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Cyclic Neutropenia

Agranulocytosis Cyclic

Cyclic neutropenia (CN) is a type of neutropenia in which neutrophil levels follow a 21-day cycle. CN comes both as a congenital and acquired disorder, with basically the same symptoms and signs for both forms.

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Presentation

The main CN symptom is the decreased neutrophil blood count in an episode of neutropenia that follows a 21-day cycle. The episode might vary from 3 to 6 days, according to the particular case, but the general trend of the cycle remains constant and consistent among patients. In addition to neutropenia episodes, it is also possible to observe abnormal levels of other blood cells, such as platelets, erythrocytes and monocytes.

During neutropenic episodes, the affected individuals are particularly exposed to bacterial infections which affect the skin as well as the gastrointestinal and respiratory tract. Infections are usually accompanied by other key symptoms, such as fever, malaise, loss of appetite [7], inflammations and ulcerations that affect the throat (pharyngitis) and the tissues around the teeth (periodontal diseases).

Fever
  • Patients with cyclic neutropenia may have myalgias, fever, pharyngitis, oral ulcers, or bilateral anterior cervical adenitis.[ncbi.nlm.nih.gov]
  • In one patient, fever and stomatitis were ameliorated, but the duration of neutropenia was increased and parotitis occurred. In another patient, aphthous stomatitis disappeared but fever persisted.[ncbi.nlm.nih.gov]
  • CASE PRESENTATION: A 3 years and 2 months old girl presented with recurrent fever and oral mucosal ulcer for 1 year.[ncbi.nlm.nih.gov]
  • Long-term, daily, or alternate-day administration reduces fever, mouth ulcers, and other inflammatory events associated with this disorder.[ncbi.nlm.nih.gov]
  • Abstract The case of a patient suffering from recurrent episodes of fever over a period of 24 months is presented.[ncbi.nlm.nih.gov]
Recurrent Infection
  • Here we report on an exceptional CVID patient with recurrent episodes of cyclic neutropenia, skin vasculitis and recurrent infections associated with a transient, but reproducible CD80 expression defect on stimulated B cells.[ncbi.nlm.nih.gov]
  • Patients with the disease suffer from recurrent infections at regular intervals of nearly three weeks.[ncbi.nlm.nih.gov]
  • The patient had a history of recurrent infections since infancy and developed goiter, proteinuria, and azotemia at age 14 years. Her SAA level was markedly increased (601.8 μg/mL, normal range[ncbi.nlm.nih.gov]
  • Recurrent infections, inflammation, and ulcers can lead to significant chronic morbidity.[ncbi.nlm.nih.gov]
  • Neutrophil deficiency causes recurrent infections, episodes of inflammation and other immune system problems in people with severe congenital neutropenia.[ivami.com]
Malaise
  • The neutropenic phase is characteristically associated with clinical symptoms such as recurrent fever, malaise, headaches, anorexia, pharyngitis, ulcers of the oral mucous membrane, and gingival inflammation.[ncbi.nlm.nih.gov]
  • Despite the profound cyclic neutropenia, most patients have a benign course of recurrent fever, malaise, oral ulceration, and minor skin and upper respiratory tract infections.[ncbi.nlm.nih.gov]
  • […] neutropenia [ noo″tro-pe ne-ah ] diminished numbers of neutrophils in the blood. cyclic neutropenia a chronic form marked by regular, periodic episodic recurrences, associated with malaise, fever, stomatitis, and various infections.[medical-dictionary.thefreedictionary.com]
  • Infections are usually accompanied by other key symptoms, such as fever, malaise, loss of appetite, inflammations and ulcerations that affect the throat (pharyngitis) and the tissues around the teeth (periodontal diseases).[symptoma.com]
  • The patient's mother mentioned that the oral ulcers seemed to coincide with malaise, fatigue and with the patient generally feeling ill and run down whilst the oral ulcers were present.[nature.com]
Anemia
  • Abstract A 20-year-old female from the Philippines developed anemia and granulocytopenia.[ncbi.nlm.nih.gov]
  • Types of blood disorders include Platelet disorders, excessive clotting, and bleeding problems, which affect how your blood clots Anemia, which happens when your blood does not carry enough oxygen to the rest of your body Cancers of the blood, such as[icdlist.com]
  • Neutropenia, refractory anemia, thrombocytopenia, marrow failure syndromes and cell mediated immune dysfunction are also part of the syndrome. Pathophysiology is unknown but hematologic characteristics are very similar to Fanconi anemia.[clinicaladvisor.com]
  • Fanconi anemia conditions that affect bone marrow According to the U.S.[healthline.com]
  • Among children, neutropenia has a number of causes, including: Inadequate bone marrow production due to other blood disorders such as aplastic anemia or cancer such as leukemia .[ucsfbenioffchildrens.org]
Fatigue
  • The patient's mother mentioned that the oral ulcers seemed to coincide with malaise, fatigue and with the patient generally feeling ill and run down whilst the oral ulcers were present.[nature.com]
  • We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: January 30, 2019[patientslikeme.com]
  • In addition to cyclic variations in the blood levels of neutrophils and other particles such as eosinophils, monocytes or platelets, the symptoms of cyclic neutropenia include other key signs such as fatigue, weakness, malaise and several forms of infections[symptoma.com]
  • More than 60% of individuals with cyclic neutropenia experience oral ulcerations, gingivitis, lymphadenopathy, fever, pharyngitis/tonsillitis, fatigue, and skin infections five or more times a year.[jpma.org.pk]
Pharyngitis
  • Abstract A 22 years old patient presented with recurrent episodes of diarrhoea, pharyngitis, apthous ulcers and fever for the past 6 months. The episodes lasted a week each time.[ncbi.nlm.nih.gov]
  • The neutropenic phase is characteristically associated with clinical symptoms such as recurrent fever, malaise, headaches, anorexia, pharyngitis, ulcers of the oral mucous membrane, and gingival inflammation.[ncbi.nlm.nih.gov]
  • She developed recurrent pharyngitis and apthous stomatitis but there was no cycling of other blood elements. Bone marrow aspiration and biopsy showed normal developing myeloid cells, a clonal chromosomal abnormality, and myelofibrosis.[ncbi.nlm.nih.gov]
  • CASE REPORT: An 8-year-old boy presented with a history of recurrent oral ulcers, periodontal destruction, pharyngitis and otitis media since the age of 3 months.[ncbi.nlm.nih.gov]
  • Various laboratory tests were performed including full blood count, bone marrow studies and various cultures which showed neutropenia, streptococcal pharyngitis and Campylobacter jejuni in stools.[jpma.org.pk]
Loss of Appetite
  • Infections are usually accompanied by other key symptoms, such as fever, malaise, loss of appetite, inflammations and ulcerations that affect the throat (pharyngitis) and the tissues around the teeth (periodontal diseases).[symptoma.com]
Heart Disease
  • Two of our patients had associated congenital defects that are known to occur in patients with G6PC3 mutations, including congenital heart disease and intermittent thrombocytopenia.[ncbi.nlm.nih.gov]
Periodontitis
  • They demonstrate that regular tooth care and professional dental treatment can prevent progressive periodontal breakdown but that neglecting oral hygiene soon leads to periodontal pathology.[ncbi.nlm.nih.gov]
  • BACKGROUND: Cyclic neutropenia (CN) is a rare congenital disease that can present with recurrent oral ulcers and periodontitis.[ncbi.nlm.nih.gov]
  • Local antibiotic application with minocycline ointment in periodontal pockets was beneficial as an ancillary treatment, especially during neutropenic periods.[ncbi.nlm.nih.gov]
  • Abstract In young patients with abnormal loosening of teeth and periodontal breakdown, dental professionals should consider a wide range of etiological factors/diseases, analyze differential diagnoses, and make appropriate referrals.[ncbi.nlm.nih.gov]
  • Due to irregular periodontal maintenance and poor oral hygiene, severe gingival inflammation and deep pockets persisted in the permanent dentition of the patient.[ncbi.nlm.nih.gov]
Aphthous Stomatitis
  • Recurrent aphthous stomatitis with a periodicity of around 3 weeks should alert the dermatologist to the possibility of cyclic neutropenia.[ncbi.nlm.nih.gov]
  • In another patient, aphthous stomatitis disappeared but fever persisted. The duration of neutropenia was prolonged and submaxillaritis and sinusitis occurred.[ncbi.nlm.nih.gov]
  • CN can easily be misdiagnosed as major recurrent aphthous stomatitis (MaRAS) or aggressive periodontitis (AP) in dental clinics. We describe the case of an 8-year-old boy with CN, and compare the oral manifestations of CN with those of MaRAS and AP.[ncbi.nlm.nih.gov]
  • All had a history of recurrent aphthous stomatitis, pharyngitis, lymphadenopathy, fever, and numerous infections during periods of neutropenia.[nejm.org]
  • This is due to oscillation in the production of neutrophils by bone marrow. 1 The symptoms include fever, aphthous stomatitis, lymphadenopathy, malaise and sometimes severe infections. It can be present in several members of the same family.[jpma.org.pk]
Cheilitis
  • Abstract An unusual case of cyclic neutropenia and hereditary myeloperoxidase deficiency complicated by noma-like gangrenous cheilitis is described. Klebsiella pneumoniae and Candida albicans were cultured from the involved area.[ncbi.nlm.nih.gov]
Neglect
  • They demonstrate that regular tooth care and professional dental treatment can prevent progressive periodontal breakdown but that neglecting oral hygiene soon leads to periodontal pathology.[ncbi.nlm.nih.gov]

Workup

The diagnosis of CN is based on a series of measurements of the absolute neutrophil count taken daily or at least three times a week for a period varying from four to six weeks [8]. At the minimum neutrophil peak, the absolute neutrophil count is generally lower than 0.2 x 109/L. It should be remembered that there are variations of this general pattern in a small group of patients (less than 5% of them), in which cycles might be longer or shorter of the theoretical 3 week period. Furthermore, CN might be present in the relatives of affected individuals, although with less obvious cycles, and blood cell counts might oscillate more strongly in children than in adults. Oscillating cycles can be seen not just for neutrophils, but also for other blood cells such as lymphocytes, eosinophils, monocytes, and platelets.

Molecular tests can also be used to diagnose CN, as ELANE variants have been found in 100% of the individuals with a clear CN clinical history [9]. Therefore, the current diagnostic approach tends to include neutrophil counts and clinical history as basic diagnostic elements [10].

HLA-B27
  • Abstract A 45-year-old female with a long history of HLA-B27-positive ankylosing spondylitis and ulcerative colitis developed cyclic neutropenia. She was hospitalized for high fever during each of three consecutive episodes of absolute neutropenia.[ncbi.nlm.nih.gov]

Treatment

It is important to address the infections associated with cyclic neutropenia immediately, in order to avoid further negative consequences. This can be done with the administration of antibiotics, in addition to other preventive measures such as careful oral and dental care or avoiding dangerous activities which might cause injuries.

The severe chronic neutropenia can be treated by using a synthetic drug which stimulates the poor bone marrow’s neutrophil production called recombinant human granulocyte-colony stimulating factor [rhG-CSF]. One of its generic form, Filgrastim, was approved by the Food and Drug Administration back in 1989 [11], after a series of studies that had proved the efficiency of rhG-CSF in increasing the number of neutrophils and reducing infections and related symptoms in long-term therapies. However, side effects such as mild bone pain and local skin reactions are frequent and therefore the administration of the drug needs careful evaluation prior to treatment and careful checks and evaluations during its administration, to ensure long-term safety and effectiveness.

Other treatments might be considered as supportive and symptomatic strategies, while genetic counseling is strongly suggested to detect inherited forms and start specific preventive measures.

Prognosis

As CN is a benign form of neutropenia, the related outcome is generally good. However, around 10% of patients might die as a result of an infection, which is usually pneumonia or peritoneal sepsis. The intensity of CN symptoms and signs tend to decrease as the patient reaches older age.

Etiology

As previously mentioned, the CN phenotypic presentation appears when cell production in the bone marrow is impaired, and this can happen under three different circumstances: the bone marrow no longer produces a sufficiently high number of neutrophils, neutrophils are somehow destroyed during their development, or even though their development has been fully completed, neutrophils do not function in a proper manner.

As previously mentioned, CN can come as an inherited or acquired pathological condition. The inherited form is associated with disruptions or mutations of the ELANE gene, located on the short arm of chromosome number 19 (19p13.3). The ELANE gene is responsible for the production of neutrophil elastase, a serine proteinase which destroys bacteria and host tissues. The inherited form is passed down from generation to generation as an autosomal dominant trait [3]. As in the other types of neutropenia, the acquired form appears in relation to a series of other pathological conditions, such as frequent and prolonged exposure to particular drugs, perhaps as a consequence of a direct stem cell toxic effect or the activation of an immune mechanism, due to causes that have yet to be completely understood.

Epidemiology

It has been estimated that CN occurs once every 1 million individuals all around the world [4]. Because of this extremely low prevalence, CN is considered by experts as a rare disease.

Sex distribution
Age distribution

Pathophysiology

CN can be ascribed to variations of neutrophil production by the bone marrow. Post-mitotic neutrophil cells are absent from the bone marrow at the beginning of CN development. Furthermore, as shown by electron microscopy studies carried out during the entire neutropenic cycle, it is possible to observe the appearance of developing cells which contain membrane blebs and nuclear condensations, the typical signs of an intense apoptotic activity going on. The death of the developing neutrophils through apoptosis is further suggested by flow cytometry studies, which reveal the presence of an increased number of annexin V-stained cells. The dead neutrophils are subsequently removed from the bone marrow by macrophages [5]. These changes are also accompanied by other oscillatory variations of the erythroid precursors, perhaps due to varied erythropoietin levels throughout the bone marrow, and this further supports the hypothesis that CN arises due to interruptions or variations of cell production [6].

It is worth remembering the results of recent investigations conducted with the use of purified bone marrow progenitor cells. According to these studies, CD34 cells from CN patients tend to form higher portions of high proliferative potential colony-forming cells (HPPC), even though these colonies remained much less differentiated in later developmental phases. These data seem to suggest that the early hematopoietic progenitor cells might proliferate normally, but the proliferative capacity is then lost before differentiating into the neutrophil lineage as the developing cells undergo apoptosis.

Prevention

The therapy with rhG-CSF has proved to improve symptoms and reduce infections in almost all affected individuals. This should be coupled with a good and constant dental care. Individuals affected by severe congenital neutropenia might consider hematopoietic stem cell transplantation as further therapeutic strategies, especially when they have become refractory to high doses of rhG-CSF or when malignant transformation in the bone marrow has started.

Summary

Cyclic neutropenia (CN) is mainly characterized by its typical 21-day pattern, in which neutrophil counts vary in a cyclical manner [1]. The details of the cycle vary from patient to patient, with the neutropenic phase lasting almost the entire cyclical period in some cases, while only a few days in others. During neutropenic phases, neutrophil blood levels might be lower than 200 cells/µl (0.2 x 109/l), and can be accompanied by low levels of other blood cells such as platelets or erythrocytes. Obviously, this also affects the frequency of infections, as those who experience longer neutropenic phases are more exposed to infections than those experiencing shorter ones. As a consequence, infections tend to follow the neutropenic pattern and this should be used as an important element for the diagnosis [2].

CN is a consequence of the fluctuations of cell production in the bone marrow, which in turn changes its cytological appearance according to the phase concerned. The condition frequently appears as an inherited form, with many cases where it is passed down from generation to generation within the same family. However, it is also possible to diagnose an acquired form with basically the same pathological presentation of the inherited one. CN often comes as a result of a series of genetic defects which, if studied, might lead to the discovery of new therapeutic approaches.

Patient Information

Cyclic neutropenia is a rare type of neutropenia in which neutrophil levels oscillate cyclically, alternating minimum and maximum peaks in a cycle that usually lasts for around 21 days. The minimum neutrophil levels in the blood generally last for 7 days. The disorder is due to impaired neutrophil production by the bone marrow, which comes as a direct consequence of a series of mutations occurring in a gene known as ELANE or of the occurrence of other associated pathological conditions. For this reason, cyclic neutropenia has an acquired and an inherited form.

In addition to cyclic variations in the blood levels of neutrophils and other particles such as eosinophils, monocytes or platelets, the symptoms of cyclic neutropenia include other key signs such as fatigue, weakness, malaise and several forms of infections. Counting the neutrophil levels in the blood (absolute neutrophil count) is the main diagnostic strategy for cyclic neutropenia, which can eventually be coupled with genetic testing, especially in those individuals with a well-documented family history.

The treatment for cyclic neutropenia is mainly based on the administration of granulocyte colony-stimulating factor, a drug which restores neutrophil production in the bone marrow. Granulocyte colony-stimulating factor has been proved to be effective in both the acquired and inherited form of the disorder, even though its use is frequently associated with side effects such as mild bone pain and local skin reactions. For this reason, treatment should be carefully considered prior to start administration, and patients should be carefully monitored and evaluated throughout it.

References

Article

  1. Lee GR, Foerster J, Lukens J, et al, eds. Wintrobe’s Hematology. 10th ed. Baltimore, Md: William and Wilkins. 1999; 1836-88.
  2. James WD, Berger TG, et al. Andrews' Diseases of the Skin: Clinical Dermatology. Saunders Elsevier. 2006; p. 811. ISBN 0-7216-2921-0.
  3. Berliner N, Horwitz M, Loughran TP Jr. Congenital and acquired neutropenia. Hematology Am Soc Hematol Educ Program. 2004; 63-79.
  4. Dale DC. ELANE-related neutropenia. In: GeneReviews, Pagon RA, Dolan CR, Stephens K (Eds), University of Washington, Seattle. 2009.
  5. Aprikyan A, Liles WC, Rodger E, et al. Impaired survival of bone marrow hematopoietic progenitor cells in cyclic neutropenia. Blood. 2001; 97:197-153.
  6. Dale D, Hammond WP. Cyclic neutropenia. A clinical review. Blood. 1988; Rev2:178-185.
  7. Migliaccio AR, Migliaccio G, Dale DC, et al. Hematopoietic progenitors in cyclic neutropenia: effect of granulocyte colony-stimulating factor in vivo. Blood. 1990; 75:1951-1959.
  8. Dale DC. Neutropenia and neutrophilia. In: Williams WJ, et al, eds. Hematology. 6 ed. New York, NY: McGraw-Hill. 2001; 823-34.
  9. Horwitz M, Benson KF, Person RE, et al. Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nat Genet. 1999; 23:433–6.
  10. Aprikyan AG, Stein S, Kutyavin T, et al. The causal role of mutations in the neutrophil elastase gene in cyclic and congenital neutropenia. Soc Exp Hematol. 2002.
  11. Hammond WP, Price TH, Souza LM, et al. Treatment of cyclic neutropenia with granulocyte colony-stimulating factor. N Engl J Med. 1989 May 18; 320(20):1306-11.

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Last updated: 2018-06-22 06:04