Cyclic neutropenia

INTRODUCTION — Cyclic neutropenia is a rare syndrome of recurrent neutropenia (typically every three weeks) and associated symptoms, including fever, malaise, mucosal ulcerations, and occasional abdominal discomfort; affected individuals are generally well between episodes. Cyclic neutropenia is associated with pathogenic variants (ie, mutations) of ELANE, the gene that encodes neutrophil elastase; pathologic variants of ELANE are also seen in most cases of severe congenital neutropenia (SCN). Previously, some patients with cyclic neutropenia and SCN were labeled as having Kostmann syndrome.

This topic reviews the pathogenesis, clinical manifestations, diagnosis, differential diagnosis, and treatment of cyclic neutropenia.

The evaluation of neutropenia in adults, neutropenic disorders in children, and other causes of congenital neutropenia are discussed separately. (See "Approach to the adult with unexplained neutropenia" and "Overview of neutropenia in children and adolescents" and "Congenital neutropenia".)

EPIDEMIOLOGY — Cyclic neutropenia is rare, with an estimated frequency of one case per million in the general population [1,2]. It is most commonly detected in children, but some affected individuals are first recognized in adulthood. It is equally common in males and females. Together with a related disorder, severe congenital neutropenia, these conditions are the most common cause of neutropenia in children. (See "Congenital neutropenia".)

PATHOGENESIS — Patients with cyclic neutropenia have a pathogenic variant (ie, mutation) of ELANE, the gene that encodes neutrophil elastase. Oscillating blood counts are caused by accelerated apoptosis of neutrophil precursors.

Cyclic neutropenia is associated with pathogenic variants that may occur throughout the ELANE genetic locus (on chromosome 19p13.3), but there is no strict correlation between genotype and phenotype [1,3-5]. Many of the variants coincide with those associated with severe congenital neutropenia; the different phenotypes of these conditions suggest that other genetic features may influence the clinical manifestations [6].

The mechanism by which pathogenic variants of ELANE cause an oscillating pattern of neutropenia is not fully explained. Expression of neutrophil elastase is an early feature of granulocytic maturation and this proteolytic enzyme is packaged within primary granules of neutrophils [7]. Aberrant neutrophil elastase is thought to accelerate apoptosis of maturing neutrophil precursors due to insufficient inhibition or abnormal packaging. This results in cycling between apoptosis of early myeloid precursors (due to endoplasmic reticulum stress) and the compensatory response to neutropenia-induced granulocyte colony-stimulating factor (G-CSF) [8]. These observations are consistent with mathematical models of hematopoiesis that predicted that oscillations in peripheral neutrophil counts would result from an aberrant feedback loop of G-CSF regulation of neutrophil production [9].

CLINICAL MANIFESTATIONS

Periodicity — The hallmark of the clinical presentation is recurrent neutropenia (typically every three weeks) with associated symptoms [10]. The average periodicity is 21 days and is usually consistent for an individual; however, cycle length can range from 14 to 35 days in different patients. Likewise, the duration of symptoms is typically consistent for an individual (generally days to one week) but may vary between patients.

The severity of clinical manifestations often reflects the degree of neutropenia. By definition, the nadir of the absolute neutrophil count (ANC) (calculator 1) is <200 neutrophils/microL (0.2 x 10⁹ cells/L). Symptoms tend to lag behind the neutropenia, so that neutrophil counts are usually about to recover when the individual starts to feel ill. Patients may report an increased sense of well-being as the neutrophil count recovers to >500/microL [11].

Recurrent fever and inflammation — Symptoms of fever, malaise, oral ulcers, and mild sore throat every three weeks is the usual presentation of cyclic neutropenia. More than 60 percent of patients have inflammation of skin and oropharynx, cervical lymphadenopathy, fever, and fatigue more than five times a year [12]. Paranasal sinuses, upper- and lower-respiratory tracts, and the perianal region may also be affected. Cellulitis (eg, of the perianal region) may occur during periods of neutropenia, but bacteremia is unusual. Affected individuals generally feel well between symptomatic episodes.

In one study, >60 percent of patients with cyclic neutropenia experienced ≥5 episodes per year of oral ulcers, gingivitis, lymphadenopathy, fever, pharyngitis, tonsillitis, fatigue, or skin infections [12]. One-third of adults reported ≥5 episodes per year of sinusitis and/or otitis media, >20 percent of children reported ≥5 episodes per year of bone pain or dental abscesses, and >10 percent of individuals reported pneumonia, bronchitis, diarrhea, or anal ulcers.

Age-associated changes — Clinical manifestations of cyclic neutropenia may change over time [12]. Individuals usually present in the first year of life, but some affected individuals are first recognized in adulthood. Most affected individuals survive to adulthood and the clinical manifestations are often milder after puberty [9,12]. Parents or caregivers may state that the affected child does not appear well for two or three days of the cycle, whether or not there is documented fever. Serious neonatal infections and sepsis are rare. In adolescents and young adults, chronic gingivitis, dental abscesses, and alveolar bone loss are common. In adults, symptoms most often relate to sinusitis, headache, and bone pain; there are fewer skin infections, fever, lymphadenopathy, and pharyngitis.

Severe complications — Patients with cyclic neutropenia are generally not at the same high risk for life-threatening infection as patients treated with chemotherapy, because of a shorter duration of neutropenia, lymphocyte-mediated immunity is not impaired, and they have active monocytosis during bouts of neutropenia.

The greatest risk of death in patients with cyclic neutropenia is from necrotizing enterocolitis, peritonitis, or sepsis involving Escherichia coli or Clostridioides (formerly Clostridium) species [13]. In a review of children with Clostridioides sepsis, cyclic neutropenia accounted in 30 percent of cases that were not caused by trauma; neutropenia due to chemotherapy accounted most of the other cases [14].

Cyclic neutropenia is not associated with malignant transformation to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), except for rare reported cases [15,16]. This differs from the related disorder, severe congenital neutropenia, in which the considerable risk of MDS and AML increases over time [17,18]. (See "Congenital neutropenia", section on 'Severe congenital neutropenia'.)

EVALUATION — Evaluation includes history, physical examination, and laboratory studies to establish the diagnosis and distinguish cyclic neutropenia from other causes of neutropenia in children and adults. (See 'Differential diagnosis' below.)

Clinical evaluation — History should document the occurrence of fever, inflammation of skin and oropharynx, respiratory tract complaints, sinus pain, cervical lymphadenopathy, perianal discomfort, and other infectious or inflammatory symptoms. A pattern of periodicity (eg, typically three weeks) should be noted; affected individuals are generally healthy between symptomatic periods. Family history should explore affected family members, though their clinical manifestations may vary in nature, severity, and periodicity. (See 'Family members' below.)

Examination of the oral mucosa may reveal gingival ulcers, inflammation, edema, and gum recession associated with recurrent infection and inflammation. Alveolar bone support may be lost in the preschool-age child, resulting in premature tooth mobility and loss (picture 1). (See "Periodontal disease in children: Associated systemic conditions", section on 'Cyclic neutropenia'.)

There may be perirectal tenderness, ulceration, or abscess formation. The presence of abdominal discomfort, pain, or tenderness, especially during the neutropenic phase of the cycle, is an emergency that may reflect necrotizing enterocolitis, peritonitis, and other abdominal crises and requires urgent evaluation and management. (See "Neonatal necrotizing enterocolitis: Clinical features and diagnosis".)

For patients with fever and neutropenia, urgent empiric broad-spectrum antibiotic coverage should be initiated immediately, even while pursuing the cause of neutropenia and the source of the fever. (See "Overview of neutropenic fever syndromes", section on 'Management'.)

Laboratory — Laboratory studies should evaluate the presence of neutropenia and determine if there is periodicity to the level of neutrophils. Detection of a pathologic variant of ELANE is needed to establish the diagnosis in a proband, but bone marrow examination is not required.

Complete blood count (CBC) — Serial CBCs with differential are required to document the absolute neutrophil count (ANC) (calculator 1) and its periodicity. Typically, the cycles in neutrophil count are approximately three weeks, but they may range from 14 to 35 days [10]. Documentation of the severity and periodicity of neutropenia in cyclic neutropenia usually requires performing a CBC two to three times per week for six to eight weeks; less frequent monitoring may miss the nadir of neutropenia [10,12,19].

By definition, the ANC nadir in cyclic neutropenia is <200/microL, but counts may return to normal between periods of neutropenia. The normal white blood cell (WBC) count in adults is 4400 to 11,000 cells/microL (4.4 to 11 x 10⁹ cells/L) and a normal ANC is ≥1500/microL. Normal values for WBC and ANC in children vary by age (table 1). Counts in children tend to oscillate more obviously than in adults. Reciprocal increases in reticulocytes, monocytes, lymphocytes, eosinophils, and/or platelets may be observed during the neutrophil nadir [2].

Bone marrow/blood smear — Bone marrow examination is not required for the diagnosis of cyclic neutropenia, but it may be performed to exclude other conditions in the differential diagnosis. (See 'Differential diagnosis' below.)

●Peripheral blood smear – The peripheral blood smear reveals variable degrees of neutropenia that varies through the cycle but no aberrant myeloid morphology. There is consistent monocytosis during neutrophil nadirs, and there may be increases in reticulocytes or platelets at times of neutropenia.

●Bone marrow examination – Bone marrow cellularity may vary during the cycle, but it does not become aplastic. At times the maturation of myeloid cells appears normal, while at other times there is maturation arrest at the promyelocyte or myelocyte stage [20-22]. During all phases of the cycle, cellular blebbing and nuclear condensation characteristic of apoptosis may be present; increased numbers of annexin V-labeled myeloid precursors are seen by flow cytometry, indicating lineage-specific apoptotic death. The percentage of monocytes or eosinophils in the bone marrow may vary during the cycle. There is no infiltration by blasts, other aberrant cells, or fibrosis. Cytogenetic analysis is normal.

Molecular testing — Detection of a pathogenic variant (ie, mutation) in ELANE is required to establish the diagnosis of cyclic neutropenia in a proband and may be used to evaluate family members. (See 'Diagnosis' below.)

Pathogenic variants of ELANE can be detected with a myeloid gene panel, single gene sequencing, or next-generation sequencing (NGS). We generally suggest sending a gene panel rather than single-gene testing, since other genetic disorders can be associated with variable or cycling neutrophil counts. (See "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Detecting known mutations' and "Next-generation DNA sequencing (NGS): Principles and clinical applications", section on 'Clinical use of next-generation sequencing'.)

Other conditions that may be associated with variable levels of neutropenia are described below. (See 'Differential diagnosis' below.)

DIAGNOSIS — Cyclic neutropenia should be suspected in an infant, child, or adult in whom recurrent fever, oral ulcers, malaise, lymphadenopathy, or other clinical findings are associated with unexplained neutropenia at intervals of approximately three weeks. Distinguishing cyclic neutropenia from other conditions in the differential diagnosis is described below. (See 'Differential diagnosis' below.)

The diagnosis of cyclic neutropenia is established in a proband by identification of a heterozygous pathogenic variant of ELANE in an appropriate clinical setting. Clinically, cyclic neutropenia is typically manifest as two to three days of neutropenia (absolute neutrophil count [ANC] (calculator 1) <200/microL), fever, mucosal ulceration, malaise, or other infectious/inflammatory findings that recur approximately every three weeks. The affected individual is generally well between bouts.

A suggested protocol for serial complete blood counts (CBC) and methods for detecting pathogenic variants of ELANE are described above. Bone marrow examination is not needed for establishing the diagnosis. (See 'Complete blood count (CBC)' above and 'Molecular testing' above.)

Diagnosis in a relative of an individual with documented cyclic neutropenia is described below. (See 'Family members' below.)

DIFFERENTIAL DIAGNOSIS — Cyclic neutropenia must be distinguished from other causes of neutropenia and/or fever in children and adults. Cyclic neutropenia is distinguished from other conditions by its periodicity, resolution of symptoms between bouts, and absence of syndromic features (eg, short stature, dysmorphic features, chronic diarrhea, hepatosplenomegaly). The approach to evaluation of neutropenia in adults and children are discussed separately. (See "Approach to the adult with unexplained neutropenia" and "Overview of neutropenia in children and adolescents".)

Severe congenital neutropenia (SCN) — SCN typically presents within the first year of life with neutropenia and diarrhea, pneumonia, and/or abscesses in the lungs, liver, and subcutaneous tissues. Compared with cyclic neutropenia, the clinical findings and neutropenia of SCN are generally more severe and sustained (ie, not episodic). The distinction between SCN and cyclic neutropenia is primarily based on clinical findings and only secondarily on genotype [23,24]. Pathogenic variants of ELANE are associated with both disorders but, unlike cyclic neutropenia, pathogenic variants of >20 other genes have been linked to SCN; although certain variants are more common with one or the other condition, there is overlap and the specific variant is not sufficient to distinguish between these syndromes. Patients with SCN have an increased risk of developing myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML); those malignancies are not associated with cyclic neutropenia. (See "Congenital neutropenia", section on 'Severe congenital neutropenia'.)

Other congenital neutropenia syndromes — Other inherited neutropenia syndromes include Shwachman-Diamond syndrome, WHIM syndrome (ie, warts, hypogammaglobulinemia, infections, myelokathexis), GATA2 deficiency/MonoMAC syndrome, primary immunodeficiency syndromes, and others. Some of these disorders are associated with syndromic findings (eg, short stature; skeletal abnormalities; cutaneous, hair, or nail abnormalities), other hematologic abnormalities, and/or increased risk for MDS or AML. They generally present in childhood, but some syndromes may first be recognized in adults. The phenotype and genetic features of these disorders are discussed separately. (See "Congenital neutropenia", section on 'Other inherited neutropenia syndromes'.)

Large granular lymphocyte (LGL) leukemia — LGL leukemia and related lymphoproliferative disorders typically present with chronic mild to moderate neutropenia, recurrent infections, and are most often encountered in the setting of rheumatoid arthritis. In some cases, fluctuating levels of neutrophils in LGL disorders may resemble the pattern in cyclic neutropenia, but they lack the regular periodicity. Patients generally manifest lymphocytosis with LGLs on the blood smear and infiltrating the bone marrow. These disorders are distinguished by the characteristic morphology and immunophenotype of LGLs and clonality demonstrated by T cell receptor (TCR) rearrangements. (See "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia", section on 'Pathologic features'.)

Periodic fever syndromes — Periodic fever syndromes (eg, periodic fever, aphthous stomatitis, pharyngitis, and adenitis [PFAPA], familial Mediterranean fever, tumor necrosis factor [TNF] receptor-1 associated periodic syndrome, hyper-immunoglobulin D [IgD] syndrome) typically present with fever, serositis, arthritis, rash, and other inflammatory findings, but they are not associated with neutropenia. Clinical manifestations and diagnosis of these conditions are described separately. (See "Periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA syndrome)" and "The autoinflammatory diseases: An overview", section on 'Hallmarks of the autoinflammatory diseases'.)

Constitutional neutropenia — Some individuals have an absolute neutrophil count (ANC) (calculator 1) <1500/microL without recurrent or severe infections, other cytopenias, or associated illnesses. This condition may be described as constitutional neutropenia and is most often encountered in individuals of African descent, Sephardic Jews, West Indians, Yemenites, Greeks, and Arabs; it was formerly called “benign ethnic neutropenia”. Associated inherited polymorphisms associated with constitutional neutropenia are described separately. (See "Approach to the adult with unexplained neutropenia", section on 'Normal variants <1500/microL'.)

Other causes of neutropenia — Numerous infectious, autoimmune, inflammatory, nutritional, toxic, and malignant disorders may cause neutropenia in children and adults. The evaluation of neutropenia in adults and children, characteristic features of these conditions, and their distinction from cyclic neutropenia are discussed separately. (See "Approach to the adult with unexplained neutropenia" and "Overview of neutropenia in children and adolescents".)

MANAGEMENT

Febrile neutropenia — Unexplained fever in a neutropenic patient requires prompt evaluation and empiric treatment until the source of fever can be identified. The presence of abdominal pain, tenderness, or vomiting associated with neutropenia raises the possibility of neutropenic ileocolitis or peritonitis from a perforated gastrointestinal ulcer and requires urgent evaluation and management. An overview of neutropenic syndromes and necrotizing enterocolitis are discussed separately. (See "Overview of neutropenic fever syndromes" and "Neonatal necrotizing enterocolitis: Clinical features and diagnosis".)

Patients with hypotension, tachycardia, tachypnea, hypoxia, or other findings that suggest a life-threatening infection require prompt initiation of empiric broad-spectrum antibiotics. Antibiotic coverage should match local patterns for infections in immunosuppressed individuals and should cover both aerobic and anaerobic organisms, including Clostridioides species [10,12]. Granulocyte colony-stimulating factor (G-CSF) should be given subcutaneously daily to promote increased neutrophil production and deployment. (See "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications" and "Management of children with non-chemotherapy-induced neutropenia and fever".)

Patients who are clinically stable can generally be managed as outpatients, and routine hospitalization for episodes of febrile neutropenia is usually not required. (See "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications" and "Management of children with non-chemotherapy-induced neutropenia and fever".)

G-CSF — G-CSF (filgrastim or pegfilgrastim) is safe and well-tolerated in individuals with cyclic neutropenia and is effective for elevating the neutrophil count, shortening the period of neutropenia, ameliorating symptoms, and reducing infectious complications. Successful treatment generally enables participation in school, work, and recreational activities without specific concerns.

Dose and schedule — For patients with cyclic neutropenia, we recommend treatment with G-CSF rather than observation alone, based on superior outcomes and modest toxicity. We generally treat with a continuous schedule of treatment, rather than episodic treatment (ie, attempting to synchronize with neutropenic cycles).

Treatment of cyclic neutropenia generally requires daily or thrice-weekly (eg, Monday, Wednesday, Friday) subcutaneous injections of filgrastim, starting at 2 to 3 mcg/kg/day [25]. Note that this dose is generally lower than that used for severe congenital neutropenia or chemotherapy-associated neutropenia, and it may require adjustment based on response to treatment. Trying to synchronize filgrastim treatment to coincide with the period of neutropenia is generally unsuccessful; G-CSF changes the periodicity of neutropenia and the patient will invariably get out of synch and end up being treated ineffectively.

The goal of treatment with G-CSF is to maintain the absolute neutrophil count (ANC) nadir ≥500/microL, which reduces the risk of severe infections and generally ameliorates gingivitis, mucosal ulceration, other infectious complications [18]. The dose may need to be adjusted to sustain that level of ANC throughout the cycle. Because levels of neutrophils fluctuate in cyclic neutropenia, ANC should be monitored periodically for several weeks after initiating G-CSF. Once an effective dose is established, we monitor the ANC every three to six months and do not alter the dose if the patient remains asymptomatic and the ANC is ≥500/microL. We find that monitoring the erythrocyte sedimentation rate (ESR) can be helpful; if the ESR is consistently normal, the average ANC has likely been adequate. Pegfilgrastim (a long-acting pegylated formulation of G-CSF) is also effective and convenient, but it is difficult to dose appropriately in children and often leads to more severe bone pain [26].

G-CSF is effective from as early as six months of age and treatment should continue lifelong, as needed. The dose can remain stable for years, even in growing children; as children grow, the dose of G-CSF should to be adjusted in accordance with symptoms and blood counts, rather than in response to body weight, per se. Neutrophil cycling may be replaced by a mild chronic neutropenia in the third decade of life; continued use of G-CSF may not be necessary unless the patient develops chronic gingivitis or other complications of neutropenia [12].

Although granulocyte-macrophage colony-stimulating factor (GM-CSF) has been administered for severe chronic neutropenia, it is less effective than G-CSF and associated with more adverse effects [27]. No studies have directly compared the efficacy and toxicity of G-CSF versus GM-CSF in this setting.

Adverse effects — The primary adverse reaction to G-CSF in children is musculoskeletal pain, but this is generally mild and typically lessens with repeated injections. Other adverse effects with ≥5 percent higher incidence in patients treated with filgrastim than with placebo are splenomegaly, anemia, epistaxis, diarrhea, hypoesthesia, and alopecia; although total infection-related events were similar, those treated with G-CSF had more upper respiratory tract and urinary tract infections [28]. All of these adverse effects are dose-related and generally mild with the doses used for cyclic neutropenia. Decreased bone density, vasculitis, rash, arthralgias, and glomerulonephritis have also been reported [29].

Outcomes — Treatment with G-CSF reduces infectious complications and increases neutrophil production in patients with chronic, severe neutropenia. Informative studies of G-CSF treatment for cyclic neutropenia and other causes of severe chronic neutropenia include:

●A prospective trial randomly assigned 120 patients (10 with cyclic neutropenia) with recurrent infections and diverse causes of severe chronic neutropenia (<500/microL) to immediate treatment with G-CSF versus a four-month period of observation prior to treatment with G-CSF [30]. Compared with observation, treatment with G-CSF reduced the incidence and duration of infection-related events by 50 percent and the duration of antibiotic use by 70 percent. G-CSF increased bone marrow production of neutrophils and increased median ANC to >1500/microL in 108 of 120 treated patients. G-CSF treatment was associated with generally mild bone pain, headache, and rash.

●Among 239 patients with cyclic neutropenia who were followed prospectively in the Severe Chronic Neutropenia International Registry (SCNIR), compared with no treatment, use of G-CSF reduced the probability of sepsis (hazard ratio [HR] 0.20; 95% CI 0.05-0.88) and was safe [18]. Prior to initiating G-CSF, patients had a consistent history of recurrent fevers, mouth ulcers, and infections, but this report did not provide comparative mortality data or the incidence of severe infections. There were no reported cases of acute myeloid leukemia (AML) after nearly 3000 patient-years of treatment with G-CSF. In other reports, G-CSF led to a 10- to 20-fold increase in mean ANC, prevented infections, and was safe in patients with cyclic neutropenia [18,29,31-34].

Supportive care — Supportive care is important to reduce the risk and severity of infections and other symptoms. Supportive care should include the following:

●Dental care – Regular and aggressive dental care and prophylaxis are important for decreasing gingivitis. Patients should be seen by dental professionals at intervals ≤6 months. Twice-daily oral rinsing with 15 mL chlorhexidine gluconate for 30 seconds after brushing and dental prophylaxis can help to decrease gingivitis.

●Bone density – Bone density should be monitored for development of osteoporosis during prolonged treatment with G-CSF, as osteoporosis is a possible side effect of this medication. Appropriate treatment should be provided, if this complication is present. We also recommend monitoring of 25-OH-vitamin D levels and appropriate supplementation to maintain adequate levels. (See "Screening for osteoporosis in postmenopausal women and men".)

●Infectious diseases – It is important to maintain age-appropriate schedules of immunizations. There is no need to avoid public places since most severe infections are associated with organisms in the intestinal biome. Common viral infections may be complicated by bacterial infections (eg, bacterial pneumonia caused by organisms in the respiratory tract may complicate a viral infection). (See "Standard immunizations for children and adolescents: Overview" and "Standard immunizations for nonpregnant adults".)

Prophylactic antibiotics are not recommended, as this may select for resistant organisms.

FOLLOW-UP — Patients with cyclic neutropenia should be evaluated clinically and have periodic blood counts to monitor the absolute neutrophil count (ANC) (calculator 1).

Monitoring the response to granulocyte colony-stimulating factor (G-CSF) is described above. Once an effective dose is established, we monitor the ANC every three to six months. Patients should be evaluated promptly in the event of fever or stomatitis, because this may reflect worsening neutropenia (eg, ANC <500/microL). (See 'G-CSF' above.)

It is not necessary to perform bone marrow examinations unless there is a change in the severity or pattern of cytopenias.

Good health practices (eg, immunizations, health screening) should continue according to expectations of age and sex. Supportive care (eg, oral hygiene) should continue, as described above. (See 'Supportive care' above.)

PREGNANCY AND PRECONCEPTION COUNSELING — Preconception counseling of patients with cyclic neutropenia is suggested and granulocyte colony-stimulating factor (G-CSF) should be continued during pregnancy.

Cyclic neutropenia is an autosomal dominant disorder. Women considering pregnancy should be counseled that there is a 50 percent chance that offspring will inherit the pathogenic variant and that manifestations in children may be either more or less severe than those in the proband. We do not counsel against pregnancy in women with cyclic neutropenia, but we indicate the availability of prenatal diagnostic testing for ELANE pathogenic variants. (See 'Family members' below.)

For women with cyclic neutropenia who become pregnant, we suggest continuing G-CSF rather than discontinuing it, based on its safety during pregnancy for mother and fetus and the potential to reduce infectious complications.

G-CSF can be administered during pregnancy without apparent adverse consequence, but no controlled studies of pregnant women with cyclic neutropenia have prospectively compared treatment with G-CSF versus no treatment. An observational study that included women with congenital, cyclic, idiopathic, or autoimmune neutropenia compared maternal and neonatal outcomes among 100 women who received G-CSF during pregnancy versus 124 women who did not receive G-CSF [35]. There were no differences between the groups with regard to spontaneous terminations, preterm labor, or other adverse events and no differences in gestational age, birth weight, or neutropenia for the neonates. Maternal minor infections (eg, cellulitis, mastitis, perirectal infection, pneumonia) occurred in both groups; each group had one severe infection (bacteremia, sepsis). G-CSF was administered in the first trimester of 82 of 100 pregnancies and was not associated with adverse events. Among the 44 women with cyclic neutropenia or severe congenital neutropenia, outcomes from the 183 pregnancies resulted in equivalent infant health between the treated and untreated women.

FAMILY MEMBERS — In most cases of cyclic neutropenia there are other affected family members, and the pattern of inheritance is autosomal dominant. However, family members may exhibit a spectrum of clinical manifestations, ranging from asymptomatic to recurrent life-threatening infections, which is more consistent with severe congenital neutropenia (SCN) [6,12]. (See "Congenital neutropenia", section on 'Severe congenital neutropenia'.)

Primary family members of probands should be evaluated for cyclic neutropenia and SCN, both of which are associated with pathogenic variants of ELANE. Affected family members may have a similar clinical presentation to the proband, or the neutropenia may differ in severity, cycle duration, degree of fluctuation, or associated clinical manifestations. We suggest evaluating parents, siblings, and children of the proband. Evaluation may include genetic testing for the documented ELANE pathologic variant and/or by serial blood counts, as described above. Testing of relatives can be performed by a hematologist, primary care provider, geneticist, or genetic counselor. (See 'Laboratory' above.)

Most patients diagnosed with cyclic neutropenia have an affected parent. In some cases, neither parent appears to be affected clinically or has the pathogenic variant of the proband. In such cases, possible explanations include a de novo pathogenic variant in the proband, alternate paternity or maternity (eg, with assisted reproduction), or germline mosaicism in a parent [6].

Affected relatives should be treated with G-CSF as described above. (See 'G-CSF' above.)

SUMMARY AND RECOMMENDATIONS

●Cyclic neutropenia is a rare syndrome in which the neutrophil count oscillates approximately every three weeks, paralleled by fever, skin and oral ulcerations, and/or cervical adenopathy; affected individuals are generally healthy between episodes.

●Cyclic neutropenia is associated with pathogenic variants (ie, mutation) of ELANE, the gene that encodes neutrophil elastase, but the mechanism by which they cause a cyclic pattern of neutropenia is incompletely understood. (See 'Pathogenesis' above.)

●The hallmark of the clinical presentation is a predictable pattern of recurrent neutropenia with associated symptoms that typically include recurrent fever, inflammation of skin and oropharynx, and cervical lymphadenopathy. The periodicity of findings is approximately three weeks, and affected individuals are generally well between episodes. Individuals usually present within the first year of life, and symptoms generally improve in adulthood. (See 'Clinical manifestations' above.)

●The history should evaluate fever, skin and oropharyngeal inflammation, cervical adenopathy, and other infectious or inflammatory findings; explore a pattern of periodicity; and determine if there are affected family members. Physical examination should include examination of the gingiva, oral mucosa, and perianal region. (See 'Clinical evaluation' above.)

●Serial complete blood counts (CBC) with differential (eg, twice or thrice per week for eight weeks) are needed to document the severity and periodicity of neutropenia. Molecular testing will identify pathogenic variants of ELANE. Bone marrow examination is not required to establish the diagnosis. (See 'Laboratory' above.)

●Cyclic neutropenia should be suspected in an infant, child, or adult in whom recurrent fever, oral ulcers, and/or lymphadenopathy parallel neutropenia at intervals of approximately three weeks.

The diagnosis is established by identification of a heterozygous pathogenic variant of ELANE in an appropriate clinical setting (eg, periodic fever, mucosal ulceration, lymphadenopathy with an approximately three-week periodicity) and documented absolute neutrophil count (ANC) (calculator 1) <200/microL. (See 'Diagnosis' above.)

●Cyclic neutropenia must be distinguished from other causes of severe neutropenia and/or fever in children and adults. Cyclic neutropenia is distinguished by its periodicity, resolution of symptoms between bouts, and absence of syndromic features. The differential diagnosis of cyclic neutropenia includes severe congenital neutropenia (SCN) and other inherited causes of neutropenia, syndromes of periodic fever, constitutional neutropenia, and various acquired causes for neutropenia (eg, infectious, autoimmune, inflammatory, nutritional, toxic, and malignant disorders) in children and adults. (See 'Differential diagnosis' above.)

●For patients with cyclic neutropenia, we recommend treatment with granulocyte colony-stimulating factor (G-CSF) rather than observation alone (Grade 1B), based on the reduction of serious infections and its modest toxicity. We generally treat with a continuous schedule of administration, rather than episodic treatment that attempts to synchronize with neutropenic cycles. The dose should be adjusted as needed to maintain the ANC nadir >500/microL and control associated symptoms. Treatment should continue lifelong, as needed. The primary adverse reaction is musculoskeletal pain, but this is generally mild and typically lessens with repeated injections. (See 'G-CSF' above.)

●Supportive care, including dental hygiene, immunizations, screening for bone density is important to reduce the risk and severity of infections and other complications of cyclic neutropenia and its treatment. (See 'Supportive care' above.)

●We suggest that pregnant women continue G-CSF therapy through the pregnancy rather than discontinuing G-CSF (Grade 2C), based on its safety during pregnancy for mother and fetus and the potential to reduce infectious complications.

Women considering pregnancy should be counseled about the autosomal dominant inheritance pattern.

ACKNOWLEDGMENT — We acknowledge the previous contributions of Laurence A Boxer, MD, who served as a Section Editor for this topic.