Cyclic neutropenia

First described in 1910,[2][3] it was suggested and confirmed to have an autosomal dominant (AD) inheritance in the 1940s and 1960s,[4] but was differentiated from congenital neutropenias until the 1990s when were analyzed pedigrees and identified genetic mutations shared by patients with severe congenital neutropenia.[5]

Cyclic neutropenia (CyN), like severe congenital neutropenia (SCN), is a rare disorder. It is considered that in the general population, CyN has a frequency of one in one million.[1] It sporadically occurs as a de novo mutation variant and/or can be present among members of the same family.[1] It is the result of autosomal dominant mutation in ELANE located on the short 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 were also located in intron 3, and exon 2 and 3.[10][11][12][13][14] The mutation causes a decrease in the "neutrophil production or excessive apoptosis (shorter half-life)" which results in a deficiency of mature neutrophils in the blood.[5]

Some mutation variants have been found in both Cyn and SCN, which indicates they are disease phenotypes with different severity.[11] The expression of the ELANE gene has been linked to GFI1 gene,[10][15] and it is considered that interaction with other genes causes the emergence and severity of one or the other phenotypic disorder.[11] It is not clear what causes that the levels of secretory leucocyte protease inhibitor (SLPI), which influences the induction of the unfolded protein response (UPR), are not diminished and as such activation of UPR is absent in CyN.[16] It is also unclear what causes the cyclic aspect in CyN.[15] According to Donadieu et al. (2011), the "cyclic aspect ... suggests the existence of a cryptic biological clock that regulates granulopoiesis. This putative clock might be revealed by particular mutations".[5]

The common symptoms of neutropenia are recurrent fever, malaise, inflammation of the tissues surrounding the teeth, mouth ulcers, inflammation and bacterial infection of the respiratory tract, digestive tract, skin, and abdominal pain.[1][3] It is considered that the greatest risk for death is from developing necrotizing enterocolitis (NEC), peritonitis, bacteremia or Clostridium and Escherichia coli sepsis and septic shock, and pneumonia.[1][9][17]

A diagnosis is usually confirmed by monitoring absolute neutrophil (ANC) count three times per week for at least six weeks.[1][9] The confirmation can be assisted with Lomb periodogram.[18] During the condition, which lasts for three to six days and tends to occur approximately every three weeks (but can range from 14 to 36 days),[3][9] the absolute neutrophil count (ANC) is less than 200-500 cells/microL (<0.2-0.5x10⁹/L), with increase of monocyte counts, and mild oscillations of other cells, including a mild anemia.[1][2] Between cycles the neutrophil count mostly peaks at subnormal or normal values.[15]

It is advised genetic testing for mutations in the ELANE and other neutropenia related genes (like HAX1, G6PC3, GFI1 etc.) to differentiate it from other secondary causes or forms of neutropenia.[1][19] In some cases, intervals and oscillations can be lower and as such it is difficult to determine with ANC analysis if the individual has severe congenital or cyclic neutropenia,[1] but as they can have the same mutation variants in ELANE it is preferable to have both ANC and genetic analysis.[2][18]

Although individuals between cycles are generally healthy and symptoms tend to improve in adulthood, it is advised avoiding activities prone to injuries, to have regular oral and dental care,[3] and BCG vaccine to be avoided.[1][5] It is advised monitoring white blood cells on some regular basis. The treatment following the symptoms should be immediate to prevent infections, especially during a fever when it requires broad-spectrum antibiotic therapy (see febrile neutropenia). The most important and often life-saving treatment is the preventative therapy of granulocyte colony-stimulating factor (G-CSF), in the form of filgrastim, which regulates the production of neutrophils within the bone marrow, but shortens the neutropenic cycle and the duration of the severe condition.[1][15] The subcutaneous injections can be given daily or once every several days, intermittently or timed possibly while monitoring ANC.[5][20] It is considered to be "safe and effective", with no significant adverse effects,[21] besides a possibility of development of osteopenia.[2] The granulocyte-macrophage colony-stimulating factor (GM-CSF) is less effective with more adverse effects. Another alternative is hematopoietic stem cell transplantation (HSCT), but is usually practiced in SCN.[1]

There is a very high risk of life-threatening infections and death at an early age.[5] The quality of life and survival greatly improves with G-CSF treatment, which is practiced since the late 1980s.[2] Unlike severe congenital neutropenia, individuals with cyclic neutropenia have a better response to G-CSF and do not have a risk of developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).[1][9] However, in long-term observation of over 300 patients with CyN, there has been one case of developing chronic myelogenous leukemia (CML) and one of AML,[2][21] indicating it is also a pre-leukemic condition, but the risk is "very low",[22] and the risk is "correlated with disease severity rather than with occurrence of an ELANE mutation".[12] According to Donadieu et al. (2011), "the cumulative risk of experiencing at least one serious (potentially life-threatening) infection by age 20 years is similar in patients with permanent and cyclic neutropenia, although the former patients tend to have earlier manifestations".[5]

• Leukopenia
• Agranulocytosis

• Severe Chronic Neutropenia International Registry
• "Understanding Neutropenia: The 20 Year Experience of the Severe Chronic Neutropenia International Registry (SCNIR)" (2014)
• "Designing Scientific Algorithm-based Dashboards: A Case Study of Cyclic Neutropenia and the Lomb-Scargle Algorithm" (2015) video presentation by Dr. David Dale and Nic Dobbins