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Type 2 Diabetes Mellitus in Children
Nupur Gupta, Boston, MA
Jacob Hen, Bridgeport, CT
Jeffrey D. Hord, Akron, OH
Alfred Tenore, Udine, Italy
Miriam Weinstein, Toronto, ON
541 and Adolescents
Kavitha Dileepan, M. Max Feldt
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 Article endocrinology

Type 2 Diabetes Mellitus in Children and

Adolescents
Kavitha Dileepan, MD, MPH*
M. Max Feldt, DO†
Author Disclosure
Drs Dileepan and Feldt
have disclosed no
financial relationships
relevant to this article.
This commentary does
contain a discussion of
an unapproved/
investigative use of
a commercial product/
device.
Educational Gaps
The growing pandemic of childhood obesity has led to marked increases in the incidence
and prevalence of type 2 diabetes mellitus (DM) and has further complicated the differ-
entiation between type 2 and type 1 DM because more children with type 1 DM are over-
weight at time of diagnosis. In addition, numerous studies have demonstrated b-cell
autoimmunity in children with type 2 DM. (1)
Objectives After completing this article, readers should be able to:
1. Differentiate between and understand the treatment of type 2 diabetes mellitus (DM)
and type 1 DM by recognizing underlying pathophysiologic characteristics, clinical
features, and laboratory markers.
2. Recognize the difficulty in distinguishing between type 2 and type 1 DM because of
the increasing prevalence of childhood obesity.
3. Understand the increased prevalence of type 2 DM in children and adolescents,
especially among certain racial/ethnic groups.
4. Recognize risk factors, appropriate screening, and diagnosis of type 2 DM, and
understand the appropriate treatment for type 2 DM in the pediatric population.
5. Recognize the comorbidities and complications associated with type 2 DM in children
and adolescents and understand that these may be present at the time of diagnosis.

Introduction
Type 2 diabetes mellitus (DM), historically considered a serious chronic medical condition only
for older individuals, now has an increased prevalence in children and adolescents. The estimated
overall incidence of type 2 DM is 22 cases per 100,000 youth or approximately 3600 youth
diagnosed with the condition each year. (2) From a public health perspective, DM is the seventh
leading cause of death in the United States, a figure that is likely underestimated. (3) The total
cost to treat DM in both adults and children is approximately $174 billion per year, and medical
expenses for individuals with diagnosed DM are 2.3 times higher than for those without DM.
(3) The clinical and financial burdens of DM are increased by the complications and comorbid-
ities of the disease. Because complications of DM develop and worsen during the disease, (2) it is
important to effectively recognize and manage type 2 DM early
when it is diagnosed during childhood and adolescence.
Abbreviations
ADA: American Diabetes Association Definition
DM: diabetes mellitus DM represents a group of endocrine disorders characterized by
FDA: Food and Drug Administration hyperglycemia caused by defective insulin secretion, defective in-
GAD: glutamic decarboxylase sulin action, or both. (4) The original division into 2 types was
HbA1c: hemoglobin A1c based on age at presentation and dependence on insulin. Now
OGTT: oral glucose tolerance test categories of DM (Table 1) are differentiated by their known
TODAY: Treatment Options for Type 2 Diabetes in underlying pathophysiologic characteristics. All forms of DM ul-
Adolescents and Youth timately lead to hyperglycemia, although there may be overlap
in the fundamental pathologic processes in each patient.

*Department of Pediatrics, University of Missouri Kansas City School of Medicine, Children’s Mercy Hospital Kansas City, MO.
Dr Dileepan was a pediatric endocrinology fellow at Children’s Mercy Hospital, Kansas City, MO, at the time this article was authored.
†
Department of Pediatrics, University of Missouri Kansas City School of Medicine, Children’s Mercy Hospital, Kansas City, MO.

Pediatrics in Review Vol.34 No.12 December 2013 541

endocrinology diabetes mellitus
Classification of Diabetes
Table 1.
Mellitus (DM) Causes
Type 1 DM: b-cell destruction, typically leading to
absolute deficiency in insulin secretion
Type 1a: immune mediated, characterized by positive
circulating autoantibodies
Type 1b: idiopathic
Type 2 DM: clinical spectrum from predominant insulin
resistance with relative insulin deficiency to
a predominant defect in insulin secretion with
accompanying insulin resistance
Gestational DM
Other types of DM
Genetic defects of b-cell function (ie, monogenic
diabetes of youth)
Genetic defects in insulin action (ie, leprechaunism,
Rabson-Mendenhall syndrome, and lipoatrophic DM)
Diseases of exocrine pancreas or pancreatic
destruction (ie, cystic fibrosis, pancreatitis, trauma,
and hemochromatosis)
Endocrinopathies (ie, Cushing syndrome, acromegaly,
glucagonoma, hyperthyroidism, and
pheochromocytoma)
Drug induced (ie, glucocorticoids, diazoxide,
b-adrenergic agonists, and asparaginase)
Infections (ie, cytomegalovirus and congenital rubella)
Other uncommon forms of immune-mediated DM
(ie, stiff man syndrome and anti-insulin receptor
antibodies)
Genetic syndromes associated with DM (ie, Down
syndrome, Turner syndrome, and Klinefelter syndrome)
Epidemiology
Recent epidemiologic studies have demonstrated that
more than 20% of new cases of DM in children and ado-
lescents are due to type 2 DM. (5) The incidence of type
2 DM in children has increased in part because of the ep-
idemic of childhood obesity and the associated insulin
resistance, although the actual incidence of type 2 DM
in children is likely higher than reported because of
underdiagnosis.
The incidence of type 2 DM increases with age. The
SEARCH for Diabetes in Youth study demonstrated that
the incidence of type 2 DM in children age 10 to 19 years
was 42 per 100,000 youth compared with 1 in 100,000
youth among children age 0 to 9 years. (2) The peak age
at onset of type 2 DM in children coincides with pubertal
timing because the mean age at diagnosis is 12 to 16
years. (6) Females have a higher incidence of type 2
DM than males, (5) likely because girls are more insulin
resistant and carry more subcutaneous fat than boys. (7)
542 Pediatrics in Review Vol.34 No.12 December 2013
Type 2 DM disproportionately affects racial and ethnic
minorities. American Indian youth have the highest inci-
dence at 174 per 100,000. Black youth also have a partic-
ularly high incidence of 105 per 100,000 compared with
19 per 100,000 in non-Hispanic whites. (2)
Epidemiologic studies report that children born to
mothers with gestational diabetes are at greater risk of de-
veloping type 2 DM. (8) Breastfeeding appears to have
protective effects against the development of type 2
DM. (9)
Etiology
The cause of type 2 DM is multifactorial, but the high
concordance rate among monozygotic twins (1) and
the frequent association with a family history of DM
(10) suggest a genetic component. Between 74% and
100% of patients with type 2 DM have a first- or
second-degree relative with the disease, in contrast to
only 5% of patients with type 1 DM with a family history
of type 1 DM. (6) Recent studies have identified multiple
genetic loci that are associated with higher risk of type 2
DM. For example, polymorphisms in the TCF7L2 gene
result in impaired insulin secretion and defective insulin
processing, which confer a 1.4 times increased risk of type
2 DM. (1) More genetic markers are being identified
with improvements in genetic testing.
Pathogenesis
Glucose Metabolism and Insulin Production
Glucose metabolism is tightly regulated by several pro-
cesses, including sensing of glucose concentration, insulin
synthesis, and secretion by pancreatic b-cells; suppression
of hepatic glucose output; and insulin action on stimu-
lated glucose uptake by the liver, intestines, and skeletal
muscle. Hyperglycemia can result from derangements in
any of these processes.
Typically, type 1 DM and type 2 DM are conceptual-
ized on a spectrum. Type 1 DM results from immune-
mediated destruction of b-cells, leading to insulinopenia.
Type 2 DM is the result of obesity-mediated insulin re-
sistance and non–immune-mediated deficiency in insulin
secretion.
The pathogenesis of type 2 DM is complex and in-
volves interactions between genetic and environmental
factors. The core defect is varying degrees of insulin re-
sistance and subsequent progressive insulinopenia. Other
factors associated with obesity, such as elevated plasma
free fatty acid concentrations and increased inflamma-
tory markers, further inhibit b-cell insulin production
and insulin-mediated glucose uptake. This leads to

a cycle of worsening hyperglycemia and further meta-
bolic derangement.
Role of Obesity
A theory called the accelerator hypothesis suggests that
obesity and weight gain contribute significantly to b-cell
stress and confer earlier onset of all types of DM. Obesity
is increasingly being accepted as a contributor to b-cell
failure in genetically susceptible children, and increasing
evidence suggests the influence of obesity in abnormal
immune modulation. (1)
Lifestyle Contributions
During the past 30 years Americans have increased their
total caloric intake by an additional 300 kcal/d. (11)
Consumption of juices and sugar-sweetened beverages
is a major source of these additional calories in the diet
of children and adolescents (12) and is strongly associ-
ated with an increased risk of obesity and type 2 DM.
(7) In addition, fewer children and adolescents are par-
ticipating in recommended levels of physical activity.
In Utero Factors
The association between lower birth weight and type 2
DM suggests that in utero programming may increase
the risk of type 2 DM. (13) A thrifty-phenotype hypothesis
suggests that poor fetal nutrition produces a postnatal
metabolism that is adapted to poor but not plentiful nu-
trition. This programming contributes to insulin resis-
tance and can predispose the development of type 2
DM in the context of excess nutrition and obesity. (14)
Clinical Aspects
Classification of DM
Because up to 24% of children and adolescents with type
1 DM are overweight at diagnosis, (6) differentiating be-
tween type 2 DM and type 1 DM has become more dif-
ficult. (15) Further complicating the clinical delineation is
the presence or absence of autoimmunity. The SEARCH
for Diabetes in Youth Study measured the presence of
glutamic decarboxylase (GAD) antibodies among dia-
betic patients. Positive GAD antibodies were found in
21% of patients with type 2 DM older than 10 years.
(5) The Treatment Options for Type 2 DM in Adoles-
cents and Youth (TODAY) study, a multicenter clinical
trial, evaluated the presence of GAD and insulinoma-
associated protein 2 antibodies. Of patients with diag-
nosed type 2 DM, 9.8% were antibody positive, 5.9%
were positive for a single antibody, and 3.9% were posi-
tive for both antibodies. Those patients diagnosed as
endocrinology diabetes mellitus
having type 2 DM who were antibody positive were more
likely to be white and male and had a lower body mass
index than antibody-negative patients. (16) A significant
controversy exists regarding the classification of antibody-
positive type 2 DM, with many authors maintaining that
antibody-positive type 2 DM should be considered early
type 1 DM and treated as such.
Clinical Signs and Symptoms
The presenting symptoms of type 1 and type 2 DM can
be similar and include polyuria, polydipsia, and polypha-
gia. Weight loss can be present in both types of DM.
Clinical signs to suggest type 2 DM include overweight
body habitus, with more than 85% of children with type 2
DM considered overweight or obese at the time of diag-
nosis. (6) Acanthosis nigricans, a darkened, thick, velvety
appearance to the skin found typically in folds or creases,
is present in 90% of patients with type 2 DM and can be
the most easily visible clinical indicator of insulin resis-
tance. (7) The frequency of acanthosis nigricans in obese
adolescents or hyperinsulinemic children varies consider-
ably by ethnicity. Up to 90% of obese or hyperinsulinemic
children in Native American populations had acanthosis
nigricans, whereas it was present in less than 5% of
non-Hispanic white counterparts. (7) Clinicians can look
for acanthosis nigricans in the nape of the neck, axilla,
groin, and over flexor surfaces. The presence of ketoaci-
dosis, normally found in patients with type 1 DM, does
not rule out type 2 DM. Some reports indicate that up to
25% of children and adolescents with type 2 DM present
with diabetic ketoacidosis. (17)
Type 2 DM generally has a more insidious onset than
type 1 DM, and many patients may be asymptomatic at
presentation. However, because of the potentially long-
standing hyperglycemia, patients may already have evi-
dence of microvascular and macrovascular complications
at the time of diagnosis. (10)
Overall, the clinical distinction between type 1 DM
and type 2 DM is increasingly obscured, especially with
the increasing obesity pandemic. Clinicians must weigh
the evidence to support their diagnosis and consider
the potential outcomes of misclassification. In the case
of significant hyperglycemia, diabetic ketoacidosis,
and/or positive antibodies, it may be prudent to treat pa-
tients as having type 1 DM and wean insulin therapy if the
future clinical course dictates.
Diagnostic Approach
The criteria for diagnosis of DM were based on data to
delineate risk for the development of retinopathy, a mi-
crovascular complication of DM, and are included in
Pediatrics in Review Vol.34 No.12 December 2013 543
endocrinology diabetes mellitus
Table 2. (10) In 2009, an international expert committee
convened and added an additional criterion for diagnosis,
a hemoglobin A1c (HbA1c) level greater than 6.5%
(0.07). (10)
Indications to test for type 2 DM according to the
Type 2 DM Consensus Panel are given in Table 3. Test-
ing should begin at age 10 years or at the age of pubertal
onset, whichever comes first, and should be repeated ev-
ery 3 years. (18) The preferred method is to measure
a fasting plasma glucose level, but a 2-hour plasma glu-
cose level measured during an oral glucose tolerance test
(OGTT) can be an alternative. (6)
Management
Ongoing Clinical Management
The American Diabetes Association (ADA) recommends
that treatment of all children with DM should include
routine follow-up every 3 months with a diabetes care
team. (18) This team should include nutritional, psycho-
logical, and educational support and a medical professional
experienced with DM care. The patient’s self-management
involves monitoring of blood glucose level, medication
compliance, attention to dietary intake, and physical ac-
tivity. Psychosocial considerations and medical compli-
ance must also be addressed to ensure optimal success
with therapy. The HbA1c level should be measured ev-
ery 3 months during outpatient visits, and the goal
HbA1c should be less than 7%. (18)(19)(20) Assessment
of lipids, liver function tests, microalbuminuria, and signs
Criteria to Diagnose
Table 2.
Diabetes Mellitus
Fasting (>8 hours) blood glucose level ‡126 mg/dL
(7 mmol/L)
OR
2-Hour plasma glucose level ‡200 mg/dL (11.1 mmol/L)
during oral glucose tolerance test with 1.75 g/kg
(maximum, 75 g/kg) of glucose
OR
Hemoglobin A1c level ‡6.5% standardized to Diabetes
Control and Complications Trial assay
OR
Random plasma glucose level ‡200 mg/dL (11.1 mmol/L)
WITH
signs and symptoms of DM (ie, polyuria, polydipsia, and
unintentional weight loss)
Modified by permission from American Diabetes Association. Type 2
diabetes in children and adolescents. Diabetes Care. 2000;23(3):381–
389.
544 Pediatrics in Review Vol.34 No.12 December 2013
Indications to Test for
Table 3.
Type 2 Diabetes Mellitus (DM)
Overweight (body mass index >85th percentile, weight
for height >85th percentile, or weight >120th
percentile for ideal height)
WITH any 2 of the following risk factors:
Family history of type 2 DM (first- or second-degree
relatives)
Race/ethnicity (American Indian, African American,
Hispanic/Latino, or Asian/Pacific Islander)
Signs of insulin resistance (acanthosis nigricans)
Comorbidities of insulin resistance (hypertension,
dyslipidemia, small for gestational age birthweight,
cardiovascular disease, hypervirilization,
steatohepatitis, and polycystic ovarian syndrome)
Modified by permission from American Diabetes Association. Type 2
diabetes in children and adolescents. Diabetes Care. 2000;23(3):381–
389.
and symptoms of sleep apnea should occur at diagnosis
and annually. (19) Coordination between the diabetes
care team and the primary care practitioner ensures
a complete medical home for the child or adolescent.
Treatment should be guided by the acuity of the clinical
presentation. If a patient is acutely ketotic, dehydrated, or
acidotic, intravenous hydration and insulin administration
with inpatient admission are warranted. If the presentation
is less acute, subspecialty referral, outpatient education,
and use of oral medications can be initiated. Once the pa-
tient is clinically stable, treatment of type 2 DM is dually
focused on weight management and minimizing compli-
cations associated with hyperglycemia.
Lifestyle Modification
Lifestyle modification is an essential component of the
management of type 2 DM and includes an emphasis
on proper diet and exercise to maintain a healthy weight
while preserving linear growth. For optimal management,
lifestyle modification should be centered around the family
unit and not strictly on individual patients. (20)
Pharmacologic Management
Pharmacologic therapy addresses various aspects of the
pathogenesis of type 2 DM (Figure) by reducing insulin
resistance, increasing insulin secretion, slowing postpran-
dial glucose absorption, or supplementing inadequate se-
cretion of insulin. Metformin, a biguanide, is the only US
Food and Drug Administration (FDA)–approved oral
medication for treatment of type 2 DM in children older
than 10 years and is considered first-line therapy in
 endocrinology diabetes mellitus

nonacute presentations. The mechanism of action is to in the upper small intestine. They can lower HbA1c levels
decrease hepatic glucose production and enhance insulin- by 0.5% to 1%, and the major adverse effects are gastroin-
mediated glucose uptake in muscle and adipose cells. Ad- testinal intolerance and flatulence. Incretins (exenatide) are
verse effects include transient abdominal pain, diarrhea, and designed to increase postprandial insulin secretion. Exen-
nausea, although it is generally well tolerated. Metformin atide is administered as a twice-daily injection. Adverse ef-
should not be given to patients with renal insufficiency, fects include nausea, vomiting, diarrhea, dyspepsia,
liver disease, or cardiac or respiratory insufficiency. Patients jitteriness, dizziness, headaches, and hypoglycemia, espe-
should be warned to discontinue metformin therapy before cially if given with a sulfonylurea. Thiazolidinediones (ro-
receiving intravenous contrast for radiographic studies be- siglitazone and pioglitazone) increase insulin sensitivity in
cause of the increased risk of lactic acidosis. In adults there muscle, adipose tissue, and the liver. In isolation, they can
is evidence that metformin can normalize blood glucose reduce HbA1c levels by 0.5% to 1.3%. Results from the
levels, decrease cholesterol levels, and reduce hypertension. TODAY study demonstrated that metformin in combi-
Metformin can also be used to normalize ovulatory abnor- nation with rosiglitazone was more successful than met-
malities in patients with polycystic ovarian syndrome. It is formin alone or metformin with lifestyle modification in
available in a liquid formulation and as an extended-release preventing an increase in HbA1c levels above 8% (0.08).
formulation, which can aid compliance and potentially re- (20) There is some evidence that this combination may
duce adverse effects. The recommended starting dose for improve lipid profiles by lowering triglyceride levels
metformin is 500 mg given orally once daily, with a maxi- and increasing high-density lipoprotein levels. (21) Ad-
mum dose of 2000 mg per day. verse effects include edema, weight gain, and anemia
Insulin is used to attain early normalization of glyce- and may infer additional cardiac risk (Figure).
mic control, especially in patients who are acutely ill or
have significant hyperglycemia, and insulin therapy Prognosis
should be started in all patients who present with diabetic The risk of DM-related complications is directly related
ketoacidosis. Recent American Academy of Pediatrics to the duration of disease. Prompt diagnosis and appro-
clinical practice guidelines on the management of newly priate therapy are paramount in reducing this risk. Be-
diagnosed type 2 DM recommend that insulin therapy be cause of its insidious onset, many patients with type 2
initiated in patients who have a random blood glucose DM have evidence of complications at the time of diag-
level greater than 250 mg/dL (13.9 mmol/L) or whose nosis. Among a sample of 100 Pima Indians with type 2
HbA1c level is greater than 9%.
(20) Once the diagnosis of type 2
DM is determined, insulin therapy
can often be reduced as metformin
therapy is initiated. Adverse effects
of insulin can include weight gain
from its anabolic effect on metabo-
lism. Hypoglycemia, a potential ad-
verse effect, is not as common among
patients with type 2 DM.
Other therapies, although not
FDA approved for patients younger
than 18 years, can be used by the di-
abetes management team to improve
glycemic control. Sulfonylureas (gly-
buride, glipizide, and glimepiride)
directly increase insulin secretion,
so they are most useful when there
is residual b-cell function. Major ad-
verse effects include hypoglycemia
and weight gain. Glucosidase inhib-
itors (acarbose and miglitol) re- Figure. Pathogenesis and therapeutic targets.
duce absorption of carbohydrates DM[diabetes mellitus.

Pediatrics in Review Vol.34 No.12 December 2013 545

endocrinology diabetes mellitus
DM, 18% had hypertension, 7% had dyslipidemia, and
22% had microalbuminuria at the time of diagnosis.
(22) Microvascular complications of type 2 DM include
nephropathy, retinopathy, and neuropathy. Macrovascu-
lar complications include hypertension and hyperlipid-
emia, which can lead to cardiovascular disease. The
ADA recommends that patients with type 2 DM have
blood pressure measurements performed at every routine
diabetes visit. (18) In the UK Prospective Diabetes
Study, hypertension was found to be a more significant
predictor of cardiovascular disease than blood glucose
control. This study also found a 25% reduction in the risk
of microvascular complications when the average HbA1c
level decreased from 7.9% to 7.0%. (23)
Patients should be screened for retinopathy with a di-
lated eye examination near the time of diagnosis and then
yearly afterward. A lipid profile should be performed
shortly after diagnosis, once glycemic control is attained,
and should be performed annually thereafter. Urine mi-
croalbumin should be measured at diagnosis to assess for
early nephropathy and followed up yearly. (18)
Primary public health prevention efforts should target
the general population to limit the prevalence of obesity.
Secondary prevention should focus on screening those
children who are at high risk for the development of type
2 DM (Table 2). Tertiary prevention in patients with type
2 DM should address reduction of complications.
Summary
• On the basis of strong research evidence and
consensus, type 1 diabetes mellitus (DM) remains the
most common form of DM in children and
adolescents. The incidence of type 2 DM in the
pediatric population is rapidly increasing because of
the obesity epidemic, and minority groups are
disproportionately affected. (2) (10) (19)
• On the basis of some research evidence and consensus,
it can be challenging to initially differentiate between
type 2 DM and type 1 DM clinically because of the
increased prevalence of obesity, the complex interplay
of autoimmunity and obesity, and common symptoms
at presentation. (1) (10) (19)
• Significant evidence and consensus support a genetic
basis for the development of type 2 DM in children.
• Physicians should routinely screen at risk children
older than age 10 years for DM. Screening criteria
include obesity, a family history of type 2 DM,
a minority racial or ethnic background, acanthosis
nigricans, or other diseases associated with insulin
resistance, including polycystic ovary syndrome,
hypertension, or dyslipidemia. (1) (10) (18) (19)
546 Pediatrics in Review Vol.34 No.12 December 2013
• On the basis of consensus, diagnosis of type 2 DM can
be confirmed by an elevated fasting blood glucose
level greater than 126 mg/dl (7.0 mmol/L), an
elevated 2-hour plasma glucose greater than 200 mg/
dL (11.1 mmol/L) on an oral glucose tolerance test, an
elevated random blood glucose greater than 200 mg/
dL (11.1 mmol/L), or a hemoglobin A1c level greater
than 6.5% with suggestive symptoms. (10)
• According to strong research evidence and consensus,
once the diagnosis has been made, treatment should
be based on the acuity of presentation and should
focus on lifestyle modification and on normalizing
hyperglycemia to minimize complications. Metformin
is currently first-line treatment for type 2 DM in
children and adolescents older than age 10 years who
present nonacutely. (18) (19)
• Strong research evidence and consensus demonstrate
that because type 2 DM has an insidious onset,
microvascular and macrovascular complications can
be present at the time of diagnosis. Patients should be
screened for the presence of complications when the
diagnosis of type 2 DM is made and in follow-up. (6)
(10)
ACKNOWLEDGMENTS. The authors wish to acknowl-
edge Babalola Faseru, MD, MPH, assistant professor,
Department of Preventive Medicine and Public Health,
University of Kansas School of Medicine, and Naim Mitre,
MD, Naim Mitre, MD, medical director of clinical services,
assistant fellowship program director, assistant professor of
pediatrics, Division of Endocrine/Diabetes, Department
of Pediatrics, University of Missouri-Kansas City/Children’s
Mercy Hospital.
Suggested Reading
Expert Panel on Integrated Guidelines for Cardiovascular Health
and Risk Reduction in Children and Adolescents; National Heart,
Lung, and Blood Institute. Expert panel on integrated guidelines
for cardiovascular health and risk reduction in children and
adolescents: summary report. Pediatrics. 2011;128(suppl 5):S213–
S256
Hannon TS, Rao G, Arslanian SA. Childhood obesity and type 2
diabetes mellitus. Pediatrics. 2005;116(2):473–480
References
1. Badaru A, Pihoker C. Type 2 diabetes in childhood: clinical
characteristics and role of b-cell autoimmunity. Curr Diab Rep.
2012;12(1):75–81
2. Liese AD, D’Agostino RB Jr, Hamman RF, et al; SEARCH for
Diabetes in Youth Study Group. The burden of diabetes mellitus
among US youth: prevalence estimates from the SEARCH for
Diabetes in Youth Study. Pediatrics. 2006;118(4):1510–1518
3. Centers for Disease Control and Prevention. National diabetes fact
sheet 2011: national estimates and general information on diabetes
and prediabetes in the United States. Available at: http://www.cdc.
gov/diabetes/pubs/factsheet11.htm. Accessed October 16,2012

4. Expert Committee on the Diagnosis and Classification of Diabetes
Mellitus. Report of the expert committee on the diagnosis and
classification of diabetes mellitus. Diabetes Care. 1997;20(7):
1183–1197
5. Dabelea D, Bell RA, D’Agostino RB Jr, et al; Writing Group for
the SEARCH for Diabetes in Youth Study Group. Incidence of
diabetes in youth in the United States. JAMA. 2007;297(24):
2716–2724
6. American Diabetes Association. Type 2 diabetes in children and
adolescents. Diabetes Care. 2000;23(3):381–389
7. Miller J, Silverstein JH, Rosenbloom AL. Type 2 diabetes in the
child and adolescent. In: Lifshitz F, ed. Pediatric Endocrinology.
Vol 1. Obesity, Diabetes Mellitus, Insulin Resistance, and
Hypoglycemia. 5th ed. New York, NY: Informa Healthcare Inc;
2007:168–187
8. Pettitt DJ, Aleck KA, Baird HR, Carraher MJ, Bennett PH,
Knowler WC. Congenital susceptibility to NIDDM: role of in-
trauterine environment. Diabetes. 1988;37(5):622–628
9. Pettitt DJ, Forman MR, Hanson RL, Knowler WC, Bennett
PH. Breastfeeding and incidence of non-insulin-dependent diabetes
mellitus in Pima Indians. Lancet. 1997;350(9072):166–168
10. American Diabetes Association. Diagnosis and classification of
diabetes mellitus. Diabetes Care. 2012;35(1 Suppl 1):S64–S71
11. Chen L, Appel LJ, Loria C, et al. Reduction in consumption of
sugar-sweetened beverages is associated with weight loss: the
PREMIER trial. Am J Clin Nutr. 2009;89(5):1299–1306
12. Welsh JA, Sharma AJ, Grellinger L, Vos MB. Consumption of
added sugars is decreasing in the United States. Am J Clin Nutr.
2011;94(3):726–734
13. Phipps K, Barker DJ, Hales CN, Fall CH, Osmond C, Clark
PM. Fetal growth and impaired glucose tolerance in men and
women. Diabetologia. 1993;36(3):225–228
14. Vignini A, Raffaelli F, Cester A, et al. Environmental and
genetical aspects of the link between pregnancy, birth size, and type
2 diabetes. Curr Diabetes Rev. 2012;8(3):155–161
Parent Resources From the AAP at HealthyChildren.org
• English: http://www.healthychildren.org/English/health-issues/conditions/chronic/Pages/Type-2-Diabetes-A-
Manageable-Epidemic.aspx
• Spanish: http://www.healthychildren.org/spanish/health-issues/conditions/chronic/paginas/type-2-diabetes-a-
manageable-epidemic.aspx
• English: http://www.healthychildren.org/English/news/Pages/AAP-Publishes-First-Guidelines-to-Manage-Type-2-
Diabetes-in-Children.aspx
endocrinology diabetes mellitus
15. Kim G, Caprio S. Diabetes and insulin resistance in pediatric
obesity. Pediatr Clin North Am. 2011;58(6):1355–1361, ix
16. Klingensmith GJ, Pyle L, Arslanian S, et al; TODAY Study
Group. The presence of GAD and IA-2 antibodies in youth with
a type 2 diabetes phenotype: results from the TODAY study.
Diabetes Care. 2010;33(9):1970–1975
17. Pinhas-Hamiel O, Zeitler P. Acute and chronic complications
of type 2 diabetes mellitus in children and adolescents. Lancet.
2007;369(9575):1823–1831
18. American Diabetes Association. Standards of medical care in
diabetes—2012. Diabetes Care. 2012;35(suppl 1):S11–S63
19. Rosenbloom AL, Silverstein JH, Amemiya S, Zeitler P,
Klingensmith GJ; International Society for Pediatric and Adolescent
Diabetes. ISPAD Clinical Practice Consensus Guidelines 2006–
2007: type 2 diabetes mellitus in the child and adolescent. Pediatr
Diabetes. 2008;9(5):512–526
20. Copeland KC, Silverstein J, Moore KR, et al; American
Academy of Pediatrics. Management of newly diagnosed type 2
diabetes mellitus (T2DM) in children and adolescents. Pediatrics.
2013;131(2):364–382
21. Zeitler P, Hirst K, Pyle L, et al; TODAY Study Group. A
clinical trial to maintain glycemic control in youth with type 2
diabetes. N Engl J Med. 2012;366(24):2247–2256
22. Olansky L, Marchetti A, Lau H. Multicenter retrospective
assessment of thiazolidinedione monotherapy and combination
therapy in patients with type 2 diabetes: comparative subgroup
analyses of glycemic control and blood lipid levels. Clin Ther. 2003;
25(suppl B):B64-B80.
23. Genuth S, Alberti KG, Bennett P, et al; Expert Committee on
the Diagnosis and Classification of Diabetes Mellitus. Follow-up
report on the diagnosis of diabetes mellitus. Diabetes Care. 2003;26
(11):3160–3167
24. Adler AI. UKPDS-modelling of cardiovascular risk assessment
and lifetime simulation of outcomes. Diab Med. 2008;25(suppl 2):
41–46
Pediatrics in Review Vol.34 No.12 December 2013 547
endocrinology diabetes mellitus

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1. Among the following factors, which is most likely to protect a 13-year-old patient against type 2 diabetes
mellitus (DM)?
A. Adolescent age.
B. Female sex.
C. History of being breastfed.
D. Mother who had gestational diabetes.
E. Native American race.

2. It can be difficult to distinguish between type 1 and type 2 DM in a child who presents with ketoacidosis.
Among the following, which clinical finding is most suggestive of type 2 DM?
A. Acanthosis nigricans.
B. Polydipsia.
C. Polyphagia.
D. Polyuria.
E. Weight loss.

3. In your management of a 7-year-old boy with type 1 DM, which of the following parameters are you likely to
assess every 3 months?
A. Albuminuria.
B. Hemoglobin A1c.
C. Lipid profile.
D. Liver function tests.
E. Signs of sleep apnea.

4. In addition to diet and exercise, you are considering pharmacotherapy for a 15-year-old girl who has had type
2 DM for the past year. Among the following, which is the only drug approved by the US Food and Drug
Administration for someone her age?
A. Acarbose.
B. Exenatide.
C. Glipizide.
D. Metformin.
E. Pioglitazone.

5. In a patient with newly diagnosed type 2 DM, initiation of insulin therapy is recommended if which one of the
following findings is present?
A. Fasting blood glucose level of 140 mg/dL (7.8 mmol/L).
B. Hemoglobin A1c level of 8.0% (0.08).
C. Hemoglobin A1c level of 8.5% (0.09).
D. Random blood glucose level of 200 mg/dL (11.1 mmol/L).
E. Random blood glucose 275 mg/dL (15.3 mmol/L).

548 Pediatrics in Review Vol.34 No.12 December 2013


Managing Feeding Problems and Feeding
Disorders
James A. Phalen, MD*
Author Disclosure
Dr Phalen has
disclosed no financial
relationships relevant
to this article. This
commentary does not
contain a discussion of
an unapproved/
investigative use of
a commercial product/
device.
Abbreviations
BMI: body mass index
CDC: Centers for Disease Control and Prevention
GERD: gastroesophageal reflux disease
g-tube: gastrostomy tube
W/L: weight-length ratio
Article nutrition
Educational Gap
Up to 50% of typically developing children and up to 80% of those who have develop-
mental disabilities have feeding problems. These may evolve into a feeding disorder, with
potential effects on psychomotor and neurologic development. (1) (2)
Objectives After completing this article, readers should be able to:
1. Understand normal feeding patterns in children.
2. Recognize that feeding problems are common.
3. Prevent or ameliorate feeding problems.
4. Distinguish between feeding problems and feeding disorders.
5. Treat a child who has a feeding disorder.
Introduction
Feeding plays a central role in the parent-infant relationship. The developmental progres-
sion of food selectivity is primarily determined by a child’s ability to manipulate, chew, and
swallow food (Table 1). Functional, safe feeding requires coordination of sensorimotor
function, swallowing, and breathing. Children self-regulate and may vary their oral intake
up to 30% per day with no ill effect on growth. Caregivers are responsible for what, when,
and where their children eat; the child is responsible for how much and whether they eat.
Normal feeding depends on the successful interaction of a child’s health, development,
temperament, experience, and environment. Altering any of these factors can result in
a feeding problem. (1)
Common Feeding Problems
Symptoms of feeding problems include food refusal, regurgitation, gagging, or swallowing
resistance (Table 2). (1) (3) Although the child maintains adequate growth, the behavior
causes distress for caretakers. Factors that increase a child’s risk for feeding problems, par-
ticularly during transition to more advanced textures, are listed in Table 3.
Between 25% and 50% of typically developing children and up to 80% of those with de-
velopmental disabilities have feeding problems. However, these problems are usually transient
and cause no serious outcomes. (1) Feeding problems are thus the norm. Practitioners must
consider cultural and ethnic differences and adjust for prematurity when setting expectations
for feeding. Some fundamental mealtime rules apply to toddlers and older children and can
prevent or resolve many feeding problems (Table 4). If a child is otherwise healthy and grow-
ing well, practitioners can reassure caregivers.
Feeding Disorder
A feeding disorder is any condition in which a child has an
inability or difficulty in eating or drinking sufficient quanti-
ties to maintain optimal nutritional status, regardless of
cause. Growth may be unaffected. Between 3% and 10%
of children are affected. Feeding disorders are multifactorial
and may begin with the child (Table 3), the parents, or the
*Developmental Pediatrics, San Antonio Military Pediatric Center, San Antonio, TX; Department of Pediatrics, University of Texas
Health Science Center at San Antonio; Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda,
MD.
Pediatrics in Review Vol.34 No.12 December 2013 549
nutrition feeding problems and disorders

Table 1. Developmental Progression of Food Selectivity Based on Motor

Skills
Age, mo Food Consistency Fine and Gross Motor Skill Oral Motor Skill
0-4 Liquid Dependent on outside support Suckling present
Head control emerging Protective reflexes
4-6 Infant cereal Sits briefly Suckles more efficiently
Puréed fruits and vegetables Head control improves Sucks foods rather than phasic biting
Brings hands to midline Eats messily from spoon
Clasps bottle but needs help
6-9 Puréed meats Independent sitting Sips messily from cup
Variety of puréed baby food Reaches for food Vertical munching
Begins to finger feed Limited lateral tongue action
Unrefined pincer grasp Clears spoon with upper lip
Holds bottle independently Bite and release pattern
Assists with spoon Breaks off pieces of meltable solids
9-12 Ground and lumpy purées Sits in variety of positions Lip closure for liquids and soft solids
Mashed table foods Refined pincer grasp Spoon clearing more efficient
Soft, dissolvable solids Finger feeding refined Cup drinking with assistance
Grasps spoon with whole hand Begins drinking from
spouted cup
Grasps cup handle Begins to drink through a straw
12-18 Finely chopped table foods Scoops food Lateral tongue action
Chews juicy foods Brings to mouth Diagonal chewing
Bites through crunchy More independent feeding Begins drinking from straw
foods (cookies, crackers)
Upper teeth clear food from lower lip
18-24 More chewable solids Handles finger foods, spoon, Rotary chewing
and cup largely independently
Booster chair Cup drinking improved
Minimal food lost during eating
24-36 Tougher solids Total self-feeding Mature chewing for tougher solids
Open cup drinking without spilling
Variety of liquids through straw
Tongue clears food from lips
‡36 Advanced textures Begins using fork to stab food Open cup independently
(meats, fried foods,
whole fruits)

environment (Table 5). (2) Regardless of its origins, it
affects the parent-child dyad and often evolves into a be-
havioral problem. Older children may experience low
self-esteem and social isolation.
Evaluation of Feeding Disorders
Initial evaluation of feeding disorders begins with the pri-
mary care practitioner, who should assess parental coping,
mental health, and bonding. Most parents whose children
have feeding disorders describe feeling frustrated and dis-
tressed at mealtime. The growth chart (length, weight,
and weight-length ratio [W/L], or body mass index
[BMI]) should be reviewed. True failure to thrive is a sus-
tained decrease in growth velocity, best defined as a W/L or
BMI below the fifth percentile. Failure to thrive usually
results from inadequate energy intake but may reflect inad-
equate nutrient absorption or increased energy require-
ments. Although growth charts exist for specific conditions,
the Centers for Disease Control and Prevention (CDC)
recommend that practitioners use the World Health Orga-
nization growth standards to monitor growth for infants
and children ages 0 to 2 years in the United States (avail-
able at http://www.cdc.gov/GrowthCharts/who_charts.
htm) and CDC growth charts to monitor growth for chil-
dren ages 2 to 20 years in the United States (available at
http://www.cdc.gov/GrowthCharts/cdc_charts.htm).
A thorough review of the child’s prenatal, birth, and
medical histories should focus on the following key areas:

550 Pediatrics in Review Vol.34 No.12 December 2013


Common Feeding
Table 2.
Problems in Children
Delayed development of oral motor and self-feeding
skills; common in infants and children with hypotonia,
global developmental delay or intellectual disability,
and neurologic disorders
Reluctance or refusal to eat based on sensory issues (eg,
taste, texture, temperature, smell, or appearance)
Food selectivity (eg, personal preference, discomfort with
certain foods because of gastroesophageal reflux
disease, or food allergy)
Decreased appetite for or interest in food
Slow feeding (ie, >30 minutes to finish)
Food pocketing (ie, holding food in cheeks or front of
mouth for prolonged periods) suggests poor oral
transport or refusal
Using feeding behaviors to comfort, self-soothe, or
self-stimulate
• Small for gestational age. Up to 15% of infants born
small for gestational age fail to achieve appropriate
catch-up growth by age 2 years and continue to expe-
rience poor growth throughout childhood. Rapid
catch-up growth before age 2 years in this group in-
creases the risk of developing metabolic disease later
in life. (4) (5) (6) Thus, practitioners must temper at-
tempts to promote catch-up growth against the risks.
It is reasonable to aim for a W/L or BMI between the
10th and 50th percentiles in this population.
Pediatric Conditions
Table 3.
Associated With Feeding
Problems and Feeding Disorders
Temperamental traits that complicate feeding and
overwhelm parents
Prematurity (especially neonates who require prolonged
respiratory support or enteral feeds or with delayed
introduction of oral feeds)
Genetic or chromosomal abnormalities (eg, Down
syndrome and inherited neuromuscular disease)
Craniofacial anomalies (eg, Pierre-Robin sequence and
cleft palate)
Acquired brain impairment (eg, cerebral palsy, stroke,
and traumatic brain injury)
Gastrointestinal disorders (eg, gastroesophageal reflux
disease and chronic constipation)
Neurodevelopmental disorders (eg, autism spectrum
disorder, global developmental delay, and intellectual
disability)
nutrition feeding problems and disorders
• Aspiration. Aspiration involves passage of secretions,
drink, or solid food below the true vocal cords. It
may occur before, during, or after swallowing or from
gastroesophageal reflux. Signs include coughing,
throat clearing, gurgling voice, noisy breathing, recur-
rent wheezing or stridor, and recurrent lower respira-
tory tract infections. Some children aspirate with no
obvious symptoms; this condition is called silent aspi-
ration and suggests lack of a protective reflex. (7) As-
piration suggests oral motor delay or oropharyngeal
dysphagia. Infants and children who have oral motor
delay typically have oral hypotonia and an underdevel-
oped suck-swallow-breathe pattern. Thus, they may
have poor lip closure, drooling after age 12 months,
lack of tongue lateralization, and loss of food from
the mouth (Table 1). Oropharyngeal dysphagia, how-
ever, is pathologic difficulty swallowing because of un-
derlying neurologic or structural abnormalities.
• Motor disabilities (eg, cerebral palsy and spina bifida). Chil-
dren with motor disabilities are less mobile than neurotyp-
ical children and thus have lower energy requirements. A
W/L or BMI greater than the 50th percentile makes hy-
giene, mobility, and transfers (eg, wheelchair to tub) more
challenging and increases the risk of medical complications
of obesity through excessive caloric intake.
• Gastroesophageal reflux disease (GERD). Signs of
GERD include regurgitation, postprandial emesis,
choking, gagging, food refusal, constant or sudden
crying, irritability, poor sleep patterns, apnea, stridor,
laryngospasm, bronchospasm, and hoarseness. Eosino-
philic esophagitis deserves consideration in any child
presenting with symptoms of GERD in whom a trial
of medical therapy with a proton pump inhibitor fails,
especially in the setting of atopy. Persistent symptoms
and food impaction (food getting stuck in the esoph-
agus) should raise additional concern.
• Constipation. Signs and symptoms of constipation in-
clude bulky, painful, or infrequent bowel movements,
failed attempts to stool, bloody stools, anal fissures,
urinary incontinence, and overflow incontinence
(encopresis). Parents often confuse the latter with diar-
rhea. Chronic constipation may cause early satiety and
reduced caloric intake. Stool withholding exacerbates
constipation and may have psychosocial consequences.
• Medications. Medications that can cause excessive se-
dation or decreased appetite include stimulants, selec-
tive serotonin reuptake inhibitors, and topiramate.
Pica and rumination are more likely to occur in individuals
who have developmental disabilities, psychiatric disorders, or
physiologic conditions (eg, iron deficiency and pregnancy).
Pediatrics in Review Vol.34 No.12 December 2013 551
nutrition feeding problems and disorders

Table 4. Mealtime Rules for Toddlers and Older Children

Feature Rules Benefit
Scheduling Regular meals with planned, low-calorie snacks Prevents “grazing”
Same room, table, and utensils for every meal Enhances sense of hunger and satiety
Limit mealtime to 30 minutes Caregivers maintain control of
(ie, “kitchen is open”) feeding schedule
Offer no liquids between meals except plain Home is less chaotic
water (ie, “kitchen is closed”)
Environment Family sits together at mealtime Focus is on socializing rather than eating
Neutral atmosphere (no forced feeding or Avoids conflict
comments regarding intake)
Eliminate distractions: turn off all Allows child to focus on mealtime
electronic devices, child sits with
back to open room
Allow younger child to explore foods by Mealtime is more pleasant
touching, smelling, and tasting
Allow older child to participate in food
purchase and meal preparation
Never use food as a reward, bribe, or incentive
Praise child for showing interest in food
Allow at least 20 exposures to new foods for
acceptance
Methods Optimal feeding posture: More likely to consume calorically dense foods
• Head midline and neck neutral or Expands food repertoire
slightly flexed
• Trunk symmetrical and elongated Promotes independence
• Pelvis stable with hips symmetrical in neutral Prevents constipation and anemia from
position excessive milk intake
• Hips, knees, and ankles each at 90o Prevents loose stools and dental caries from
excessive juice intake
Serve food at table for everyone from same
container
Small portions
Small easily chewed bites or long thin
strips child can grasp
Offer liquids only after child begins eating solids
Offer plain, unflavored water as primary beverage
Limit daily intake of low-fat or fat-free white or
flavored milk to:
• 2 cups for children ages 2 to 3 years
• 2½ cups for children ages 4 to 8 years
• 3 cups for those 9 years and older
Do not dilute fruit juice, and limit to
4 to 6 oz per day
Discourage sweetened beverages (soft
drinks and sports or energy drinks)
Encourage self-feeding (eg, finger feeding
and holding spoon)
Food chaining: offer unfamiliar or
nonpreferred foods first and paired with
familiar or preferred foods
Avoid excessive coaxing, threatening, or
forced feeding
Remove food without comment if child
loses interest
Wipe face and clean up only when
meal completed

552 Pediatrics in Review Vol.34 No.12 December 2013

 nutrition feeding problems and disorders

Parental and Environmental Factors Associated With Feeding

Table 5.

Disorder
Factor Result
Conditioned aversion Pairing eating with a painful medical condition or procedure (eg, airway suctioning and
intubation)
Lack of opportunity Delayed introduction of breast, bottle, or solids is associated with delayed attainment of
appropriate eating skills
Positive reinforcement Caretakers coax or bribe infant who bats away the spoon, turns the head away, or cries
Negative reinforcement Caretakers terminate meal when child acts out
Forced feeding Results in aversion to meals and evokes inappropriate behavior at future meals
Overly rigid parents Undermines child’s ability to regulate food intake and impairs child’s psychosocial development
Chaotic parents Fail to provide child with appropriate food, support, structure, or opportunity to learn to enjoy
a variety of foods or to master eating-related social patterns

Neither should be diagnosed unless symptoms are of an
unusual extent or cause health concerns. (8) (9)
• Pica disorder. Pica disorder is the recurring ingestion of
nonfood, nonnutritive substances for at least 1 month in
a child at least 2 years of age, which is inappropriate to
the child’s developmental level and sociocultural norms.
• Rumination disorder. Rumination disorder is the re-
peated regurgitation of food for at least 1 month. Re-
gurgitated food may be rechewed, reswallowed, or spit
out, most often during or shortly after meals. It is not
associated with nausea or a medical condition. It is vo-
litional, distinguishing it from vomiting and gastro-
esophageal reflux.
Feeding History
It is important to have caretakers describe the mealtime en-
vironment (Table 5) and the child’s feeding habits (Table 6).
Feeding Observation
If time and resources allow, the practitioner or clinic
nurse may observe (in person or by video) the child feed-
ing. Such observation allows identification of appropriate
child positioning and posture, the child’s hunger and sa-
tiety cues, the caretaker’s response to and interactions
with the child, any delayed oral motor or self-feeding
skills, and difficulty managing or tolerating liquids or sol-
ids (eg, oropharyngeal dysphagia).
A complete physical, neurologic, and oral motor ex-
amination must be performed. The oral motor examina-
tion includes evaluating facial symmetry, hard and soft
palate for (submucous) cleft, and dentition; symmetry
and movement of lips and tongue; vocal intensity, pitch,
and quality; and cranial nerves. Prolonged inadequate en-
ergy and nutrient intake may have broad effects beyond
physical growth, with potential effects on psychomotor
and neurologic development. It may also affect the im-
mune, skeletal, and cardiovascular systems.
Practitioners should select diagnostic laboratory stud-
ies based on the history and physical examination find-
ings. The following are reasonable:
• In cases of failure to thrive: complete blood cell count,
urinalysis, blood urea nitrogen, serum electrolytes, and
serologic screening for celiac disease (usually IgA anti-
bodies to tissue transglutaminase).
• In cases of pica disorder: serum iron and lead levels.
Classification of Feeding Disorders
The Diagnostic and Statistical Manual of Mental Dis-
orders, Fifth Edition (DSM-5), informed by available
research and extensive discussion of expert clinical expe-
rience and opinion, takes a lifespan approach to how age
and development affect psychiatric diagnoses. Avoidant/
restrictive food intake disorder replaces the previous term
feeding disorder of infancy or early childhood (Table 7).
Other classification systems exist; however, none is uni-
versally accepted, and few are evidence based.
Management of Feeding Disorders
The long-term goals of treatment are to improve nutritional
status, growth, feeding safety, and quality of life. Recognition
and treatment of GERD and constipation are essential. On
the basis of findings, practitioners may consult the following:
• A pediatric speech-language pathologist to perform
a clinical swallowing evaluation coupled with a video
fluoroscopic swallow study to evaluate for oral motor
delay and oropharyngeal dysphagia.
• A registered pediatric dietitian to assess caloric intake,
nutritional quality, and dietary practices and to coman-
age enteral feeds.

Pediatrics in Review Vol.34 No.12 December 2013 553

nutrition feeding problems and disorders
Table 6. Components of a Feeding History
Ask Caretakers
How they prepare infant formula
Whether they add infant cereal, puréed solids, or
proprietary thickeners to formula
About food preferences and nutritional deficits (eg, convenience
foods, inadequate intake of fruits and vegetables, and excessive
juice or milk intake)
About grazing (eg, overly frequent breastfeeding in older infants;
toddlers and older children eating and drinking throughout the
day); these children may come to your clinic snacking and
drinking.
About reliance on dietary supplements (eg, multivitamins,
megavitamins, toddler formula, and breakfast drinks) or appetite
stimulants (eg, megestrol acetate and cyproheptadine)
About difficulty chewing, excessive drooling, or food
or liquid leaving the mouth or nose
Patient’s age at and difficulty with transitions
from liquids to purées to solids
Whether child gags, chokes, coughs, or vomits during feeds or has
disruptions in breathing, apnea, or cyanosis during feeds
About refusal, tantrums, rumination, pica, avoidance of certain
food textures, temperatures, and colors
• A pediatric gastroenterologist to evaluate severe recal-
citrant constipation, GERD, and eosinophilic esopha-
gitis and to comanage enteral feeds.
• A developmental pediatrician to further evaluate for
contributing causes (eg, global developmental delay,
autism spectrum disorder, and parent-child conflict).
• An interdisciplinary feeding team that includes some
combination of the above professionals along with
a clinical child and pediatric psychologist.
Oral motor skills usually improve over time but can be
promoted in a more organized and efficient manner with
therapy. Pediatric speech-language pathologists and oc-
cupational therapists generally use noninvasive treat-
ments, such as proper positioning and posture, thickened
liquids, modification of bolus size, oral motor and desen-
sitization exercises, specialized nipples and bottles, and
altering the temperature, texture, or presentation of food.
The evidence base for these interventions is limited. (7)
(10) Transcutaneous neuromuscular electrical stimula-
tion is an emerging therapy for dysphagia in children.
It involves noninvasive, external electrical stimulation
of peripheral motor nerves of the anterior throat to acti-
vate the pharyngeal muscles involved in swallowing.
554 Pediatrics in Review Vol.34 No.12 December 2013
Clinical Significance
Healthy infants require a concentration of 20 kcal/oz,
whereas those who have medical problems (eg,
cardiac disease) or failure to thrive may require
more concentrated or specialized formula
Poor tolerance of nonthickened formula may indicate
oral motor delay or oropharyngeal dysphagia;
premature introduction of solids may reflect
cultural practices
May suggest the child’s preferences or that caretakers
have difficulty setting limits
Grazing may lead to reduced energy intake, increases
the risk for dental caries, and suggests caretakers
have difficulty setting limits
Indicates caretaker or practitioner concern and may
reveal inappropriate feeding practices
Indicates delayed oral motor skills
May indicate delayed oral motor skills or behavioral
preferences
Raises concern for oropharyngeal dysphagia
Identifies maladaptive mealtime behaviors
Dietary interventions aim to establish a balanced,
healthful diet. Because liquids are usually easier than sol-
ids to consume, the tendency is to supplement the diet
with toddler formula. Often formulas come to replace
meals, leading to grazing and inadequate energy and nu-
trient intake, further aggravating the child’s nutritional
deficiency. Clinicians should thus discourage overreliance
on toddler formulas and other liquid supplements. Reg-
istered dietitians may recommend nutrient- and energy-
dense foods and/or specialized formula.
Behavioral feeding therapy is implemented most ap-
propriately in the context of an interdisciplinary team,
typically including a registered dietitian, speech-language
pathologist, and clinical child and pediatric psychologist.
Effective therapy aims to eliminate factors that reinforce
maladaptive mealtime behavior. (2) Settings include out-
patient, partial day, and inpatient facilities. Treatment
should start with the least intrusive approach, generally
outpatient. The literature does not support pharmaco-
logic treatment with appetite stimulants (eg, megestrol
acetate and cyproheptadine) for behavioral feeding disor-
ders. Caregiver compliance is strongly associated with
skills maintenance and generalization.

DSM-5 Diagnostic Criteria
Table 7.
for Avoidant/Restrictive Food
Intake Disorder (307.59)
A. An eating or feeding disturbance (eg, apparent lack of
interest in eating or food; avoidance based on the
sensory characteristics of food; concern about
aversive consequences of eating) as manifested by
persistent failure to meet appropriate nutritional and/
or energy needs associated with one (or more) of the
following:
1. Significant weight loss (or failure to achieve
expected weight gain or faltering growth in children)
2. Significant nutritional deficiency
3. Dependence on enteral feeding or oral nutritional
supplements
4. Marked interference with psychosocial functioning
B. The disturbance is not better explained by lack of
available food or by an associated culturally
sanctioned practice.
C. The eating disturbance does not occur exclusively
during the course of anorexia nervosa or bulimia
nervosa, and there is no evidence of a disturbance in
which one’s body weight or shape is experienced.
D. The eating disturbance is attributable to a concurrent
medical condition or better explained by another
mental disorder. When the eating disturbance occurs
in the context of another condition or disorder, the
severity of the eating disturbance exceeds that
routinely associated with the condition or disorder
and warrants additional clinical attention.
Reprinted with permission from the American Psychiatric Association.
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.
Washington, DC: American Psychiatric Association; 2013.
Those who cannot consume sufficient energy and nu-
trients or do so safely by mouth require enteral (ie, tube)
nutrition. Enteral nutrition can be delivered via nasogas-
tric tube, orogastric tube, or gastrostomy tube (g-tube).
For those requiring enteral nutrition for longer than 6
weeks, the latter is preferred. Minimally invasive percuta-
neous endoscopic gastrostomy and laparoscopic gastro-
stomy have largely supplanted the open laparotomy for
placement of g-tubes. To preserve oral activity and feed-
ing habits, along with hunger and satiety cues, oral feeds
(when safe) should precede supplemental tube feeds. En-
teral nutrition is delivered either intermittently or contin-
uously. The preferred method is intermittent bolus
feedings, which is more physiologic; however, if the pa-
tient does not tolerate bolus feeds then continuous feeds,
either intragastric or transpyloric (through a gastrojeju-
nostomy), is reasonable. Although the decision to initiate
nutrition feeding problems and disorders
enteral nutrition is emotionally challenging for parents, it
eliminates the pressure for oral feeding. It allows the child
to be fed safely and efficiently, reducing the risk of aspi-
ration and allowing for catch-up growth. Rapid or volu-
minous feeds may trigger retching or aggravate GERD.
Excessive caloric intake can cause overweight or obe-
sity, leading to problems handling and lifting children
who have physical disabilities. Bypassing the oral route
deprives the child of the experiences associated with feed-
ing, thus delaying oral sensorimotor skills and increasing
the risk for sensory-based food aversions when oral feeds
are reintroduced. The earlier in life that a g-tube is placed,
the more difficult it becomes to wean the child from it
later in life. Finally, continuous feeds are less physiologic
than are bolus feeds, resulting in decreased appetite and
increasing the risk of grazing and reliance on the g-tube.
Tube dependency occurs when the child has the ability to
ingest and digest food but cannot be weaned from tube
feeding, regardless of medical criteria. For these reasons,
children who have g-tubes should be exposed to the
mealtime environment, be encouraged to touch and in-
teract with food without regard to intake, be given bolus
feeds if tolerated, and have oral feeds advanced when pos-
sible. This, along with oral motor and/or behavioral
feeding therapy involving the parents, helps the child
progress to g-tube independence. Children who receive
no feeds, fluids, or flushes through their g-tube for 12
months are candidates to have the device removed. Pre-
mature removal may increase the child’s risk for compli-
cations, such as failure to thrive.
Summary
• On the basis of strong research evidence, feeding
problems and feeding disorders are common,
especially in children who have developmental
disabilities. (1) (3)
• On the basis of strong research evidence, a variety of
prenatal, medical, environmental, behavioral, and
parental factors contribute to childhood feeding
disorders. (1) (3)
• On the basis of some research evidence plus
consensus, many feeding problems are preventable or
easily treated.
• On the basis of strong research evidence, left
untreated, feeding disorders may result in
complications, including aspiration pneumonitis,
failure to thrive, and parent-child conflict.
• On the basis of some research evidence plus consensus,
treatment of feeding disorders improves nutritional
status, growth, feeding safety, and quality of life.
Pediatrics in Review Vol.34 No.12 December 2013 555
nutrition feeding problems and disorders

ACKNOWLEDGMENT. The author acknowledges past
and present members of the Interdisciplinary Feeding
Team at San Antonio Military Pediatric Center for their
clinical expertise and guidance, without which this article
would not be possible.
(The views expressed are those of the author and do not
reflect the official policy or position of the US Air Force, De-
partment of Defense or the US Government.)
Suggested Reading
American Speech-Language-Hearing Association. Swallowing and
Feeding Disorders. Available at http://www.asha.org/slp/
clinical/dysphagia/. Accessed October 29, 2013
Ellyn Satter Associates. Available at http://www.EllynSatter.com.
Accessed October 29, 2013
References
1. Bryant-Waugh R, Markham L, Kreipe RE, Walsh BT. Feeding and
eating disorders in childhood. Int J Eat Disord. 2010;43(2):98–111
2. Sharp WG, Jaquess DL, Morton JF, Herzinger CV. Pediatric
feeding disorders: a quantitative synthesis of treatment outcomes.
Clin Child Fam Psychol Rev. 2010;13(4):348–365
3. Eicher PS. Feeding and its disorders. In: Batshaw M, ed.
Children With Disabilities. 7th ed. Baltimore, MD: Brookes
Publishing; 2012
4. Ong KK, Loos RJ. Rapid infancy weight gain and subsequent
obesity: systematic reviews and hopeful suggestions. Acta Paediatr.
2006;95(8):904–908
5. Baird J, Fisher D, Lucas P, Kleijnen J, Roberts H, Law C. Being
big or growing fast: systematic review of size and growth in infancy
and later obesity. BMJ. 2005;331(7522):929
6. Monteiro POA, Victora CG. Rapid growth in infancy and child-
hood and obesity in later life—a systematic review. Obes Rev. 2005;6
(2):143–154
7. Miller CK. Aspiration and swallowing dysfunction in pediatric
patients. Infant Child Adolesc Nutr. 2011;3:336–343
8. Uher R, Rutter M. Classification of feeding and eating disorders:
review of evidence and proposals for ICD-11. World Psychiatry.
2012;11(2):80–92
9. American Psychiatric Association. Diagnostic and Statistical
Manual of Mental Disorders, Fifth Edition. Washington, DC:
American Psychiatric Association; 2013
10. Morgan AT, Dodrill P, Ward EC. Interventions for oropha-
ryngeal dysphagia in children with neurological impairment.
Cochrane Database Syst Rev. 2012;10:CD009456

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1. A previously well 7-month-old infant is developing normally. She sits and holds her bottle independently,
reaches for food, and finger feeds herself. What is the most appropriate food choice for this infant?
A. Chewable solids.
B. Finely chopped table foods.
C. Mashed table foods.
D. Pureed meats.
E. Whole fruits.

The vignette below will be used for questions 2 and 3.

2. A healthy 14-month-old boy refuses solids at mealtime and prefers milk and juice. He has grown and
developed normally. He has no siblings. His mother is frustrated and concerned because nothing has worked to
change the behavior. His physical examination findings are unremarkable. What is the first step in treatment?
A. Ordering a comprehensive metabolic panel.
B. Prescribing a proton pump inhibitor.
C. Reassuring the mother.
D. Referring to a gastroenterologist.
E. Referring to an occupational therapist.

556 Pediatrics in Review Vol.34 No.12 December 2013

 nutrition feeding problems and disorders

3. The mother of the 14-month-old boy asks for some healthful behavior-shaping tips. In response you would
have her:
A. Arrange special mealtimes for her son.
B. Encourage him to self-feed.
C. Make the child sit alone at the table until his plate is clean.
D. Offer a cup of diluted juice if he eats some solids.
E. Permit the boy to watch videos during mealtime.

4. Which of the following 14-month-old boys who are growing normally has a feeding disorder rather than just
a feeding problem?
A. Drools constantly and dribbles food from mouth.
B. Feeds slowly but finishes most meals.
C. Pockets foods in mouth he does not like.
D. Refuses solids but loves milk and juice.
E. Spits out lima beans and broccoli.

5. A 14-month-old girl has severe oropharyngeal dysphagia related to hypoxic-ischemic brain injury secondary to
abruptio placentae. She now requires enteral feeding to provide adequate nutrition. Assuming the gut works
normally, the child is exposed to the family mealtime environment, and the child is encouraged to touch food
without regard to intake, optimal management would include:
A. Continuous gastrostomy tube feeding.
B. Continuous gastrojejunostomy tube feeding.
C. Continuous nasogastric tube feeding.
D. Intermittent bolus gastrostomy tube feeding.
E. Intermittent bolus nasogastric tube feeding.

Parent Resources From the AAP at HealthyChildren.org

• English: http://www.healthychildren.org/English/ages-stages/baby/feeding-nutrition/Pages/Signs-of-Feeding-
Difficulties.aspx
• Spanish: http://www.healthychildren.org/spanish/ages-stages/baby/feeding-nutrition/paginas/signs-of-feeding-
difficulties.aspx

Pediatrics in Review Vol.34 No.12 December 2013 557

Article infectious diseases

Human Metapneumovirus
Jennifer E. Schuster, MD,*
Educational Gaps
John V. Williams, MD*
1. Respiratory viruses are a leading cause of global pediatric morbidity and mortality.
Human metapneumovirus is the second leading cause of pediatric viral lower
Author Disclosure respiratory tract infection. Because human metapneumovirus is a newly recognized
Dr Schuster has pathogen, many clinicians are unfamiliar with the epidemiology, pathogenesis, and
disclosed no financial clinical signs and symptoms of infection.
relationships relevant 2. Knowledge of the biology of human metapneumovirus is important to understand the
to this article. Dr pathogenesis of human metapneumovirus and how best to treat it.
Williams has disclosed 3. Diagnosis of human metapneumovirus is challenging, and clinicians should be aware
that he serves on the of the sensitivity and specificity of available tests.
Scientific Advisory
Board of Quidel. This
Objectives After completing this article, readers should be able to:
commentary does
contain a discussion of 1. Discuss the current epidemiology of human metapneumovirus.
an unapproved/ 2. Recognize clinical manifestations of human metapneumovirus.
investigative use of 3. Identify populations most susceptible to human metapneumovirus.
a commercial product/ 4. Discuss laboratory studies available for the diagnosis of human metapneumovirus.
device.
Report of a Case
A 3-year-old girl undergoing induction chemotherapy for pre–B-cell acute lymphoblastic
leukemia presents with a history of temperatures to 38.9°C. She has a 2-day history of
cough and nasal congestion. She is refusing solid food and taking minimal liquids. She
had one episode of nonbloody, nonbilious emesis. On physical examination, she appears
ill and is having difficulty breathing. Her temperature is 39.5°C, heart rate is 130 beats
per minute, respiratory rate is 40 breaths per minute, blood pressure is 90/60 mm Hg,
and oxygen saturation on room air is 92%. She has a bulging, erythematous, nonmobile
right tympanic membrane and clear rhinorrhea. Her lung examination findings are notable
for tachypnea with retractions and diffuse wheezing.
Viral infection is suspected, but because she is undergoing chemotherapy, she merits
evaluation for serious bacterial infection. White blood cell count is 1200/mL (12.0

109/L) (80% lymphocytes, 10% neutrophils, 10% monocytes), hemoglobin level is 8.9
mg/dL (89 g/L), and platelet count is 169
103/µL (169
109/L). Blood culture
is performed. Chest radiography reveals diffuse perihilar infiltrates. Because she is febrile
and neutropenic, broad-spectrum antibiotics are administered, and she is admitted to the hos-
pital. She receives intravenous fluids and oxygen via nasal cannula.
During the next 48 hours, her respiratory status worsens, and she requires intubation
and mechanical ventilatory support. Blood culture result re-
mains negative. After 5 days, her respiratory status improves,
Abbreviations and she is extubated. A nasopharyngeal wash result is posi-
tive for human metapneumovirus by polymerase chain reac-
HIV: human immunodeficiency virus
tion (PCR) testing and negative for other pathogens.
MPV: metapneumovirus
PCR: polymerase chain reaction
PIV: parainfluenza virus Introduction
RSV: respiratory syncytial virus Human metapneumovirus (MPV) is a respiratory pathogen
with worldwide prevalence that produces disease clinically

*Vanderbilt University School of Medicine, Nashville, Tennessee.

558 Pediatrics in Review Vol.34 No.12 December 2013


similar to respiratory syncytial virus (RSV). Although the
virus was not identified until 2001, antibodies to MPV
were detected in archived human sera, demonstrating that
the virus has been circulating since at least the 1950s. Mul-
tiple reasons likely contributed to the delayed identifica-
tion of the virus. Trypsin supplementation is required
for growth in culture, and slow replication kinetics lead
to delayed cytopathic effect and identification in cell cul-
ture. Furthermore, many laboratory cell lines are not per-
missive for MPV infection. Within the last 12 years,
researchers have defined the epidemiology of MPV, devel-
oped rapid diagnostic testing, and are investigating host
immune responses to guide vaccine development.
Virology
MPV, like other members of the Paramyxovirus family, is
an enveloped, single-stranded, negative-sense RNA virus.
It is most closely related to avian metapneumovirus type C,
the other member of the Metapneumovirus genus, and it
is in the Pneumovirinae subfamily with RSV. The fusion
protein is required for attachment and entry and requires
trypsin for cleavage to the active form. The other external
proteins, glycoprotein and small hydrophobic protein, are
not required for entry. The virus contains 9 structural pro-
teins. Integrins and heparan sulfate have been identified as
host receptors. The genome is approximately 13 kb in
length. Phylogenetic analysis identifies 2 groups (A and
B), each with 2 subgroups (A1, A2, B1, and B2). Clinical
disease is similar for all subgroups.
Viral Replication
Similar to other respiratory viruses, MPV spreads by re-
spiratory droplets. The incubation period is thought to
be 4 to 9 days, although in nonhuman primate models
a shorter period has been observed. Shedding occurs
for 7 to 14 days. Virus can remain infectious on fomites
for 8 hours, although viral RNA has been isolated from
noninfectious particles up to 7 days after inoculation.
MPV has been implicated in both hospital and institutional
nosocomial outbreaks, emphasizing the importance of ap-
propriate precautions, particularly around immunocom-
promised children.
Epidemiology
MPV has a worldwide prevalence, with the incidence
varying yearly and by geographic location. The virus
has been isolated year-round, but the peak seasonal inci-
dence in temperate regions is February to April, later than
the usual peak of RSV infection. In subtropical climates,
MPV is most prevalent during the spring and summer
infectious diseases metapneumovirus
seasons. Incidence varies from 5% to 20% and is generally
lower than RSV. Rates of MPV are comparable to other
respiratory viruses, such as influenza and parainfluenza vi-
rus (PIV) types 1 to 3 combined. One large, multicenter,
prospective study enrolled children with acute respiratory
infection among inpatient, emergency department, and
clinic settings; MPV was the second most common virus
after RSV in this study. In retrospective, multiyear, epidemi-
ologic studies, researchers have noted that one subgroup
may dominate, but this varies among geographic locations
and from year to year. Coinfection with other respiratory
pathogens, such as rhinoviruses, RSV, PIV, and adenovirus,
has been documented in a few MPV infections. Most stud-
ies have found that viral coinfections are not more severe
clinically than MPV-alone infection. In addition, data from
animal and small human studies suggest that MPV may be
associated with increased development of bacterial coinfec-
tions with Streptococcus pneumoniae.
Large-scale evaluation of adult serum samples has dem-
onstrated that nearly all adults are seropositive for MPV. In
most geographic locations, seroprevalence is 100% in chil-
dren older than 5 years. The mean age of children hospi-
talized with MPV-associated lower respiratory tract
infection is 6 to 12 months, older than those hospitalized
with RSV. Maternal antibodies may provide protection to
young infants. Studies have demonstrated symptomatic
subsequent infection with viruses from different subgroups
in young children, although in animal models evidence
of serologic cross-protection occurs. MPV is less fre-
quently identified in older children, likely because of
this cross-protective immunity.
Prospective studies demonstrate that MPV is a leading
cause of viral respiratory infections in older adults, with hos-
pitalization rates similar to influenza and RSV. The virus has
been identified as a cause of community-acquired pneumo-
nia and chronic obstructive pulmonary disease exacerbations
in adults. However, healthy young adults may demonstrate
MPV seroconversion without clinical illness.
Pathology
Cotton rat and mouse models exhibit peribronchial in-
flammation with an increase in mononuclear and lym-
phocytic cells. Perivascular edema is present. The most
severe condition in these models has been noted on days
5 to 7, although abnormalities are present on days 1 to
14. Nonhuman primate models demonstrate inflamma-
tory and erosive changes in the airway mucosa. Replication
occurs only in ciliated epithelial cells of the respiratory
tract; there is no evidence of viremia in humans or animal
models. Lung disease in humans is more difficult to char-
acterize because of barotrauma related to ventilation,
Pediatrics in Review Vol.34 No.12 December 2013 559
infectious diseases metapneumovirus
although increased alveolar macrophages are present, similar
to nonhuman primates.
Host Response
Multiple studies have evaluated the cytokine response to
MPV. Although a vigorous cytokine response is described,
the interaction between the virus and production of differ-
ent cytokines remains unclear. Despite the variable findings
regarding the increase and decrease of assorted cytokines,
several studies have demonstrated decreased interferon g
secretion after infection.
Antibodies alone can protect against infection, includ-
ing cross-protection from infection with other subgroups.
However, immunity appears to wane over time. In nonhu-
man primates, low-level replication with secondary infec-
tion by a virus from the same subgroup occurred 12
weeks after primary infection despite detectable serum
antibodies. In the same study, no evidence of protection
was seen when animals were challenged 11 months after
primary infection. Subsequent infection in children has
been documented, usually with a virus from a different
subgroup; most of these presented with lower respiratory
tract illness during primary infection and upper respiratory
tract illness during secondary MPV infection. Some studies
have identified a decrease in MPV-specific antibody in el-
derly adults compared with younger adults. Additional
prospective studies have noted that baseline MPV anti-
body levels are lower in patients who subsequently become
infected with the virus compared with those who do not
acquire infection.
Studies that evaluated cytotoxic T-cell responses have
identified responses to multiple proteins, including the
fusion protein, which is highly conserved in subgroups.
However, recent studies suggest that MPV and other respi-
ratory viruses cause impairment of lung CD8þ T lympho-
cytes, leading to increased viral replication. Impairment of
cytotoxic CD8þ T cells and decreased levels of interferon g
provide potential avenues for further investigation of MPV
and other viruses’ ability to hijack the host immune system.
Further, this T-cell impairment may contribute to the abil-
ity of the virus to reinfect individuals despite preexisting
antibodies.
Clinical Manifestations
MPV causes both upper and lower respiratory tract dis-
ease. Rhinorrhea and coryza are common, whereas laryn-
gitis and croup are described but are less frequent.
Children also experience dysphagia associated with de-
creased oral intake, and pharyngitis has been associated
with more than 40% of cases in studies that evaluated
560 Pediatrics in Review Vol.34 No.12 December 2013
upper respiratory tract disease. Fever is present in up to
50% of children with MPV-associated respiratory tract in-
fection. Conjunctivitis has been identified in a small subset
of patients. Large epidemiologic studies have identified
MPV as a cause of upper respiratory tract infections at
a similar rate as RSV, influenza, and PIV.
Acute otitis media is a common complication of MPV.
In one case series, almost one-quarter of children with
MPV had acute otitis media. Another report noted that
13% of children with acute otitis media had MPV-positive
nasopharyngeal specimens. The virus has been isolated
alone in tympanic fluid; however, in most cases, middle
ear fluid cultures yield other bacterial pathogens, partic-
ularly S pneumoniae.
Manifestations of lower respiratory tract infection in-
clude cough, wheeze, rhonchi, and dyspnea. Epidemiologic
studies have demonstrated that a greater number of chil-
dren infected with MPV are diagnosed as having pneumo-
nia vs bronchiolitis, especially when compared with RSV
(Table 1). Hypoxia and cyanosis can occur with severe
lower respiratory tract disease. Radiographic abnormalities
include diffuse findings, such as perihilar infiltrates and alve-
olar disease, and focal findings, including bronchopneu-
monic changes, lobar pneumonia, and effusions (Fig 1).
MPV has been isolated in both children and adults
hospitalized for asthma exacerbations. In one study, 7%
of children with asthma exacerbations had MPV isolated
from nasopharyngeal swabs. Another large-scale epidemi-
ologic study noted that 14% of children with MPV had
asthma as a discharge diagnosis. This finding was similar
to the percentage of children with RSV and a discharge
diagnosis of asthma; however, rhinovirus was more fre-
quently associated with asthma exacerbations in the same
study. Another study noted that MPV bronchiolitis in in-
fancy was more associated with a subsequent asthma di-
agnosis between 3 and 5 years of life than RSV bronchiolitis
in infancy. In children ages 2 to 17 years hospitalized with
asthma, MPV was the second most commonly (5%) iso-
lated viral pathogen after rhinovirus.
Other clinical symptoms of MPV infection may in-
clude nonrespiratory manifestations. In some studies,
up to half of all children with MPV had vomiting and/
or diarrhea. Between 5% and 10% of children develop
a rash during the infection. Febrile seizures have been re-
ported uncommonly in patients with MPV infection.
MPV has been isolated rarely by PCR from nasal washes
of children with encephalitis, and one report detected
MPV in the cerebrospinal fluid of a child with encepha-
litis. Identification of MPV outside the respiratory tract is
rare, and children are generally not thought to be viremic
during infection.
 infectious diseases metapneumovirus

Comparison of general clinical and epidemiologic features of

Table 1.

MPV- and RSV-associated lower respiratory tract infection.

Feature MPV RSV
Peak age Older infant (6-12 months) Young infant (<6 months)
Sex Slight male predominance Slight male predominance
Seasonality February-April November-January
Clinical symptoms Fever, rhinorrhea, cough, wheezing, vomiting, Fever, rhinorrhea, cough, wheezing, vomiting,
and diarrhea and diarrhea
Radiographic Consolidation, perihilar infiltrates, atelectasis, Peribronchial thickening, consolidation,
findings hyperinflation atelectasis, hyperinflation
Diagnosis Pneumonia Bronchiolitis
Bronchiolitis Pneumonia
Asthma exacerbation Asthma exacerbation
Risk factors Prematurity, underlying comorbidity, young age Prematurity, young age, underlying comorbidity,
daycare
MPV¼metapneumovirus; RSV¼respiratory syncytial virus.

High-Risk Patients infants without medical problems. A prospective study

Premature infants have increased morbidity and mortality in Argentina following up high-risk and premature in-
from MPV infection. Multiple studies have demonstrated fants noted that 30% of children with MPV infection
that premature and high-risk infants are more likely to be had moderate to severe disease. Other epidemiologic
hospitalized with MPV infection when compared with studies have noted that between 34% and 88% of children

Figure 1. A. Portable chest radiograph of a 5-month-old girl with fever, cough, and increased work of breathing. The lungs are mildly
hyperexpanded, with perihilar interstitial prominence, peribronchial cuffing, and fine alveolar perihilar opacities. There is a confluent
density seen in the right mid lobe, silhouetting the heart border. B. Portable chest radiograph of a 4-month-old boy with fever, cough,
and increased work of breathing. The lungs are hyperinflated, with multifocal atelectasis affecting the right upper lobe and medial lung
bases bilaterally. The airspace opacities affecting the right upper lobe are more confluent compared with elsewhere.

Pediatrics in Review Vol.34 No.12 December 2013 561

infectious diseases metapneumovirus
hospitalized with MPV infection had underlying medical
conditions, including prematurity, cardiopulmonary dis-
ease, or immunodeficiency. In a South African study, human
immunodeficiency virus (HIV)–positive children were sig-
nificantly more likely than HIV-negative children to be in-
fected with MPV.
In an adult population, MPV was identified in 3% of
bronchoalveolar lavage specimens in patients who under-
went hematopoietic stem cell transplantation and had
lower respiratory tract symptoms. Of these patients, 80%
of the patients died of respiratory failure, indicating that
in a susceptible population MPV can cause high mortality.
Therefore, the host immune system may play a significant
role not only in clearing the infection but also in disease
morbidity.
In the pediatric population, prolonged shedding has
been observed in solid organ transplant recipients. Fur-
thermore, active infection was associated with acute graft
rejection. Mortality has been reported in pediatric patients
with leukemia, including one patient who was infected
with 2 genetically different strains of MPV during 10
months and died of acute respiratory distress syndrome
during the second MPV infection. Another case report de-
tailed a premature infant who required extracorporeal
membrane oxygenation due to MPV-associated acute re-
spiratory distress syndrome.
Although the predominance of morbidity and mortality
occurs in high-risk children, case reports describe previously
healthy children without underlying immunodeficiency
succumbing to MPV infection. These children typically
Figure 2. Cytopathic effect caused by human metapneumovirus (MPV). A. Uninfected LLC-MK2 cell monolayer. B. MPV-infected
LLC-MK2 cells. Arrows indicate syncytia.
562 Pediatrics in Review Vol.34 No.12 December 2013
present with sepsis and can develop pulmonary hemor-
rhage and/or acute respiratory distress syndrome. One
study demonstrated that higher MPV viral loads were
associated with increased disease severity as manifested
by fever, prolonged hospital stay, and increased bron-
chodilator use.
Daycare does not seem to be as significant a risk factor
for MPV infection compared with other respiratory viruses.
Prospective studies of children in daycare demonstrate
a lower transmission rate of MPV compared with RSV
and PIV. Other prospective studies in daycare identified
MPV infection in approximately 10% of all children; how-
ever, this accounted for 2% of all acute respiratory tract
infections.
Diagnosis
MPV was initially identified in cell culture; LLC-MK2
monkey kidney cells are commonly used for the growth
of MPV, but viral cultures take up to 10 to 14 days and
are, therefore, not useful clinically. MPV produces small
round plaques with occasional syncytia and can take be-
tween 3 and 23 days to produce a cytopathic effect (Fig
2). Shell vial culture has demonstrated increased sensitiv-
ity compared with traditional culture. Direct and indirect
fluorescent antibody testing has similar sensitivity and
specificity to shell vial culture. Currently, the gold stan-
dard for diagnosis is PCR testing. Reverse transcriptase–
PCR testing has a high sensitivity for virus detection,
and laboratories have developed primers targeted at many
of the conserved proteins. In many clinical laboratories,

MPV has been incorporated into multiplex diagnostic
PCR assays used to simultaneously evaluate for multiple
respiratory pathogens.
Treatment
No Food and Drug Administration–approved antiviral
drug against MPV exists. Supplementary oxygen and as-
sisted ventilation may be needed in the hospitalized set-
ting. Intravenous fluids can be used for hydration when
vomiting and diarrhea occur or a patient is unable to tol-
erate oral hydration because of tachypnea or dyspnea.
Bronchodilators and steroids may be used in the manage-
ment of MPV contributing to asthma or chronic obstruc-
tive pulmonary disease exacerbations, and antibiotics may
be needed in cases of bacterial superinfection, such as
acute otitis media or suspected community-acquired bac-
terial pneumonia.
In vitro data suggest that ribavirin and intravenous im-
munoglobulin inhibit MPV infection. Ribavirin has been
found to decrease inflammation in a mouse model. Riba-
virin and intravenous immunoglobulin have been used
together to treat immunocompromised adults and chil-
dren in isolated case reports. However, data are limited,
and no case-control studies have been performed. In an-
imal models, monoclonal antibodies have been effective
prophylactically and therapeutically at decreasing viral ti-
ter, although no data are available in humans.
Prevention
Similar to other respiratory viruses, good hand hygiene
and curtailing respiratory secretions are currently the only
preventive measures. However, vaccine discovery efforts
are under way. The fusion protein is immunogenic and
highly conserved, making it an excellent target for vac-
cine research. Soluble fusion protein vaccines reduce viral
titers in animal models, and vectored vaccines encoding
the fusion protein are protective.
Researchers have generated live-attenuated temperature-
sensitive strains of MPV, which produce low levels of
replication in the upper respiratory tract and no active dis-
ease in the lower respiratory tract. High antibody titers
were produced, and subsequent infection with wild-type
virus in a hamster model demonstrated no lower respira-
tory tract infection and decreased viral replication in the
upper respiratory tract. Thus, cold-passaged MPV may
prove to be a useful vaccine approach. Other recombi-
nant strains that lack the small hydrophobic protein
and glycoprotein are attenuated and demonstrate evi-
dence of subsequent reduction in viral titers on wild-type
infection. Therefore, recombinant viruses may prove to
infectious diseases metapneumovirus
be an effective vaccine strategy. Other strategies for pre-
vention include the generation of monoclonal antibodies
that could potentially be used as prophylaxis in high-risk
populations.
Summary
• On the basis of strong research evidence and
consensus, (1) (2) (3) (4) human metapneumovirus is
a leading cause of upper and lower respiratory tract
infections in children.
• On the basis of research evidence and consensus, (3)
(5) (6) (7) the clinical features of MPV-associated
disease are similar to those of RSV. MPV is an
important cause of asthma exacerbations,
bronchiolitis, and pneumonia. Bacterial
superinfection can occur.
• On the basis of research evidence and consensus, (2)
(3) (8) the mean age of infection is 6 to 12 months,
and nearly all school-age children are seropositive.
However, infection can recur, likely in part due to
impaired CD8D T-cell response.
• On the basis of research evidence and consensus,
(9) (10) (11) morbidity and mortality are the
highest in patients who are premature, are
immunosuppressed, or have underlying
cardiopulmonary abnormalities.
• On the basis of research evidence and consensus, (2)
commercially available diagnostic tests exist, and
reverse transcriptase–PCR is the most commonly
used.
• On the basis of consensus, because of a lack of
relevant clinical studies, recombinant virus vaccines
and monoclonal antibodies may be useful as
prophylactics or therapeutics. (10)
References
1. Edwards KM, Zhu Y, Griffin MR, et al; New Vaccine Surveil-
lance Network. Burden of human metapneumovirus infection in
young children. N Engl J Med. 2013;368(7):633–643
2. van den Hoogen BG, de Jong JC, Groen J, et al. A newly
discovered human pneumovirus isolated from young children with
respiratory tract disease. Nat Med. 2001;7(6):719–724
3. Williams JV, Harris PA, Tollefson SJ, et al. Human meta-
pneumovirus and lower respiratory tract disease in otherwise
healthy infants and children. N Engl J Med. 2004;350(5):
443–450
4. Widmer K, Zhu Y, Williams JV, Griffin MR, Edwards KM,
Talbot HK. Rates of hospitalizations for respiratory syncytial virus,
human metapneumovirus, and influenza virus in older adults.
J Infect Dis. 2012;206(1):56–62
5. Jartti T, van den Hoogen B, Garofalo RP, Osterhaus AD,
Ruuskanen O. Metapneumovirus and acute wheezing in children.
Lancet. 2002;360(9343):1393–1394
Pediatrics in Review Vol.34 No.12 December 2013 563
infectious diseases metapneumovirus

6. Madhi SA, Ludewick H, Kuwanda L, et al. Pneumococcal
coinfection with human metapneumovirus. J Infect Dis. 2006;193
(9):1236–1243
7. Williams JV, Tollefson SJ, Heymann PW, Carper HT, Patrie J,
Crowe JE. Human metapneumovirus infection in children hospital-
ized for wheezing. J Allergy Clin Immunol. 2005;115(6):1311–1312
8. Erickson JJ, Gilchuk P, Hastings AK, et al. Viral acute lower
respiratory infections impair CD8þ T cells through PD-1. J Clin
Invest. 2012;122(8):2967–2982
9. Englund JA, Boeckh M, Kuypers J, et al. Brief communication:
fatal human metapneumovirus infection in stem-cell transplant
recipients. Ann Intern Med. 2006;144(5):344–349
10. Schildgen V, van den Hoogen B, Fouchier R, et al. Human
Metapneumovirus: lessons learned over the first decade. Clin
Microbiol Rev. 2011;24(4):734–754
11. Pelletier G, Déry P, Abed Y, Boivin G. Respiratory tract
reinfections by the new human Metapneumovirus in an immuno-
compromised child. Emerg Infect Dis. 2002;8(9):976–978

PIR Quiz
This quiz is available online at http://pedsinreview.org. NOTE: Learners can take Pediatrics in Review quizzes and claim credit online only. No paper
answer form will be printed in the journal.

New Minimum Performance Level Requirements

Per the 2010 revision of the American Medical Association (AMA) Physician’s Recognition Award (PRA) and credit system, a minimum performance
level must be established on enduring material and journal-based CME activities that are certified for AMA PRA Category 1 CreditTM. To successfully
complete 2013 Pediatrics in Review articles for AMA PRA Category 1 CreditTM, learners must demonstrate a minimum performance level of 60% or
higher on this assessment, which measures achievement of the educational purpose and/or objectives of this activity.
In Pediatrics in Review, AMA PRA Category 1 CreditTM may be claimed only if 60% or more of the questions are answered correctly. If you score less
than 60% on the assessment, you will be given additional opportunities to answer questions until an overall 60% or greater score is achieved.

1. A 12-month-old boy is admitted to the hospital with rhinorrhea, cough, wheezing, and respiratory distress. The
results of studies on nasopharyngeal fluid wash for respiratory syncytial virus, influenza, and parainfluenza are
negative. Which of the following laboratory studies on nasopharyngeal fluid wash should be ordered to
diagnose the most likely etiologic agent?
A. Direct fluorescent antibody testing.
B. Indirect fluorescent antibody testing.
C. Reverse transcriptase–polymerase chain reaction testing.
D. Shell viral culture.
E. Viral culture.

2. Acute otitis media (AOM) is a common complication of metapneumovirus (MPV) respiratory infection in
children. Research data regarding MPV and increased risk of bacterial coinfection are consistent clinically with
which of the following pathogens identified in children with MPV-associated AOM?
A. Anaerobic bacteria.
B. Haemophilus influenzae.
C. Moraxella catarrhalis.
D. Streptococcus pneumoniae.
E. Streptococcus pyogenes.

3. A 2-year-old child presents in early April with fever, rhinorrhea, and coryza. A viral cause is suspected for this
child’s illness. Which of the following additional signs or symptoms is most likely to indicate that MPV is the
etiologic agent?
A. Conjunctivitis.
B. Cough.
C. Croup.
D. Laryngitis.
E. Pharyngitis.

564 Pediatrics in Review Vol.34 No.12 December 2013

 infectious diseases metapneumovirus

4. In which group of pediatric patients has prolonged viral shedding of MPV been observed?
A. Chronic pulmonary disease patients.
B. Congenital heart disease patients.
C. Human immunodeficiency virus–positive patients.
D. Premature infants.
E. Solid organ transplant recipients.

5. A few pediatric patients with severe morbidity and mortality secondary to MPV disease are previously healthy
children without underlying disorders. Which of the following is a typical presentation for this group of
children?
A. Encephalitis.
B. Pneumonia.
C. Seizures.
D. Sepsis.
E. Vomiting, diarrhea, and dehydration.

Corrections
In the print version of the November 2013 article “Cephem Antibiotics: Wise Use Today Preserves Cure for Tomorrow”
(Parker S, Mitchell M, Child J. Pediatrics in Review. 2013(34);11:510–524, doi: 10.1542/pir.34-11-510), in the Selected
References introduction, the link to the complete reference list should be: http://pedsinreview.aappublications.org/
content/34/11/510/suppl/DCSupplementary_Data. The link is correct in the online version of the journal. The journal regrets
the error.
In the print version of the November 2013 article “Chronic Cough in Children: a Primary Care and Subspecialty Collab-
orative Approach” (Kaslovsky R and Sadof M. Pediatrics in Review. 2013;34(11):498–509, doi: 10.1542/pir.34-11-498), the
following phrase appeared above the quiz questions but should have been part of Question 1: “Some clinical signs are highly
suggestive of a given condition. In the scenarios below, match the clinical presentation with the most likely cause of the
patient’s cough.” The phrase appears correctly in the online version of the journal CME quiz. The journal regrets the error.

Pediatrics in Review Vol.34 No.12 December 2013 565

index of suspicion
The reader is encouraged to write
possible diagnoses for each case before
turning to the discussion.
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 Deepak
Kamat at DKamat@med.wayne.edu.
Author Disclosure
Drs Sankararaman, Patra, Wells,
Sarker, Kitchen, Jasty, Benza, and
Sahai have disclosed no financial
relationships relevant to this article.
This commentary does not contain
discussion of unapproved/
investigative use of a commercial
product/device.
566 Pediatrics in Review Vol.34 No.12 December 2013
Case 1: Swelling Behind the Knee in a 15-Year-Old
Boy
Case 2: Fatigue, Weight Loss, Fever, and Atypical Skin
Lesion in an Adolescent Boy
Case 3: New-Onset Murmur and Signs of Shock in
a 15-Year-Old Girl
Case 1 Presentation
A 15-year-old boy presents to the pe-
diatric clinic with a 3-week history of
a mass behind his right knee. He
found it incidentally while bathing
and experiences no pain or discomfort
in his right knee during sports activi-
ties. He denies a history of preceding
trauma. His medical history, including
personal history and family history,
are negative for inflammatory arthritis
and malignant tumor.
Physical examination reveals a teen-
age boy with an ovoid, nontender, mo-
bile mass with a cystic feeling in the
posteromedial aspect of the right knee
(Fig 1). The mass is approximately
9.8
3
2 cm, firm, and noncompress-
ible. The swelling becomes prominent
on extension of the knee. The swell-
ing is also brilliantly transilluminant.
The rest of the examination findings
are within normal limits. A radiologic
test confirms the physical finding.
Case 2 Presentation
A 15-year-old previously healthy boy
presents with a 2-month history of
a red skin lesion on the right upper
thigh that has progressively increased
in size. He also has a 3-week history
of fatigue, decreased appetite, weight
loss of 7.2 kg, worsening lower back
pain, and a painful lump in the right
groin. For the last 3 to 4 days, he has
had fevers and night sweats. There is
a history of contact with 2 indoor cats
and travel to Mexico as a tourist 9
months before this visit.
Physical examination reveals a pale
and ill-looking adolescent boy. His
weight is 71 kg, height is 177 cm, tem-
perature is 37.4°C, heart rate is 102
beats per minute, respiratory rate is
16 breaths per minute, and blood pres-
sure is 113/67 mm Hg. There is a 3

2-cm, raised lesion that is erythematous
with a violaceous hue and areas of
crusting and scaling on the upper me-
dial aspect of the right thigh (Fig 2).
He has a 2-cm, single, firm, nontender,
mobile lymph node in the right ingui-
nal region. The rest of the findings on
physical examination are normal, with
no other adenopathy, hepatospleno-
megaly, or bone tenderness.
Laboratory examination reveals
the following: white blood cell count,
9200/mL (9.2
109/L), with 75%
neutrophils, 12% lymphocytes, 11%
monocytes, 1% eosinophils, and 1%
basophils; hemoglobin, 13 g/dL
(130 g/L); platelet count, 439

10 3 /mL (439
109/L); normal pe-
ripheral smear; erythrocyte sedimen-
tation rate (ESR), 103 mm/h; and
C-reactive protein (CRP), 1.0 mg/L
(9.5 nmol/L) (reference range,
0-0.08 mg/dL [0-0.76 nmol/L]).
Results of a comprehensive metabolic
panel, as well as serum lactic dehydro-
genase and uric acid levels, are normal.
Further testing and a biopsy specimen
from the enlarged right inguinal lymph
node lead to the diagnosis.
Case 3 Presentation
A 15-year-old African American girl
presents with fever (maximum temper-
ature of 39.2°C), sore throat, decreased
oral intake, headache, vomiting, and
dizziness of 2- to 3-day duration. She

Figure 1. Clinical photograph showing
a popliteal cyst in the posteromedial
aspect of the right knee (white arrows).
also experiences breathlessness, which
has not been responding to multiple in-
haled albuterol treatments at home.
On examination, her pulse is 128
beats per minute, respiratory rate is
30 breaths per minute, temperature
is 38.5°C, and blood pressure is
90/55 mm Hg in both arms. Her
weight is 72.70 kg (>90th percen-
tile), and her height 183.00 cm
(99th percentile). She is found to
Figure 2. A 3 3 2-cm, raised erythematous lesion with a violaceous hue and areas of
crusting and scaling on the upper medial aspect of the right thigh.
have pharyngeal erythema. Her pe-
ripheral pulses are hyperdynamic,
and she has 2/6 harsh holosystolic
murmur, which is loudest at apex.
Findings on the rest of the physical
examination are normal.
Laboratory results are as follows:
white blood cell count, 18,600/mL
(18.6
109/L), with 75% neutro-
phils, 14% lymphocytes, and 10%
monocytes; hemoglobin, 10.5 g/dL
(105 g/L); and platelet count,
553
103/mL (553
109/L). Elec-
trocardiography reveals normal sinus
rhythm. The CRP level is 12.0 mg/L
(114.3 nmol/L), ESR is 109 mm/h,
serum electrolytes are normal, and
ASO titer is 160 U/L. Urine analysis
reveals the following: specific gravity,
1.031; pH 7; protein, 1þ; urobilino-
gen, 4þ; ketones, 3þ; nitrites, posi-
tive; LE, 2þ; white blood cells, 5 to
10 per high-power field; and red
blood cells, less than 2 per high-power
field. The results of chest and abdom-
inal radiography are normal. Echocar-
diography reveals flow acceleration
across the left pulmonary artery with
a peak gradient of 31 mm Hg. She
index of suspicion
is prescribed ceftriaxone and vanco-
mycin and admitted with the diagno-
sis of sepsis. Additional tests reveal the
diagnosis.
Case 1 Discussion
A radiograph of the knee did not
reveal any abnormality. However,
ultrasonography demonstrated a well-
circumscribed hypoechoic cystic swell-
ing in the posteromedial aspect of the
right knee without joint effusion (Figs
3 and 4). A popliteal cyst was diag-
nosed in view of the benign nature
of this cystic swelling.
The Condition
A popliteal cyst is a synovial fluid–
filled mass located in the popliteal
fossa. It is commonly seen in both
adults and children, although only
approximately one-third of popliteal
cysts are reported in children. Popli-
teal cysts are also referred to as Baker
cysts, named after William Morrant
Baker, who described it in 1877.
Popliteal cysts in children are mostly
idiopathic. The occurrence in boys out-
numbers the occurrence in girls in a
ratio of 2:1, and most cases occur uni-
laterally. The patients are often asymp-
tomatic, and most cases are detected
incidentally by the patient, parent, or
physician as a painless mass behind
the knee. In one study, the prevalence
of asymptomatic popliteal cysts in chil-
dren detected by ultrasonography was
reported as 2.4%. The mass gradually
increases in size and may be fairly large
when the patient first notices it. Physi-
cal examination reveals a firm cystic
mass located in the medial aspect of
the popliteal fossa, usually distal to
the popliteal crease. It also becomes
prominent on extension of the knee
joint. Positive transillumination is a use-
ful bedside diagnostic test. Secondary
popliteal cysts are commonly encoun-
tered in children with underlying
Pediatrics in Review Vol.34 No.12 December 2013 567
index of suspicion
Figure 3. Ultrasonogram of the right knee (posterior sagittal view) showing the
hypoechoic cystic mass (white arrows) with internal debris.
joint disorders that cause knee ef-
fusions, such as juvenile idiopathic
arthritis, septic arthritis, psoriatic ar-
thritis, meniscal tears, hemophilia,
pigmented villonodular synovitis, or
unstable osteochondritis dissecans.
The common mean age of presen-
tation of idiopathic popliteal cysts is
6 years, with a range of 2 to 14 years.
The most common site of origin is the
bursa of the gastrocnemius and semi-
membranosus muscles. Another com-
mon site of origin is herniation of the
synovium through the posterior joint
capsule of the knee. In adults, pop-
liteal cysts are usually secondary to
osteoarthritis, meniscal tears, and in-
flammatory joint conditions. Unlike
in adults, the presence of underlying
intra-articular disease is rare in chil-
dren. However children with knee
pain or joint swelling should undergo
evaluation for an underlying cause,
such as septic arthritis, Lyme disease
(for patients living in, or visiting, en-
demic areas in the last year), inflam-
matory arthritis, or structural injury.
568 Pediatrics in Review Vol.34 No.12 December 2013
Normal debris inside the cyst can be
seen as echogenic internal signals on
ultrasonography (Fig 3). In a recent
study in children, the presence of
these echogenic internal signals was
frequently encountered in patients
with arthritis and further investigation
with magnetic resonance imaging
(MRI) was recommended.
Differential Diagnosis
Soft tissue tumors, such as lipoma,
xanthoma, hemangioma, fibrosarcoma,
synovial cell sarcoma, and tumors of
the tendon sheath, should be in-
cluded in the differential diagnosis.
In older children and adults, a rup-
tured popliteal cyst may mimic deep
vein thrombosis or thrombophlebitis.
Knee radiographs should be obtained
to evaluate bony lesions, such as osteo-
chondromas, osteochondritis dissecans,
and malignant bone tumors. The diag-
nosis of a popliteal cyst is confirmed by
ultrasonography, which differentiates
a solid mass from a hypoechoic cystic
lesion. Aspiration of the cyst in children
is seldom required for diagnosis. In
some instances, MRI may be required
if the ultrasonogram is equivocal in de-
lineating cystic mass from solid tumors.
The presence of a solid mass warrants
urgent referral to a specialist for further
evaluation, possible biopsy, and appro-
priate treatment (including excision,
chemotherapy, and/or radiotherapy).
MRI is also recommended for further
evaluation if there is clinical suspicion
for underlying joint conditions due to
persistent knee pain, joint swelling, or
systemic symptoms.
Management
Most authors report a spontaneous
resolution of idiopathic popliteal cysts
within a period of 20 months. Hence,
conservative management by watchful
waiting is strongly recommended in
children. On the contrary, in adults,
treatment is directed toward intra-
articular disease and recurrence of pop-
liteal cyst is common. Rupture of the
cyst, hemorrhage, infection, or malig-
nant transformation can occur rarely
in children, so new or increased pain
should warrant immediate evaluation.
Surgical treatment is indicated in chil-
dren only in the presence of symptoms
(pain and/or increasing size that limits
motion).
Our patient is older than the typ-
ical patient with idiopathic popliteal
cysts, and ultrasonography also revealed
echogenic internal signals. Hence,
we recommended further evaluation
with MRI for the presence of under-
lying joint diseases. However, the pa-
tient’s family decided to wait because
he is mostly asymptomatic. He par-
ticipates in basketball without any
pain or discomfort and is under
follow-up.
Lessons for the Clinician
• Baker cysts or popliteal cysts are
common in children.

Figure 4. Ultrasonogram (posterior transverse view) showing the relationship of the
popliteal cyst (black and white arrows) with the knee joint.
• Popliteal cysts are mostly asymp-
tomatic and incidentally found as
painless masses behind the knee.
• In children, most cases are idio-
pathic and resolve spontaneously,
so surgical excision is not required.
• Ultrasonography confirms the cys-
tic nature of the swelling, which is
also helpful in the evaluation of the
characteristics of the swelling and
also reveals the presence or ab-
sence of the joint effusion.
• On the basis of clinical or radio-
logic suspicion, MRI is recom-
mended for further evaluation of
underlying joint disorders in sec-
ondary popliteal cysts.
(Senthilkumar Sankararaman, MD,
Kamakshya Patra, MD, and Wanda
Wells, MD, Louisiana State University
Health Sciences Center, Shreveport, LA)
Case 2 Discussion
The results of serologic tests for an in-
fectious cause of lymphadenitis, includ-
ing Bartonella henselae, histoplasmosis,
blastomycosis, coccidiomycosis, asper-
gillosis, syphilis, and human immuno-
deficiency virus, were negative, and a
tuberculin skin test result was nonreac-
tive. Evaluation for vasculitis included
a proteinase 3 antineutrophil cyto-
plasmic antibody and myeloperoxidase
antineutrophil cytoplasmic antibody,
and both results were negative. Com-
puted tomography (CT) of the neck,
chest, abdomen, and pelvis revealed
lymphadenopathy in the upper medias-
tinum (largest diameter, 1 cm), retro-
peritoneal region (largest diameter,
1.4 cm), right inguinal region (largest
diameter, 2 cm), and a focal area of skin
index of suspicion
and soft tissue density in the right inner
thigh.
An excisional biopsy specimen of
the right inguinal lymph node revealed
complete replacement by a large cell
neoplasm with a moderate amount
of amphophilic cytoplasm containing
generally a single round to slightly
spindled nucleus that is pleomorphic
with clumped chromatin and promi-
nent nucleoli. Whole-body positron
emission tomography (PET)–CT re-
vealed extensive fludeoxyglucose-avid
adenopathy in the right inguinal re-
gion, in the right internal and external
iliac chain, throughout the retroperi-
toneum, in the right hilum, in the su-
perior anterior mediastinum, and in
the base of the left side of the neck.
Bone marrow biopsy and cerebrospi-
nal fluid test results were negative for
malignant neoplasms.
Immunoperoxidase staining was
positive for CD30 (Ki-1), anaplastic
lymphoma kinase 1 (ALK-1), BCL6,
and CD43 and weakly positive for
epithelial membrane antigen. Ap-
proximately 60% to 70% of nuclei
were positive for Ki-67. The patient
was diagnosed as having ALK-positive
stage 3 anaplastic large cell lymphoma
(ALCL).
The Condition
Non-Hodgkin lymphoma represents
approximately 60% of all lymphomas
in the pediatric population. ALCL
accounts for 10% to 15% of all child-
hood non-Hodgkin lymphomas and
is typically associated with a T-cell
(65%) or null cell (35%) phenotype.
There are 2 clinical presentations of
childhood ALCL. One is a primary
cutaneous form that can present as
a single or multiple cutaneous
lesion(s). This presentation is rare in
pediatric patients but when present
poses a diagnostic challenge in distin-
guishing it from systemic ALCL with
secondary cutaneous involvement. In
the primary systemic form of ALCL
Pediatrics in Review Vol.34 No.12 December 2013 569
index of suspicion
more than 90% of patients present
with nodal disease. However, a high
incidence of extranodal involvement
(involving the skin in 25%, bone
in 17%, lung in 10%, and liver in
8%) has been reported previously.
Central nervous system or bone mar-
row involvement is rare with this
lymphoma. Approximately 75% of
children with ALCL can present with
B symptoms described as tempera-
tures greater than 38°C for 3 consec-
utive days, night sweats, or unexplained
weight loss of more than 10% of body
weight in the prior 6 months. (In the
Ann Arbor staging of lymphomas, A
indicates absence of systemic symp-
toms, whereas B indicates their pres-
ence.) Our patient had the systemic
form of ALCL with secondary cuta-
neous involvement.
CD30 (Ki-1) is strongly expressed
in most ALCL, although this is not
unique to this lymphoma. Recently,
in addition to the CD30 expression,
ALK positivity has not only helped
with the diagnosis but has led to
a better understanding of the disease
at the molecular level. More than
90% of children with systemic ALCL
are reported to be ALK positive. ALK
is a membrane-bound tyrosine kinase
normally expressed in neural cells but
not in lymphoid tissue. The charac-
teristic t(2;5) translocation between
chromosomes 2 and 5 (t[2:5] [p23:
q35]) is present in 83% of the pedi-
atric cases with systemic ALCL. This
translocation involves a fusion of
the cytoplasmic domain of the
ALK gene on 2p23 to the NPM
gene coding for the nuclear phos-
phoprotein on 5q35. NMP-ALK
acts as a constitutively active tyro-
sine kinase that can trigger malignant
transformation or activate antiapop-
totic pathways. The fluorescent in
situ hybridization probe from the in-
guinal lymph node of our patient re-
vealed the presence of t(2;5) in 34%
of the nuclei.
570 Pediatrics in Review Vol.34 No.12 December 2013
The staging of ALCL is based on
the St Jude system modified from
Murphy. Stages 1 and 2 are consid-
ered localized disease, and stages 3
and 4 are disseminated disease. Bone
marrow involvement in ALCL, if
present, carries a worse prognosis.
ALK positivity in the primary sys-
temic form, as is seen in our patient,
is associated with a better prognosis,
whereas ALK negativity carries a poor
prognosis.
Management
Primary cutaneous forms of ALCL
typically are treated with surgical ex-
cision or localized radiotherapy. The
systemic form of ALCL is treated
with combination chemotherapy. Mul-
tiple treatment regimens have been
used by various cooperative groups
worldwide. Our patient was treated
according to Pediatric Oncology
Group trial 9315, which includes
doxorubicin, prednisone, and vin-
cristine with methotrexate given
later during consolidation for a total
treatment duration of 52 weeks.
This regimen has a 4-year event-free
survival and overall survival of 71.8%
and 88.1%, respectively, in advanced
stage pediatric ALCL, which is com-
parable to other regimens with fewer
associated toxic effects. Using this
regimen, our patient went into a com-
plete remission within 3 weeks.
Lessons for the Clinician
• ALCL can mimic a skin lesion of
infectious origin or vasculitis.
• Nodal involvement and constitu-
tional B symptoms (fever, night
sweats, and weight loss) are
common features of ALCL in
children.
• The presence of atypical skin le-
sions and B symptoms even in
the absence of significant periph-
eral lymphadenopathy should
direct the clinician to search
for a malignant tumor, such as
lymphoma.
• Primary cutaneous ALCL is rare in
children. Even in the absence of
constitutional symptoms, patients
presenting with skin lesions that
are diagnostic of ALCL should
have a thorough evaluation, in-
cluding CT of the neck, chest, ab-
domen, and pelvis, and a PET scan
to rule out systemic ALCL with
secondary skin involvement be-
cause management is more aggres-
sive in the latter.
(Tania Sarker, MD, MPH, Univer-
sity of Toledo College of Medicine,
Toledo, OH, and Brenda Kitchen,
MD, and Rama Jasty, MD, Univer-
sity of Michigan Medical School, Ann
Arbor, MI)
Case 3 Discussion
On further questioning it was found
that the patient was diagnosed as hav-
ing uveitis and juvenile idiopathic ar-
thritis in the past. However, she was
undergoing no treatment because
she is in remission and asymptomatic.
The patient’s sister was on a liver
transplantation list because of auto-
immune hepatitis. Our differential
diagnosis at this time included sys-
temic inflammatory response syn-
drome (SIRS) due to sepsis, lupus,
antiphospholipid syndrome, vasculi-
tis, bacterial endocarditis, and pyelo-
nephritis. To investigate this further,
we ordered a rapid streptococcal an-
tigen test, mononucleosis spot test, Ep-
stein-Barr virus serologic test, blood
cultures on 3 different occasions,
thyroid function tests, serum ferritin
level, autoantibody panel (antinu-
clear antibody, extractable nuclear
antigen, antineutrophil cytoplasmic
antibody, and anti–double-stranded
DNA), rapid plasma reagin, lupus anti-
coagulant test, serum cytomegalovirus

IgG and IgM antibody titers, and
tuberculin test. The results were all
negative.
The patient remained febrile and
tachycardic, with clinical manifesta-
tions consistent with SIRS despite
broad-spectrum antibiotics and a
large volume of intravenous fluid
support, and her ESR and CRP level
remained markedly elevated. Dopp-
ler ultrasonography of her neck
performed to look for evidence of
Lemierre syndrome (infectious throm-
bosis of the jugular vein caused by
Fusobacterium necrophorum in most
cases, usually seen after a dental infec-
tion, tonsillitis, or pharyngitis) revealed
circumferential wall thickening of
both common carotid arteries. On
the basis of these findings, MRI of
the chest was performed, which re-
vealed circumferential wall thickening
and enhancement that involved multi-
ple large vessels, including the aorta,
pulmonary arteries, and the common
carotids, suggesting a diagnosis of
vasculitis, such as Takayasu arteritis
(TA).
The Condition
The first case of TA was described in
1908 by Dr Mikito Takayasu at the
annual meeting of the Japan Oph-
thalmology Society as “a case of pe-
culiar changes in the central retinal
vessels” in a 21-year-old female pa-
tient. Today we know that TA is
the most common large and me-
dium vessel vasculitis in children. It
is an uncommon condition, which
manifests in the first or second de-
cade of life, with a mean age of pre-
sentation of 13 years and reported
female-male ratio ranges from 1.2:1
in Israel to 6.9:1 in Mexico. TA is
an idiopathic chronic inflammatory
disease with granulomatous panar-
teritis. TA is associated in some
countries with tuberculosis infec-
tion, but in most cases the cause is
unknown. (1)
Diagnosis
In 2010, the adult criteria for TA were
adapted to the pediatric population by
the European League against Rheu-
matism (EULAR) and Pediatric Rheu-
matology European Society (PRES).
TA diagnosis using these criteria re-
quires typical angiographic abnormal-
ities of the aorta or its main branches
and pulmonary arteries (mandatory
criteria) plus 1 of 5 clinical and labora-
tory criteria, such as pulse deficit or
claudication, blood pressure discrep-
ancy in any limbs, bruits, systolic
and diastolic blood pressure above
the 95th percentile for height, and el-
evated acute phase reactants. (2)
TA diagnosis is challenging in the
early prepulseless phase, where there
is only thickening of intima due to an
inflammatory infiltrate and no evi-
dence of stenosis or aneurysm forma-
tion. The symptoms if any at this
stage are nonspecific and presumed
to be due to the production or secre-
tion of inflammatory cytokines. The
symptoms include fever, weight loss,
fatigue, and myalgias and may be eas-
ily mistaken for an infection, as in our
patient. Patients may also have hyper-
tension, cardiac murmurs, vascular
bruits, aortic arch dilatation, cardiac
failure due to a high-output state
from the aortic regurgitation, and
myocardial dysfunction, such as our
patient displayed. Carotid and verte-
bral artery involvement causes reduc-
tion in cerebral blood flow, leading
to headaches, vertigo, and syncope.
Ophthalmologic features are amau-
rosis fugax and retinopathy. Once
the disease progresses to the pulseless
stage due to chronic fibrosis and
subsequent vessel wall stenosis, the
clinical findings are related to the re-
stricted blood flow from the affected
arteries. Claudication (stenosis of ab-
dominal aorta), hypertension (stenosis
of renal arteries), and blood pressure
differential are part of the pulseless
index of suspicion
stage as described in the diagnostic
criteria developed by EULAR and
PRES.
Imaging may include routine radio-
graphy and Doppler ultrasonography,
which looks not only at vessel wall
thickness but also at blood flow.
Conventional angiography is still
the gold standard, but it is an invasive
procedure, requires injection of con-
trast, and exposes the patient to radi-
ation. More specific and sensitive
vessel wall imaging by CT, MRI, or
magnetic resonance angiography is
preferred and an essential method
for diagnosing and monitoring the
disease.
Management
Glucocorticoids are the first line of
treatment, and if remission is not
achieved, methotrexate or azathio-
prine can also be added. Surgical by-
pass and percutaneous transluminal
angioplasty are reserved for situations
where arterial stenosis is affecting a vi-
tal organ.
For patients who do not respond
to immunosuppressive therapy, many
other immunomodulatory therapies,
including anti–tumor necrosis factor
agents, have been tried. Morbidity
and mortality at a young age are very
high; therefore, early recognition and
intervention may help improve the
outcome.
Our patient was prescribed high-
dose intravenous methylprednisolone
and then switched to oral prednisone,
which was tapered. She has respond-
ed to this therapy.
Lessons for the Clinician
• Even though sepsis is the most
common cause of SIRS, autoim-
mune disorders such as vasculitis
should be considered in the differ-
ential diagnosis of patients who
present with clinical manifestations
of SIRS.
Pediatrics in Review Vol.34 No.12 December 2013 571
index of suspicion

• When clinical examination reveals a
new murmur and echocardiography
reveals an increase in flow in the
pulmonary artery, it may raise
suspicion for a vasculitis, such as
TA.
(Natalia Benza, MD, and Shashi
Sahai, MD, Children’s Hospital of
Michigan, Detroit, MI)
References
1. Brunner J, Feldman BM, Tyrrell PN,
et al. Takayasu arteritis in children and
adolescents. Rheumatology (Oxford). 2010;
49(10):1806–1814
2. Ozen S, Pistorio A, Iusan SM, et al;
Paediatric Rheumatology International
Trials Organisation (PRINTO). EULAR/
PRINTO/PRES criteria for Henoch-
Schönlein purpura, childhood polyarteritis
nodosa, childhood Wegener granulo-
matosis and childhood Takayasu arteritis:
Ankara 2008, part II: final classification
criteria. Ann Rheum Dis. 2010;69(5):
798–806
To view Suggested Reading lists
for these cases, visit http://pedsinreview.
aappublications.org and click on the
“Index of Suspicion” link.

Parent Resources From the AAP at HealthyChildren.org

Case 2
• English: http://www.healthychildren.org/English/health-issues/conditions/cancer/Pages/Symptoms-of-Childhood-
Cancers.aspx
• Spanish: http://www.healthychildren.org/spanish/health-issues/conditions/cancer/paginas/symptoms-of-childhood-
cancers.aspx

572 Pediatrics in Review Vol.34 No.12 December 2013


In Brief
Down Syndrome
Wendy L. Hobson-Rohrer, MD, MSPH
Lisa Samson-Fang, MD
University of Utah, Salt Lake City, UT
Author Disclosure
Drs Hobson-Rohrer and Samson-Fang
have disclosed no financial
relationships relevant to this article.
This commentary does not contain
discussion of unapproved/
investigative use of a commercial
product/device.
Health Supervision for Children With
Down Syndrome. American Academy
of Pediatrics Committee on Genetics.
Pediatrics. 2011;128(2):393–406
Updated National Birth Prevalence
Estimates for Selected Birth Defects in
the United States, 2004-2006. Parker
SE, Mai CT, Canfield MA, et al; for the
National Birth Defects Prevention
Network. Birth Defects Res A Clin Mol
Teratol. 2010;88(12):1008–1016
Down Syndrome. In: Jones K. Smith’s
Recognizable Patterns of Human
Malformation. 5th ed. Philadelphia,
PA: Saunders; 1997:8–13
Current Dilemmas in Down Syndrome
Clinical Care: Celiac Disease, Thyroid
Disorders, and Atlantoaxial Instability.
Cohen WI. Am J Med Genet C Semin
Med Genet. 2006;142C(3):141–148
Down syndrome (DS) is one of the most
common genetic conditions. Incidence
of DS is 1 in 691 births but varies greatly
with maternal age (eg, for women age
35–39 years, the incidence increases to
1 in 270). Most cases of DS are due to
sporadic mutations that result in an extra
chromosome 21. Generally, the recur-
rence risk is approximately 1% or the
maternal age–related risk (whichever is
higher). Yet, the risk of having another
child with DS is greater for a young
woman who is a carrier of a balanced
translocation than for a middle-aged
woman. It is critical that all children
born with DS have chromosome anal-
ysis to identify those having a translo-
cation and ensure accurate genetic
counseling for the family.
Screening for DS should be offered
to all pregnant women. Prior screening
guidelines identified 50% of infants in
utero, whereas new screening guide-
lines have first trimester detection rates
of 82% to 85% and second trimester
rates of 80%; combination screening
during both trimesters identifies 95%
of cases. When an infant is born with
DS, parents wish to be congratulated
on the birth and then receive disclosure
of the diagnosis in a sensitive manner.
Principles of sharing the difficult news
aspects of the infant’s condition appro-
priately include disclosing concern as
soon as suspicion exists, telling both
parents at the same time, and explain-
ing the range of variability of presen-
tations and the potential associated
medical conditions.
Physical features of DS are variable
and include hypotonia, epicanthal folds,
flat nasal bridge, slanted palpebral fis-
sures, speckling of the iris, abnormal
auricles, hyperflexibility, excessive skin-
folds in the posterior aspect of the neck,
a single transverse palmar crease, and
a wide gap between the first and sec-
ond toes.
Certain medical problems occur with
a high prevalence in children born with
DS, forming the basis for the recom-
mendations for the health supervision
of these children. Many common ill-
nesses occur more frequently, including
in brief
acute and serous otitis media, sinusitis,
and vision problems. Because 40% to
50% of children with DS may have a
cardiac anomaly, all infants should un-
dergo screening echocardiography.
Clinicians should evaluate infants
with any sign that may suggest a gastro-
intestinal malformation because these
conditions comprise the second most com-
mon major area of congenital anomaly
occurring in DS and include duode-
nal atresia, tracheoesophageal fistula,
Hirschsprung disease, and imperforate
anus. By adulthood, up to 75% of indi-
viduals with DS will develop hearing
problems, 15% will develop cataracts,
50% to 75% will develop obstructive
sleep apnea, and 5% will develop celiac
disease. Up to 13% of children with DS
may develop a seizure disorder.
Autoimmune thyroid disease in-
creases in prevalence with age, and
60% develop hypothyroidism by adult-
hood. Children with DS tend to have
weaker immune systems and should be
monitored closely when ill. The 2011
updated guidelines published by the
American Academy of Pediatrics should
be followed, which recommend annual
screening for many of the above condi-
tions and periodic surveillance for others.
Hematologic problems are also rela-
tively common in children born with DS.
Ten percent will have a transient mye-
loproliferative disorder at birth, whereas
1% of patients with DS will develop
leukemia during a lifetime. Congenital
myeloproliferative conditions generally
resolve but are a risk factor for later de-
velopment of leukemia. Guidelines rec-
ommend a complete blood cell count at
birth. If a newborn has a normal blood
cell count, no further monitoring is rec-
ommended; however, if the child man-
ifests signs such as petechiae, weight
Pediatrics in Review Vol.34 No.12 December 2013 573
in brief

loss, pallor, or fevers, a complete blood
cell count should be obtained. Guide-
lines also recommend yearly monitoring
of hemoglobin concentration (with a
ferritin level and C-reactive protein
measurement) if the child has any risk
factors for iron deficiency.
Although earlier 2001 American
Academy of Pediatrics health supervi-
sion guidelines recommended cervical
spine radiographs performed between
ages 3 and 5 years in children born
with DS, the 2011 guidelines do not. Al-
though children with DS have a 1% to
2% risk of atlantoaxial instability, evi-
dence does not support routine radio-
graphic screening. However, careful
surveillance is imperative. Because cer-
tain sports place children with DS at
an increased risk of spinal cord injury,
the Special Olympics organization may
require radiographs for participation.
At least twice a year, the clinician
should review with parents that the
cervical spine must be protected and
that excessive extension or flexion dur-
ing anesthetic, surgical, or radiographic
procedures must be avoided. The clini-
cian should also perform a neurologic
examination to monitor for emergence
of increased tone or hyperreflexia. Chil-
dren with DS should avoid sports such
as soccer, football, gymnastics, and
trampoline use. Parents should be ad-
vised that if they note changes in gait,
arm or hand function, or bowel or blad-
der control, as well as weakness, atyp-
ical head positioning, or chronic neck
pain, they should consult their primary
care physician promptly because further
evaluation is warranted.
Comments: DS was first described
by J. L. H. Down in 1866. Because there
is great variability in presentation, par-
ents must receive a balanced perspec-
tive when being counseled. Prenatal
imaging may help in better defining car-
diac and gastrointestinal malformations.
Parents and families benefit from the
support of a skilled primary care phy-
sician who provides evidence-based
health anticipatory guidance and assists
them in understanding the developmen-
tal abilities of the child while establish-
ing realistic expectations. Parents value
having access to other parents who have
children with DS within a practice or
through local or national organizations
and benefit from counseling regarding
the emotional health of siblings and
family members. DS is another example
of a disease with broad phenotypic dif-
ferences. Transitions to adult medical
care are imperative to address issues
of fertility and contraception, along with
future employment opportunities and liv-
ing arrangements as these patients enter
adulthood.
Janet R. Serwint, MD
Consulting Editor, In Brief

Parent Resources From the AAP at HealthyChildren.org

• English: http://www.healthychildren.org/English/health-issues/conditions/developmental-disabilities/Pages/Children-
with-Down-Syndrome-Health-Care-Information-for-Families.aspx
• English: http://www.healthychildren.org/English/health-issues/conditions/developmental-disabilities/Pages/Down-
Syndrome.aspx

Answer Key for December 2013 Issue:

Type 2 Diabetes Mellitus: 1. C; 2. A; 3. B; 4. D; 5. E.
Managing Feeding Problems and Feeding Disorders: 1. D; 2. C; 3. B; 4. D; 5. D.
Human Metapneumovirus: 1. C; 2. D; 3. E; 4. E; 5. D.

574 Pediatrics in Review Vol.34 No.12 December 2013


An 11-Month-Old With Nausea,
Vomiting, and an Abdominal Mass
Figure 1. Abdominal bulge due to underlying mass.
Author Disclosure
Drs Whittington, Stevens, Jones, and Mayo have disclosed no
financial relationships relevant to this article. This
commentary does not contain discussion of unapproved/
investigative use of a commercial product/device.
*Department of Pediatrics, University of South Dakota Sanford School of Medicine, Sioux Falls, SD.
†
Pediatric Hospital Service/Sanford Children’s Hospital, Sioux Falls, SD.
visual diagnosis
Laura A. Whittington, DO,* David C. Stevens, MD,* Sarah
A. Jones, MD,* Julie M. Mayo, DO*†
Presentation
An 11-month-old girl presents to the emergency depart-
ment (ED) with 12 episodes of nonbilious, nonbloody
vomiting and decreased activity for the past 24 hours.
Her medical history and family history are notable for
the following. She was born at term via an uncomplicated,
induced vaginal delivery. There is a paternal history of di-
abetes. The patient’s half-sister, who has phenylketonuria,
was ill with nausea without vomiting 2 days before the pa-
tient’s presentation. Yesterday the patient was seen in the
ED for nausea and 5 bouts of emesis. She was discharged
after receiving one dose of ondansetron and could tolerate
clear liquids by mouth. She now returns to the ED for con-
tinued vomiting.
On physical examination the patient’s temperature is
37.9°C, heart rate is 114 beats per minute, respira-
tory rate is 30 breaths per minute, blood pressure is
105/65 mm Hg, and oxygen saturation is 98% in room
air. She is comfortable and sleeping but awakens when
physically examined. Mucous membranes are slightly dry,
and her posterior oropharynx is erythematous. Cardiac aus-
cultation reveals normal S1 and S2 heart sounds without
a murmur. She has good peripheral perfusion and normal
capillary refill. Her lungs are clear to auscultation. She has
no abdominal scars, and bowel sounds are normal. Her ab-
domen is soft and nontender, and no masses are palpable.
The spleen and liver are not enlarged. Abdominal radiog-
raphy reveals a normal bowel gas pattern.
The patient is admitted for intravenous hydration. De-
spite treatment with ondansetron, frequent vomiting per-
sists. During her second hospital night, she has several
large bowel movements that contain blood and mucus.
Her father notices a visible mass in her abdomen (Fig 1).
Laboratory evaluation reveals that her stool sample is neg-
ative for Shiga-like toxin and rotavirus. An abdominal ra-
diograph is suggestive of underlying disease (Fig 2). On
the basis of the radiographic findings, a water-soluble con-
trast enema is performed (Fig 3) that confirms the sus-
pected underlying diagnosis.
Pediatrics in Review Vol.34 No.12 December 2013 e47
visual diagnosis
Figure 2. Abdominal radiograph showing paucity of air in
bowel and a curvilinear mass within the course of the colon.
Diagnosis
Intussusception
The patient’s history of bloody stools, a palpable abdom-
inal mass, and the soft tissue opacification on abdominal
radiography are highly suggestive of ileocecal intussuscep-
tion. Subsequent contrast enema revealed a large intussus-
ception that involves the ileum, cecum, and ascending and
transverse colon.
Discussion
Intussusception occurs when a portion of the proximal
segment of the bowel (the intussusceptum) invaginates into
a distal bowel segment (the intussuscipiens). Without treat-
ment, bowel obstruction, necrosis, perforation, and death
can ensue. Fortunately, most intussusceptions can be re-
duced by contrast enema. However, some patients require
surgical intervention with manual reduction or excision of
the affected portion of the bowel. Longer duration of intus-
susception is associated with increased morbidity and mortal-
ity. Thus, prompt recognition and treatment are imperative.
Diagnosis is contingent on clinical suspicion and confirma-
tion by abdominal ultrasonography or contrast enema.
Intussusception is the most common cause of bowel ob-
struction in children between age 6 and 36 months. Infants
e48 Pediatrics in Review Vol.34 No.12 December 2013
Figure 3. Water-soluble contrast enema reveals an intra-
intestinal mass.
between age 4 and 7 months are most commonly affected.
Intussusception rarely occurs in children younger than 2
months, and 70% of cases occur in the first year of life. Most
cases are idiopathic, but some, particularly those occurring
in children outside the normal age range, form around path-
ologic lead points, such as a Meckel diverticulum, intestinal
polyp, or edema caused by Henoch-Schönlein purpura. Males
develop intussusception at roughly twice the rate of females.
The incidence is estimated to be 18 to 56 per 100,000 live
births, and there is evidence in the United States and abroad
that the incidence is decreasing overall.
Infants and children with intussusception present with
a variety of signs and symptoms. Emesis, abdominal pain,
bloody stool, and lethargy are among the most common.
Unfortunately, these symptoms are nonspecific and carry
a vast differential diagnosis. The classic currant jelly stool
is generally a late finding that occurs when the bowel wall
undergoes significant vascular injury and blood mixes
with mucoid material to produce this characteristic ap-
pearance. Either gross or occult blood in the stool is present
in more than half of children with confirmed intussuscep-
tion. The classic triad of abdominal pain, vomiting, and
bloody stool is observed in less than 50% of affected in-
dividuals and should not be relied on for diagnosis. How-
ever, this triad is highly predictive of intussusception. To
date, no reliable individual discriminating factors have
been identified, and the diagnosis of intussusception con-
tinues to rely on a high degree of clinical suspicion and
confirmatory imaging studies.

Abdominal radiography, ultrasonography, and contrast
enema are the 3 most common imaging modalities used
in the evaluation of a child with possible intussusception.
Abdominal radiography is occasionally indicative of intus-
susception, but the sensitivity of radiography is too low
(29%-50%) to safely exclude the diagnosis. When intussus-
ception is suspected, it must be definitely ruled out with
either ultrasonography or contrast enema. The sensitivity
and specificity of both studies approach 100%. However,
ultrasonography is the preferred initial test because it is
not invasive and does not expose the patient to ionizing
radiation. If intussusception is found on ultrasonography,
stable patients should proceed to contrast enema under
ultrasonic or fluoroscopic guidance for initial therapy. Un-
stable patients and those with evidence of bowel rupture
should have emergent surgical consultation.
Differential Diagnosis
The differential diagnosis depends on the presenting symp-
toms. Gastrointestinal bleeding and abdominal pain in
children can be caused by Henoch-Schönlein purpura, he-
molytic uremic syndrome, and allergic colitis. Vomiting and
abdominal pain have an equally broad differential diagnosis,
including infectious gastroenteritis and malrotation with
volvulus. From a surgical standpoint, the presence of hem-
atochezia, a palpable abdominal mass, and a curvilinear
mass within the course of the colon with a paucity of air in
the bowel on abdominal radiography suggests segmental
bowel obstruction from either volvulus or a persistent om-
phalomesenteric duct besides an intussusception.
Management
Contrast enema continues to be the diagnostic gold stan-
dard and first-line therapy for an intussusception. A total
of 46% to 80% of intussusceptions can be reduced with
enema. Traditionally, a liquid enema was performed un-
der fluoroscopic guidance; however, the current trend is
toward air enemas under ultrasonic guidance, which do
not use ionizing radiation. The efficacy of the 2 treat-
ments is similar, and the choice of technique primarily de-
pends on the experience of the attending radiologist.
Before any planned contrast enema, intravenous access
should be obtained, the child should be fully fluid resus-
citated, and a pediatric surgeon should be notified. Many
physicians will also administer a dose of intravenous antibi-
otics. When contrast enema reduces intussusception, the
child should be closely monitored because 10% of patients
will experience intussusception again. Primary surgical treat-
ment is indicated for unstable patients and those with signs
of bowel perforation. Surgical treatment is also necessary
when contrast enema fails to reduce the intussusception.
visual diagnosis
Figure 4. Necrotic ileum within the intussuscepted colon.
Most pediatric surgeons approach uncomplicated, irreduc-
ible intussusception with laparoscopic reduction. If neces-
sary, manual reduction of the intussusception is often
successful; however, bowel excision may also be necessary.
A delay in definitive diagnosis may lead to greater bowel
ischemia and greater likelihood of resection.
Patient Course
Unfortunately, the patient’s intussusception could not be
reduced by contrast enema. The patient was taken to the
operating room for an exploratory laparotomy and man-
ual reduction of the intussusception. During the explor-
atory laparotomy, the patient was found to have necrotic
ileum within the intussuscipiens (Fig 4). A right hemico-
lectomy with primary anastomosis was performed. Two
days later the patient had abdominal distention with free
air seen on abdominal radiography. She returned to the
operating room, where an anastomotic leak was repaired.
After 3 weeks in the pediatric intensive care unit, she was
discharged home in good condition.
Summary
• Children with intussusception can present with a wide
variety of symptoms, including vomiting, fever,
lethargy, and abdominal pain. The classic triad of
abdominal pain, hematochezia, and palpable
abdominal mass is seen in a few patients.
• Early diagnosis of intussusception depends on a high
level of clinical suspicion in any child with nonspecific
abdominal findings followed by appropriate
radiographic or ultrasonographic evaluation and
confirmation with a contrast enema.
• Abdominal radiography, although an appropriate
component of the initial workup for gastrointestinal
Pediatrics in Review Vol.34 No.12 December 2013 e49
visual diagnosis
symptoms, lacks the sensitivity to reliably exclude the
presence of intussusception.
• Because ultrasonography is a safe, sensitive, and
specific test for the diagnosis of intussusceptions, it
should be performed early whenever there is clinical
suspicion of intussusception.
• Contrast enema is the gold standard for diagnosis and
first-line treatment of intussusception. There is an
increasing trend for pneumatic reduction of
intussusception compared with hydrostatic reduction.
Intravenous placement, fluid resuscitation, and
notification of the pediatric surgeon should be
completed before contrast enema.
e50 Pediatrics in Review Vol.34 No.12 December 2013
Suggested Reading
Fischer TK, Bihrmann K, Perch M, et al. Intussusception in early
childhood: a cohort study of 1.7 million children. Pediatrics.
2004;114(3):782–785
Kaiser AD, Applegate KE, Ladd AP. Current success in the
treatment of intussusception in children. Surgery. 2007;142
(4):469–475.
Mandeville K, Chien M, Willyerd FA, Mandell G, Hostetler MA,
Bulloch B. Intussusception: clinical presentations and imag-
ing characteristics. Pediatr Emerg Care. 2012;28(9):842–
844
Samad L, Marven S, El Bashir H, et al. Prospective surveillance
study of the management of intussusception in UK and Irish
infants. Br J Surg. 2012;99(3):411–415