eukopenia with neutropenia was first recognized
as a racial characteristic by Forbes et al10in
1941. He and his coinvestigators found that a
small group of healthy black sharecroppers working in
the cotton fields of Mississippi had a lower mean WBC
and ANC (4.8 × 109/L and 2.3 × 109/L) than a compa-
rable group of white laborers (7.6 × 109/L and 4.6 ×
109/L). Since then, the observation has been con-
firmed.11-28According to the second National Health
and Nutrition Examination Survey in 1978 to 1980,28
42.6% of black females 3 to 74 years of age but only
27.1% of white females in that age group had WBC lev-
els below 5.0 × 109/L. Among black males 3 to 74 years
of age, 48.1% had WBC levels below 5.0 × 109/L com-
pared with only 25.2% of white males. Similar obser-
vations have been made among ethnic groups in
Definition.When neutropenia, defined by normative
data in white populations, occurs in individuals of other
ethnic groups who are otherwise healthy and who do
not have repeated or severe infections, the condition
may be referred to as benign ethnic neutropenia.27
Other descriptive terms include pseudoneutropenia,19,20
nongenetic neutropenia,21“benign” neutropenia of the
black,25familial neutropenia,31benign hereditary neu-
tropenia,34benign familial leukopenia and neutrope-
Benign ethnic neutropenia: What is a normal absolute
THERESA B. HADDY, SOHAIL R. RANA, and OSWALDO CASTRO
WASHINGTON, DISTRICT OF COLUMBIA
Approximately 25% to 50% of persons of African descent and some ethnic groups
in the Middle East have benign ethnic neutropenia, with low leukocyte and neu-
trophil counts. It is important to recognize the existence of this condition, the most
common form of neutropenia throughout the world, and thus avoid both under-
and overevaluation. Although there is no scientific basis for an absolute neutrophil
count of 1.5 3 109/L to be considered minimal, counts below this level are empiri-
cally regarded as inadequate in persons of all ethnic groups who are above the
age of 1 year.1-4Many individuals, however, maintain consistently low absolute
neutrophil counts without evidence of increased susceptibility to infection or any
other adverse effect. The important determination is not how many neutrophils are
present in the peripheral blood, but whether the bone marrow is able to produce
enough normally functioning cells when needed.5-9A description of benign eth-
nic neutropenia, as set forth in this review, suggests that the lower limit now con-
sidered acceptable for the absolute neutrophil count should be readjusted down-
ward for all ethnic groups. (J Lab Clin Med 1999;133:15-22)
Abbreviations: ANC = absolute neutrophil count; WBC = white blood cell count
From the Department of Pediatrics and Child Health and the Sickle
Cell Center, Howard University College of Medicine.
Submitted for publication June 1, 1998; revision submitted Sept 11,
1998; accepted Sept 23, 1998.
Reprint requests: Theresa B. Haddy, MD, 10804 Whiterim Drive,
Potomac, MD 20854-1784.
Copyright © 1999 by Mosby, Inc.
0022-2143/99 $8.00 + 0
An editorial relevant to this article appears on p.
10 of this issue of the Journal.
nia,35and chronic benign idiopathic neutropenia.36The
latter term described a group of Jordanian patients who
probably had benign ethnic neutropenia, although the
term is usually reserved for patients who have mildly
symptomatic chronic benign neutropenia.
Although the need for separate WBC and ANC ref-
erence values for people of African descent37and some
persons of Middle Eastern descent has become
accepted, the imprecise nature of racial or ethnic defi-
nition should be noted. Most researchers have not
described their criteria racial or ethnic assignments but
rather have referred to membership in a group or
tribe.10-37Self-selection has been used by a few authors
to define race or ethnicity,26,28,37but appearance has
seldom been mentioned.10,35The great diversity within
populations including those in Africa points to how dif-
ficult it is to make such assignments.
Standard values. Neutropenia is commonly defined
for adults and children older than 1 year of age as a
reduction in circulating polymorphonuclear and band
form neutrophils with an absolute neutrophil count
below 1.5 × 109/L,1-4although other definitions have
been used. For example, Mason et al25considered 2.0
× 109/L to be the lower limit of normal for adults.
Neutrophil counts are generally higher in women and
are further elevated during pregnancy.37Newborns
characteristically have elevated WBC and ANC val-
ues,4but the lower limit of normal for infants from 2
weeks to 1 year of age is 1.0 × 109/L.4,23Neutrope-
nia can result from decreased production or increased
destruction of granulocytes but also from retention of
the mature neutrophils in the bone marrow storage
pool, among the marginal granulocytes adhering to
the endothelium of blood vessels, or in the splenic
Clinical significance. Neutropenia, the single most
important risk factor for infection, may be classified as
mild (1.0 to 1.5 × 109/L), moderate (0.5 to 1.0 × 109/L),
or severe (<0.2 × 109/L,2< 0.5 × 109/L38). According
to Pizzo,38neutropenia in patients undergoing cancer
chemotherapy becomes a serious concern when the
ANC falls below 0.5 × 109/L, and the lower the ANC
is, the higher the degree of risk is. Other factors that
increase the risk of infection are the duration of neu-
tropenia, status of the patient’s cellular and humoral
immune system, phagocyte function, alterations of
physical defense barriers (eg, the presence of
indwelling catheters), and the patients’s own microflora
or acquired organisms.38Persons with low ANC levels
are at increased risk of infection, especially from pyo-
genic and enteric bacteria, and fungal infections super-
vene when neutropenia is severe and prolonged.38
The relationship between neutropenia and infection
was first recognized in 1902 by Brown and Ophuls,39
who described a patient with a fatal infectious pharyn-
gitis and severe leukopenia. In 1930, Roberts and
Kracke40clearly established that neutropenia may pre-
cede infection. Shortly afterward, Doan41differentiated
acute from chronic neutropenia and showed that some
patients with the chronic variety had bone marrow
insufficiency. The term “maturation arrest” was coined
by Fitz-Hugh and Krumbhaar42to describe decreased
numbers of mature cells in a bone marrow cell line.
Differential diagnosis of neutropenia. A useful classifi-
cation by Roskos and Boxer2categorizes the neutrope-
nias of childhood as congenital (Table I) or acquired
(Table II). The congenital neutropenias are divided into
those with abnormal43-48and normal phenotypes (with
and without physical anomalies). Those without physi-
cal anomalies are further subdivided into the more
severe congenital neutropenias, in which repeated
infections occur,49-60and the benign congenital neu-
tropenias, in which few infections occur.61-70The
acquired neutropenias, many involving multiple cell
lines, are divided into those with and without underly-
ing disease.71-86Agents that have been implicated in
idiosyncratic drug-induced neutropenias are listed in
Benign congenital neutropenias with normal pheno-
types. Several different mechanisms appear to underlie
the chronic benign congenital neutropenias, and clini-
cal severity ranges from mild to completely benign.
Because of the heterogeneity of this condition, Pincus
et al93suggested simple terms for all chronic neu-
16 Haddy, Rana, and C astro
J Lab C lin Med
Table I. Differential diagnosis of c ongenital
Congenital neutropenia with abnormal phenotype
(with physical anomalies)
Congenital neutropenia with normal phenotype
(without physical anomalies)
Severe congenital neutropenia with normal phenotype
T and B cell abnormalities51,52
(infantile genetic agranulocytosis, severe
(severe congenital dysgranulopoietic neutropenia)
Benign congenital neutropenia with normal phenotype
Chronic benign neutropenia61-70
*According to a classification proposed by Roskos and Boxer.2
tropenic states: cases without an inherited factor should
be called chronic neutropenia, and cases with docu-
mented evidence of genetic transmission should be
called hereditary chronic neutropenia. Another practi-
cal classification, designed by Falk et al,94is based on
frequency and severity of infections: benign, no
increased incidence of infection; mild, increased inci-
dence but not requiring hospitalization; moderately
severe, 4 to 6 hospitalizations each year; and severe,
more than 6 hospitalizations each year.
Chronic idiopathic neutropenia, as described by Kyle
et al,61-62is known also as chronic neutropenia,63-65
congenital neutropenia,66chronic idiopathic neutrope-
nia,67chronic benign idiopathic neutropenia,68and
familial benign chronic neutropenia.69Other names are
chronic benign neutropenia, congenital agranulocyto-
sis, genetic agranulocytosis, and hypoplastic neutrope-
nia.70Reported mostly in adults, and more common in
female patients, this variable entity is poorly under-
stood. It is sometimes familial,66,69but not always.70
The bone marrow may be normal or may show delayed
myeloid cell maturation. Various proliferative defects
and survival and distribution defects have been sug-
gested. Infections occur in only approximately 25% of
the patients. Spontaneous remissions are rare and are
more likely to occur in young children.64Patients with
ethnic neutropenia, as it is presently defined, belong in
the category of benign congenital neutropenias with
normal phenotypes, and it may be difficult to rule out
the milder forms of chronic idiopathic neutropenia.
EPIDEMIOLOGY OF BENIGN ETHNIC NEUTROPENIA
Benign ethnic neutropenia occurs in American and British
children and adults of African descent.10,12,14,19,20,23,25-28
Broun et al12reported significant granulocytopenia in
25% of black patients admitted for elective surgery, and
Karayalcin et al19,20found that 30% to 40% of 231 black
hospital employees had low WBC values attributed to a
significant decrease in granulocytes. Rippey13reported
that 50% of African and West Indian patients in a Lon-
don hospital had WBC values of less than 4.0 × 109/L
and ANC values of less than 2.5 × 109/L. An increased
incidence of neutropenia has also been observed in
Africans,11,13-18,21,22,24West Indians,13,14and Middle
Haddy, Rana, and C astro 17
J Lab C lin Med
Volume 133, Number 1
Table II. Differential diagnosis of acquired neu-
Acquired neutropenia with underlying disease
Leukemia, lymphoma, metastatic disease
Viral, bacterial, fungal, and protozoan infections
Acquired neutropenia without underlying disease
Immune (antibody-mediated) neutropenia
Isoimmune neonatal neutropenia71,72
(active maternal isoimmunization)
Transient neonatal neutropenia73
(passive transfer of antibody from mother)
Autoimmune neutropenia of infancy and early childhood74-76
Associated with other autoimmune disorders
Coombs positive autoimmune hemolytic anemia
Immune thrombocytopenic purpura
Systemic lupus erythematosus
Drug induced or dependent neutropenia with antibody77
Low birth weight babies of hypertensive mothers78-81
(caused by placental inhibitor)
Drug induced or dependent neutropenia
Cytotoxic, anti-cancer agents
Toxic bone marrow injury
*According to a classification proposed by Roskos and Boxer.2
Table III. Idiosyncratic drug-induced neutropenia:
a partial list of related agents1,2,83
Eastern people including Yemenite Jews,29-35black
Beduin Arabs,35Ethiopian Jews,35and Jordanians.36
At first there was a good deal of discussion about
whether ethnic neutropenia is inherited10or acquired
as a result of culturally determined environmental fac-
tors such as poor nutrition.21,22Most investigators have
now accepted a genetic hypothesis. Shaper and Lewis18
noted that the finding was present in children and
adults. Shoenfeld et al31found that 75 (37.5%) of 200
randomly selected healthy Yemenite Jews had leukope-
nia, defined as a WBC below 5.0 × 109/L. The leukope-
nia involved 20 families, 17 with at least 3 affected
members, and was considered to be transmitted as an
autosomal dominant trait. Human leukocyte antigen
distribution did not differ between the leukopenic and
nonleukopenic subjects. The possibility of a genetic
contribution from Africans was ruled out by examin-
ing human leukocyte antigens.31,32,95Shoenfeld et al35
also identified an ethnic phenomenon in black Beduin
Arabs and in black “Falasha” Ethiopian Jews. They
reported a Beduin family pedigree in which 5 of 9
members were neutropenic. Ethiopian women in their
study had lower WBC values during the last stage of
pregnancy than non-Ethiopian women. Furthermore
cord blood samples from infants born to the neu-
tropenic Ethiopian women had cell counts similar to
those of the mothers.
MECHANISM OF BENIGN ETHNIC NEUTROPENIA
Mintz and Sachs30showed that neutropenic Yemenite
Jews had a normal bone marrow pattern with adequate
numbers of mature granulocytes and without evidence
of degenerating hypersegmented mature granulocytes
(“myelokathexis”) or increased numbers of immature
granulocytes in the peripheral blood. Bone marrow cells
from these patients with neutropenia formed approxi-
mately twice the number of granulocyte colonies as
bone marrow cells from non-neutropenic persons, thus
establishing that the neutropenia was not caused by a
deficiency of granulocyte colony-forming cells. The
pseudoneutropenia theory of increased retention in the
marginal pool suggested by Karyalcin et al19,20was
disproved when Schoenfeld et al33demonstrated a sig-
nificantly lower increase in the peripheral WBC of neu-
tropenic compared with non-neutropenic Yemenite
Jews after an ergometric workout.
Mason et al25confirmed that bone marrow aspirates
from healthy neutropenic black adults had normal cel-
lularity and normal maturation of all cell lines. They
postulated a defect in the release of mature granulo-
cytes from the bone marrow storage pool to the circu-
lating blood and confirmed their hypothesis by show-
ing that healthy neutropenic black adults responded to
a corticosteroid challenge with significantly lower neu-
trophil increments than white adults. Significantly
lower mean neutrophil increments in neutropenic
Yemenite Jews and significantly lower increments in
Yemenite than in non-Yemenite Jews after intravenous
hydrocortisone injection were also demonstrated by
Shoenfeld et al.34As in the study of black patients by
Mason et al,25the deficit appeared to characterize all
members of the ethnic group, whether “overt” neu-
tropenia was present or not.
A report by Ash et al96of a black patient with severe
aplastic anemia supports the idea that benign ethnic
neutropenia may be a normal condition. In attempting
to identify an allogeneic bone marrow donor, most of
his human leukocyte antigen-mixed lymphocyte culture
matched siblings turned out to be neutropenic, without
evidence of significant previous infections. In vitro
hemopoietic studies showed normal numbers of
pluripotential and committed hemopoietic progenitors
in the siblings, whereas the patient had markedly sub-
normal in vitro hemopoietic colony formation, as would
be expected in a patient with aplastic anemia. Bone
marrow transplanted from 1 of the neutropenic siblings
produced full hemopoietic reconstitution in the patient
(WBC 8.2 × 109/L, ANC 2.1 × 109/L) with normal in
18 Haddy, Rana, and C astro
J Lab C lin Med
Table IV. Responses to hydrocortisone stimulation reported in the medical literature
×109/L ± SEM
× 109/L ± SEM
ANC (hr) SubjectsNumber Dose
Dale et al 197591
Mason et al 197925
Mason et al 197925
Mason et al 197925
Shoenfeld et al 198234
Shoenfeld et al 198234
Junean et al 198336
Haddy & Rana 199427
Haddy & Rana 199427
Neutropenic black adults
Normal black adults
Normal white adults
Neutropenic Yemenite adults
Normal Yemenite adults
Neutropenic Jordanian adults
Neutropenic black children
Normal black children
3.586 ± 0.326
1.6 ± 0.59
3.0 ± 1.07
3.3 ± 0.66
1.471 ± 0.118
3.673 ± 0.205
1.188 ± 0.225
0.819 ± 0.041
2.789 ± 0.28
4.216 ± 0.324
2.63 ± 0.76
3.97 ± 1.58
5.57 ± 2.01
2.413 ± 0.245
4.431 ± 0.467
3.65 ± 0.891
2.818 ± 0.091
3.48 ± 0.344
ANC , Absolute neutrophil count.
vitro culture studies. This case disproved the hypothe-
sis that chronic neutropenia in blacks is a bone marrow
progenitor cell disorder and supported the concept of a
genetically determined alteration in granulocyte kinet-
DIAGNOSIS OF BENIGN ETHNIC NEUTROPENIA
If the ethnic background is appropriate, the diagnosis
of benign ethnic neutropenia should not be difficult in a
person who is physically normal and lacks a history of
susceptibility to infection. It is important to confirm the
presence of neutropenia by repeating the blood count, to
rule out involvement of other blood cell lines, and to
establish that morphologic characteristics of the blood
cells are normal. By 2 months of age the neutropenias
of infancy need no longer be considered. The medical
history should include questions about frequency and
severity of infections, exposure to drugs and toxins, and
symptoms of malabsorption. The physical examination
should rule out growth failure; the presence of infection,
with attention particularly to the ears, lungs, soft tissues,
oral mucosa, gingiva, and perianal mucosa; enlarged
organs such as the spleen, liver, and lymph nodes; and
physical anomalies, especially abnormalities of the hair,
skin, and nails. Recurrent mouth lesions are suggestive
of cyclic neutropenia; the diagnosis of cyclic neutrope-
nia can be confirmed by checking WBC and differential
values twice weekly for 6 to 8 weeks. The nadir usually
occurs at approximately 21-day intervals. Invasive stud-
ies such as bone marrow sampling, especially when chil-
dren are being evaluated, can be kept to a minimum. A
corticosteroid challenge is not necessary if the diagnosis
appears to be uncomplicated.
Steroid mobilization. A number of agents including
corticosteroids, endotoxin, and etiocholanalone can
be used to assess the size of the bone marrow stor-
age neutrophil pool.97-103The latter 2 agents are not
easily available, and their injection is likely to be fol-
lowed by fever, malaise, and pain at the site of injec-
tion.91Corticosteroids, on the other hand, are easy
to obtain, and administration of 1 dose is unlikely to
cause side effects. Dale et al97observed no abdomi-
nal discomfort, bleeding, or mood changes after a
single corticosteroid dose. De Alarcon et al31con-
sidered a normal response to be a 50% rise in neu-
trophil count in combination with a peak neutrophil
count of at least 2.5 × 109/L. Cream98suggested that
an ANC increment greater than 2.0 × 109/L is ade-
quate for normal people. Mean ANC increments for
patients reported in the medical literature25,27,34,36,97
have all been higher than 2.0 × 109/L (Table IV).
Children who respond normally to intravenous
hydrocortisone stimulation are more likely to have a
benign course than children who do not2,3; thus the
test may be useful for ruling out marrow suppression
or an underlying blood dyscrasia.25Epinephrine
administration mobilizes marginal granulocytes
adhering to blood vessel endothelium or residing in
the splenic pool, but this test should rarely be nec-
Is it important to make the diagnosis? As long as the
current definition of neutropenia, an ANC below 1.5 ×
109/L, is used, awareness of ethnic differences among
normal persons should help to avoid overevaluating
healthy individuals with excessive numbers of diagnos-
tic procedures. Undervaluation must also be avoided,
especially in diagnosing infectious diseases, for exam-
ple, appendicitis106and meningitis,107in which such
patients would be likely to have lower WBC and ANC
levels than expected. Patients who are likely to have
ethnic neutropenia should be carefully evaluated, if pos-
sible, before beginning anticonvulsive, antiviral, or
bone marrow suppressive therapy.108-112
Because benign ethnic neutropenia is usually an inci-
dental finding in patients who lack a history of frequent
or severe infections, should it not be considered a normal
rather than an abnormal condition? Crosby113pointed out
that neutrophils are merely transported by the blood.
Whether enough are produced by the bone marrow and
whether the cells can perform an anti-inflammatory func-
tion in the tissues are the important issues. Research con-
cerning the physiology of granulocyte kinetics and
hemapoietic growth factors in persons with benign eth-
nic neutropenia, clinical findings such as infections and
physical characteristics (eg, skin color, blood group,
human leukocyte antigen antigens, and gene structure),
and pedigrees of families would be valuable in defining
the range of normal for the ANC.
Benign ethnic neutropenia, the most common form
of neutropenia seen throughout the world, appears to
confer no clinical disadvantage and can be considered
to be a variation of normal. Patients with an appropri-
ate ethnic background who have no physical abnormal-
ities and no history of increased frequency or severity
of infections do not require extensive or invasive test-
ing. A closer look at benign ethnic neutropenia would
offer an opportunity to re-evaluate the normal range of
the ANC for all ethnic groups and reliably establish
the number of neutrophils required to prevent and com-
bat infection. If studies confirm that the lower level for
normal should be placed below the current, conven-
tional 1.5 × 109/L, large numbers of people now con-
sidered to have benign ethnic neutropenia will auto-
matically fall within the normal range, and the
diagnosis of benign ethnic neutropenia could no longer
Haddy, Rana, and C astro19
J Lab C lin Med
Volume 133, Number 1
1. Boxer LA, Blackwood RA. Leukocyte disorders: quanti-
tative and qualitative disorders of the neutrophil, part 1.
Pediatr Rev 1996;17:19-28.
2. Roskos RR, Boxer LA. Clinical disorders of neutropenia.
Pediatr Rev 1991;12:208-12.
3. de Alarcon PA, Goldberg J, Nelson DA, Stockman JA III.
Chronic neutropenia: diagnostic approach and prognosis.
Am J Pediatr Hematol Oncol 1983;5:3-9.
4. Bernini JC. Diagnosis and management of chronic neu-
tropenia during childhood. Pediatr Clin North Am 1996;
5. Finch CA, Harker LA, Cook JD. Kinetics of the formed
elements of human blood. Blood 1977;50:699-707.
6. Cartwright GE, Athens JW, Wintrobe MM. The kinetics of
granulopoiesis in normal man. Blood 1964;24:780-803.
7. Erdman SH, Christensen RD, Bradley PP, Rothstein G.
Supply and release of storage neutrophils: a developmen-
tal study. Biol Neonate 1982;41:132-7.
8. Christensen RD. Neutrophil kinetics in the fetus and
neonate. Am J Pediatr Hematol Oncol 1989;11:215-23.
9. Christensen RD, Rothstein G. Exhaustion of mature mar-
row neutrophils in neonates with sepsis. J Pediatr 1980;
10. Forbes WH, Johnson RE, Consolazio F. Leukopenia in
Negro workmen. Am J Med Sci 1941;201:407-12.
11. Shaper AG, Kyobe J, Stansfield D. Haematological obser-
vations in an East African student population. East Afr
Med J 1962;39:1-4.
12. Broun GO Jr, Herbig FK, Hamilton JR. Leukopenia in
Negroes. N Engl J Med 1966;275:1410-3.
13. Rippey JJ. Leucopenia in West Indians and Africans.
14. Davis LR, Barnard HF. Leucopenia in West Indians and
Africans. Lancet 1967;2:213.
15. Neser ML. The leucocyte picture in white, Bantu, coloured
and Indian school children of 6-15 years as observed dur-
ing the Pretoria nutrition status surveys of 1962-1965. S
Afr Med J 1968;42:444-50.
16. Kasili EG, Cardwell CL, Taylor JR. Leucocyte counts on
blood donors in Nairobi. East Afr Med J 1969;46:676-9.
17. Hawgood BC. Leucocyte levels in East Africa. East Afr
Med J 1969;46:680-2.
18. Shaper AG, Lewis P. Genetic neutropenia in people of
African origin. Lancet 1971;2:1021-3.
19. Karayalcin G, Rosner F, Sawitsky A. Pseudo-neutropenia
in Negroes: a normal phenomenon. NY State J Med 1972;
20. Karayalcin G, Rosner F, Sawitsky A. Pseudo-neutropenia
in American Negroes. Lancet 1972;1:387.
21. Ezeilo GC. Non-genetic neutropenia in Africans. Lancet
22. Ezeilo GC. Normal haematological values in adult Zam-
bians. East Afr Med J 1972;49:93-100.
23. Caramihai E, Karayalcin G, Aballi AJ, Lanzkowsky P.
Leukocyte count differences in healthy white and black
children 1 to 5 years of age. J Pediatr 1975;86:252-4.
24. Rougemont A, Boisson M-E. Racial differences in leuco-
cyte count. Br Med J 1975;2:684-5.
25. Mason BA, Lessin L, Schechter GP. Marrow granuocyte
reserves in black Americans: hydrocortisone-induced gran-
ulocytosis in the “benign” neutropenia of the black. Am J
26. Reed WW, Diehl LF. Leukopenia, neutropenia, and
reduced hemoglobin levels in healthy American blacks.
Arch Intern Med 1991;151:501-5.
27. Haddy TB, Rana SR. Leukocyte response to administra-
tion of corticosteroid in healthy black children with neu-
tropenia. J Pediatr 1994;124:739-41.
28. National Center for Health Statistics; Fulwood R, Johnson
CL, Bryner JD. Hematological and nutritional biochem-
istry reference data for persons six months to 74 years of
age: United States, 1976-80. Vital and Health Statistics.
Series II No 232. DHHS Pub No (PHS) 83-1682. Public
Health service, Washington. US Government Printing
Office, December 1982.
29. Djaldetti M, Joshua H, Kadleron M. Familial leukopenia-
neutropenia in Yemenite Jews: observations on eleven fam-
ilies. Bull Res Counc Israel 1961;9E:24-8.
30. Mintz U, Sachs L. Normal granulocyte colony-forming
cells in the bone marrow of Yemenite Jews with genetic
neutropenia. Blood 1973;41:745-51.
31. Shoenfeld Y, Weinberger A, Avishar R, Zamir R, Gazit E,
Joshua H, Pinkhas J. Familial leukopenia among Yemenite
Jews. Isr J Med Sci 1978;14:1271-4.
32. Weinberger A, Shoenfeld Y, Zamir R, Gazit E, Joshua H,
Pinkhas J. HLA antigens in genetic neutropenia of
Yemenite Jews. Vox Sang 1979;36:105-8.
33. Shoenfeld Y, Aloni D, Keren G, Shaklai M, Djaldetti M,
Pinkhas J. Effect of physical effort on the white blood cells
in benign familial leukopenia. Acta Haematol 1981;
34. Shoenfeld Y, Modan M, Berliner S, Yair V, Shaklai M,
Slusky A, Pinkhas J. The mechanism of benign hereditary
neutropenia. Arch Intern Med 1982;142:797-9.
35. Shoenfeld Y, Alkan ML, Asaly A, Carmeli Y, Katz M.
Benign familial leukopenia and neutropenia in different
ethnic groups. Eur J Haematol 1988;41:273-7.
36. Jumean HG, Sudah FI. Chronic benign idiopathic neu-
tropenia in Jordanians. Acta Haematol 1983;69:59-60.
37. Rana SR, Castro OL, Haddy TB. Leukocyte counts in
7,739 healthy black persons: effects of age and sex. Ann
Clin Lab Sci 1985;15:51-4.
38. Pizzo PA. Management of fever in patients with cancer and
treatment-induced neutropenia. N Engl J Med
39. Brown PK, Ophuls W. A fatal case of acute primary infec-
tious pharyngitis with extreme leukopenia. Am Med 1902;
40. Roberts SR, Kracke RR. Agranulocytosis: report of a case.
J Am Med Assoc 1930;95:780-7.
41. Doan CA. The neutropenic state: its significance and ther-
apeutic rationale. J Am Med Assoc 1932;99:194-202.
42. Fitz-Hugh T Jr, Krumbhaar EB. Myeloid cell hyperplasia
of the bone marrow in agranulocytic angina. Am J Med
43. Shwachman H, Diamond LK, Oski FA, Khaw K-T. The
syndrome of pancreatic insufficiency and bone marrow
dysfunction. J Pediatr 1964;65:645-63.
44. Shmerling DH, Prader A, Hitzig WH, Giedion A, Hadorn
ZB, Kuhni M. The syndrome of exocrine pancreatic insuf-
ficiency, neutropenia, metaphyseal dysostosis and
dwarfism. Helv Paediatr Acta 1969;24:547-74.
45. Tada H, Ri T, Yoshida H, Ishimoto K, Kaneko M,
Yamashiro Y, Shinohara T. A case of Shwachman syn-
drome with increased spontaneous chromosome breakage.
Hum Genet 1987;77:289-91.
46. McKusick VA, Eldridge R, Hostetler JA, Ruangwit U, Ege-
20 Haddy, Rana, and C astro
J Lab C lin Med
Egeland JA. Dwarfism in the Amish. II. Cartilage-hair
hypoplasia. Bull Johns Hopkins Hosp 1965;116:285-326.
47. Lux SE, Johnston RB Jr, August CS, Say B, Penchaszadeh
VB, Rosen FS, et al. Chronic neutropenia and abnormal
cellular immunity in cartilage-hair hypoplasia. N Engl J
48. Trowbridge AA, Sirinavin C, Linman JW. Dyskeratosis
congenita: hematological evaluation of a sibship and
review of the literature. Am J Hematol 1977;3:143-52.
49. de Vaal OM, Seynhaeve V. Reticular dysgenesia. Lancet
50. Roper M, Parmley RT, Crist WM, Kelly DR, Cooper MD.
Severe congenital leukopenia (reticular dysgenesis):
immunologic and morphologic characterizations of leuko-
cytes. Am J Dis Child 1985;139:832-5.
51. Buckley RH, Rowlands DT Jr. Agammaglobulinemia, neu-
tropenia, fever, and abdominal pain. J Allergy Clin
52. Kozlowski C, Evans DIK. Neutropenia associated with X-
linked agammaglobulinemia. J Clin Pathol 1991;44:388-
53. Kostmann R. Infantile genetic agranulocytosis (agranulo-
cytosis infantilis hereditaria): a new recessive lethal dis-
ease in man. Acta Paediatr 1956;45(suppl 105):1-78.
54. Kostmann R. Infantile genetic agranulocytosis: a review
with presentation of ten new cases. Acta Paediatr Scand
55. Amato D, Freedman MH, Saunders EF. Granulopoiesis in
severe congenital neutropenia. Blood 1976;47:531-8.
56. Parmley RT, Crist WM, Ragab AH, Boxer LA, Malluh A,
Lui VK, et al. Congenital dysgranulopoietic neutropenia:
clinical, serologic, ultlrastructural, and in vitro prolifera-
tive characteristics. Blood 1980;56:465-75.
57. Wright DG, Dale DC, Fauci AS, Wolff SM. Human cyclic
neutropenia: clinical review and long-term follow-up of
patients. Medicine 1981;60:1-13.
58. Dale DC, Hammond WP IV. Cyclic neutropenia: a clini-
cal review. Blood Rev 1988;2:178-85.
59. Zuelzer WW. “Myelokathexis”—a new form of chronic
granulocytopenia: report of a case. N Engl J Med 1964;
60. Lightsey AL, Parmley RT, Marsh WL Jr, Garg AK, Thomas
WJ, Wolach B, et al. Severe congenital neutropenia with
unique features of dysgranulopoiesis. Am J Hematol 1985;
61. Kyle RA, Linman JW. Chronic idiopathic neutropenia: a
newly recognized entity? N Engl J Med 1968;279:
62. Kyle RA. Natural history of chronic idiopathic neutrope-
nia. N Engl J Med 1980;302:908-9.
63. Jonsson OG, Buchanan GR. Chronic neutropenia during
childhood: a 13-year experience in a single institution. Am
J Dis Child 1991;145:232-5.
64. Dale DC, Guerry D IV, Wewerka JR, Bull JM, Chusid MJ.
Chronic neutropenia. Medicine 1979;58:128-44.
65. Price TH, Lee MY, Dale DC, Finch CA. Neutrophil kinet-
ics in chronic neutropenia. Blood 1979;54:581-94.
66. Rich K, Falk PM, Stiehm ER, Feig S, Golde DW, Cline
MJ. Abnormal in vitro granulopoiesis in phenotypically
normal parents of some children with congenital neutrope-
nia. Pediatrics 1977;59:396-400.
67. Greenberg PL, Mara B, Steed S, Boxer L. The chronic
idiopathic neutropenia syndrome: correlation of clinical
features with in vitro parameters of granulocytopoiesis.
68. Mant MJ, Gordon PA, Akabutu JJ. Bone marrow granulo-
cyte reserve in chronic benign idiopathic neutropenia. Clin
Lab Haematol 1987;9:281-8.
69. Cutting HO, Lang JE. Familial benign chronic neutrope-
nia. Ann Intern Med 1964;61:876-87.
70. Peterson L, Foucar K. Granulocytosis and granulocytope-
nia. In: Bick RL, editor. Hematology: clinical and labora-
tory practice. Baltimore: Mosby-Year Book, Inc; 1993. p.
71. Lalezari P, Nussbaum M, Gelman S, Spaet TH. Neonatal
neutropenia due to maternal isoimmunization. Blood 1960;
72. Boxer LA,Yokoyama M, Lalezari P. Isoimmune neonatal
neutropenia. J Pediatr 1972;80:783-7.
73. Stefanini M, Mele RH, Skinner D. Transitory congenital
neutropenia: a new syndrome: report of two cases. Am J
74. Boxer LA, Greenberg MS, Boxer GJ, Stossel TP. Autoim-
mune neutropenia. N Engl J Med 1975;293:748-53.
75. Lalezari P, Khorshidi M, Petrosova M. Autoimmune neu-
tropenia of infancy. J Pediatr 1986;109:764-9.
76. Conway LT, Clay ME, Kline WE, Ramsay NKC, Krivit W,
McCullough J. Natural history of primary autoimmune
neutropenia in infancy. Pediatrics 1987;79:728-33.
77. Castro O, Nash I. Quinidine leukopenia and thrombocy-
topenia with a drug-dependent leukoagglutinin. N Engl J
78. Koenig JM, Christensen RD. The mechanism responsible
for diminished neutrophil production in neonates delivered
of women with pregnancy-induced hypertension. Am J
Obstet Gynecol 1991;165:467-73.
79. Mouzinho A, Rosenfeld CR, Sanchez PJ, Risser R.
Revised reference ranges for circulating neutrophils in
very-low-birth-weight neonates. Pediatrics 1994;94:76-82.
80. Makhlouf RA, Doron MW, Bose CL, Price WA, Stiles AD.
Administration of granulocyte colony-stimulating factor
to neutropenic low birth weight infants of mothers with
preeclampsia. J Pediatr 1995;126:454-6.
81. La Gamma EF, Alpan O, Kocherlakota P. Effect of granu-
locyte colony-stimulating factor on preeclampsia-associ-
ated neonatal neutropenia. J Pediatr 1995;126:457-9.
82. Sievers EL, Dale DC. Non-malignant neutropenia. Blood
83. Young NS. Agranulocytosis. J Am Med Assoc 1994;
84. MacManus M, Lamborn K, Khan W, Varghese A, Graef L,
Knox S. Radiotherapy-associated neutropenia and throm-
bocytopenia: analysis of risk factors and development of a
predictive model. Blood 1997;89:2303-10.
85. Marks LB, Cuthbertson D, Friedman HS. Hematologic
toxicity during craniospinal irradiation: the impact of prior
chemotherapy. Med Pediatr Oncol 1995;25:45-51.
86. Plowman PN. Haematologic toxicity during craniospinal
irradiation—the impact of prior chemotherapy. Med Pedi-
atr Oncol 1997;28:238-9.
87. Pisciotta AV. Drug induced agranulocytosis peripheral
destruction of polymorphonuclear leukocytes and their
marrow precursors. Blood Rev 1990;4:226-37.
88. Mamus SW, Burton JD, Groat JD, Schulte DA, Lobell M,
Zanjani ED. Ibuprofen-associated pure white-cell aplasia.
N Engl J Med 1986;314:624-5.
89. The International Agranulocytosis and Aplastic Anemia
Study. Risks of agranulocytosis and aplastic anemia: a first
report of their relation to drug use with special reference
to analgesics. J Am Med Assoc 1986;256:1749-57.
Haddy, Rana, and C astro21
J Lab C lin Med
Volume 133, Number 1
90. Weitzman SA, Stossel TP, Desmond M. Drug-induced Download full-text
immunological neutropenia. Lancet 1978;1:1068-71.
91. Sassim N, Grohmann R. Adverse drug reactions with
clozapine and simultaneous application of benzodi-
azepines. Pharmacopsychiat 1988;21:306-7.
92. Sievers EL, Dale DC. Non-malignant neutropenia. Blood
93. Pincus SH, Boxer LA, Stossel TP. Chronic neutropenia in
childhood: analysis of 16 cases and a review of the litera-
ture. Am J Med 1976;61:849-61.
94. Falk PM, Rich K, Feig S, Stiehm ER, Golde DW, Cline
MJ. Evaluation of congenital neutropenic disorders by in
vitro bone marrow culture. Pediatrics 1977;59:739-48.
95. Payne R, Feldman M, Cann H, Bodmer JG. Comparison
of HLA data of the North American black with African
black and North American Caucasoid populations. Tissue
96. Ash RC, Mendelsohn LA, Marshall ME. Hemopoietic
marrow function in chronic neutropenia of blacks: cure of
aplastic anemia by allogeneic marrow transplantation from
a neutropenic sibling donor. Am J Hematol 1986;22:205-
97. Dale DC, Fauci AS, Guerry D IV, Wolff SM. Comparison
of agents producing a neutrophilic leukocytosis in man:
cholanolone. J Clin Invest 1975;56:808-13.
98. Cream JJ. Prednisolone-induced granulocytosis. Br J
99. Fauci AS, Dale DC, Balow JE. Glucocorticosteroid ther-
apy: mechanisms of action and clinical considerations. Ann
Intern Med 1976;84:304-15.
100. Perry S, Weinstein IM, Craddock CG Jr, Lawrence JS. The
combined use of typhoid vaccine and P32 labeling to
assess myelopoiesis. Blood 1957;12:549-58.
101. Vogel JM, Yankee RA, Kimball HR, Wolff SM, Perry S.
The effect of etiocholanolone on granulocyte kinetics.
102. Godwin HA, Zimmerman TS, Kimball HR, Wolff SM
Perry S. The effect of etiocholanolone on the entry of gran-
ulocytes into the peripheral blood. Blood 1968;31:461-70.
103. Gunz FW, Mani MK, Ravich RBM, Speden J, Vincent PC.
The use of etiocholanolone for the measurement of mar-
row granulocyte reserves. Med J Aust 1970;1:763-7.
104. Schaffner A, Fehr J. Granulocyte demargination by epi-
nephrine in evaluation of hypersplenic states. Scand J
105. Schaffner A, Augustiny N, Otto RC, Fehr J. The hyper-
spenic spleen: a contractile reservoir of granulocytes and
platelets. Arch Intern Med 1985;145:651-4.
106. Hyman P, Westring DW. Leukocytosis in acute appendici-
tis: observed racial difference. J Am Med Assoc 1974;
107. Sadowitz PD, Oski FA. Differences in polymorphonuclear
cell counts between healthy white and black infants:
response to meningitis. Pediatrics 1983;72:405-7.
108. Fink ME, Calabresi P. The granulocyte response to endo-
toxin (Pyrexal) as a measure of functional marrow reserve
in cancer chemotherapy. Ann Intern Med 1962;57:732-42.
109. Hellman S, Fink ME. Granulocyte reserve following radi-
ation therapy as studied by the response to bacterial endo-
toxin. Blood 1965;25:310-24.
110. DeConti RC, Kaplan SR, Calabresi P. Endotoxin stimula-
tion in patients with lymphoma: correlation with the
myelosuppressive effects of alkylating agents. Blood
111. Deinard AS, Fortuny IE, Theologides A, Anderson GL,
Boen J, Kennedy BJ. Studies on the neutropenia of cancer
chemotherapy. Cancer 1974;33:1210-8.
112. Chanock SJ, Pizzo PA. Fever in the neutropenic host.
Infect Dis Clin North Am 1996;10:777-96.
113. Crosby WH. How many “polys” are enough? Arch Intern
22 Haddy, Rana, and C astro
J Lab C lin Med