NORD gratefully acknowledges David C. Dale, MD, Professor of Medicine, Department of Medicine, University of Washington, and Laurence A. Boxer, MD (deceased), 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 regularly recurring severe decrease in certain white blood cells (neutrophils). In most cases, episodes of neutropenia recur every 21 days (a cyclic phenomenon), and the severe neutropenia 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 (anemia), changes in levels of the blood particles that assist in clotting (platelets), presence of immature red blood cells (reticulocytes), and cyclic changes in other white blood cells can occur. An almost constant feature is an increase in blood monocytes at the lowest point in the neutrophil cycle.
During episodes of neutropenia, affected individuals may experience fever, a general feeling of ill health (malaise), inflammation and deep ulceration of the mucous membranes of the mouth (aphthae and 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. Periodontal disease may result in loosening of teeth and early tooth loss in young children and adults.
Individuals with cyclic neutropenia are abnormally susceptible to 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 is usually a hereditary disease, but there are a few reported cases of acquired cyclic neutropenia. There are reports in the medical literature of several multigenerational families (kindreds) with increased incidence of cyclic neutropenia. Based on these genetic studies, we know that it is an autosomal dominant disease and can be passed on from one affected parent.
Investigators have determined that sporadic and autosomal dominant cyclic neutropenia are caused by disruption or changes (mutations) of the ELANE gene responsible for production of a neutrophil protein called neutrophil elastase. Mutations in this gene cause production of abnormal neutrophil elastase and this is the fundamental cause of cyclic neutropenia. Neutrophils are produced in the cavities in many bones (bone marrow). Neutropenia, fever and infections occur when the bone marrow fails to produce sufficient numbers of neutrophils.
Cyclic neutropenia affects males and females in equal numbers. Most cases of cyclic neutropenia are thought to be present at birth (congenital); however, in some cases, the diagnosis may not become obvious until childhood, adolescence, or early adulthood.
Cyclic neutropenia is a subdivision of severe chronic neutropenia. Severe chronic neutropenia affects approximately 0.5 to 1 per million people in the United States. (For more information on severe chronic neutropenia, see the Related Disorders section of this report.)
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.
Since 1987 the human grow factor called recombinant human granulocyte-colony stimulating factor [rhG-CSF]) has been used to treat cyclic neutropenia and other forms of severe chronic neutropenia. One form, the orphan drug neupogen (Filgrastim) was approved by the Food and Drug Administration for use in the treatment of cyclic and other types 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.
Genetic counseling is recommended for individuals with inherited forms of cyclic neutropenia and their families. Other treatment is symptomatic and supportive.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
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Severe Chronic Neutropenia International Registry
University of Washington, Seattle WA 98195
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Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Cyclic Neutropenia. Entry No: 162800. Updated 06/02/2016. https://www.omim.org/entry/162800 Accessed July 1, 2019.
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