Benign Ethnic Neutropenia: Low Neutrophils That Are Normal

Neutrophils are the white blood cells that act as the first line of defence against bacterial infection. Lab Tests Online UK says a low neutrophil count, called neutropenia, raises the risk of infection, and adds an important note: the normal level of neutrophils varies between ethnic groups, and doctors take this into account when looking at results.

Benign ethnic neutropenia is the best-known example of that variation. The NHS Genomics Education Programme's GeNotes uses the name ACKR1/DARC-associated neutropenia (ADAN), and notes that it is also called benign ethnic neutropenia (BEN) and Duffy-null associated neutrophil count (DANC). Each of these describes the same observation: a neutrophil count that sits below the usual laboratory range in a person who is well and has no unusual infections.

The reason this matters is that standard reference ranges were built mainly from populations in which the variant is uncommon. A person with the variant can therefore be labelled neutropenic by a computer flag when their count is, for them, normal.

GeNotes explains that the condition is associated with a homozygous variant in ACKR1 (c.-67T>C, rs2814778), commonly known as the Duffy-null genotype, which prevents the ACKR1 protein from being made on red blood cells. GeNotes says that about 30 percent of people with this genotype have persistently low counts, which is thought to be due to abnormal neutrophil migration from the blood into the tissues. In other words, the measured count in the blood is lower, but the explanation is a change in where the cells travel, not a failure of the bone marrow to make them.

Inheritance is autosomal recessive, meaning a person must inherit two copies of the variant, one from each parent. The Duffy-null genotype is prevalent in people with African or Middle Eastern ancestry, at roughly 80 percent and 25 percent respectively, and uncommon, under 1 percent, in people with European or East Asian ancestry. GeNotes suggests this may have arisen because it gives partial resistance to Plasmodium vivax malaria.

Not everyone with the genotype has a low count, which is why a normal neutrophil count does not rule out carrying the variant.

GeNotes says a diagnosis requires confirmation by a haematologist, and that other potential causes of neutropenia must be ruled out. Features that suggest it include persistently low absolute neutrophil counts over multiple blood measurements, no history of recurrent infections or other significant physical illness, and African or Middle Eastern ethnicity, although it points out that self-reported ethnicity can be an unreliable measure of genetic ancestry.

Genomic testing for the homozygous ACKR1 variant can help confirm the diagnosis. GeNotes notes that this test is not currently available through the National Genomic Test Directory, although some haematology services can order it. If a person has the Duffy-null genotype and isolated neutropenia without significant illness, a diagnosis can be made in adults. The guidance applies to adults only, and suspected cases in children may need specialist consultation.

GeNotes states that people with the condition are at risk of being excluded from treatments that require blood neutrophil counts to remain above a predefined threshold. The two examples it gives are clozapine and some types of chemotherapy, where mandatory monitoring means a low reading can interrupt treatment.

Where the condition is confirmed, GeNotes advises that the managing clinician discuss implications with the patient, with multidisciplinary input as needed from a haematologist, psychiatrist or oncologist, and that existing guidelines for ADAN within these treatment groups be followed to prevent unnecessary treatment interruption.

Outside those situations, the practical effect is much smaller. A person who knows their low count is a normal variant is spared repeat tests, referrals and worry. It is worth keeping a note of the diagnosis and telling any new clinician about it.

Not every low neutrophil count in a person of African or Middle Eastern ancestry is benign. A new drop, a falling trend, additional abnormal blood counts or fever and unexplained illness should always prompt assessment, because the other causes of a low white cell count apply to everyone. Lab Tests Online UK lists certain medicines, viral infections, bone marrow failure, liver disease, alcohol excess, autoimmune conditions and an enlarged spleen among them.

GeNotes makes this point by requiring other causes to be excluded before the diagnosis is made. If you have been told your count is low and nobody has explained why, ask whether the pattern has been checked against this variant and whether a haematology opinion is appropriate.