NORD gratefully acknowledges Peter E. Newburger, MD, Editor, Pediatric Blood & Cancer; Professor of Pediatrics and Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, 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 bloodstream (neutropenia) not explained by medication use, infections or another underlying health condition like blood cancers or systemic autoimmune diseases associated with 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), inflammation of the tissues that surround and support the teeth (periodontitis) and inflammation of the sinuses (sinusitis), throat (pharyngitis) and/or ear (otitis). Due to low levels of neutrophils, affected individuals may be more susceptible to recurring bacterial infections that, in some patients, 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, autoimmune 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 three main subdivisions of severe chronic neutropenia are congenital, autoimmune and idiopathic.
The congenital forms of severe chronic neutropenia are often the most severe of all types of SCN and can be detected by doing a blood count in infancy or during early childhood.
Findings common to all congenital forms of SCN include fevers; ear infections; acute inflammation of the lungs (pneumonia); skin infections; and inflammation of the delicate mucous membranes that line the mouth (stomatitis), the gums (gingivitis) and/or the tissue that surrounds and supports the teeth (periodontitis). Recurrent oral ulcerations are also common. Some patients may experience premature loss of teeth.
Individuals with congenital forms of severe chronic neutropenia are especially susceptible to various bacterial infections that affect the skin, digestive (gastrointestinal) tract and respiratory system, with the source of bacteria usually from the patient’s own skin and gut flora. Such bacterial infections vary in severity and, in some patients may result in life-threatening complications. Importantly, patients with congenital neutropenia still have normal immunity to viruses and so are no more susceptible to viral infections than the average person and can receive all immunizations, including live virus vaccines.
Patients with congenital forms of SCN are at greater risk of developing leukemia than are other people, especially in cases associated with certain gene mutations and cases that require higher medication doses. Yearly bone marrow examinations where chromosomes are examined can detect leukemia at its earliest development.
In cyclic neutropenia, a rare form of congenital neutronia, the primary finding is a periodic severe decrease in the levels of neutrophils. In most patients, episodes of severe neutropenia recur on an average of every 21 days (hence “cyclic”) and may last for approximately three to six days. The cycling period usually remains constant and consistent among affected individuals, but the severity of the low point may improve with age. Although other forms of neutropenia can show striking variability of neutrophil counts, only cyclic neutropenia causes such consistent, lifelong cycling of neutrophils, and often other types of blood cells.
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. Less frequently, adults may develop this disorder, with a peak incidence from 20 to 30 years of age. This disorder is characterized by the presence of neutrophil-specific antibodies in the blood that increase the rate of destruction of the patient’s neutrophils. Although the blood level of neutrophils can be very low in children with autoimmune neutropenia, they are only rarely affected by severe bacterial infections and neutropenia usually resolves without treatment several months to years after onset. Unfortunately, spontaneous remission of autoimmune SCN is not at all common in the adult-onset version but clinical symptoms are usually mild and only occasionally severe. Other potential findings with autoimmune neutropenia in adults are low red blood cells (anemia) and platelet levels (thrombocytopenia). Autoimmune neutropenia is distinct from congenital neutropenia in terms of the cause of neutropenia. The congenital neutropenias arise from the failure of the bone marrow to produce adequate numbers of neutrophils which circulate in the blood. Autoimmune neutropenias, due to destruction of neutrophils in the blood, usually feature a reserve pool of neutrophils in the bone marrow and good delivery of neutrophils to sites of bacterial invation, leading to the observed low incidence of serious infection.
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), but most likely represent an autoimmune process in many patients. In most patients, the symptoms associated with idiopathic neutropenia are less severe than those associated with congenital neutropenia and may not require specific treatment. However, in some severely affected patients with idiopathic neutropenia, infections may result in life-threatening complications.
Genetics
Congenital forms of severe chronic neutropenia may be inherited in either an autosomal dominant, autosomal recessive or X-linked (sex-linked) pattern. However, some cases of congenital neutropenia are the result of acquired spontaneous mutations that aren’t inherited. Changes or mutations in the ELANE gene are the most common cause of the autosomal dominant form of severe congenital neutropenia and virtually all cases of cyclic neutropenia. Mutations in the SRP54 and GFI1 genes are also linked to rare autosomal dominant congenital neutropenia cases. The autosomal recessive form of congenital neutropenia can be caused by mutations in the genes HAX1 (Kostmann disease), G6PC3, JAGN1, among others. Mutations in these genes can cause isolated neutropenia or be associated with other signs/symptoms such as neurological deficits with HAX1 mutations or cardiac abnormalities with G6PC3 mutations. Very rare mutations in the WAS gene can cause X-linked congenital neutropenia in males.
Dominant genetic disorders occur when only a single copy of an altered gene is necessary for the appearance of the disease. The altered gene can be inherited from either parent, or can be the result of a new mutation in the affected individual. The risk of passing the altered gene from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females.
Recessive genetic disorders occur when an individual inherits an alteration in a gene for the condition 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 altered 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 is 25 percent. The risk is the same for males and females.
X-linked genetic disorders are conditions caused by an altered gene on the X chromosome and manifest mostly in males. Females that have an altered gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the altered gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an aleterd gene he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder is able to reproduce, he will pass the altered gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
Most cases of chronic idiopathic neutropenia and autoimmune neutropenias are not inherited, although there can be a familial predisposition to adult autoimmune disease, and some cases of persistent childhood autoimmune neutropenia are associated with inherited disorders of the immune system.
Other disorders associated with SCN include Shwachman-Diamond syndrome, glycogen storage disease type 1b, and multiple other syndromes affecting the bone marrow and other organs.
Severe chronic neutropenia is a rare blood disorder that appears to affect females more than males in its idiopathic and autoimmune forms, with less discrepancy between the sexes in congenital forms. Both children and adults may be affected. Severe congenital neutropenia is estimated to affect approximately 1-4 people per million population in the United States.
The congenital forms of severe chronic neutropenia are typically apparent in early infancy or during early childhood. Chronic idiopathic neutropenia usually affects adults but may present in early childhood.
Severe chronic neutropenia can be diagnosed with a bone marrow aspirate, blood counts and genetic testing. The aspirate is collected after a detailed patient history, 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.
For diagnosing cyclic SCN, blood counts should be examined 3 times per week over two 21-day cycles or preferably by genetic testing for mutations in the ELANE gene.
Autoimmune neutropenia may be tested for by measuring antibody levels to neutrophils, but these tests are not highly accurate, so a negative test result does not rule out the diagnosis. Positive antibody tests can also occur in congenital SCN.
Clinical observations, bone marrow findings and genetic testing are gold standards for differentiating between congenital and autoimmune neutropenia. As there are many genetic causes of congenital neutropenia, it is most efficient and cost-effective to test a panel of possible genes rather than one at a time.
Treatment
Prompt, appropriate treatment of infections associated with severe chronic neutropenia is essential. Such infections are usually managed with antibiotics. Even though patients have a normal immune response to viruses, good hygiene measures including avoiding crowds and adequate hand-washing are recommended to prevent secondary bacterial infections that can start after the immune system has been weakened from fighting off viral infections. Good dental hygiene, including regular dental exams, is required to prevent tooth loss.
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 hormone that stimulates the bone marrow to produce neutrophils. G-CSF increases the number of neutrophils generated by the bone marrow and improves their bacteria-killing ability. It is recommended in patients with severe congenital neutropenia or with any form of SCN resulting in frequent infections and oral health problems. All forms of SCN have the potential to respond to G-CSF, and autoimmune forms respond better to G-CSF than immunosuppressive treatments used in other autoimmune diseases. In cyclic neutropenia, G-CSF shortens the number of days that neutrophil levels drop, and improves neutrophil levels at the low point, so that infections cannot develop. Side effects of G-CSF include headaches and bone, joint and muscle pain. Lower doses administered more frequently can lessen side effects. Prolonged use of G-CSF in congenital neutropenias has been associated with development of pre-leukemia or leukemia, but this complication is extremely rare in cyclic neutropenia and has not been reported in autoimmune or idiopathic neutropenias.
Some affected individuals, mostly those with neutropenia due to systemic autoimmune diseases, such as lupus, may benefit from therapy with specific glucocorticoids, anti-inflammatory drugs that suppress the immune system. Glucocorticoids stimulate neutrophils to enter the blood stream from the bone marrow but don’t acutally stimulate production of new neutrophils, and they might worsen neutrophil function. IVIG may also be helpful in autoimmune neutropenia but benefits are very short-lived and only about 50% of patients have a response to it. Typical immunosuppressant medications used in other autoimmune diseases, like methotrexate are not very effective in autoimmune neutropenia and are only tried if first-line treatment with G-CSF is not successful.
Bone marrow transplantation has been used to treat patients with SCN and should be considered for any patient with severe congenital neutropenia with a matched sibling or 10/10-matched unrelated donor. Bone marrow transplants have the potential to cure SCN but bring additional risks into the management of the disorder. With bone marrow transplants, chemotherapy is administered to destroy existing bone marrow that is then replaced with bone marrow from a donor through an IV infusion.
Genetic counseling is recommended for individuals with familial forms of severe chronic neutropenia and their families.
G-CSF is to date the most effective therapy for SCN and few other options exist. Mavorixafor is a newer medication under investigation for severe congenital and idiopathic neutropenia. Originally used to treat neutropenia in an immunodeficiency disorder known as WHIM syndrome, mavorixafor increases the release of neutrophils from the bone marrow by blocking a receptor known as CXCR4 present on immune cells.
Ezatiostat is another investigational drug for patients with idiopathic chronic neutropenia, including cases that haven’t responded to G-CSF. It stimulates the production of bone marrow cells that develop into neutrophils by blocking the enzyme glutathione S-transferase P.
Laboratory studies of gene therapy are underway, but have not yet reached clinical application.
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:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
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/
JOURNAL ARTICLES
Dale D, Firkin F, Bolyard A, et. al. Results of a phase 2 trial of an oral CXCR4 antagonist, mavorixafor, for treatment of WHIM syndrome. Blood. 2020; 136(26):2994-3003
Bellanne-Chantelot C, Schmaltz-Panneau B, Marty C, et. al. Mutations in the SRP54 gene cause severe congenital neutropenia as well as Shwachman-Diamond-like syndrome. Blood. 2018;132(12):1318-1331.
Dale D, Bolyard A. An update on the diagnosis and treatment of chronic idiopathic neutropenia. Curr Opin Hematol. 2017;24(1):46-53.
Dale D. How I diagnose and treat neutropenia. Curr Opin Hematol. 2016;23(1):1-4.
Fontbrune F, Moignet A, Beaupain B, et al. Severe chronic primary neutropenia in adults: report on a series of 108 patients. Blood. 2015; 126(14): 1643-50.
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.
Newburger P, Dale D. Evaluation and management of patients with isolated neutropenia. Semin Hematol. 2013;50(3):198-206.
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.
Lyons R, Wilks S, Young S, et. al. Oral ezatiostat HCl and idiopathic chronic neutropenia: a case report of complete response of a patient with G-CSF resistant ICN following treatment with ezatiostat, a glutathione s-transferase P-1-1 inhibitor. J Heamtol Oncol. 2011;4:43.
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.
Capsoni F, Sarzi-Puttini P, Zanella A. Primary and secondary autoimmune neutropenia. Arthritis Res Ther. 2005; 7(5): 208-214.
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
Zeidler C. Understanding severe chronic neutropenia: A handbook for patients and their families. Last Edited 2017. Available at: https://severe-chronic-neutropenia.org/sites/default/files/handbook_en.pdf. Accessed June 16, 2021.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Neutropenia, Severe Congenital, 1, Autosomal Dominant; SCN1. Entry No: 202700. Last Edited01/31/2020. Available at: http://omim.org/entry/202700 Accessed June 21, 2021.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Cyclic Neutropenia. Entry No: 162800. Last Edited06/02/2016. Available at: http://omim.org/entry/162800 Accessed June 21, 2021.
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