Hematology

Constitutional/ethnic neutropenia

Constitutional/ethnic neutropenia

What every physician needs to know about constitutional neutropenia:

Constitutional neutropenia is defined as an absolute neutrophil count (ANC) less than 1,500 in an otherwise healthy individual. As it is often seen in specific ethnic groups, that is, African populations, Yemenite Jews, and Arab populations, it is often termed ethnic neutropenia. Most individuals have a neutrophil count between 1,000 and 1,500, although a small number may have neutrophil counts below 1,000.

Constitutional neutropenia is a benign syndrome that is not associated with any increase in infections and is characterized by a normal bone marrow. Other peripheral counts are normal. The depressed neutrophil count probably represents an ethnic variation that shifts the normal distribution of neutrophil counts downward, and should not be considered a disease. The basis for the decreased neutrophil counts in African populations has been linked to the Duffy -/- phenotype (see below). Whether this explains the lower counts in other ethnic populations remains to be established.

The main imperative in assessing these individuals is to recognize that this is a benign constitutional syndrome that does not require further evaluation in the absence of other abnormalities.

What features of the presentation will guide me toward possible causes and next treatment steps:

Patients with constitutional neutropenia are apparently healthy individuals with no history of excessive infections. They may frequently have other family members with a mildly depressed leukocyte count in the same range.

Severe neutropenia (ANC less than 500) should direct the physician toward evaluation for another disease. Counts between 500 and 1,000 require clinical judgment as to the necessity for further evaluation. A history of excess infections, increased dental caries, aprhous ulcers, skin infections, and the like, should suggest another diagnosis. In the absence of these, no further evaluation is necessary.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

It should be confirmed that the remainder of the complete blood count (CBC) is completely normal. If that is the case, and the patient is otherwise healthy, further evaluation is not necessary. At most, a survey of standard chemistries (electrolytes, liver function studies, renal function tests) can be obtained to reassure the physician that there is no other underlying illness. It is important not to label the patient as having an illness, since this may present difficulties with employment, insurance, etcetera.

What conditions can underlie constitutional neutropenia:

The important thing to recognize is that consitutional neutropenia is essentially a normal variant and is not associated with underlying disease.

When do you need to get more aggressive tests:

Further tests are not necessary. If the patient has other abnormalities, including anemia, thrombocytopenia, recurrent fevers, adenopathy, or anything else to suggest an underlying illness, then other diagnoses should be considered based on the other abnormalities. Bone marrow aspirate and biopsy is not necessary unless there are other manifestations of disease.

What imaging studies (if any) will be helpful?

N/A

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

N/A

What other therapies are helpful for reducing complications?

N/A

What should you tell the patient and the family about prognosis?

Constitutional neutropenia is actually a normal variant reflecting ethnic differences in the determinants of neutrophil count. As such, it has no negative prognostic significance. It is very likely that other members of the family will have similarly low WBC and ANC.

“What if” scenarios.

You are referred a patient who has been identified to have neutropenia on an employment physical

If the patient has a benign history with no fevers or other symptoms, presents with mild neutropenia with an otherwise normal CBC, and is in one of the ethnic groups known to be associated with constitutional neutropenia, it is important that the patient not be labeled as having a "disease." No further work-up should be performed and the prospective employer should be reassured that the patient is normal.

The patient had a history of recurrent infections

The patient probably does not have constitutional neutropenia. Work-up should be undertaken as outlined in the chapter on leukopenia.

The patient has an ANC of 450

This is a level of neutropenia that is too profound to attribute to ethnic neutropenia. Patient should be evaluated as outlined in the chapter on neutropenia. It is still possible that this is a completely benign syndrome, especially in an otherwise healthy patient with a negative clinical history; however, it should not be attributed to constitutional neutropenia until other illnesses are excluded. A bone marrow aspirate and biopsy should be performed with cytogenetics and flow cytometry to rule out an underlying hematologic malignancy.

Pathophysiology

Recent studies have established by linkage analysis that the genetic basis for constitutional neutropenia in African populations is the Duffy antigen/receptor chemokine gene (DARC). This polymorphism leads to the Duffy-null phenotype that is present in 70 to 75% of individuals from African populations. Nearly all individuals who are neutropenic are homozygous for the null allele; however, only a small percentage of Duffy -/- individuals are neutropenic. This suggests that the effect of the polymorphism is to shift the normal distribution of neutrophil number downward, such that 10 to 20% of individuals will now have neutrophil counts that fall out of the normal range.

The gene frequency of the Duffy-null polymorphism is highest in areas where malaria is endemic, and it confers resistance to infection of erythrocytes with Plasmodium vivax. This probably explains its selection in the populations in which it is found to be highly prevalent. For example, Yemenites Jews also have an increased frequency of the Duffy-null allele, though it is not as prevalent as in African populations.

The contribution of the Duffy-negative phenotype to ethnic neutropenia in other populations still remains to be determined. In some Arab populations, benign neutropenia has been suggested to have an autosomal dominant inheritance pattern, which might suggest that it is not a reflection of the Duffy-null phenotype, but that will only be clarified by direct studies of the gene frequency of the DARC polymorphism.

The mechanism by which the Duffy-null phenotype contributes to neutropenia is unknown. The Duffy antigen is expressed in non-erythroid cell types, including endothelial cells. Expression is disrupted by the Duffy-null polymorphism solely on erythrocytes, since the change disrupts a binding for the erythroid-specific transcription factor GATA-1. DARC is known to bind inflammatory cytokines including CXCL8 (IL-8 [interleukin-8]) and CCL5 (RANTES). Both of these cytokines are involved in neutrophil recruitment, although it is not clear whether their binding to erythroid cells is important in moderating circulating neutrophil mass. Linking the phenotype to neutropenia will require future research.

What other clinical manifestations may help me to diagnose constitutional neutropenia?

None. This is disease is marked by an absence of clinical manifestations.

What other additional laboratory studies may be ordered?

N/A

What’s the evidence?

Bain, BJ. "Ethnic and sex differences in the total and differential white cell count and platelet count". J Clin Pathol. 1996. pp. 49: 664-666.

[Early description of ethnic neutropenia.]

Denic, S, Showqui, S, Klein, C. "et al Prevalence, phenotype and inheritance of benign neutropenia in Arabs". BMC Blood Disorders. vol. 9. 2009. pp. 3-10.

[Examination of the prevalence of ethnic neutropenia in Arab populations, suggesting that at least some cases follow an autosomal dominant inheritance pattern.]

Grann, VR, Ziv, E, Joseph, CK. "Duffy (Fy), DARC, and neutropenia among women for the United States, Europe and the Caribbean". Brit J Haematol. vol. 143. 2008. pp. 288-293.

[Study confirming that the Duffy-null phenotype is the single most important determinant of neutropenia in diverse populations, primarily African-derived populations, in the US, Europe, and the Caribbean.]

Hsieh, MM, Everhart, E, Byrd-Hoyt, DD, Tisdale, JF, Rodgers, GP. "Prevalence of neutropenia in the US population: Age, sex, smoking status, and ethnic differences". Ann Intern Med. vol. 146. 2007. pp. 486-492.

[Documentation of the prevalence of neutropenia in the NHANES (The National Health and Nutrition Examination Survey) survey of over 25,000 individuals. Using a lower limit of normal of the ANC of 1,500/μl, they document that 4.5% of black participants were neutropenic. Less than 1% of Caucasians or Mexican-Americans were neutropenic.]

Paz, A, Nalls, M, Ziv, E. "The genetics of benign neutropenia". IMAJ. vol. 13. 2011. pp. 625-629.

[Review of the identification of DARC-related polymorphism as the genetic determinant of ethnic neutropenia in African populations and speculation as to its role in causing neutropenia.]

Reich, D, Nalls, MA, Kao, WHL. "Reduced neutrophil count in people of African descent is due to a regulatory variant in the Duffy antigen receptor for chemokines gene".

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