Cyclic neutropenia
Synonyms and keywords: Cyclic hematopoiesis

# Overview
Cyclic neutropenia is a condition in which the neutrophil count periodically and regularly rises and falls. It is rarely observed in humans, but has been observed in the Grey Collie dog.

# Historical Perspective
- Cyclic neutropenia first described in the year 1910 in an infant with recurrent fever.

# Classification
- There is no established system for the classification of cyclic neutropenia.

# Pathophysiology
- Normal neutrophilic counts is typically between 1500 to 8500 cells/l after the age of one year.
- Cyclic neutropenia is caused by heterozygous mutation in the ELA2 (ELANE) gene.
- The disease occurs in autosomal dominant mode of inheritance.
- The culprit gene is responsible for encoding the neutrophil granule serine protease, neutrophil elastase.
- Mutation results in abnormal gene product that damages cells while they mature, leading to to failure of cell production.
- Theoretically, this disorder can be cured by bone marrow transplantation. This demonstrates its pathogenesis] as the stem cell abnormality.
- This stem cell abnormality leads to the myelocyte maturation arrest during neutropenia episodes.

# Causes
- Cyclic neutropenia is caused by heterozygous mutation in the ELA2 (ELANE) gene.

# Differentiating Cyclic neutropenia from Other Diseases
- Cyclic neutropenia should be differentiated from other disorders manifesting with recurrent fever, aphthous stomatitis, and pharyngitis. These include PFAPA syndrome, monogenic autoinflammatory disorders such as FMF, CAPS, and TRAPS, as well as primary immunodeficiencies.
- Shwachman-Diamond syndrome may also present with neutropenia. However, its diagnosis requires some dysmorphic features which are not present in patients with cyclic neutropenia.
- For more information on cyclic neutropenia differential diagnosis please click here.

# Epidemiology and Demographics
- The incidence of cyclic neutropenia is 0.010-0.02 per 100,000 individuals worldwide.
- There is no racial predilection to cyclic neutropenia.
- Cyclic neutropenia affects men and women equally.

# Risk Factors
- There are no established risk factors for cyclic neutropenia.

# Screening
- There is insufficient evidence to recommend routine screening for cyclic neutropenia.

# Natural History, Complications, and Prognosis
- Disease manifests in early years of life with episodes of fever occurring every 21 days (range from 14 to 35 days).
- The hallmark of this disorder is the predictability of the fever episodes.
- Patients may be asymptomatic or develop life-threatening infections depending on the severity of neutropenia.
- During episodes, patients are neutropenic and it increases their risk for dental and gingival complications.
- Although patients with cyclic neutropenia are not as immunodeficient as the post-chemotherapy patients, they still should not be assumed normal.
- Serious complications of this disorder include pneumonia, mastoiditis, and bacterial cutaneous and subcutaneous infections.
- Death induced by infections are a possible complication of this disorder and has been reported in 10% of the patients.

# Diagnosis
- Diagnosis of cyclic neutropenia is based on the clinical picture and the exclusion of other possible causes of neutropenia.
- Absolute necrophiliac count (ANC) should be <200/microL, usually for at least two to three days, in each of two to three regularly spaced cycles.
- Genetic analysis may be done for the confirmation of the diagnosis. However, it usually turns positive for gene mutation in 90% of the patients.
- Bone marrow aspiration is not considered helpful for the diagnosis.

## Diagnostic Criteria
- There is no diagnostic criteria for the diagnosis of cyclic neutropenia.

## History and Symptoms
- Symptoms of cyclic neutropenia include fever, malaise, oral ulcers, gingival inflammation, edema, and sore throat.

## Physical Examination
- Physical examination of patients with cyclic neutropenia include fever, pharyngitis, and gingival inflammation and edema.

## Laboratory Findings
- Laboratory findings associated with the diagnosis of cyclic neutropenia include:
Low absolute neutrophilic count
Neutropenia may be mild or severe with a nadir of 100/L for 36 days in each cycle. However, the duration of neutropenia varies between the patients.
- Low absolute neutrophilic count
- Neutropenia may be mild or severe with a nadir of 100/L for 36 days in each cycle. However, the duration of neutropenia varies between the patients.

## Electrocardiogram
- There are no ECG findings associated with cyclic neutropenia.

## X-ray
- There are no x-ray findings associated with cyclic neutropenia.

## Echocardiography or Ultrasound
- There are no echocardiography/ultrasound findings associated with cyclic neutropenia.

## CT Scan
- There are no CT scan findings associated with cyclic neutropenia.

## MRI
- There are no MRI findings associated with cyclic neutropenia.

## Other Imaging Findings
- There are no other imaging findings associated with cyclic neutropenia.

## Other Diagnostic Studies
- There are no other diagnostic studies associated with cyclic neutropenia.

# Treatment

## Medical Therapy
- The mainstay of treatment for cyclic neutropenia is medical therapy.
- It is recommended that all patients receive Granulocyte colony-stimulating factor (G-CSF). However, the mainstay of treatment is supportive.
- G-CSF should be administered subcutaneously starting at 2 to 3 mcg/kg every one to two days.
- Patients with following features should receive G-CSF:
Patients with recurrent symptoms
Patients with evidence of gingival disease or severe infection
- Patients with recurrent symptoms
- Patients with evidence of gingival disease or severe infection
- Regular dental care is recommended.

## Surgery
- Surgical intervention is not recommended for the management of cyclic neutropenia.

## Primary Prevention
- There are no established measures for the primary prevention of cyclic neutropenia.

## Secondary Prevention
- There are no established measures for the secondary prevention of cyclic neutropenia.