NORD gratefully acknowledges Laurence A. Boxer, MD, Henry and Mala Dorfman Family Professor of Pediatric Hematology/Oncology, University of Michigan, for assistance in the preparation of this report.
Severe chronic neutropenia (SCN) is a rare blood disorder characterized by abnormally low levels of certain white blood cells (neutrophils) in the body (neutropenia). Neutrophils play an essential role in fighting bacterial infections by surrounding and destroying invading bacteria (phagocytosis). Symptoms associated with severe chronic neutropenia include recurring fevers, mouth sores (ulcers), and/or inflammation of the tissues that surround and support the teeth (periodontitis). Due to low levels of neutrophils, affected individuals may be more susceptible to recurring infections that, in some cases, may result in life-threatening complications. SCN may last for months or years and can affect both children and adults. Clinicians recognize three forms of the disorder: congenital, cyclical, and idiopathic neutropenia. The term idiopathic neutropenia is used when severe chronic neutropenia occurs for unknown reasons.
Symptoms and physical findings associated with severe chronic neutropenia vary greatly depending on how low the level of neutrophils in the blood falls. As earlier noted, the four main subdivisions of severe chronic neutropenia are congenital, cyclical, idiopathic, and autoimmune.
The congenital forms of severe chronic neutropenia are usually can be suspected by doing a blood count at birth (congenital) or during early childhood and are often the most severe. Findings common to all severe congenital neutropenia (SCN) forms of severe chronic neutropenia include fevers, acute inflammation of the lungs (pneumonia), ear infections, and/or inflammation of the gums (gingivitis), the delicate mucous membranes that line the mouth (stomatitis), and/or the tissue that surrounds and supports the teeth (periodontitis). Recurrent oral ulcerations are also common. In addition, in some cases, affected individuals may experience premature loss of teeth.
Individuals with congenital forms of severe chronic neutropenia are 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. The most severe form of congenital neutropenia is known as severe congenital neutropenia. (For more information on this disorder, see the Related Disorders section of this report.)
The primary finding associated with cyclical neutropenia is a severe, chronic decrease in the levels of certain white blood cells (neutrophils). In most cases of cyclical neutropenia, episodes of severe neutropenia recur on an average of every 21 days (cyclic) and may last for approximately three to six days. The cycling period usually remains constant and consistent among affected individuals. (For more information on this disorder, choose “cyclic neutropenia” as your search term in the Rare Disease Database.)
Chronic idiopathic neutropenia refers to 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). In most cases, the symptoms associated with idiopathic neutropenia are less severe than those associated with congenital neutropenia and may not require specific treatment. However, in some severe cases of idiopathic neutropenia, infections may result in life-threatening complications.
Autoimmune neutropenia usually strikes children between the ages of 6 months and 4 years and is the most common form of SCN in this age group. This disorder is characterized by the presence of neutrophil-specific antibodies in the blood that increases the rate of destruction of the patient’s neutrophils. Curiously enough, although the blood level of neutrophils is low in patients with autoimmune neutropenia, these children are not commonly affected by severe bacterial infections. Even less frequently, young adults from 20 to 30 years of age may develop this disorder. Autoimmune neutropenia is distinct from severe chronic neutropenia in terms of the cause of neutropenia. The severe chronic neutropenias arise from the failure of the bone marrow to produce adequate numbers of neutrophils which circulate in the blood.
It appears that patients with SCN are at greater risk of developing leukemia than are other people.
Congenital forms of severe chronic neutropenia may be inherited as either an autosomal dominant or an autosomal recessive genetic trait. In addition, many cases of SCN are the result of spontaneous, random mutations. The mutated genes, known as ELA2, responsible for severe autosomal dominant form of congenital neutropenia have been tracked to gene map loci 19p13.3 and 1p22.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 19p13.3” refers to band 13.3 on the short arm of chromosome 19, and “chromosome 1p22” refers to band 22 on the short arm of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.
All individuals carry several abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
In cases of chronic idiopathic neutropenia, the exact cause is unknown. Usually cyclical neutropenia may be inherited or rarely acquired. Some cases of cyclic neutropenia are present at birth (congenital) and appear to occur randomly, for no apparent reason (sporadically).
Most blood cells, including neutrophils, are produced by bone marrow, the soft tissue within the hollow parts of bone. 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. Other disorders that SCN are associated with include Shwachman-Diamond syndrome, rarely Wiscott-Aldrich syndrome and glycogen storage disease Type 1b.
Severe chronic neutropenia is a rare blood disorder that appears to affect males and females in equal numbers. Both children and adults may be affected. Severe cyclic and congenital neutropenia respectively are estimated to affect approximately 0.5 to 1 case per million population in the United States.
The congenital forms of severe chronic neutropenia are typically apparent at birth or during early childhood. Chronic idiopathic neutropenia usually affects adults. However, in some cases, the disorder may present in early childhood. Most cases of cyclic neutropenia are thought to be present at birth. However, in some cases, symptoms may not become apparent until childhood, adolescence or early adulthood, or the disorder may be acquired.
The most conclusive processes for the diagnosis of severe chronic neutropenia include a bone marrow aspirate, blood counts, and ELA2 genetic testing. The aspirate follows a detailed patient history, a thorough clinical evaluation, and blood tests (i.e., white blood cell count) that measure the various types of blood cells in the circulation. In individuals with severe chronic neutropenia, such blood counts demonstrate abnormally low levels of neutrophils. Normal counts of neutrophils range between 1.5 and 7 billion cells per liter of blood. If the neutrophil count falls below 0.5, then severe neutropenia is suggested.
Treatment
Prompt, appropriate treatment of infections associated with severe chronic neutropenia is essential. Such infections are usually managed with antibiotics. Some affected individuals may benefit from therapy with specific glucocorticoids, anti-inflammatory drugs that suppress the immune system.
At the present time, the treatment of choice for SCN is the administration of granulocyte-colony stimulating factors (G-CSF). G-CSF is a manufactured version of the natural hormones that stimulate the bone marrow to produce neutrophils. G-CSF increases the number of neutrophil generated by the bone marrow and improves the efficiency of their bacteria-killing ability.
In SCN cases unresponsive to G-CSF or if leukemia has developed, bone marrow transplants have been tried with varying success. Bone marrow transplants bring additional risks into the management of the disorder.
Genetic counseling will be of benefit for individuals with familial forms of severe chronic neutropenia and their families.
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TEXTBOOKS
Lichtman MA, Beutler E, Kipps TJ, Selisohn U, et al, eds. Williams Hematology. 7th ed. New York, NY: McGraw-Hill Companies; 2006:899-901, 907-20.
JOURNAL ARTICLES
Makaryan V, Zeidler CB, Bolyard AA, et al. The diversity of mutations and clinical outcomes for ELANE-associated neutropenia. Curr. Opin. Hematol. 2015; 22:3-11.
Walkovich K, Boxer LA. How to approach neutropenia. Pediat. Rev. 2013; 34:173-184.
Dale DC, Welte K. Cyclic and chronic neutropenia. Cancer Treat Res. 2011;157:97-108.
Donadieu J, Fenneteau O, Beaupain B, Mahlaoui N, Chantelot CB. Congenital neutropenia: diagnosis, molecular bases and patient management. Orphanet J Rare Dis. 2011;6:26.
Newburger PE, Pindyck TN, Zhu Z, et al. Cyclic neutropenia and severe congenital The neutropenia in patients with a shared ELANE mutation and paternal haplotype: evidence for phenotype determination by modifying genes. Pediatr Blood Cancer. 2010;55(2):314-317.
Rosenberg PS, Alter BP, Link DC, et al. Neutrophil elastase mutations and risk of leukaemia in severe congenital neutropenia. Br J Haematol. 2008;140(2):210-213.
Klein C, Grudzien M, Appaswamy G, et al. HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nat Genet. 2007;39(1):86-92.
Boxer LA, Newburger PE. A molecular classification of congenital neutropenia syndromes. Pediatr Blood Cancer. 2007;49(5):609-614.
Dale DC, Cottle TE, Fier CJ, et al. Severe chronic neutropenia: treatment and follow-up of patients in the Severe Chronic Neutropenia International Registry. Am J Hematol. 2003;72(2):82-93.
Dale DC, Person RE, Bolyard AA, et al. Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood. 2000;96(7):2317-2322.
INTERNET
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Neutropenia, Severe Congenital, 1, Autosomal Dominant; SCN1. Entry No: 202700. Last Edited 09/23/2014. Available at: http://omim.org/entry/202700 Accessed May 13, 2015.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Cyclic Neutropenia. Entry No: 162800. Last Edited 06/08/2011. Available at: http://omim.org/entry/162800 Accessed May 13, 2015.
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