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Neutropenia in PediatricPracticeGeorge B. Segel, MD,* Jill
S. Halterman, MD, MPH†
Author Disclosure
Drs Segel and
Halterman did not
disclose any financial
relationships relevant
to this article.
Objectives After completing this article, readers should be able to:1. Describe when a patient has true neutropenia, understanding the variation with age
and ethnic background.
2. Know the relative risk of infection at various values of the absolute neutrophil count.
3. Discuss the differences between inherited and acquired causes of neutropenia.
4. List the initial studies to evaluate patients who have neutropenia.
IntroductionThe significance of neutropenia is a common query to hematology specialists from primary
care physicians. Severe neutropenia is defined as an absolute neutrophil count (ANC) of
fewer than 500/mcL (0.5109
/L) and is a common and expected complication of chemotherapy for childhood neoplasms. This article considers those patients who have
neutropenia unrelated to chemotherapy toxicity. This type of neutropenia may be noted
when a complete blood count (CBC) is performed in a sick newborn, a febrile child, a child
taking chronic medication, or as part of a routine evaluation. Severe hereditary conditions
such as Kostmann syndrome and certain immunodeficiency syndromes associated with
neutropenia are rare, perhaps 1 per 100,000, and are more likely to present in neonates and
infants, although acquired conditions such as immune neutropenia and neutropenia
related to infection also occur in this age group. A mild-to-moderate decrease in the ANC
(percent neutrophils times the total white count) frequently is seen in viral illness or related
to medication use as well as in some healthy persons of African ancestry. A number of
inherited conditions associated with neutropenia are associated with other congenital
anomalies such as dysplastic thumbs in Fanconi anemia, albinism in Chediak-Higashisyndrome, and dwarfism in the cartilage hair or Shwachman-Diamond syndromes.
When to Order a CBC A CBC is not ordered routinely for well children examined in the pediatrician’s office or
when children present with common febrile illnesses such as upper respiratory tract
infections or otitis media. A CBC is warranted if clinical findings suggest a more severe
bacterial infection. Such clinical findings include, but are not limited to, recurrent
infections; prolonged or extreme fever (103°F [39.5°C]); the spreading of localized
bacterial infection; infection of the lung, peritoneum, genitourinary tract, or central
nervous system; and suspicion of chronic inflammatory disease, immunodeficiency, or
malignancy. A CBC also may be warranted if a patient’s clinical course is atypical,
prolonged, or complicated by signs and symptoms suggesting the development of asecondary bacterial infection.
Normal Values for the ANC and the Definition of NeutropeniaNormal values for the ANC vary by age, particularly during the first weeks after birth.
Normal leukocyte counts and ANCs for children from birth to age 21 years are shown in
Table 1. The ANC range is shown for each age, as well. The lower limit of normal is
6,000/mcL (6.0109/L) during the first 24 hours after birth, 5,000/mcL (5.0109/L)
for the first week, 1,500/mcL (1.5109/L) during the second week, 1,000/mcL
*Professor, Department of Pediatrics, Division of Hematology Oncology.†Associate Professor of Pediatrics, Division of General Pediatrics, University of Rochester School of Medicine & Dentistry,
Rochester, NY.
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(1.0109/L) between 2 weeks and 1 year of age, 1,500/
mcL (1.5109/L) from ages 1 year through 10 years,
and 1,800/mcL (1.8109/L) thereafter. However,
most reports use 1,500/mcL (1.5109/L) as the lowerlimit of normal for white adults. Adults and children of
African extraction may have ANCs between 1,000 and
1,500/mcL (1.0 and 1.5109/L), which overlaps the
values observed in patients who have “mild neutrope-
nia.” We estimate from the data available that at least 3%
to 5% of persons of African ancestry have ANCs below
1,500/mcL (1/5109/L).
Risk AssessmentFor patients older than 1 year of age, mild neutropenia is
defined as an ANC of 1,000 to 1,500/mcL (1.0 to
1.5109
/L), moderate neutropenia as an ANC of 500 to 1,000/mcL (0.5 to 1.0109/L), and severe
neutropenia as an ANC of less than 500/mcL
(0.5109/L). Usually, patients are highly susceptible to
bacterial infection if the ANC is less than 500/mcL
(0.5109/L), with the risk of infection greatest at the
lowest ANCs. Increased infection risk also is related to
longer durations of neutropenia and is highest if the
neutrophil count remains low without recovery. If neu-
trophils can be mobilized to respond, infection is less
likely to occur, as can be seen in immune neutropenia, a
condition in which there is myeloid hyperplasia and
heightened neutrophil production. Although serious
bacterial infections are observed when the ANC is be-
tween 500 and 1,000/mcL (0.5 and 1.0109/L), they
are much less frequent or severe. There is little or no
heightened infectious risk if the ANC is greater than1,000/mcL (1.0109/L).
Pyogenic Infections Associated WithNeutropeniaModerate-to-severe neutropenia may portend an inade-
quate neutrophil response to bacterial infection. The
clinical signs of neutropenia may include ulcerations of
the oral mucosa or gingival inflammation. Otitis media,
skin infections that include cellulitis and pustules, adeni-
tis, pneumonia, and bacterial sepsis may occur. The
source of the infection may be the child’s own skin or
bowel flora. Perianal infection and ischiorectal fossa ab-scesses sometimes are seen. The most common offending
organisms are Staphylococcus aureus and the gram-
negative bacteria (see section on fever and neutropenia).
Initial Evaluation of the Patient Who HasNeutropeniaThe initial evaluation (Table 2) should include a history
and physical examination. It is critical to know whether
the child has had recurrent bacterial infections, whether
there is a family history of neutropenia or infection, and
after physical examination, whether there are any associ-
ated congenital anomalies that suggest an inherited syn-
Table 1. Normal Blood Leukocyte Counts*
Age
Total Leukocytes Neutrophils Lymphocytes Monocytes Eosinophils
Mean (Range) Mean (Range) % Mean (Range) % Mean % Mean %
Birth 18.1 (9.0 to 30.0) 11.0 (6.0 to 26.0) 61 5.5 (2.0 to 11.0) 31 1.1 6 0.4 212 h 22.8 (13.0 to 38.0) 15.5 (6.0 to 28.0) 68 5.5 (2.0 to 11.0) 24 1.2 5 0.5 224 h 18.9 (9.4 to 34.0) 11.5 (5.0 to 21.0) 61 5.8 (2.0 to 11.5) 31 1.1 6 0.5 21 wk 12.2 (5.0 to 21.0) 5.5 (1.5 to 10.0) 45 5.0 (2.0 to 17.0) 41 1.1 9 0.5 42 wk 11.4 (5.0 to 20.0) 4.5 (1.0 to 9.5) 40 5.5 (2.0 to 17.0) 48 1.0 9 0.4 31 mo 10.8 (5.0 to 19.5) 3.8 (1.0 to 9.0) 35 6.0 (2.5 to 16.5) 56 0.7 7 0.3 36 mo 11.9 (6.0 to 17.5) 3.8 (1.0 to 8.5) 32 7.3 (4.0 to 13.5) 61 0.6 5 0.3 31 y 11.4 (6.0 to 17.5) 3.5 (1.5 to 8.5) 31 7.0 (4.0 to 10.5) 61 0.6 5 0.3 32 y 10.6 (6.0 to 17.0) 3.5 (1.5 to 8.5) 33 6.3 (3.0 to 9.5) 59 0.5 5 0.3 34 y 9.1 (5.5 to 15.5) 3.8 (1.5 to 8.5) 42 4.5 (2.0 to 8.0) 50 0.5 5 0.3 36 y 8.5 (5.0 to 14.5) 4.3 (1.5 to 8.0) 51 3.5 (1.5 to 7.0) 42 0.4 5 0.2 3
8 y 8.3 (4.5 to 13.5) 4.4 (1.5 to 8.0) 53 3.3 (1.5 to 6.8) 39 0.4 4 0.2 210 y 8.1 (4.5 to 13.5) 4.4 (1.8 to 8.0) 54 3.1 (1.5 to 6.5) 38 0.4 4 0.2 216 y 7.8 (4.5 to 13.0) 4.4 (1.8 to 8.0) 57 2.8 (1.2 to 5.2) 35 0.4 5 0.2 321 y 7.4 (4.5 to 11.0) 4.4 (1.8 to 7.7) 59 2.5 (1.0 to 4.8) 34 0.3 4 0.2 3
*Numbers of leukocytes are in thousands/mcL (109/L), ranges are estimates of 95% confidence limits, and percentages refer to differential counts.Neutrophils include band cells at all ages and a small number of metamyelocytes and myelocytes in the first few postnatal days.From Dallman PR. Blood and blood-forming tissues. In: Rudolph AM, ed. Rudolph’s Pediatrics . 16th ed. New York, NY: Appleton-Century-Crofts;1977:1178, with permission.
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drome. Mouth ulcers may occur in association with
neutropenia, and the presence of gingivitis is a good
indicator that the patient cannot mobilize adequate neu-
trophils and, thus, may be susceptible to severe infection.
If neutropenia is suspected, it is important to determine if the patient has isolated neutropenia or neutropenia asso-
ciated with anemia or thrombocytopenia. The clinical
implication of deficits of more than one cell type is
different from that of an isolated neutropenia. Anemia or
thrombocytopenia in conjunction with neutropenia of-
ten reflects a more generalized marrow failure syndrome
such as aplastic anemia or a marrow infiltrative process
such as leukemia. The neutropenia must be confirmed by
repeating the CBC to avoid an extensive evaluation due
to a laboratory error.
It is reasonable to observe the patient who has a viral
illness and mild-to-moderate neutropenia and otherwise
appears well. If the neutropenia persists or progresses
after 1 to 2 weeks, additional evaluation is necessary. If
the neutropenia is recurrent, obtaining blood counts two
to three times per week for several weeks can establish
any cycles of neutropenia. If additional evaluation is
warranted, the presence of antineutrophil antibodies
suggests immune neutropenia, and quantifying immu-
noglobulins, including IgG, IgA, and IgM, and the
distribution of lymphocyte subsets may indicate an un-
derlying immunodeficiency syndrome. In addition,
screening tests for systemic lupus erythematosus, includ-
ing an antinuclear antibody titer and anti-double-
stranded DNA, can be helpful. If a patient has severe
neutropenia, referral to a hematologist is necessary. If
severe congenital neutropenia is suspected, assessing forthe HAX1 mutation for Kostmann disease and ELA2
mutation for dominant or sporadic severe congenital
neutropenia is indicated. A detailed presentation of the
potential laboratory evaluation by hematology is shown
in Table 3.
Acquired NeutropeniaInfection
When evaluating the child who has neutropenia, the
acquired neutropenias are considered first because of
their greater frequency (Table 4). The most common
underlying cause for mild-to-moderate neutropenia istransient marrow suppression due to a variety of viral
infections. Neutropenia is seen in patients who have
Epstein-Barr virus, respiratory syncytial virus, influenza A
and B, hepatitis, and human herpesvirus 6 infections
as well as the exanthems (to which most children are
immunized), including varicella, rubella, and rubeola.
Neutropenia occurs often during the first few days of the
viral illness and persists for 3 to 8 days. Severe bacterial
infection also may cause neutropenia rather than neutro-
philia, which can be transient if the bacterial infection is
treated effectively. Other bacterial or rickettsial diseases
such as typhoid fever, tuberculosis, and Rocky Mountainspotted fever may cause neutropenia.
Drug-induced A variety of medications (Table 5), including antibiotics,
anticonvulsants, and anti-inflammatory agents, have
been associated with neutropenia, a frequent reason for
referral to hematology. The dilemma is how to treat the
patient who requires the particular medication that is
causing a potentially dangerous adverse effect. If the
drug-induced neutropenia is idiosyncratic, its severity
and persistence may be impossible to predict, and it is
difficult to avoid discontinuing the drug. A similar situ-
Table 2.
Initial Evaluation forPatients Who HaveNeutropenia
History
● History of underlying disease, congenital anomalies,medication exposure, or recent infection or mouthulceration
● Other family members who have neutropenia andserious infections, hospitalizations, or blood diseases
Physical Examination
● Short stature, malnutrition, skeletal abnormalities
● Abnormal skin pigmentation, dystrophic nails,leukoplakia, warts, albinism, fine hair, eczema, skininfections, adenopathy, and organomegaly
CBC With Differential Count and ReticulocytePercentage
● Confirm the finding of neutropenia, evaluateneutrophil morphology, and assess whether red cellproduction is increased or decreased
● If the neutropenia resolves and is recurrent, repeattwo to three times per week for 6 weeks
Other Laboratory Tests
● Blood smear● Coombs test (direct antiglobulin test) for associated
hemolytic anemia● Immunoglobulins (IgA, IgG, IgM)● Serology (Epstein-Barr virus, cytomegalovirus,
respiratory syncytial virus, parvovirus, etc, asindicated clinically)
● Antineutrophil antibodies
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per day administered orally in two divided doses, and theinitial dose of G-CSF is 5 mcg/kg administered subcu-
taneously once a day. These therapies usually are admin-
istered under the guidance of a pediatric hematologist.
Secondary autoimmune neutropenia more often af-
fects adults and is seen in systemic autoimmune diseases,
such as systemic lupus erythematosus, rheumatoid arthri-
tis (Felty syndrome), or systemic sclerosis; in certain
infections, such as those due to human immunodefi-
ciency virus, parvovirus B19, or Helicobacter pylori; or in
drug-induced neutropenia. Secondary autoimmune neu-
tropenia also has been reported in association with Wilms
tumor and Hodgkin disease. Treatment of secondary neutropenias is directed toward the primary disease. Ad-
ministration of G-CSF may be considered if the neutro-
penia is severe and protracted.
Chronic IdiopathicChronic idiopathic neutropenia likely represents a variety
of disorders and is not well characterized. Some of the
patients classified as having chronic idiopathic neutrope-
nia actually may have immune neutropenia or familial
benign neutropenia. The “idiopathic” diagnosis may be
considered when other known causes have been elimi-
nated. The clinical severity appears to be related to the
severity of neutropenia, and the marrow findings are notconsistent. Ineffective or decreased production of neu-
trophils may be seen in this condition. Many hematolo-
gists watch patients whose conditions appear truly “idio-
pathic” and whose neutropenia is mild and not associated
with an increase in infections, keeping the evaluation to a
minimum rather than pursuing a more extensive evalua-
tion that often yields nothing. When therapy is indicated,
glucocorticoids and G-CSF have been used.
Sequestration
Splenomegaly and hypersplenism from any cause may result in mild neutropenia (1,000 to 1,500/mcL [1.0 to
1.5109/L]) due to sequestration. Enlarged spleens
may be present in patients who have chronic hemolytic
anemias, liver disease, or portal hypertension and in
metabolic disorders such as Gaucher disease. These con-
ditions also may result in anemia and thrombocytopenia.
Results of the marrow examination are normal or show
mild hyperplasia of all elements. Usually, this problem
does not require treatment unless the cytopenias are
profound or management of the underlying condition
requires treatment. In some cases, splenectomy is neces-
sary.
Table 4. Acquired Neutropenia
Condition Pathogenesis Occurrence Associated Findings
Infection Viral marrow suppression orviral-induced immuneneutropenia
Common EBV/parvovirus/HHV6 and other viruses
Bacterial sepsis-endotoxinsuppression
Less common Severe infection
Drug-induced Direct marrow suppression Common Underlying conditionImmune destruction Less common
Autoimmune Primary (molecularmimicry)
Secondary (SLE, Evanssyndrome)
Common Monocytosis common
Newborn Immune Alloimmune—maternal
sensitization
Rare Antigen difference in newborn and
motherDue to maternalautoimmune neutropenia
Maternal neutropenia
Chronic Idiopathic Ineffective or decreasedproduction
Common Consider also familial benignneutropenia
Often asymptomaticSequestration Hypersplenism Common if spleen is enlarged Mild neutropenia
Enlarged spleen—many causesNutritional Vitamin B
12 or folic acid
deficiencyRare in children Marrow megaloblastic
Impaired DNA processing Hypersegmented neutrophils
EBV Epstein-Barr virus, HHV human herpesvirus, SLEsystemic lupus erythematosus.
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Nutritional DeficiencyBoth vitamin B12 and folic acid deficiency may result in
ineffective hematopoiesis with megaloblastic erythropoi-
esis. Patients who develop megaloblastic anemia gener-
ally are adults. In addition to megaloblastic anemia, the
impairment in DNA processing may result in neutrope-
nia. Neutrophil nuclear maturation is impaired, leading
to hypersegmentation of the neutrophil nuclei in theblood as well as ineffective marrow proliferation and
maturation. Treatment involves replacement of the defi-
cient factor.
Inherited Neutropenia (Table 6)Severe Congenital
Severe congenital neutropenia may present as early as
infancy with umbilical infection, pyoderma, oral ulcers,
pulmonary infections, or perineal infections of the labia
or perirectal area. The ANC is less than 500/mcL
(0.5109/L) and often less than 200/mcL (0.2109/
L). Severe congenital neutropenia may be inherited as an
autosomal recessive condition (Kostmann syndrome) in-
volving mutations in the HAX1 gene that is involved in
signal transduction. It also may be inherited as an auto-
somal dominant condition, with mutations in the neu-
trophil elastase gene (ELA2 ) or, more rarely, in the GFI1
gene that targets ELA2 . It has been suggested that such
gene mutations result in accelerated apoptosis of myeloid
precursors. Examination of the marrow reveals an arrestat the promyelocyte stage of development (a picture of
bone marrow in severe congenital neutropenia is avail-
able in the online edition of this issue of Pediatrics in
Review [www.pedsinreview.org]). Few or no myelo-
cytes, metamyelocytes, bands, or mature neutrophils are
seen, and there may be an associated monocytosis and
eosinophilia in the blood. Affected patients have a very
high risk of developing a myelodysplastic syndrome or
acute myelogenous leukemia, a consequence that has
become more evident as patients live longer with treat-
ment using G-CSF. Table 7 describes G-CSF administra-
tion.
Table 5. Partial List of Drugs Associated With Idiosyncratic Neutropenia
Possible Mechanism
DrugDirectSuppression
MetaboliteSuppression
ImmuneDestruction
Analgesics/Anti-inflammatory AgentsAminopyrine XIbuprofen XIndomethacin XPhenylbutazone X
AntibioticsChloramphenicol XPenicillins X XSulfonamides X
Anticonvulsants
Phenytoin XCarbamazepine X
Antithyroid AgentsPropylthiouracil X
Cardiovascular AgentsHydralazine XProcainamide XQuinidine X
Hypoglycemic AgentsChlorpropamide X
TranquilizersChlorpromazine XPhenothiazines X
Other
Cimetidine, ranitidine XLevamisole X
Reproduced from Dinauer MC. The phagocyte system and disorders of granulopoiesis and granulocyte function. In: Nathan DG, Orkin SH, Look AT,Ginsburg D, eds Nathan andOski’s Hematology of Infancy andChildhood. 6th ed. Philadelphia, Pa: WB Saunders Company; 2003:923–1010 withpermission.
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Table 6. Inherited Neutropenia
Condition Inheritance Pathogenesis Occurrence Associated Findings
Severe Congenital(Kostmann)
AR HAX1 mutationscausing disturbedregulation of myeloidhomeostasis
Marrow arrest at thepromyelocyte stage
Rare (1/1 to 200,000) ANC
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CyclicCyclic neutropenia is characterized by approximately
21-day cycles of changing neutrophil counts, with neu-
tropenia spanning 3 to 6 days. The nadir of the neutro-
phil count may be in the severe range. Fever and oral
ulcerations usually are seen during the nadir. Patients
also may develop gingivitis, pharyngitis, and skin infec-
tions. However, by the time the patient comes to medical
attention, the neutrophil count may be recovering.
Therefore, diagnosing cyclic neutropenia may require
obtaining blood counts two to three times per week for
4 to 6 weeks in an effort to observe the periodicity of the
cycle.
More serious infections include pneumonia, necrotiz-ing enterocolitis with peritonitis, and Escherichia coli or
Clostridium sepsis. Marrow findings reflect the state of
neutropenia. Prior to the ANC nadir, the marrow may
resemble that associated with severe congenital neutro-
penia before proceeding to a recovery phase. The peri-
odicity of marrow activity also may be seen in the ery-
throid series. As in severe congenital neutropenia,
mutations occur in the ELA2 gene, but at different
locations (Table 6). Also, there does not appear to be an
increased risk of myelodysplasia or acute myelogenous
leukemia. Prophylactic G-CSF has been recommended
to prevent severe symptoms at the nadir of the cycle.
Table 6. Inherited Neutropenia Continued
Condition Inheritance Pathogenesis Occurrence Associated Findings
Chediak-Higashi Syndrome AR CHS1 ?defect inlysosomal fission
Abnormal proteintrafficking
Decreased neutrophilchemotaxis,degranulation,and killing
Rare 2NK and T-cell functionAlbinismNeurologic damage and giant
lysosomes
Reticular Dysgenesis AR Stem cell failure inlymphoid andmyeloid development
Rare Severe combinedimmunodeficiency withneutropenia
Cartilage Hair AR RMRP mutations
Defect in a ribonuclearprotein ribonuclease
Rare Fine hair, short-limbed,
dwarfism, lymphopenia,2CD4 and 2CD8 cellsInfections, particularly varicella
zosterMetabolic Glycogen
Storage Disease 1b(also aminoacidopathies)
AR G6PT1 mutations(glucose-6-phosphatetranslocase) in 1b
1/105 live births Hypoglycemia, dyslipidemia,1uric acid, 1lactic acid, andneutropenia in most patients
Griscelli Syndrome Type 2 AR RAB27A mutationsImpaired lytic granule
release
Rare Partial albinism, neutropenia,infections, andthrombocytopenia withhemophagocytosis and T-celldefect
Barth Syndrome XR TAZ mutation on the Xchromosome
Cardiolipin defect
Rare Dilated cardiomyopathySkeletal myopathy
Mitochondrial abnormalitiesWiscott-Aldrich Syndrome XR Mutations in the Cdc42
binding site in theWASP gene
Results in X-linkedneutropenia
1 to 10/106 Impaired lymphoid developmentand maturation of monocytes
Associated with eczema,thrombocytopenia, andimmune deficiency
Selective IgA Deficiency Unknown ormultifactorial
Unknown Common (1/600) Infections of the upper andlower respiratory tracts inone third of patients
AR autosomal recessive, ADautosomal dominant, ANCabsolute neutrophil count, Igimmunoglobulin, NK natural killer, RBCred blood cell,XR X-linked recessive.
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Shwachman-Diamond SyndromePatients who have Shwachman-Diamond syndrome usu-
ally have a mild-to-moderate degree of neutropenia in
association with exocrine pancreatic insufficiency, short
stature, metaphyseal dysplasia, marrow failure, and the
risk of myelodysplasia and acute myelogenous leukemia.
A defect in RNA processing leads to a failure of neutro-
phil development. Malabsorption and failure to thrive
are common problems, and affected patients may de-
velop infections because of the neutropenia and a possi-
ble defect in chemotaxis. G-CSF has been used when theneutropenia is symptomatic; pancreatic replacement
therapy is required.
Marrow Failure SyndromesFANCONI ANEMIA. Fanconi anemia is characterized
by pancytopenia (with all cell lines affected). It presents
most commonly in the second half of the first decade of
life, and thrombocytopenia may precede the develop-
ment of anemia and neutropenia. The marrow is hypo-
plastic and resembles aplastic anemia. The disease is
characterized by a defect in DNA repair leading to exten-
sive chromosomal breakage, and there is hypersensitivity to DNA cross-linking agents such as diepoxybutane in
vitro. Affected patients have mutations in the FANC
genes, primarily in FANC A , C , and G . Clinically, pa-
tients may have short stature; dysplastic thumbs; or heart,
kidney, or eye abnormalities. They have a nearly 10% risk
of developing a myelodysplastic syndrome or acute my-
elogenous leukemia. The pancytopenia may respond to
androgen treatment, which is particularly difficult to use
in young women. G-CSF and other cytokines may be
effective, but their efficacy may not be sustained. The
only curative treatment for Fanconi anemia is stem cell
transplantation.
DYSKERATOSIS CONGENITA (ZINSSER-ENGMAN-COLE
SYNDROME). This abnormality results from a mutation
in the DKC1 gene that encodes dyskerin, a component
of the telomerase complex, which is responsible for the
elongation of DNA. Affected patients exhibit abnormal
skin pigmentation, leukoplakia, and dystrophic nails. The
skin and mucosal lesions appear in the second decade,
and marrow failure develops in early adulthood. Patients
may present with isolated neutropenia, but more often,
all cell lines are affected. Hematopoietic growth factors,
such as G-CSF, may be useful in treating the neutrope-nia. Abnormalities of T-helper cells and dysgamma-
globulinemia may contribute to a susceptibility to infec-
tion in some patients.
Syndromes Associated With Neutropenia andImmunodeficiency
A variety of syndromes include neutropenia and abnor-
malities in T, B, or natural killer cell function. The
combined problem of neutropenia and immunodefi-
ciency makes patients who have these syndromes more
susceptible to infectious complications. One condition is
the hyper-IgM syndrome, in which concentrations of
IgG and IgA are diminished and IgM is heightened. The
nature of the neutropenia is not known, but may be
immune in origin, although antineutrophil antibodies
are negative. Other syndromes associated with neutrope-
nia and immunodeficiency are listed in Table 6; their
associated findings are particularly important for defining
these rare syndromes.
Fever and Neutropenia A very difficult issue is how best to treat a patient who has
fever and neutropenia. Although detailed guidelines have
Table 7. Treatment of Neutropenia
Granulocyte Colony-stimulating Initially 5 mcg/kg per day subcutaneouslyFactor If no response after 1 wk, the dose may be doubled repeatedly up to 100 mcg/kg per day
Glucocorticoids Prednisone 2 mg/kg per day PO for immune neutropeniaNutritional Vitamin B
12 1,000 mcg each week for 5 to 6 wk, then q 1 mo subcutaneously if B
12-
deficientFolic acid 1 mg/d PO
Splenectomy Prior immunization to encapsulated bacterial (pneumococcus, Haemophilus influenzae type b, meningococcus) required
Prophylactic penicillin after splenectomy 125 mg bid age 5 yMedication Revision If possible, reduce dosage or discontinue any medications associated with neutropeniaAntibiotics As appropriate for patient’s age, type and location of infection, and if possible, culture
resultsGranulocyte Transfusion May be useful in invasive bacterial or fungal infections for patients who have severe
neutropenia (ANC
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been formulated for patients who have chemotherapy-
induced neutropenia, relatively few data are available for
patients who have neutropenia not associated with can-
cer treatment. Fever is defined as a temperature greater
than 101°F(38.3°C) or a temperature of at least 100.4°F(38°C) for longer than 1 hour. Most authors categorize
the severity of neutropenia into three groups (Table 8).
The decision surrounding treatment and potential hos-
pitalization depends on the likelihood of bacterial infec-
tion, the location and severity of the infection, the sever-
ity of the neutropenia, and the likelihood and timeframe
of neutrophil recovery. Furthermore, the age of the
patient, the proximity of specialized medical care, and
the reliability of the guardians should be considered in
the management decision. Table 8 presents a starting
point for consideration of “what to do” and is based on
the principles used in the care of neutropenic chemother-
apy patients and the concerns of pediatric hematologists
and infectious disease specialists.
Specific recommendations for initial broad-spectrum
antibiotic coverage depend on the prevalence of organ-
isms in each community and hospital and their suscepti-bility patterns. Approximately two thirds of isolated or-
ganisms are gram-positive (Table 9). Initial antibiotic
treatment may employ a single broad-spectrum antibi-
otic such as ceftazidime or cefepime. Alternatively, an
aminoglycoside can be combined with a beta-lactam
drug such as a third- or fourth-generation cephalosporin
for broad antibiotic coverage. The initial addition of
vancomycin is controversial, but should be done if resis-
tant organisms are suspected because of their prevalence
in the community.
When to discontinue antibiotic treatment is a partic-
ular problem for physicians caring for patients who have
Table 8. Fever and Neutropenia
ANC Etiology of Fever Management Outpatient/Hospital
1,000 to 1,500/mcL Viral (frequent) Supportive Outpatient
(1.0 to 1.5109 /L)Mild
Bacterial: URI(sinusitis, purulentrhinitis), otitismedia, local skininfections
Indicated PO antibiotics Outpatient
Bacterial pneumonia,systemicsymptoms, GUinfections,lymphadenitis
Blood culturesSpecific culturesBest estimate
antibioticsObservation for
progression
Outpatient unlessprogression
500 to 1,000/mcL Viral Supportive Outpatient
(0.5 to 1.0109 /L)Moderate
Bacterial: URI(sinusitis, purulentrhinitis), otitismedia, local skininfections
Blood and othercultures
Indicated PO or IV antibiotics
Outpatient/Hospital*
Bacterial pneumonia,systemicsymptoms, GUinfections,lymphadenitis
Blood culturesSpecific culturesSepsis evaluationParenteral broad-
spectrum antibiotics
Hospital
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neutropenia. If the blood cultures are negative and the
child becomes afebrile, antibiotics can be stopped, even if
the neutropenia persists. Usually, antibiotics are contin-ued if the cultures are negative and the child remains
febrile and neutropenic. Fever generally resolves quickly
with antibiotic therapy if the neutropenia resolves. If the
cultures are positive and the child is no longer febrile and
neutropenic, the prescribed antibiotic treatment may be
completed with oral antibiotics at home. If the cultures
are positive and the child is afebrile but persistently
neutropenic, the course of antibiotics usually is com-
pleted in the hospital. The child then is observed for
24 to 48 hours prior to discharge. The persistence of
neutropenia requires the additional evaluation described
in this article and consideration of treatment with G-CSF
if the neutropenia is profound and there are frequent
infections.
The Medical Emergency of Fever With SevereNeutropeniaHospitalization is required for patients who have severe
neutropenia (specifically neutrophil counts less than
500/mcL [0.5109/L]), moderate neutropenia and se-
vere infection, or any level of neutropenia combined with
ill appearance, as well as consultation with pediatric
hematology and pediatric infectious disease services. Pa-
tients who have immune neutropenia of infancy often
can be treated as outpatients because they can mobilize
neutrophils transiently. The hematologist can help estab-
lish the cause of the neutropenia, and the infectiousdisease specialist can help identify the type and suscepti-
bility of the infecting bacteria in the specific community.
If the patient is seen in the office, a blood culture(aerobic
and anaerobic) and a urinalysis and urine culture (no
catheter should be used) can be obtained and the initial
dose of antibiotics administered. If possible, an intrave-
nous line should be kept open. The patient should be
transported to the hospital by ambulance because septic
shock may occur after administration of the first dose of
antibiotics.
On arrival at the emergency department, venous ac-
cess should be ensured, and vital signs with oxygensaturation, a CBC with differential count and platelet
count, and a metabolic profile should be obtained. No
rectal temperatures should be taken, rectal examinations
performed, or rectal medications administered because
of the risk of generating a perianal or perirectal infection.
However, careful examination of the mouth, oral mu-
cosa, lungs, abdomen, and perineal/perianal area is im-
portant. A chest radiograph may be warranted if there are
respiratory signs or symptoms, but its usefulness may be
limited because the lack of neutrophils may not produce
a visible infiltrate in patients who have severe neutro-
penia.
Anticipatory Guidance for the Patient WhoHas NeutropeniaParents of patients who have neutropenia need to contact
a health-care practitioner at the onset of any febrile illness
to assure prompt, appropriate care. The parents must
know what is required for the evaluation (including the
history and physical examination, blood counts and
ANC, blood and other cultures) and the initial treatment
(usual antibiotic recommendation and route of adminis-
tration for their child) because they may not be near a
major medical center, particularly when traveling. A per-
Table 9.
Bacterial Causes of Febrile Episodes inNeutropenic Patients
Aerobic Bacteria (90%)*
Gram-positive Cocci (45%)
Staphylococcus Coagulase-positive (S aureus )Coagulase-negative (S epidermidis and others)
Streptococcus S pneumoniae S pyrogenes viridans group
Enterococcus faecalis/faeciumGram-positive bacilli (rare)
Corynebacterium spGram-negative Bacilli (45%)
Escherichia coli Klebsiella spPseudomonas aeruginosa
Anaerobic Bacteria (4% to 5%) (Often Polymicrobial)
Gram-positive Cocci (normal mouth flora)PeptococciPeptostreptococci
Gram-negative BacilliBacteroides fragilis Fusobacterium sp
*Percentages observed in patients receiving chemotherapy who wereimmunocompromised (Mathur P, Chaudry R, Kumar L, Kapil A,Dhawan B. A study of bacteremia in febrile neutropenic patients at atertiary-care hospital with special reference to anaerobes. Med Oncol .2002;19:267–272). Specific organisms were reported by Hughes WT,
Armstrong D, Bodey GP, et al. 1997 guidelines for the use of antimi-crobial agents in neutropenic patients with unexplained fever. Infec-tious Diseases Society of America. Clin Infect Dis. 1997;25:551–573 and Merck & Co, Inc, Whitehouse Station, NJ, USA: 1995–2007(http://www.merck.com/mmpe/sec14/ch178/ch178j.html).
hematology/oncology neutropenia
22 Pediatrics in Review Vol.29 No.1 January 2008
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mission form may be necessary to allow carrying of
injectable medications, such as G-CSF, syringes, and
hypodermic needles on airplanes. Parents should carry a
current written summary of the child’s condition and
laboratory values and the contact numbers of their pri-
mary institution and physicians.
It is important to maintain good oral hygiene and
appropriate preventive dental visits, particularly for pa-
tients who have chronic neutropenia, to avoid chronic
gingival or dental infection. Good skin care and prompt
cleansing of superficial cuts, abrasions, and bruises where
the skin is broken help to prevent local infection. All
immunizations can and should be given according to
the routine vaccination schedule, as long as the pa-
tient’s neutropenia is not associated with an immunode-ficiency syndrome. Children who have impaired T- or
B-lymphocyte function should not receive live or
attenuated-live vaccines. Recommendations for the ad-
ministration of specific vaccines can be found in the
American Academy of Pediatrics Red Book and in the
“Pink Book” produced by the Centers for Disease Con-
trol and Prevention, “Epidemiology and Prevention of
Vaccine-preventable Diseases.”
Child care and school attendance are reasonable for
most children who have mild-to-moderate neutropenia,
although contact with obviously ill children should be
avoided. Children who have severe neutropenia or ahistory of serious infections with neutropenia require
greater isolation to avoid exposure to infectious agents.
Genetic counseling for the family of patients who have
inherited neutropenias is indicated, and siblings should
be tested for the disorder. Families of patients who have
neutropenia may experience significant stress due to feel-
ing responsible for the disease if it is an inherited condi-
tion or for exposing the child to infectious complications,
caring for a child who has a chronic illness, and managing
multiple physician and hospital visits. Most pediatric
hematology/oncology units have social workers, parent
advocates, and advanced-practice nurses who can pro- vide the types of support services required by patients and
their parents.
SummaryNeutropenia unrelated to chemotherapy toxicity occurs
in a number of clinical settings. The most common
conditions associated with neutropenia are those that are
acquired, including viral infection, neutropenia associ-
ated with various medications, and immune neutropenia.
Inherited neutropenias are rarer and often more pro-
found. These disorders include the dominant or sporadic
types of severe congenital neutropenia (often with mu-
tations in the ELA2 gene), the recessive type or Kost-
mann syndrome, and the marrow failure syndromes such
as Fanconi anemia. Cyclic neutropenia may be severe at
the nadir of the cycle. Of particular concern is the occur-
rence of fever in conjunction with neutropenia. This
combination creates a medical emergency that must be
addressed with appropriate evaluation and prompt ad-
ministration of antibiotics. The actual risk of severe in-
fection and the likelihood of recovery depend not only
on the level of the ANC, but on the duration of the
neutropenia. If recovery from the neutropenia is not
expected, as in severe congenital types, G-CSF adminis-
tration may be indicated.
To view an additional Suggested Reading list and
figures related to this article, visit www.pedsinreview.
org and click on Neutropenia in Pediatric Practice.
Suggested Reading Atallah E, Schiffer CA. Granulocyte transfusion. Curr Opin Hema-
tol. 2006;13:45–49Baehner RL. Drug-induced neutropenia and agranulocytosis. Up-
ToDate. 2007. Available at: www.uptodate.comBertuch AA, Strother D. Fever in children with non-chemotherapy-
induced neutropenia. UpToDate. 2007. Available at: www.up-todate.comBertuch AA, Strother D. Management of fever in children with
non-chemotherapy-induced neutropenia. UpToDate. 2007. Available at: www.uptodate.com
Beutler E, West C. Hematologic differences between African- American and whites: the roles of iron deficiency and alpha-thalassemia on hemoglobin levels and mean corpuscular vol-ume. Blood. 2005;106:740–745
Boxer LA. Neutrophil abnormalities. Pediatr Rev. 2003;24:52–62Boxer LA, Stein S, Buckley D, Bolyard AA, Dale DC. Strong
evidence for autosomal dominant inheritance of severe congen-
ital neutropenia associated with ELA2 mutations. J Pediatr.
2006;148:633–636Hughes WT, Armstrong D, Bodey GP, et al. 1997 guidelines for
the use of antimicrobial agents in neutropenia patients withunexplained fever. Clin Infect Dis. 1997;25:551–573
Klein C, Grudzien M, Appaswamy G, et al. HAX1 deficiency causesautosomal recessive severe congenital neutropenia (Kostmanndisease). Nat Genet. 2007;39:86–92
Lehrnbecher T, Welte K. Haematopoietic growth factors in chil-dren with neutropenia. Br J Haematol. 2002;116:28–56
Palmblad JEW, von dem Borne AEG Jr. Idiopathic, immune,
infectious and idiosyncratic neutropenias. Semin Hematol.
2002;39:113–120Skokowa J, Germeshausen M, Zeidler C, Welte K. Severe congen-
ital neutropenia: inheritance and pathophysiology. Curr Opin
Hematol. 2007;14:22–28
hematology/oncology neutropenia
Pediatrics in Review Vol.29 No.1 January 2008 23
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PIR QuizQuiz also available online at www.pedsinreview.org.
6. A 6-year-old boy presents with a history of a temperature to 103°F (39.4°C) and ulcerations on his lipsand buccal mucosa 2 days ago. The child has some small, slightly ulcerated areas on his lips and isafebrile. His mother reports two similar episodes in the past 2 months. He has a white blood cell count of 2.9103 /mcL (2.9109 /L), hemoglobin of 11.4 g/dL (114 g/L), and platelet count of 349103 /mcL(349109 /L). His differential count is 40% neutrophils, 49% lymphocytes, 9% monocytes, and 2%eosinophils. Of the following, the best laboratory test to evaluate this child is:
A. Antineutrophil antibodies.B. Blood counts two to three times a week for 4 to 6 weeks.C. Bone marrow aspiration.D. Herpes cultures.E. Repeat of the count in 1 week to see if it normalizes.
7. A previously well 3-year-old boy presents with 4 days of temperature up to 104°F (40°C). He is in noacute distress and does not appear ill. The only abnormal physical finding is mild rhinitis. A completeblood count reveals a white blood cell count of 1.5103 /mcL (1.5109 /L), hemoglobin of 12.8 g/dL(128 g/L), and platelet count of 349103 /mcL (349109 /L). His differential count is 2% neutrophils,80% lymphocytes, 10% monocytes, and 6% eosinophils. A blood culture is obtained. After a single doseof acetaminophen, the child becomes afebrile. Of the following, the most appropriate next step is to:
A. Give a dose of broad-spectrum antibiotics and admit the child for continuing intravenous antibiotics.B. Give a dose of ceftriaxone and see the child the following morning.C. Observe the child in the emergency department overnight.D. See the child the following morning but tell the parents to call sooner if he becomes more ill.E. Start amoxicillin and clavulanic acid orally and see the child the following morning.
8. The mother of a well 4-month-old child would like you to obtain a complete blood count to make sureher baby is “OK.” You determine that she has no specific anxieties or reasons for suspecting a problem. Of the following, the most appropriate response is to:
A. Explain that a routine complete blood count is obtained at 9 months of age.B. Explain that only a hemoglobin or hematocrit is measured routinely in well children at 9 to 12 months
of age.C. Explain that there is no reason to obtain any blood counts for well children at any time.D. Order a complete blood count.E. Order a complete blood count with a differential white blood cell count.
9. What is the most common underlying cause for mild-to-moderate neutropenia?
A. Exposure to medications such as antibiotics.B. Immune neutropenia.C. Shwachman-Diamond syndrome.D. Sequestration.E. Transient marrow suppression due to a viral infection.
10. At what age does alloimmune neutropenia usually resolve?
A. 2 to 3 days.B. 2 to 3 weeks.C. 5 to 6 weeks.D. 2 to 3 months.E. 6 to 7 months.
hematology/oncology neutropenia
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DOI: 10.1542/pir.29-1-252008;29;25-30Pediatr. Rev.Bhende, Grace Pecson and Carolyn Leedy
Cherilyn Hall, Allen Friedland, Sumathi Sundar, Kathryn S. Torok, Mananda S. Index of Suspicion
http://pedsinreview.aappublications.org/cgi/content/full/29/1/25located on the World Wide Web at:
The online version of this article, along with updated information and services, is
Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2008 by the American Academy ofpublished, and trademarked by the American Academy of Pediatrics, 141 Northwest Pointpublication, it has been published continuously since 1979. Pediatrics in Review is owned,Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
at Health Internetwork on December 31, 2007http://pedsinreview.aappublications.orgDownloaded from
http://pedsinreview.aappublications.org/cgi/content/full/29/1/25http://pedsinreview.aappublications.org/cgi/content/full/29/1/25http://pedsinreview.aappublications.org/http://pedsinreview.aappublications.org/http://pedsinreview.aappublications.org/http://pedsinreview.aappublications.org/http://pedsinreview.aappublications.org/cgi/content/full/29/1/25
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The reader is encouraged to write
possible diagnoses for each case before
turning to the discussion. We invite
readers to contribute case
presentations and discussions.Please inquire first by contacting Dr.
Nazarian at [email protected].
Author Disclosure
Drs Hall, Friedland, Sundar, Torok,
Bhende, Pecson, and Leedy did not
disclose any financial relationships
relevant to these cases.
Case 1 Presentation A 12-year-old girl has had abdominal
pain for 3 hours. The pain developed
suddenly and is severe, sharp, con-
stant, and located in the epigastrium
and lower quadrants, with no radia-
tion. She has had five episodes of
bilious, nonbloody emesis. The pain
worsens with movement and vomit-
ing, and she has found no way to
relieve it. Her last bowel movement
was yesterday and was normal. She
has had no fever, diarrhea, bloody
stools, or back pain. Past medicalhistory reveals intermittent constipa-
tion.
On physical examination, her
temperature is 96.3°F (35.7°C),
heart rate is 106 beats/min, respira-
tory rate is 14 breaths/min, and
blood pressure is 103/60 mm Hg.
Her abdomen is soft and slightly dis-
tended, with hypoactive bowel
sounds and both right and left lower
quadrant tenderness. Slight volun-
tary guarding is noted. The rest of the physical findings are normal.
Her WBC is 9.6103/mcL
(9.6109/L), Hgb is 11.4 g/dL
(114 g/L), Hct is 33.3% (0.333),
and platelet count is 406103/mcL
(406109/L). Values for electro-
lytes, BUN, creatinine, liver en-
zymes, amylase, and lipase are within
normal limits; a pregnancy test is
negative.
Abdominal/pelvic CT scan with
intravenous contrast reveals a moder-ate amount of free fluid around the
cecum; the appendix is not visible.
Pelvic and abdominal ultrasonogra-
phy is read as normal, but the appen-
dix is not visible.
Following intravenous hydration,
she experiences persistent bilious
vomiting and abdominal pain and
undergoes a diagnostic laparoscopy,
which is converted to an exploratory
laparotomy when no colon is located
on the right side of her abdomen.
The cause of her pain and vomiting is
revealed at surgery.
Case 2 Presentation A 14-year-old girl is seen in the ED
because of 2 days of lower abdominal
and back pain. The pain is a constant,
dull, bandlike ache of 9/10 in inten-
sity. She denies fever, nausea, vomit-
ing, diarrhea, melena, hematochezia,
dysuria, hematuria, vaginal dis-
charge, or constitutional symptoms.
She is premenarchal and denies sex-
ual activity.She had an appendectomy at age 5
years complicated by the develop-
ment of necrotic bowel, requiring a
small bowel resection. After recover-
ing from surgery, she developed
chronic intermittent abdominal pain,
ultimately diagnosed as being func-
tional. She describes her current pain
as different from her chronic abdom-
inal pain.
On physical examination, the girl
is uncomfortable but in no apparentdistress and looks healthy. All vital
signs are normal. Her breast develop-
ment is at Sexual Maturity Rating 5.
She is thin and easy to examine. Her
back is straight, with no tenderness
to palpation over the spine, paraspi-
nal muscles, or costovertebral angles.
Her abdominal examination reveals a
10-cm linear, well-healed vertical
scar down the midline and a slightly
protuberant lower abdomen. Palpa-
tion reveals a large, well-defined, firmmass extending from the pelvis half-
way to the umbilicus in the mid-line.
Mild pain is elicited on deep palpa-
tion of the left lower quadrant, with
no guarding or rebound tenderness.
Additional examination reveals the
diagnosis.
Case 3 Presentation A 6-month-old boy is readmitted be-
cause of respiratory distress and hyp-
Frequently Used Abbreviations
ALT: alanine aminotransferase
AST: aspartate aminotransferase
BUN: blood urea nitrogen
CBC: complete blood count
CNS: central nervous system
CSF: cerebrospinal fluid
CT: computed tomography ECG: electrocardiography
ED: emergency department
EEG: electroencephalography
ESR: erythrocyte sedimentation
rate
GI: gastrointestinal
GU: genitourinary
Hct: hematocrit
Hgb: hemoglobin
MRI: magnetic resonance imaging
WBC: white blood cell
index of suspicion
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oxia 1 day after a 2-week hospitaliza-
tion for bronchiolitis with hypoxia.
Despite resolution of signs of a respi-
ratory tract infection, he was difficult
to wean from supplemental oxygen,
having percutaneous oxygen satura-
tions of 88% to 92% in room air. He
was discharged after his percutane-
ous oxygen saturations remained at
90% to 96% for 24 hours in room air.
He was a small-for-gestational age
neonate, born via caesarean section
at 36 weeks’ gestation for maternal
double uterus, and remained in theneonatal intensive care unit for
2 weeks for feeding and weight gain.
He did not receive any mechanical
ventilation, and his growth and de-
velopment have been normal.
On physical examination, the pa-
tient’s weight is in the 10th percen-
tile, height is in the 5th percentile,
and head circumference is below the
3rd percentile. His blood pressure,
heart rate, and respiratory rate are
normal. Percutaneous oxygen satura-tions in room air are 91%. He is re-
ceiving 2 L of supplemental oxygen
by nasal cannula and has no respira-
tory distress. Wheezing is audible bi-
laterally, and there is no heart mur-
mur. He has a left facial nerve palsy
present since birth. Adequate perfu-
sion and palpable pulses are noted in
all extremities. The remaining physi-
cal findings are normal.
A chest radiograph reveals multi-
focal atelectasis, a left-sided aortic
arch, and a cardiac silhouette that
measures at the upper limit of nor-
mal. Additional evaluation reveals
the diagnosis.
Case 1 Discussion At laparotomy, intestinal malrotation
with small bowel obstruction at the
level of the distal ileum was found.
The ConditionIntestinal malrotation is an anatomic
anomaly caused by arrest of normal
rotation and mesenteric fixation of
the embryonic gut, a failure of nor-
mal embryologic gut formation that
occurs between the 5th and 10th
weeks of gestation. The result of a
nonrotated gut is location of the co-
lon on the left side and a narrow-
based mesentery in the upper mid-
abdomen that is fixed to the right
abdominal wall by adhesions known
as Ladd bands. Anomalies commonly
associated with intestinal malrotationinclude duodenal atresia (50%) and
jejunal atresia (33%). Disorders of in-
testinal rotation and mesenteric fixa-
tion to the posterior abdominal cav-
ity are also common in infants and
children who have congenital dia-
phragmatic hernia, gastroschisis, and
omphalocele.
Intestinal malrotation is believed
tooccurin1per200to1per500live
births, with symptomatic malrota-
tion occurring in 1 per 6,000 livebirths. Symptomatic malrotation is
evident clinically in the first postnatal
month in 64% of patients, and 82%
are diagnosed in the first postnatal
year; 18% to 25% of symptomatic pa-
tients are diagnosed at 1 year of age
and older. Because malrotation is dis-
covered incidentally in some pa-
tients, the true number of patients
who have malrotation that is never
detected can only be estimated.
Malrotation can cause duodenalobstruction because of impingement
on the bowel by the Ladd bands. The
most serious consequence is a mid-
gut volvulus, a life-threatening con-
dition in which the intestine twists on
the mesenteric stalk and compro-
mises its blood supply, which can
lead rapidly to infarction of the entire
small bowel. Both duodenal obstruc-
tion from Ladd bands and volvulus
may occur intermittently, character-
ized by chronic and sometimes vague
complaints of abdominal pain with or
without vomiting.
Symptomatic malrotation with
volvulus presents as duodenal ob-
struction. In infancy, the clinical pic-
ture includes bilious emesis, abdom-
inal pain, diffuse tenderness, and
bloody stool. Some clinicians warn
that the cause of bilious vomiting in a
neonate should be considered me-
chanical intestinal obstruction until
proven otherwise. Older children
and adults can present with acute or
chronic symptoms. Acute symptoms
include bilious vomiting, diffuse ab-dominal pain, and bloody stool.
Among the chronic symptoms are
intermittent vomiting and abdomi-
nal pain, constipation, malabsorption
syndrome, chronic diarrhea due to
protein-losing enteropathy, and fail-
ure to thrive. Older children and
adults who have chronic symptoms
may have received a previous diagno-
sis of irritable bowel syndrome or
cyclic vomiting. Some individuals
who are diagnosed later in childhoodare believed to have been experienc-
ing intermittent, self-resolving vol-
vulus.
Differential DiagnosisThe differential diagnosis for intesti-
nal malrotation varies according to
the age of presentation. In infancy
and childhood, conditions to con-
sider include necrotizing enterocoli-
tis, pyloric stenosis, intussusception,
ileus due to sepsis or meconium,Hirschsprung disease, appendicitis,
and duodenal atresia. In older chil-
dren and adults, similar symptoms
can result from inflammatory bowel
syndrome, pancreatitis, or acute ab-
dominal conditions such as appendi-
citis.
DiagnosisDiagnostic evaluation generally re-
quires a degree of suspicion for vol-
vulus and, in a stable patient, can
index of suspicion
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include abdominal radiography,
upper GI radiographic series, or ab-
dominal CT scan. Adjunctive imag-
ing techniques are abdominal ultra-
sonography and barium enema.
Radiographs often reveal a gasless
colon with a “double-bubble” sign
due to duodenal obstruction. An ab-
dominal radiograph was not per-
formed in this patient because appen-
dicitis was believed to be likely, and
abdominal radiography would not
have been an optimal study for ap-
pendicitis.
An upper GI contrast study usu-ally is considered the imaging study
of choice in a stable patient suspected
of having intestinal malrotation com-
plicated by volvulus. An upper GI
radiographic series reveals failure of
the duodenal-jejunal junction to
cross the midline and a corkscrew
appearance of volvulus at the level of
the duodenum. CT scan may reveal
duodenal obstruction (in the case of
mid-gut volvulus) or appear normal
in the absence of volvulus. Ultra-sonographic findings suggestive of
volvulus include identification of the
superior mesenteric vein on the left
rather than the right.
TherapyIntestinal malrotation requires surgi-
cal intervention. The Ladd proce-
dure is recommended for intestinal
malrotation regardless of age or
symptoms. This operation includes
lysis of adhesions, widening of themesenteric base, and positioning of
the bowel in a place of nonrotation as
well as appendectomy and resection
of any necrotic bowel. The urgency
of the operation is dictated by the
presence of intestinal ischemia
caused by volvulus. In the setting of
malrotation without volvulus, most
surgeons advocate the Ladd proce-
dure as a prophylactic maneuver to
reduce the probability of volvulus.
This patient underwent a Ladd
procedure, and Doppler ultrasonog-
raphy at the time of surgery showed
normal blood flow to the distal il-
eum. Postoperatively, she developed
pancreatitis, which resolved after ap-
proximately 1 week of bowel rest and
fluid resuscitation. She was dis-
charged with no additional compli-
cations.
Lessons for the ClinicianMost symptomatic cases of malrota-
tion occur during infancy and usually
present with bilious vomiting. Fewercases present after infancy and have
varied presentations related to inter-
mittent volvulus, with symptoms
that include abdominal pain, vomit-
ing, and diarrhea. Volvulus can
mimic an acute abdominal inflamma-
tory process, and diagnosis requires a
high degree of suspicion because
progressive intestinal ischemia may
become life-threatening. Patients
who present after infancy usually
have a history of chronic abdominalcomplaints. (Cherilyn Hall, MD,
Allen Friedland, MD, Sumathi
Sundar, MD, Christiana Care
Health System, Newark, Del.)
Case 2 DiscussionExamination of the patient’s genita-
lia revealed a normal vulva and labia
with Sexual Maturity Rating 5 distri-
bution of pubic hair. A bulging, blu-
ish membrane that was firm to palpa-tion protruded from the introitus
(Figure). Abdominal and pelvic ul-
trasonography performed to confirm
the diagnosis of imperforate hymen
revealed a grossly dilated vagina filled
with homogeneous, echogenic mate-
rial consistent with hematocolpos.
No other urogenital abnormalities
were present. The patient was admit-
ted for a hymenectomy and evacua-
tion of retained clotted blood. After
an uncomplicated hymenectomy, the
patient was discharged in good con-
dition with relief of pain.
The ConditionImperforate hymen is the most com-
mon obstructive genital tract anom-
aly occurring in females, having an
incidence of 1 in 1,000 to 1 in
10,000 individuals. Most commonly,
imperforate hymen is detected dur-
ing adolescence either during an
evaluation for asymptomatic primary
amenorrhea or an investigation of
abdominal, back, or pelvic pain in the
premenarchal female. Other com-plaints include urinary retention and
pain with defecation. The pain is due
to the collection of menstrual blood
in the vagina and uterus. An imper-
forate hymen also can be detected on
prenatal ultrasonography as hydro-
colpos if it is associated with urinary
obstruction and a urogenital fistula,
during a newborn examination as a
mucocolpos from maternal estrogen-
induced secretions, or during a
health supervision visit as a mem-brane that bulges when the child per-
forms a Valsalva maneuver. The term
hydrometrocolpos is used when both
vagina and uterus are dilated with
fluid.
Imperforate hymen is a sporadic
congenital outflow obstruction
anomaly resulting from the failure of
canalization of the tissue joining the
müllerian ducts and the urogenital
sinus during development. Embryo-
logically, the female genital tract in- volves the medial migration and mid-
line (horizontal) fusion of the paired
müllerian (paramesonephric) ducts
to form the uterus, cervix, and upper
vagina and the vertical fusion of the
developing ductal system with the
invaginating urogenital sinus to form
the lower vagina and introitus. Hor-
izontal fusion defects result in vaginal
agenesis (also known as müllerian
agenesis or Mayer-Rokitansky-
Kuster-Hauser syndrome) and may
index of suspicion
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have associated urinary system ab-
normalities. Failure of vertical fusion
results in low obstruction abnormal-
ities, such as imperforate hymen,
transverse vaginal septum, and cervi-cal atresia, which usually are not as-
sociated with urinary abnormalities.
All of the previously noted condi-
tions result in an accumulation of
menstrual fluid above the level of
obstruction.
The ovarian structures are derived
from a separate embryologic source,
the genital ridge. Therefore, ovarian
hormonal and endocrinologic func-
tion is normal in patients who have
genital outflow tract abnormalities, which causes an apparent discrepancy
between physical findings of ad-
vanced secondary sexual characteris-
tics and lack of menses.
An imperforate hymen is diag-
nosed by genital examination, which
reveals a translucent thin membrane
inferior to the urethral meatus that
bulges when the patient performs the
Valsalva maneuver. If hematocolpos
is present, a bluish discoloration is
apparent behind the membrane. The
volume of blood that collects can be
great enough to fill and distend the
uterus (hematometra), which may
present as an abdominal or pelvic
mass. Prolonged menses in a girl whohas an imperforate hymen may lead
to hematosalpinges and retrograde
menses into the abdomen, which
may cause intra-abdominal endome-
triosis and adhesions.
Differential Diagnosis Although an imperforate hymen
should be obvious on physical exam-
ination, several conditions may
present with similar complaints and
findings. A history of primary amen-orrhea in the presence of a blind or
absent vagina indicates a variety of
developmental anomalies of the gen-
ital outflow tract, including imperfo-
rate hymen, low-lying transverse vag-
inal septum, cervical atresia, vaginal
(müllerian) agenesis, and androgen
insensitivity syndrome (AIH). Of
these conditions, imperforate hy-
men, transverse septum, and cervical
atresia commonly present at the ex-
pected time of menarche in a girl
who has well-developed secondary
sexual characteristics and the com-
plaint of cyclical lower abdominal,
back, or pelvic pain. On examination,
imperforate hymen appears typically
as a thin, bulging blue membrane;
transverse septa and cervical atresia
can be associated with a normal vag-
inal opening but shortened vaginal
canal. Ultrasonography can help
evaluate the level and volume of se-
questered menses; MRI provides su-
perior anatomic detail to define the
nature of anomalies further, includ-
ing those of the upper urinary tract.Only in rare instances is laparoscopy
required to clarify an anatomic devel-
opmental anomaly.
Vaginal (müllerian) agenesis and
AIH usually are asymptomatic pre-
sentations of primary amenorrhea as-
sociated with a vaginal anomaly. Pa-
tients born with vaginal agenesis
experience variable uterine develop-
ment, with only 2% to 7% having a
uterus that has a functioning endo-
metrium. This group may present with cyclic or chronic abdominopel-
vic pain due to hematometra, but this
clinical picture is the exception.
Extragenital anomalies are com-
mon in vaginal agenesis and should
be screened for, particularly urologic
(30%) and skeletal (15%) abnormali-
ties. AIH differs from the other men-
tioned anomalies in that it is a genetic
disorder of a chromosomal male
(XY) but phenotypic female due to
an androgen receptor mutation caus-ing androgen insensitivity in the tis-
sues and resulting in a blind vagina,
absent uterus, and testes in the ingui-
nal canal. Imaging, along with evalu-
ation of karyotype and hormone con-
centrations, further delineates this
disorder.
TreatmentHymenectomy is the definitive treat-
ment for an imperforate hymen.
Abdominal ultrasonography is rec-
Figure. External genitalia showing bulging hymeneal membrane.
index of suspicion
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ommended before surgery to dem-
onstrate that the true diagnosis is not
an obstructing transverse septum or
other genital anomaly. If abnormali-
ties are present, the condition may be
more complex than a simple imper-
forate hymen, and surgery should be
delayed until the appropriate evalua-
tion is performed, including MRI of
the abdomen and pelvis.
Surgical treatment of an imperfo-
rate hymen is not an emergency pro-
cedure. If a preadolescent is found to
have an imperforate hymen on exam-
ination but otherwise is asymptom-atic, surgery often is delayed until
puberty to allow the hymen to be-
come estrogenized, optimizing the
surgical outcome. A more urgent
hymenectomy is needed if the patient
also has urinary obstruction.
In addition to hymenectomy,
treatment for an imperforate hy-
men consists of evacuating copious
amounts of retained blood prod-
ucts and suturing the vaginal epi-
thelium to the hymeneal ring. Theoutcome of imperforate hymen
treated with hymenectomy is excel-
lent. Follow-up in patients who
have had imperforate hymen
treated has shown normal preg-
nancy rates and sexual function.
Gynecologists have observed that if
endometriosis develops from retro-
grade menses, it is more likely to
resolve and have no significant ef-
fect on fertility compared with
spontaneous endometriosis occur-ring in the general population.
Lessons for the Clinician A teenage girl who has lower abdom-
inal pain and back pain may bring to
mind an extensive differential diag-
nosis, leading to extensive laboratory
and radiologic testing. However, the
history and physical examination re-
main the most useful tools at the
physician’s disposal to make the diag-
nosis. In this case, the patient’s ad-
vanced breast development and lack
of menses did not correlate and, in
the presence of recurring abdominal
and back pain, led to the suspicion of
imperforate hymen. Imperforate hy-
men is the most common cause of
vaginal outflow obstruction, and sur-
gical repair can relieve the obstruc-
tion and ensure commencement of
normal menses. (Kathryn S. Torok,
MD, Mananda S. Bhende, MD, Chil-
dren’s Hospital of Pittsburgh, Pitts-
burgh, Pa.)
Case 3 DiscussionThe baby continued to require sup-
plemental oxygen and demonstrated
respiratory distress with feedings.
A video swallow study showed no
evidence of aspiration. CT scan of the
chest performed to evaluate pulmo-
nary anatomic abnormalities as a
cause for prolonged hypoxia revealed
a vascular structure to the left of the
aorta consistent with a duplicated su-
perior vena cava or anomalous pul-monary venous connection. An ECG
showed right atrial enlargement and
findings consistent with right ven-
tricular hypertrophy. Echocardiogra-
phy confirmed the diagnosis of un-
obstructed supracardiac total anom-
alous pulmonary venous connection
(TAPVC), with the pulmonary veins
draining into the innominate vein.
A large secundum atrial septal defect
(ASD) with right-to-left shunting
also was present.
The ConditionTAPVC is a cyanotic heartdefect that
represents approximately 1% to 3% of
all congenital heart defects. Males are
affected more often than females (4:
1). Some 33% of affected patients
have additional cardiac malforma-
tions, and 33% have other noncardiac
malformations.
TAPVC results from a develop-
mental error that prevents a direct
communication of the pulmonary
veins to the left atrium. The pulmo-
nary veins drain into the systemic ve-
nous system or directly into the right
atrium. In this malformation, an
obligatory right-to-left shunt nearly
always occurs at the atrial level. For-
merly called total anomalous pulmo-
nary venous return, the condition
more appropriately is called TAPVC.
The abnormality is the connection,
not the return, because the veins can
empty circuitously into the left
atrium or blood can flow into the left
atrium through an ASD.The four types of TAPVC are based
on the location of the pulmonary vein
connection: supracardiac (50%, com-
monly into the left innominate vein or
right superior vena cava), cardiac (20%,
commonly into the coronary sinus),
infracardiac/subdiaphragmatic (20%,
commonly into the portal vein, duc-
tus venosus, hepatic vein, or inferior
vena cava), and mixed (10%).
The presence of an obstructed
pulmonary venous connection affectsthe clinical presentation. Typically,
tachypnea and cyanosis occur within
the first few days after birth as pulmo-
nary blood flow increases. The ob-
structed flow causes pulmonary
edema and decreased lung compli-
ance, which manifests as increased
work of breathing and hypoxia.
Feeding difficulties and other signs of
heart failure often are present. In ad-
dition, there is a fixed and widely split
second heart sound due to a delay inpulmonary valve closure caused by
right ventricular volume overload.
Some infants also develop pulmonary
hypertension because of the obstruc-
tion.
Without obstruction, there may
be no symptoms at birth. However,
symptoms usually appear within the
first postnatal year. Signs may include
dyspnea on exertion and visible cya-
nosis with crying. Examination usu-
ally reveals a pulmonary murmur
index of suspicion
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caused by increased flow across the
valve. The murmur may be difficult
to hear if there is pulmonary vein
obstruction. It can be distinguished
from pulmonic valve stenosis by the
absence of a pulmonary valve click.
An ASD causes a similar pulmonary
flow murmur and fixed splitting of
the second heart sound.
Rhonchi may be present in some
patients. As with this child, percuta-
neous oxygen saturations may be de-
creased only slightly because initial
pulmonary blood flow remains high
and a large interatrial connection al-lows oxygenated blood to flow into
the left atrium and systemic circula-
tion. Progressive cyanosis results
from increasing pulmonary edema
that impairs oxygenation and de-
creasing right heart compliance that
increases the interatrial right-to-left
shunt. Both obstructed and unob-
structed types can cause congestive
heart failure, growth restriction, and
multiple pulmonary infections.
Chest radiography may show anenlarged heart with increased pulmo-
nary flow, a “snowman” shape (in
supracardiac TAPVC), or an en-
larged upper right heart border.
ECG shows right atrial and right ven-
tricular enlargement. The diagnosis
is confirmed by identifying a pulmo-
nary venous connection to the sys-
temic veins, coronary sinus, or right
atrium on echocardiography.
PrognosisMost patients who have TAPVC do
not survive beyond the first year
without surgery. Emergent surgery
may be necessary for neonates who
are in cardiogenic shock due to
TAPVC. Infants afflicted with infra-
cardiac TAPVC die before 2 months
after birth without surgery. Advance-
ments in surgical correction have
lowered mortality rates to near zero
and increased long-term survival to
98% at 7 years.
Cyanotic Heart DefectsMany nurseries routinely check per-
cutaneous oxygen saturations at
birth. This screening is nearly 100%
specific in detection of cyanotic heartdefects. (1) Without screening and a
high level of suspicion, a subset of
patients born with congenital heart
disease will be missed. Patients who
manifest cyanotic heart disease out-
side of the neonatal period may
present with growth restriction or
failure to thrive, a history of recurrent
respiratory infections, mild or epi-
sodic cyanosis, or irritability.
As with this patient, persistent hy-
poxemia despite resolution of an in-fectious respiratory process is a major
sign of cyanotic heart disease. In-
deed, many patients who have cya-
notic congenital heart defects are
asymptomatic at birth because of the
presence of intracardiac mixing of
oxygenated and deoxygenated blood
that increases the arterial oxygen sat-
uration. Infants born with hypoplas-
tic left heart syndrome or left heart
obstruction or who experience in-
creasing pulmonary blood flow as thepulmonary vascular resistance falls
naturally (single ventricle without
pulmonary stenosis, large ventricular
septal defect) eventually show signs
and symptoms of heart failure or pul-
monary edema. Unfortunately, for
those who have left heart obstruc-
tion, symptoms of heart failure may
be subtle and the phase of decom-
pensation rapid.
Signs and symptoms of congestive
heart failure include irritability, poor
feeding, failure to thrive, tachypnea
without respiratory distress (“happy
tachypnea”) or tachypnea with respi-
ratory distress due to pulmonary
edema or pleural effusion, and hepa-
tomegaly. Any patient suspected of having a cyanotic heart defect or con-
gestive heart failure should be
screened with a chest radiograph and
ECG. Echocardiography provides
the definitive diagnosis.
Lessons for the ClinicianRecognizing signs and symptoms of
cyanotic heart defects and early
symptoms of congestive heart failure
is critical to the early recognition,
management, and surgical correction
of these lesions. (Grace Pecson, MD,
Carolyn Leedy, MD, University of
Texas Southwestern Medical Center,
Children’s Medical Center, Dallas,
Tex.)
Reference1. ReichJD,MillerS, Brogdon B, etal. Theuse of pulse oximetry to detect congenitalheart disease. J Pediatr. 2003;142:268–272
To view Suggested Reading lists for
these cases, visit www.pedsinreview.org
and click on Index of Suspicion.
index of suspicion
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DOI: 10.1542/pir.29-1-252008;29;25-30Pediatr. Rev.
Bhende, Grace Pecson and Carolyn LeedyCherilyn Hall, Allen Friedland, Sumathi Sundar, Kathryn S. Torok, Mananda S.
Index of Suspicion
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CommentaryA Flood of InformationMany elements in our lives can over-
whelm us and overload our circuits,
including responsibilities, worries, and
conflicting appointments. Even some
treats we enjoy can get to be too much,
such as tomatoes in the garden at the
peak of the season, photographs wait-
ing to be organized, and exceptionalbooks crying out to be read. Another
flood that threatens to engulf us is
information. Even if we ignore the ob-
viously misleading or irrelevant rivers of
data flowing toward our minds, there is
enough worthwhile, relevant, desirable
information coming our way to sweep
us over the falls.
Restricting our focus to medical
knowledge, and even further to an un-
derstanding of pediatric medicine, we
still find that sector of the informationocean stretching out to the horizon and
getting bigger every year. There used to
be lectures, seminars, workshops, text-
books, and journals. All of these sources
have multiplied, and we have added
continuing medical education courses,
teleconferences, CDs and DVDs, and
that infinite highway to knowledge
about everything under the sun and
beyond, the Internet. No wonder many
practitioners feel they are lost at sea
and going down for the third time.Pediatrics in Review ® (PIR) and the
PREP program exist to throw you a life
preserver and a compass. Our primary
mission is to focus on the essentials of
pediatric medicine and to present cur-
rent thinking about each aspect of that
body of knowledge to keep readers up
to date. We are fortunate to have
access to the content specifications of
the American Board of Pediatrics,
which has created a database that de-
fines that core. In any given 5-year
period, PIR and the PREP Self-
Assessment cover that content, allow-
ing readers to refresh their knowledge
in a constant, renewing fashion. In the
process, steady readers are preparing
themselves for the cognitive testing
involved in maintenance of certifica-
tion.We continue to recruit our material
from t