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40 years!
Last updated:
August 15, 2019
Years published: 1989, 1992, 1996, 1997, 1998, 2002, 2007, 2009, 2012, 2015, 2019
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.
Treatment
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.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll Free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Severe Chronic Neutropenia International Registry
University of Washington, Seattle WA 98195
Website: https://depts.washington.edu/registry/
TEXTBOOKS
Kliegman, et al. Nelson Textbook of Pediatrics, 19th ed. Philadelphia, PA: Elsevier Saunders Company; 2011:750.
Dale DC, Williams Hematology, 9th ed. New York, NY: McGraw-Hill, Inc.; 2016: 991.
JOURNAL ARTICLES
Dale DC, Bolyard AA, Marrero T, Bonilla MA, Link DC, Newburger P, Shimamura A, Boxer LA, C Spiekerman. Long-term effects of G-CSF therapy in cyclic neutropenia. N Engl J Med. 2017;377:1-2.
Dale DC. How I manage children with neutropenia. Br J Haematol. 2017;178:351-363. PMID: 28419427
Skokowa J, Dale DC, Touw IP, Zeidler C, Welte K. Severe congenital neutropenias. Nat Rev Dis Primers. 2017;8(3):17032.
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. Mutations in the gene encoding 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.
INTERNET
Dale DC, Makaryan V. ELANE-Related Neutropenia. 2002 Jun 17 [Updated 2018 Aug 23]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1533/ Accessed July 1, 2019.
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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NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.
Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.
Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.
Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/