leukemia or myelodysplastic syndromes, aplastic anemia or other diseases of the bone marrow, and a family history of certain genetic diseases.

Etiology and Genetics

Infantile agranulocytosis, also known as severe congenital neutropenia, is associated with mutations in at least five separate autosomal genes. The GCSFR gene, found on the short arm of chromosome 1 at position 1p35-p34.2, encodes a protein called the granulocyte colony-stimulating factor receptor. Without a functional receptor protein, white blood cell proliferation is drastically diminished. The ELA2 gene (at position 19p13.3) specifies a protein called neutrophil elastase-2, which is a key player in cellular defense against bacterial cells. Neutrophil elastase degrades the outer membrane portion of the cell walls of gram-negative bacteria. A related gene, GFI1 (at position 1p22), encodes the growth factor independent-1 protein, which stimulates the transcription of the ELA2 gene, so a deficiency in the growth factor protein results in a drastically reduced amount of neutrophil elastase in cells. The HCLS1-associated protein X1 is specified by the HAX1 gene, found at position 1q21.3 on chromosome 1. This protein represses programmed cell death of white blood cells, so absence of this protein as a result of a mutation in the gene will result in a diminished white cell count due to these cells’ premature death. Finally, the G6PC3 gene (at position 17q21) encodes the beta catalytic subunit of the glucose-6-phosphatase. Its absence as a result of mutation also results in premature death of white blood cells.

All these forms of infantile agranulocytosis, with the exception of those stemming from a mutation in the ELA2 gene, are inherited in an autosomal recessive fashion. This means that both copies of the gene must be deficient in order for the individual to be afflicted. Typically, an affected child is born to two unaffected parents, both of whom are carriers of the recessive mutant allele. The probable outcomes for children whose parents are both carriers are 75 percent unaffected and 25 percent affected. If one parent has infantile agranulocytosis and the other is a carrier, there is a 50 percent probability that each child will be affected. Mutations in the ELA2 gene are inherited in an autosomal dominant manner, meaning that a single copy of the mutation is sufficient to cause full expression of the disease. An affected individual has a 50 percent chance of transmitting the mutation to each of his or her children.

Many cases of autosomal dominant infantile agranulocytosis, however, result from a spontaneous new mutation, so in these instances affected individuals will have unaffected parents. Cases of sex-linked recessive congenital neutropenia have also been reported, but these are associated with specific defined syndromes, such as severe combined immunodeficiency syndrome and Wiskott-Aldrich syndrome.

Symptoms

Individuals who experience any of the symptoms of agranulocytosis should not assume that their symptoms are due to the condition. These symptoms may be caused by other, less serious health conditions. Individuals who experience any of the symptoms should see their physicians.

Symptoms include rapid onset of fever, chills, jaundice, weakness, or sore throat; bacterial pneumonia; ulcers in the mouth; bleeding gums; a low white blood cell count; and infections, including fungal.

Screening and Diagnosis

The doctor will ask about a patient’s symptoms and medical history and will perform a physical exam. Tests may include a blood test to determine white blood cell count. Urine or other fluids may be tested for infectious agents if the patient has a fever. A bone test (biopsy and aspiration) may be conducted, and genetic tests may be needed for some patients. Patients with autoimmune disease may need to be tested for antineutrophil antibodies.

Treatment and Therapy

Individuals should talk with their doctors about the best plans for them. A transfusion of leukocytes (white blood cells) to replace a deficit may be beneficial for certain patients.

Antibiotics may be used to treat an infection that could be causing agranulocytosis or resulting from agranulocytosis. Depending on the cause, some patients may benefit from white blood cell-stimulating treatments with granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF). Removing a toxin/drug or treating a primary disorder are other treatment options for agranulocytosis.

Prevention and Outcomes

To help reduce their chances of getting agranulocytosis, individuals should talk to their doctors about preventive measures when receiving white blood cell-reducing therapies. These therapies include white blood cell-stimulating treatments, such as G-CSF or GM-CSF, and treatments to prevent the loss of white blood cells.

Bibliography

"Agranulocytosis." Cleveland Clinic, 23 Mar. 2023, my.clevelandclinic.org/health/diseases/15262-agranulocytosis. Accessed 10 Sept. 2024.

Hoffman, Ronald, et al. Hematology: Basic Principles and Practice. 6th ed. Philadelphia: Churchill, 2012. Print.

Klein, Christoph. “Genetic Defects in Severe Congenital Neutropenia: Emerging Insights into Life and Death of Human Neutrophil Granulocytes.” Annual Review of Immunology 29.1 (2011): 399–413. Print.

Mandell, Gerald L., John E. Bennett, Raphael Dolin, et al. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 6th ed. New York: Churchill, 2009. Print.

Mehta, Parang. "What to Know About Agranulocytosis." WebMD, 25 Aug. 2022, www.webmd.com/a-to-z-guides/what-to-know-about-agranulocytosis. Accessed 10 Sept. 2024.

Tajiri, J., et al. “Antithyroid Drug-Induced Agranulocytosis: The Usefulness of Routine White Blood Cell Count Monitoring.”Archives of Internal Medicine 150.3 (1990): 621–24. Print.

Van Staa, T. P., et al. “Neutropenia and Agranulocytosis in England and Wales: Incidence and Risk Factors.” American Journal of Hematology72.4 (2003): 248–54. Print.