Clinical and Laboratory Characteristics of Pediatric Patients with <i>ACKR1/Darc</i>-Associated Neutropenia

Background: ACKR1/DARC-associated neutropenia (ADAN), resulting from homozygosity for a single nucleotide polymorphism (SNP) in the ACKR1/DARC gene (rs2814778), is a common cause of benign neutropenia that primarily affects individuals of African and Jewish Yemenite descent. We aimed to characterize ADAN in pediatric patients in Israel, given its ethnically diverse population. Procedure: We assessed children with isolated neutropenia treated during 2018-2023 at one pediatric center, for the ACKR1/DARC polymorphism, using Sanger sequencing or targeted next-generation sequencing. Results: Of 115 patients evaluated, 55 (47.8%) were diagnosed with ADAN; of these, 27 (49%) were in the severe range (neutrophil count 0-0.5X109/L). The allele distribution revealed 40.0% of Muslim Arab and 58.2% of Jewish origin. The diverse geographical range included Yemenite, Ethiopian, Mediterranean, Asian, and European ancestry. Fifty-one percent had a family history of neutropenia. The median age at the first neutropenia detection was 1.1 years; nearly 90% were identified during routine blood counts. The median absolute neutrophil count at diagnosis was 0.5X109/L (interquartile range 0.3). Patients did not show an increased susceptibility to infections either before or during the median follow-up period of 2.5 years (interquartile range 1.54) after the diagnosis of ADAN. In 42 patients (75.0%), neutrophil counts increased during febrile illnesses. Conclusions: We identified ADAN in individuals of variable ethnicities, almost half with severe neutropenia. We recommend testing for ADAN in all children with isolated neutropenia without severe infections. This suggests that homozygosity for the ACKR1/DARC rs2814778 SNP eliminates the need for further investigation, follow-up, or treatment in this clinical scenario.