Clinical and immunological features in ACKR1/DARC-associated neutropenia

Blood Adv. 2024 Feb 13;8(3):571-580. doi: 10.1182/bloodadvances.2023010400.


ACKR1/DARC-associated neutropenia (NP; ADAN; Online Mendelian Inheritance in Man 611862), caused by a variation in the ACKR1/DARC gene (rs2814778), is common in persons of African or Middle Eastern descent. In a cohort of 66 genetically confirmed subjects with ADAN, we show that absolute neutrophil counts (ANCs) may occasionally be lower than previously recognized (0.1 × 109-0.49 × 109/L for 9% of the subjects), which is similar to ANCs in severe congenital NP (SCNP). ANCs often normalized during inflammation, even mild. Individuals with ADAN (of 327 observed person-years) showed no cases of myelodysplastic syndrome (MDS), which is frequently encountered in SCNP. Unexpectedly, 22% presented with autoantibodies to neutrophils, compared with <1% in controls. Compared with healthy donors, subjects with ADAN demonstrated significantly lower human cationic antimicrobial protein-18/pro-leucin leucin-37 plasma levels; higher levels of nonclassical, proinflammatory, 6-sulfo LacNac-expressing monocytes; and differentially expressed plasma levels of 28 of the 239 analyzed cytokines related to immunity/inflammation, cell signaling, neutrophil activation, and angiogenesis. Collectively, more severe neutropenia in ADAN than previously assumed may complicate differential diagnoses compared with other SCNPs, and various (auto)immune/inflammatory reactions with a distinct profile may be a cause or consequence of this hereditary neutropenia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Duffy Blood-Group System* / genetics
  • Humans
  • Inflammation
  • Leukocyte Count
  • Neutropenia* / genetics
  • Neutrophils
  • Receptors, Cell Surface* / genetics


  • ACKR1 protein, human
  • Receptors, Cell Surface
  • Duffy Blood-Group System