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NORD is very grateful to Laurence A. Boxer, MD, Division of Pediatric Hematology/Oncology, University of Michigan School of Medicine, for assistance in the preparation of this report.
Cyclic neutropenia is a rare blood disorder characterized by recurrent episodes of abnormally low levels of certain white blood cells (neutrophils) in the body. Neutrophils are instrumental in fighting off infection by surrounding and destroying bacteria that enter the body. Symptoms associated with cyclic neutropenia may include fever, a general feeling of ill health (malaise), and/or sores (ulcers) of the mucous membranes of the mouth. In most cases, individuals with low levels of neutrophils (neutropenia) are abnormally susceptible to recurrent infections.
The primary finding associated with cyclic neutropenia is a severe chronic decrease in certain white blood cells (neutrophils). In most cases, episodes of neutropenia recur every 21 days (cyclic) and may last for three to six days. The cycling period usually remains constant and consistent among affected individuals. In addition, abnormal levels of red blood cells that assist in clotting (platelets), immature red blood cells (reticulocytes), and other types of white blood cells (monocytes) may occur. The monocyte count invariable increases during the periods of neutropenia.
During episodes of neutropenia, affected individuals may experience fever, a general feeling of ill health (malaise), inflammation and ulceration of the mucous membranes of the mouth (stomatitis), inflammation of the throat (pharyngitis), inflammation and degeneration of the tissues that surround and support the teeth (periodontal disease), and/or loss of appetite. Peridontal disease may result in loosening of teeth and early tooth loss in young children.
Individuals with cyclic neutropenia may be abnormally susceptible to various bacterial infections that often affect the skin, digestive (gastrointestinal) tract, and respiratory system. Such bacterial infections vary in severity and, in some cases, may result in life-threatening complications.
Cyclic neutropenia may be inherited or acquired. Some cases are present at birth (congenital) and appear to occur randomly for no apparent reason (sporadically). There have been reports in the medical literature in which individuals within several multigenerational families (kindreds) have an increased incidence of cyclic neutropenia. In such familial cases, the disorder may be inherited as an autosomal dominant trait.
Investigators have determined that cases of sporadic and autosomal dominant cyclic neutropenia may be caused by disruption or changes (mutations) of the ELANE gene located on the short arm (p) of chromosome 19 (19p13.3). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q". Chromosomes are further subdivided into bands that are numbered. For example, "chromosome 19p13.3" refers to band 13.3 on the short arm of chromosome 19.
Most blood cells, including neutrophils, are produced by the soft tissue in bone cavities (bone marrow). Symptoms associated with neutropenia occur when the bone marrow fails to produce sufficient numbers of neutrophils, when neutrophils are destroyed prematurely, or when neutrophils fail to function properly.
Cyclic neutropenia appears to affect males and females in equal numbers. Most cases of cyclic neutropenia are thought to be present at birth (congenital); however, in some cases, the symptoms may not become obvious until childhood, adolescence, or early adulthood.
Cyclic neutropenia is a subdivision of severe chronic neutropenia. Severe chronic neutropenia is estimated to affect approximately 0.5 to 1 per million population in the United States. (For more information on severe chronic neutropenia, see the Related Disorders section of this report.)
Symptoms of the following disorders may be similar to those of cyclic neutropenia. Comparisons may be useful for a differential diagnosis:
There are many different causes of neutropenia. Neutropenia may result from viral infection, due to use of certain drugs, and/or following exposure to certain poisons. In addition, in some cases, the body may produce antibodies against neutrophils (autoimmune neutropenia) causing an abnormal decrease in these white blood cells. Some individuals may develop neutropenia following therapy with certain chemotherapeutic medications for the treatment of cancer. Neutropenia may also occur as a secondary finding due to other primary disorders (e.g., leukemia).
Severe chronic neutropenia is a group of disorders characterized by abnormally low levels of certain white blood cells (neutrophils) in the body. The three main classifications of severe chronic neutropenia are congenital, idiopathic, and cyclic. The congenital forms of severe chronic neutropenia are usually present at birth (congenital) or during early childhood and are often the most severe. Idiopathic neutropenia is a group of disorders that cannot be classified into one of the other categories of neutropenia. The exact cause of these disorders is not known (idiopathic). Congenital forms of severe chronic neutropenia may be inherited as an autosomal dominant or recessive genetic trait. (For more information on these disorders, choose "severe chronic neutropenia" as your search term in the Rare Disease Database.)
A diagnosis of cyclic neutropenia is made based upon a detailed patient history and thorough clinical evaluation. A diagnosis may be confirmed by monitoring an individual's neutrophil count twice or three times per week for six weeks. Individuals with cyclic neutropenia should be genetically tested for mutations in the ELANE gene.
Prompt, appropriate treatment of the infections associated with cyclic neutropenia is important. Such treatment may include antibiotic therapy. Careful oral and dental care is also required. In addition, individuals with cyclic neutropenia should avoid activities that may cause minor injuries.
A synthetic drug that stimulates the bone marrow's production of neutrophils (recombinant human granulocyte-colony stimulating factor [rhG-CSF]) has been used to treat severe chronic neutropenia. One form, the orphan drug neupogen (Filgrastim), has been approved by the Food and Drug Administration for use in the treatment of severe chronic neutropenia. Studies have shown that long-term therapy can elevate the numbers of neutrophils to normal range in most individuals, thereby reducing infections and other associated symptoms. Careful evaluation prior to initiation of such therapy and ongoing observation during therapy are essential to ensure the long-term safety and effectiveness of such treatment in individuals with severe chronic neutropenia. Neupogen is manufactured by Amgen, Inc., 1840 Dehaviland Dr., Thousand Oaks, CA 91320-1789.
Genetic counseling may be of benefit for individuals with inherited forms of cyclic neutropenia and their families. Other treatment is symptomatic and supportive.
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Dale DC, Williams Hematology, 8th ed. New York, NY: McGraw-Hill, Inc.; 2010:942.
Newburger PE, Pindyck TN, Zhu Z, et al. Cyclic neutropenia and severe congenital neutropenia in patients and shared ELANE mutation and paternal haplotype: Evidence for phenotype determination by modifying genes. Pediatric Blood and Cancer. 2010;55:314-317.
Dale DC, et al. Cyclic neutropenia. Semin Hematol. 2002;39:89-94.
Lubitz PA, et al. Cyclic neutropenia: an unusual disorder of granulopoiesis effectively treated with recombinant granulocyte colony-stimulating factor. Pediatr Dermatol. 2001;18:426-32.
Da Fonseca MA, Fontes F. Early tooth loss due to cyclic neutropenia: long-term follow-up of one patient. Spec Care Dentist. 2000;20:187-90
Dale DC, et al. Mutations in the gene econding neutrophil elastase in congenital and cyclic neutropenia. Blood. 2000;96:2317-22.
Palmer SE, et al. Genetics, phenotype, and natural history of autosomal dominant cyclic hematopoiesis. Am J Med Genet. 1996;66:413-22.
Hammond WP, et al. Treatment of cyclic neutropenia with granulocyte colony-stimulating factor. N Engl J Med. 1989;320:1306-11.
Dale DC, et al. Cyclic neutropenia: a clinical review. Blood Review. 1988;2:178-85.
Wright DG, et al. Human cyclic neutropenia: clinical review and long-term follow-up of patients. Medicine. 1981;60:1-13.
Dale DC. (Updated July 14, 2011). ELANE-Related Neutropenia. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2012. Available at http://www.genetests.org. Accessed March 1, 2012.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Cyclic Neutropenia. Entry No: 162800. Last Edited June 8, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed March 1, 2012.
Report last updated: 2012/03/19 00:00:00 GMT+0