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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.

Article hematology/oncology

12 Pediatrics in Review Vol.29 No.1 January 2008


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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).




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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




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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.




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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

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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 involves 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




18/50

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




19/50

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




20/50

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

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DOI: 10.1542/pir.29-1-252008;29;25-30Pediatr. Rev.

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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

01-pediatrics in review-january 2008

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