Case Presentation: A 59-year-old woman with a history of recurrent hospital admissions over several years for neutropenic fever who presented for generalized body weakness and fever of 102F for one day. On presentation the patient had a temperature of 102.9F, HR 106, BP 128/96. Physical exam was notable for tender cervical lymphadenopathy and pharyngeal erythema. Laboratory tests were significant for leukopenia of 2.6 with 0% neutrophils, 0% bands, 72% lymphocytes, 26% myocytes, 0% eosinophils. Absolute neutrophil count (ANC) of 0. Lactic acid, H/H, platelets, and CMP were all within normal limits. The patient was started on subcutaneous filgrastim and IV Cefepime. Results of infectious workup which included blood and urine cultures, HIV serology, febrile agglutinins, EBV serology, and respiratory PCR panel were negative. The patient subsequently underwent a bone marrow biopsy which revealed severe absolute neutropenia. Flow cytometry showed lymphoid predominance and T-granular lymphocytosis (8.9%). Cytogenetic studies showed a normal karyotype and was negative for molecular T-cell gene or T-cell receptor rearrangements. The patient’s ANC remained low for several days but at the time of discharge her ANC had normalized to 4,800. After discharge the patient was readmitted to the hospital three more times within a span of four months with the same chief complaint of fever and neutropenia. Extensive workup remained negative for any infectious or autoimmune cause for neutropenia. In each admission the patient responded well to filgrastim, with recovery of her ANC to a normal level before discharge. She is currently managed with oral steroids and methotrexate for presumed adult-onset cyclic neutropenia and has maintained an adequate neutrophil count since starting these medications.
Discussion: Cyclic neutropenia is a rare, autosomal dominantly inherited disorder with variable expression and an estimated incidence of 1-2 per million. Symptoms usually begin during the first years of life and consist of recurrent malaise, fever, pharyngitis, gingivitis, and stomatitis. The most common cause of disease is the result of an autosomal dominant mutation in ELANE, the gene encoding neutrophil elastase. This mutation causes a decrease in the neutrophil production which results in a deficiency of mature neutrophils in the blood. Neutropenia typically recurs every 14 to 35 days. Treatment consists of recombinant granulocyte colony-stimulating factor (G-CSF) and bone marrow transplant for severe cases.Many patients present in the first years of life however there is a form of adult-onset cyclic neutropenia that is related to the presence of cytotoxic lymphocytes. The adult form has been associated with a clonal proliferation of CD56+ large granular lymphocytes. The mainstay of therapy is immunosuppression. In our patient we hypothesize that the etiology of her neutropenia is likely related to cytotoxic lymphocytes based on the results of her flow cytometry, age of presentation and improvement once she started immunosuppressive medications.
Conclusions: Cyclic neutropenia is a rare disorder that should be included in the differential diagnosis for a patient with recurrent cycles of neutropenia and no obvious sources of infection or autoimmune disease. The mainstay of treatment is G-CSF with patients typically achieving a complete normalization of their ANC within days of starting therapy.