Progress in diagnosis and treatment of cyclic neutropenia / 国际儿科学杂志

Cyclic neutropenia (CN) is a kind of hereditary disease with periodic onset of neutrophil reduction and recurrent infection,which can be sporadic or familial.CN was firstly reported in 1910,and it was not until 1999 that the cause of the CN was further identified by investigators.Because the incidence of CN is low,the disease is rarely reported in China.CN is caused by mutations in the gene for neutrophil elastase (ELA-2 or ELANE),and it is a rare,inherited autosomal dominant disorder.Diagnosis of CN is based on the medical history and blood cycle characteristics.With the continuous development of medical technology,gene testing has certain significance for the diagnosis of CN.For the treatment,the most important is infection prevention,symptomatic treatment,the use of granulocyte colony-stimulating factor,and so forth.Although CN is a hematological disease,most cases have good prognosis,and will not result in malignant hematological diseases such as leukemia.At present,the doctors' awareness of CN has been lacking,which leads to misdiagnosis.The symptom and sign are not specific at the onset of CN,thus there is often misdiagnosis.In order to deepen the understanding of this disease and improve the skills of diagnosis and treatment,this review summarizes the pathogenesis,clinical manifestation,clinical characteristics,diagnosis and treatment of CN.

Neutropenia cíclica. Reporte de un caso / Cyclic neutropenia. Clinical case report

La neutropenia cíclica ocurre debido a que los niveles de producción celular por parte de las células madre de la médula ósea fluctúan, es decir, cambian durante el ciclo; aunque el número es recurrentemente bajo, su función es normal. Fue descrita por primera vez por Leale en 1910, con carácter autosómico dominante. Se presenta aproximadamente cada 21 días con un rango de 14 a 36 días durando un total de 3 a 6. Durante el periodo en el que existen pocos neutrófilos circulantes, el paciente es susceptible a las infecciones. Dentro del cuadro clínico se presentan: susceptibilidad a infecciones, cuadros febriles, fatiga, úlceras orales, impétigo, aumento de ganglios linfáticos, periodontitis, estomatitis. Es importante manejar estomatológicamente a estos pacientes, previa interconsulta con médico tratante, prevenir cuadros infecciosos bajo un esquema profiláctico a base de amoxicilina 50 mg/kg peso o clindamicina 20 mg/kg peso, revisar biometría hemática reciente (máximo 10 días previos al tratamiento); en tratamientos de urgencia se manejará de forma conservadora el dolor e infección; uso de enjuagues con clorhexidina al 0.12% y solución Philadelphia en caso de ser necesario.

Cyclic neutropenia occurs due to the fluctuation of cellular production levels of bone marrow stem cells. This is to say, they change during the cycle, and although numbers are recurrently low, function is normal. Cyclic neutropenia was first described by Leale in 1910 with dominant autosomal character. It manifests approximately every 21 days, with range of 14 to 36 days, lasting 3-6 days per episode. During the time when there are few circulating neutrophils, the patient is susceptible to infections. The clinical picture of this process includes: susceptibility to infection, feverish conditions, oral ulcers, impetigo, increased lymph nodes, periodontitis and stomatitis. It is important to stomatologically handle these patients; after inter-consultation with treating physician, prevent infection in a prophylactic scheme based on amoxicillin 50 mg/per kg weight or clindamycin 20 mg/per kg weight, review recent blood count results (maximum ten days before treatment). In emergency treatments pain and infection will be handled conservatively, with use of 0.12% chlorhexidine mouthwashes and Philadelphia solution when necessary.

Adult-onset Cyclic Neutropenia Diagnosed in a Patient with Acute Arthritis

Cyclic neutropenia (CN) is a rare disorder characterized by repetitive episodes of neutropenia and is generally associated with fever, oral mucosal ulcers, and bacterial infections in the neutropenic episodes. It usually manifests initially in infancy or childhood as an autosomal dominant or sporadic condition; however, adult-onset CN may have an autoimmune etiology. Here, we report the first case of a 22-year old man with CN in Korea. 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. Further, laboratory examination for neutropenia, including neutrophil elastase gene sequencing, did not reveal any abnormality. His arthritis and periarthritis fluctuated during his course. Under the diagnosis of CN, he received regular G-CSF therapy with partial improvement.

Adult-onset Cyclic Neutropenia Diagnosed in a Patient with Acute Arthritis

Cyclic neutropenia (CN) is a rare disorder characterized by repetitive episodes of neutropenia and is generally associated with fever, oral mucosal ulcers, and bacterial infections in the neutropenic episodes. It usually manifests initially in infancy or childhood as an autosomal dominant or sporadic condition; however, adult-onset CN may have an autoimmune etiology. Here, we report the first case of a 22-year old man with CN in Korea. 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. Further, laboratory examination for neutropenia, including neutrophil elastase gene sequencing, did not reveal any abnormality. His arthritis and periarthritis fluctuated during his course. Under the diagnosis of CN, he received regular G-CSF therapy with partial improvement.

A Case of Cyclic Neutropenia Treated by Uzu-zai with Mengen, Unexpected Reaction / 日本東洋医学雑誌

A 51-year-old male with cyclic neutropenia, on whom we previously reported, was admitted to our hospital with severe abdominal pain and diarrhea four years and seven months after his last hospitalization. Since then, he has received Kampo treatment at our hospital every three weeks, with good clinical results. This time, he was at first treated with Kampo daikenchuto combined with bushikobeito, which had been effective during his last hospitalization, although this time the remedy had no effect. From the viewpoint of Japanese traditional (Kampo) medicine, it was considered that the patient had severe cold syndrome. He was given uzukeishito three times a day (at 10.00, 15.00 and 20.00 hours). The dose of uzu in uzukeishito was gradually increased. Daiuzusen, in which the dose of uzu (an aconite) was 1g or 2g, was also administered five times a day due to the patient's very severe abdominal pain. On the fourth day of uzukeishito administration, the patient felt very hot and still had severe abdominal pain, although this pain was different from the previous pain, thirty minutes after daiuzusen (with 2g dose of uzu) was administered. This reaction can better be explained as <I>mengen</I> rather than uzu poisoning. Very soon he had a good appetite, his abdominal pain was reduced and the cycle of neutropenia was normalized. The case suggests that in cases of very severe cold syndrome, frequent and high-dose administration of aconite component medicine can be effective.

A Case of Cyclic Neutropenia Treated by Uzu-zai with Mengen, Unexpected Reaction / 日本東洋医学雑誌

A 51-year-old male with cyclic neutropenia, on whom we previously reported, was admitted to our hospital with severe abdominal pain and diarrhea four years and seven months after his last hospitalization. Since then, he has received Kampo treatment at our hospital every three weeks, with good clinical results. This time, he was at first treated with Kampo daikenchuto combined with bushikobeito, which had been effective during his last hospitalization, although this time the remedy had no effect. From the viewpoint of Japanese traditional (Kampo) medicine, it was considered that the patient had severe cold syndrome. He was given uzukeishito three times a day (at 10.00, 15.00 and 20.00 hours). The dose of uzu in uzukeishito was gradually increased. Daiuzusen, in which the dose of uzu (an aconite) was 1g or 2g, was also administered five times a day due to the patient's very severe abdominal pain. On the fourth day of uzukeishito administration, the patient felt very hot and still had severe abdominal pain, although this pain was different from the previous pain, thirty minutes after daiuzusen (with 2g dose of uzu) was administered. This reaction can better be explained as <i>mengen</i> rather than uzu poisoning. Very soon he had a good appetite, his abdominal pain was reduced and the cycle of neutropenia was normalized. The case suggests that in cases of very severe cold syndrome, frequent and high-dose administration of aconite component medicine can be effective.

A Case of Cyclic Neutropenia Satisfactorily Treated with Kampo Medicine / 日本東洋医学雑誌

A 44-year-old male with cyclic neutropenia who had suffered from repeated general fatigue and severe abdominal pain over twenty-six years was admitted to our hospital. Various active treatments such as steroid, granulocyte colony-stimulating factor and immunosuppressive regimen had been attempted, but a lasting cure could not obtained. In addition, the cycle of neutropenia had gradually been disturbed and abdominal pain occurred even at the period of normal neutrocyte. The patient fell into severe asthenia and cold syndrome judging from Japanese traditional Kampo medicine. Tsumyaku-shigyaku-to and Dai-kenchu-to combined with Busi-koubei-to were administered alternately, and then abdominal pain was reduced, accompanied by improvement of his cold and strengthening of his constitution. Furthermore, several Kampo formulas such as modifications of Chu-kenchu-to were administered on the basis of abdominal symptom and the cycle of neutropenia was regularized. This suggests that the genus Kenchu-to may be an effective treatment for cyclic neutropenia.

Serum Level of G-CSF and GM-CSF and CFU-GM Response to Hematopoietic Growth Factors in a Patient with Cyclic Neutropenia

PURPOSE: Serum levels of G-CSF and GM-CSF were measured and CFU-GM assay using G- CSF, GM-CSF and SCF was conducted to evaluate the influence of hematopoietic growth factor on the precursor cells of cyclic neutropenia. METHODS: A 7-year-old male with cyclic neutropenia was studied. Marrow mononuclear cells were isolated at neutrophil nadir and recovery and cultured in methylcellulose media with or without G-CSF, GM- CSF and SCF. CD34 positive cells were evaluated using flow cytometry. Serum levels of G-CSF and GM-CSF were measured by ELISA. RESULTS: The Numbers of CFU-GM without growth factors were 50 at neutrophil nadir and 33 at the recovery phase in the patient and show increased colony forming capacity. CD34 positive cells were 9.32% at nadir and 14.17% at recovery. Increasement of CFU-GM with G-CSF at nadir and recovery were 46% and 118% and those with GM-CSF were 70% and 78% respectively, compared with 54.4% and 78.2% in control groups. In contrast, the presence of SCF did not enhance CFU-GM number in the patient, but in the control group, increasement with SCF was 28.9 %. There an was inverse relationship between serum G-CSF levels and peripheral neutrophil count whereas those of GM-CSF were constant. CONCLUSION: Serum G-CSF level showed inverse relationship with neutrophil counts. The response of progenitor cells to G-CSF and GM-CSF was not impaired. The presence of SCF did not enhance CFU-GM number in the patient. This result suggests that the abnormality in hematopoiesis in cyclic neutropenia may involve more immature progenitor cells responsive to SCF.

A Case of Cyclic Hematopoiesis / 대한혈액학회지

Classical cyclic neutropenia is the most frequent of the cyclic hematopoietic disorders and a rare condition characterized by regular and predictable oscillations in the peripheral neutophil counts with the cycle length varying from 14 to 28 days and in many cases simultaneous fluctuation in the other blood cell line. The etiology of cyclic neutropenia is unknown, but has usually been considered as stem-cell disorder. We have observed a 17-year-old boy with a cyclic pancytopenia with a constant and predictable oscillation period of about 120 days. Serial bone marrow biopsies showed a similar fluctuating pattern and myelodysplatic change. We report this case and review the literature regarding this unusal long period cyclic neutropenia.

A case of cyclic neutropenia

Cyclic Neutropenia is a benign, unusual hematologic disorder characterized by regularly recurring episodes of severe neutropenia occurring approximately every 21 days. Beside neutrophils, monocytes, lymphocytes, platelets and reticulocytes all cycle with strict periodicity suggest that this disease should be viewed as cyclic hematopoiesis, not merely as cyclic neutropenia. During neutropenic periods, patients regularly experience aphthous stomatitis, fever, malaise, cervical lymphadenitis, cutaneous infections and occasional pneumonia and otitis media. The exact cause of cyclic neutropenia is unknown. But it is strongly suggested that cyclic neurtopenia is due to an abnormality in the regulation of early hematopoietic precursor cells. We have documented a case of cyclic neutropenia for a period of 2.5 years in a 11 year-old boy who had suffered from recurrent fever, stomatitis, gingival swelling, cervical lymphadenitis and skin infections at 3 weeks intervals since 5 years of age. A brief review of the related literatures is presented.