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

  Long-term, daily, or alternate-day administration reduces fever, mouth ulcers, and other inflammatory events associated with this disorder. [iths.pure.elsevier.com]

  Affected infants may have fever, pneumonia, septicemia, and other infections that can be fatal. [medical-dictionary.thefreedictionary.com]

  Fever of unknown origin (FUO) is the diagnosis associated with a variety of infectious, neoplastic, or rheumatic/inflammatory disorders. [ncbi.nlm.nih.gov]

• Anemia

  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]

  Shwachman-Diamond syndrome and X-linked dyskeratosis congenita (DC), cartilage-hair hypoplasia (CHH), and Diamond-Blackfan anemia (DBA) all appear to share common gene defects involved in ribosome synthesis. [emedicine.medscape.com]

  Neutropenia due to ineffective bone marrow production can occur in megaloblastic anemias caused by vitamin B 12 deficiency or folate deficiency. Usually, macrocytic anemia and sometimes mild thrombocytopenia develop simultaneously. [merckmanuals.com]

• Malaise

  […] 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]

  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]

  The clinical symptoms of cyclic neutropenia include fever, malaise, headaches and oral findings associated with painful soft tissue ulceration where lips, tongue and gingiva are typically involved. [journal.kapd.org]

  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. [rarediseases.org]

• 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]

  It presents itself with recurrent infections in the body like repetitive episodes of fever and mouth ulcers. Incidence It occurs in 1 in 1 million people in the world. [askdrshah.com]

• 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]

  Fatigue Fever Sores in the mouth Recurring gum problems and loose teeth Sore throat Skin infections Lung infections Digestive system infections An overall feeling of not being well Get useful, helpful and relevant health + wellness information enews More [my.clevelandclinic.org]

  We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: May 13, 2019 [patientslikeme.com]

  A few patients who have transiently interrupted G-CSF; almost all have resumed G-CSF because of recurrence of fever, mouth ulcers, infections or fatigue. [ashpublications.org]

• Pharyngitis

  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]

  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]

  A case of PFAPA (Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis) syndrome. Korean J Infect Dis 2001;33:219–222. Chae JH, Hwang AR, Park SH, Suh BK. [piv.or.kr]

• Persistent Cough

  The patient reported that she was admitted for the first time at the Mexico's Children's Hospital «Federico Gómez» in August 1994, due to a two-month evolution, persisting cough. A series of possible diagnoses were presented to the family. [elsevier.es]

• 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]

• 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]

  The clinical picture of this process includes: susceptibility to infection, feverish conditions, oral ulcers, impetigo, increased lymph nodes, periodontitis and stomatitis. [elsevier.es]

• 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]

  A case of PFAPA (Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis) syndrome. Korean J Infect Dis 2001;33:219–222. Chae JH, Hwang AR, Park SH, Suh BK. [piv.or.kr]

  All had a history of recurrent aphthous stomatitis, pharyngitis, lymphadenopathy, fever, and numerous infections during periods of neutropenia. [nejm.org]

• Cheilitis

  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]

  […] to incidence it can be said that frequency is 2 cases per million subjects.3 The clinical picture might include the following manifestations: susceptibility to infections, fever, fatigue, impetigo, increase in the size of lymph nodes, periodontitis, cheilitis [elsevier.es]

  […] and Nic Dobbins Classification D ICD-9-CM: 288.02 OMIM: 162800 MeSH: C536227 C536227, C536227 DiseasesDB: 30103 External resources GeneReviews: ELANE-Related Neutropenia v t e Oral and maxillofacial pathology (K00–K06, K11–K14, 520–525, 527–529) Lips Cheilitis [en.wikipedia.org]

• Dental Caries

  The dental treatment, including regular tooth care and appropriate treatment of dental caries or gingivitis, is essential for patients suffering cyclic neutropenia. [journal.kapd.org]

  caries and bad oral hygiene. [ijabmr.org]

• Short Arm

  The inherited form is associated with disruptions or mutations of the ELANE gene, located on the short arm of chromosome number 19 (19p13.3). [symptoma.com]

  arm (p) of chromosome 19 (19p13.3), the gene encoding neutrophil elastase, which is also the most common cause of the SCN.[1][6][7][8] In the case of CyN, the mutation variants have been found to mostly cluster in intron 4 and exon 4 and 5,[7][9] but [en.wikipedia.org]

• Arthralgia

  He developed acute arthralgia and fever 4 weeks after an episode of lower gastrointestinal symptoms. Serial blood cell counts showed recurrent neutropenia at 3 week intervals. [kci.go.kr]

  Vasculitis, rashes, arthralgias, and glomerulonephritis have been infrequently reported [ Dale et al 2003 ]. Note: (1) When affected individuals are given G-CSF and their ANC normalizes, their resistance to infection improves greatly. [ncbi.nlm.nih.gov]

• Speech Disorder

  The list presented was the following: • At 6 years of age, the patient was diagnosed with toxic neutropenia and speech disorders. • At 7 years of age, a physiological murmur was detected, with presence of peri-anal abscesses and mild anemia. • At 8 years [elsevier.es]

• Incontinence

  […] cytoreductive surgery 腫瘍量減少外科手術/腫瘍細胞減量術 cytoskeleton 細胞骨格 cytotoxic drug 細胞障害性薬剤/細胞傷害性薬剤/細胞毒性薬剤 cytotoxicity 細胞毒性/細胞傷害性/細胞障害性 cytotoxin 細胞毒 d-transposition of great arteries d型大血管転位/d型大血管転位症/d型大血管転換/d型大血管転換症 d-TGA daily energy intake 一日エネルギー摂取量 daytime incontinence [jpeds.or.jp]

  Clinically, it was additionally found that the patient suffered from urinary incontinence and 2nd degree malnutrition. [elsevier.es]

• Urinary Incontinence

  Clinically, it was additionally found that the patient suffered from urinary incontinence and 2nd degree malnutrition. [elsevier.es]

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].

• Neutropenia

  Cyclic neutropenia is a rare hematologic disorder, characterized by repetitive episodes of fever, mouth ulcers, and infections attributable to recurrent severe neutropenia. [iths.pure.elsevier.com]

  […] estrus regularly but not being submitted for mating; deferral of mating. neutropenia a diminished number of neutrophils in the blood. cyclic neutropenia periodic neutropenia. [medical-dictionary.thefreedictionary.com]

  […] of other origin, and 2 cases with cyclic neutropenia). [ncbi.nlm.nih.gov]

• Leukopenia

  The diagnosis of cyclic neutropenia is straightforward if leukopenia is present when the patient is symptomatic. [ncbi.nlm.nih.gov]

  Agranulocytosis, granulocytopenia and leukopenia are often used synonymously with neutropenia but in fact have slightly different meanings. [clinicaladvisor.com]

  A patient afflicted with severe leukopenia is susceptible to infections and periodontal disease. These potential problems can become severe when related to dental treatment. [elsevier.es]

• Neutrophil Count Decreased

  Cyclic neutropenia (CyN) is a rare hematological condition with neutrophil counts decreasing to <0.2 x 109/L, usually at 21 day intervals, accompanied by fever, mouth ulcers and the risk of severe sepsis during the neutropenic periods. [ashpublications.org]

• Candida

  The authors report the case of an 8-month-old Omani female infant with cyclic neutropenia presenting as severe fungal (Candida) invasive laryngitis, needing life-saving tracheostomy and i.v. antifungal treatment. [ncbi.nlm.nih.gov]

  Staphylococcus aureus, Staphylococcus epidermidis, streptococci, enterococci, Pseudomonas aeruginosa, Candida, Aspergillus 등에 의해 감염된다. 3. [hema-research.or.kr]

  Colonies of Candida albicans was grown on Sabouraud Agar plate [Figure 5]. One of the routine investigations showed child has neutropenia and so was referred to hematology department. [ijabmr.org]

  Candida albicans infections may also occur. Mixed flora may be found in the oral cavity. Viral infections often lead to mild or moderate neutropenia. Agranulocytosis is uncommon but may occur. [emedicine.medscape.com]

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.

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.

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.

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.

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.

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.

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.

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.

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