Cyclic Neutropenia, Congenital and Idiopathic Neutropenia

Background: Cyclic neutropenia (CyN) is an autosomal dominant disease usually attributable to mutations in the gene for neutrophil elastase, ELANE . The diagnosis depends upon serial blood counts (at the minimum every other day or three days a week for 6 weeks) showing periods of severe neutropenia (absolute neutrophil count [ANC] < 0.2 x 10⁹/L) recurring at approximately 21 day intervals. The diagnosis can be confirmed by Lomb periodogram analysis. Genetic testing is helpful but not diagnostic because of the overlap of the mutational patterns in ELANE for CyN and severe congenital neutropenia (SCN).

Methods: We reviewed clinical and laboratory data for 87 patients enrolled in the Severe Chronic Neutropenia International Registry (SCNIR) with a diagnosis of CyN in 41 kindreds. Their family histories indicated that there were 117 other neutropenic family members. For this review we focused on 53 CyN patients in 15 kindreds who met the following criteria: two or more patients within the kindred had 10 or more CBCs available for analysis. Using data collected before treatment with G-CSF by the patients' primary physicians, we examined graphically displayed serial ANC's for each affected family member and performed periodogram analysis. We compared patterns of ANC fluctuations within families and for patients of similar ages within these families.

Findings and implications:

• Within families, if 1 patient has a mutation in ELANE, all other neutropenic members will have the same mutation in ELANE.

• Within families if the index case has typical and diagnostic oscillations in blood neutrophils, other affected family members often have neutropenia without clear or diagnostic oscillations in their counts. If the patient has a mutation in ELANE, the diagnosis of SCN is sometimes assigned.

• In familial CyN the oscillations tend to dampen with lower peaks and somewhat less severe neutropenia in older adults (> 30 years of age). Unless these patients have genetic testing showing a mutation in ELANE or another gene associated with neutropenia, they may be given the diagnosis of chronic idiopathic neutropenia.

• The Lomb periodogram is very useful for diagnosing CyN. It is a web-based tool readily accessible on the SCNIR web site, https://depts.washington.edu/registry/. However, it is necessary to collect sufficient number of counts (usually at least 20 counts spaced at regular intervals) to use this method to make the diagnosis of CyN. Although visually there was cycling in at least one member of the 15 families, only 5 families had a member who had CyN with a 95 or 99 percent confidence level based on the Lomb periodogram.

Conclusions:

Careful family history and serial measurements of ANCs are the foundations for the diagnosis of CyN. Genetic sequencing and identification of specific mutations in ELANE are helpful for prognosis. The Lomb periodogram is helpful, but requires a robust series of counts to assure that cycling is present with a high (95%) confidence level.