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Editor-in-Chief: Lawrence F. Nazarian, Rochester, NY
Associate Editors: Tina L. Cheng, Baltimore, MD
Joseph A. Zenel, Sioux Falls, SD
Editor, In Brief: Henry M. Adam, Bronx, NY
Consulting Editor, In Brief: Janet Serwint, Baltimore, MD
Editor, Index of Suspicion:
contents
Deepak M. Kamat, Detroit, MI
Consulting Editor Online and Multimedia
Projects: Laura Ibsen, Portland, OR
PediatricsinReview姞 Vol.32 No.1 January 2011
Editor Emeritus and Founding Editor:
Robert J. Haggerty, Canandaigua, NY
Managing Editor: Luann Zanzola
Medical Copy Editor: Deborah K. Kuhlman
Commentary
Editorial Assistants: Sydney Sutherland, Kathleen Bernard
Editorial Office: Department of Pediatrics
University of Rochester
3 The Pediatrician as Teacher
Lawrence F. Nazarian
School of Medicine & Dentistry
601 Elmwood Avenue, Box 777
Rochester, NY 14642
kbernard@aap.org
Editorial Board
Articles
Hugh D. Allen, Columbus, OH
Margie Andreae, Ann Arbor, MI
Richard Antaya, New Haven, CT
Denise Bratcher, Kansas City, MO
Jacob Hen, Bridgeport, CT
Hal B. Jenson, Springfield, MA
Donald Lewis, Norfolk, VA
Gregory Liptak, Syracuse, NY
5 Infants of Drug-dependent Mothers
Lauren M. Jansson, Martha L. Velez
George R. Buchanan, Dallas, TX Susan Massengill, Charlotte, NC
Brian Carter, Nashville, TN Jennifer Miller, Gainesville, FL
Joseph Croffie, Indianapolis, IN
B. Anne Eberhard, New Hyde Park, NY
Philip Fischer, Rochester, MN
Rani Gereige, Miami, FL
Blaise Nemeth, Madison, WI
Renata Sanders, Baltimore, MD
Thomas L. Sato, Milwaukee, WI
Sarah E. Shea, Halifax, Nova Scotia
14 Inflammatory Bowel Disease
Sarah R. Glick, Ryan S. Carvalho
Lindsey Grossman, Springfield, MA Andrew Sirotnak, Denver, CO
Patricia Hamilton, London, United Kingdom Nancy D. Spector, Philadelphia, PA
Publisher: American Academy of Pediatrics
Visual Diagnosis: Perceived Fevers and
27
Michael J. Held, Director, Division of Scholarly Journals and Professional Periodicals
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Index of Suspicion
Pediatrics in Review Case 1: Recurrent Oral Ulcers in an Adolescent
Print Issue Editorial Board Disclosures Case 2: Visual Impairment in an Autistic Child
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e4 Delayed Tooth Emergence

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 The Pediatrician as Teacher
Lawrence F. Nazarian
Pediatr. Rev. 2011;32;3-4
DOI: 10.1542/pir.32-1-3

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/cgi/content/full/32/1/3

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2011 by the American Academy of
Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.

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Commentary
The Pediatrician as Teacher
Author Disclosure
Dr Nazarian has disclosed no
financial relationships relevant to
this commentary. This commentary
does not contain a discussion of an
unapproved/investigative use of a
commercial product/device.
The word “doctor” means “teacher,” and
like all physicians, pediatricians func-
tion as teachers in many contexts. Ev-
ery time a patient is cared for, some
teaching is accomplished, even in a
brief visit. When performing health
maintenance or managing chronic ill-
ness, teaching becomes a major com-
ponent of care. Patients, parents, and
caregivers are the students (although
the complete physician will be learning
constantly from those folks as well).
In a pediatric office, physician part-
ners teach and learn from each other,
and that type of interchange extends to
the entire health-care team. I acknowl-
edge with gratitude the invaluable les-
sons I have learned from nurses and
nurse practitioners, and I hope I have
repaid in kind. Secretaries, reception-
ists, business personnel – we can teach
all of them, and their contribution to
our education is critical.
Many in our profession have de-
voted their careers to teaching, and
those of us in practice who have
learned so much from academic physi-
cians, both in our training years and
through our experiences in the office,
are grateful for their dedication and
expertise. However, the practitioner can
provide a great deal of education to
students and residents if there is a
symbiotic relationship with an aca-
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demic program. A student can be incor-
porated into a busy office schedule,
first as an observer, then in a more
direct role. This time-honored appren-
ticeship model works well, especially if
the academic department can provide
guidance and follow-up. Office teach-
ing also works well for students in
nursing and physician assistant pro-
grams.
Visiting a patient in the hospital
offers opportunities for conversations
with residents that can be mutually
educational, and contributing time to
round on the wards can be tremen-
dously rewarding. Some of the most
fruitful experiences I have enjoyed have
come from the dual rounding system, in
which an academic specialist and a
general pediatrician form a teaching
team in the hospital. The ability to
complement each other’s perspectives
makes for a full and balanced learning
experience. Office-based pediatricians
can contribute to conferences and
grand rounds as well, especially when
the topic involves activities they know
intimately, such as telephone manage-
ment or well child care, as well as
subjects in which they might have a
particular interest.
The general public can benefit from
the teaching pediatrician. From ad-
dressing a group of nursery school
teachers and parents to appearing on
national television, we are in a position
to pass along information that is accu-
rate and evidence-based. Exerting this
influence has become more important
than ever with the proliferation of in-
accurate information in the media, es-
pecially on the Internet.
Pediatrics in Review (PIR) has as its
mission to improve the health and wel-
commentary
fare of all children by educating pedi-
atricians and other clinicians who care
for children. As you are reading this
commentary, authors are crafting arti-
cles, reviewers are critiquing papers,
editors are planning and refining mate-
rial, and other staff are working in
myriad ways to allow our readers to
stay current across the whole spectrum
of pediatric medicine. We are grateful
for all of these contributions, many of
which are made on a volunteer basis.
We appreciate also the feedback we get
from readers, which we take seriously
and on which we follow up.
It is important for readers to know
that the Accreditation Council for Con-
tinuing Medical Education sets stan-
dards and establishes criteria for certi-
fying organizations that grant credit for
continuing medical education. The
American Academy of Pediatrics (AAP)
adheres to these guidelines, which are
updated constantly, in its role as an
educational institution. Adherence in-
volves such activities as identifying
learning gaps, making specific plans for
filling those gaps, and monitoring the
effects of learning and continuing ed-
ucation on competence and actual
practice. Making such measurements is
a considerable task, and techniques
vary with the type of education; medi-
cal journals are different from single-
session workshops and multiday con-
ferences. Conflict of interest is another
facet of education that is addressed by
these standards. Be assured that all
who are involved in the AAP’s educa-
tional efforts are working hard to
achieve the highest standards.
We are also on the alert for new
modalities to make our teaching more
effective. Realizing that social networks
Pediatrics in Review Vol.32 No.1 January 2011 3
commentary
are important to many of our readers,
we recently debuted a website called
“In the Loop” (http://intheloop.aap.org)
that features social media links for
many of the AAP’s publications as well
as current news for each journal. Be
sure to check it out! Both PIR and
NeoReviews have pages on Facebook
that amplify the ways in which we can
communicate with our readers, and
such involvement in networking will
only grow.
We would like to introduce a new
4 Pediatrics in Review Vol.32 No.1 January 2011
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resource that should be of great help in
assisting you as a teacher of patients
and parents. The AAP has an online web-
site (www.healthychildren.org) that
contains a wealth of material on a
broad range of pediatric topics written
by experts for the lay public. Pediatric
clinicians should familiarize themselves
with this site and direct patients, par-
ents, and caregivers to it. Material can
be taken from the site and given out.
When appropriate, we link resources on
this site to specific articles published in
the journal, but you can help your
patients at any time by going to the site
yourself or directing them to it.
Just as the AAP and PIR are working
constantly to improve the ways in
which we educate you, we encourage
you to be aware of the importance of
your role as a teacher and to take steps
that will enhance this critical function.
Lawrence F. Nazarian, MD
Editor-in-Chief
 The Pediatrician as Teacher
Lawrence F. Nazarian
Pediatr. Rev. 2011;32;3-4
DOI: 10.1542/pir.32-1-3

Updated Information including high-resolution figures, can be found at:

& Services http://pedsinreview.aappublications.org/cgi/content/full/32/1/3
Permissions & Licensing Information about reproducing this article in parts (figures,
tables) or in its entirety can be found online at:
http://pedsinreview.aappublications.org/misc/Permissions.shtml
Reprints Information about ordering reprints can be found online:
http://pedsinreview.aappublications.org/misc/reprints.shtml

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 Infants of Drug-dependent Mothers
Lauren M. Jansson and Martha L. Velez
Pediatr. Rev. 2011;32;5-13
DOI: 10.1542/pir.32-1-5

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/cgi/content/full/32/1/5

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2011 by the American Academy of
Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.

Downloaded from http://pedsinreview.aappublications.org. Provided by Health Internetwork on April 20, 2011


Infants of Drug-dependent Mothers
Lauren M. Jansson, MD,*
Martha L. Velez, MD*
Author Disclosure
Drs Jansson and Velez
have 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.
Downloaded from http://pedsinreview.aappublications.org. Provided by Health Internetwork on April 20, 2011
Article fetus and newborn
Objectives After completing this article, readers should be able to:
1. Recognize the effects of maternal substance use on the developing fetus, neonate, and
growing child.
2. Describe the effect of maternal substance use on the mother-infant dyad.
3. Discuss the factors that may serve as mediators and moderators of the effects of
maternal substance use on the child.
4. Understand the complex context within which the substance-abusing mother and her
infant must be considered.
5. Evaluate and manage the substance-exposed dyad.
Introduction
In utero substance exposure continues to pose a public health and societal dilemma.
Prenatal exposure to legal and illegal substances is a substantial and preventable risk factor
for developmental alterations in infants. Intrauterine substance exposure affects more
newborns than many other common major medical conditions, making the problem of the
substance-exposed infant an inevitable concern for all pediatricians. Of the 4.3 million
infants born annually in the United States, between 800,000 and 1 million are born to
women who used drugs during pregnancy; approximately 1 in 9 infants is exposed to
alcohol, 1 in 5 is exposed to nicotine, and 1 in 20 is exposed to illegal drugs. Opioid use
during pregnancy is a growing concern due to the rise in abuse of prescription opioids (eg,
hydrocodone, oxycodone) in women of childbearing age.
Currently, 5.4 million children live with a parent who has a substance use disorder, and
3.4 million live with a mother who has a substance use disorder in the United States. (1)
Resumption of drug use following childbirth is an additional concern; in a recent report,
cigarette, alcohol, binge alcohol, and marijuana use rates were higher in women with a
child younger than 3 months of age (20.4%, 31.9%, 10.0%, and 3.8%, respectively)
compared with rates of use in the third trimester of pregnancy (13.9%, 6.2%, 1.0%, and
1.4%, respectively). (2) Pregnant adolescents represent a special population because
young women ages 15 to 17 years report a higher rate of use of illicit drugs and misuse of
prescription drugs than same-age nonpregnant peers. (3) Even a woman who has decided
not to use substances during a pregnancy may do so inadvertently during the early stages
before the pregnancy is recognized.
Initial studies examining specific effects of maternal drug use on the infant did not
account for the wide spectrum of associated risk factors for birth outcomes, particularly
psychosocial risk factors, or failed to estimate the proportion of risk attributable to a
presumed biologic mechanism versus these other factors. For these reasons, the traditional
teratology model has been replaced by a transactional or multiple-risk model in which the
psychoactive substance exposure is considered a marker or risk indicator in a contextual
framework to explain the outcome of the prenatally substance-exposed newborn.
Multiple risk and protective factors have been investigated for their roles as mediators or
moderators of the effects of maternal drug use on the developing child. Factors such as
amount of drug, timing of use during gestation, use of several (illicit and licit) substances,
and issues related to the postnatal caregiving environment need to be considered. Medical
complications in the neonatal period, such as prematurity and low birthweight (LBW), can
affect the expression of the effects of the substances in the infant and child. Furthermore,
*Department of Pediatrics, The Center for Addiction and Pregnancy, The Johns Hopkins University School of Medicine,
Baltimore, MD.
Pediatrics in Review Vol.32 No.1 January 2011 5
fetus and newborn infants of drug-dependent mothers
substance abuse frequently is associated with multiple
social, psychosocial, behavioral, and biomedical maternal
and child risk factors, including poverty, stress, psychiat-
ric comorbidity, violence exposure, lack of social sup-
port, physical abuse, sexually transmitted infections,
poor nutrition, and poor medical care.
The prevalence of psychiatric disorders among the
population of substance-dependent women is of partic-
ular importance because these disorders frequently war-
rant the need for prescribed medications that have psy-
choactive effects. It is estimated that nearly half of all
substance-abusing pregnant women have a coexistent
axis I disorder, as described in the Diagnostic and Statis-
tical Manual of Mental Disorders. (4) Depression is es-
pecially prevalent in drug-dependent pregnant popula-
tions, and anxiety and personality disorders are frequent
comorbid conditions. Psychotropic medications are pre-
scribed for women nearly twice as often as they are for
men, and these maternal medications can affect infant
functioning, as can the disorder for which the medication
is prescribed.
The purpose of this review is to examine the current
and relevant scientific literature regarding the effects of
maternal substance use on the developing child and the
factors that may serve as mediators and moderators of the
effects of maternal substance use on the child as well as
provide some recommendations for clinicians evaluating
and treating substance-abusing mothers and their
substance-exposed infants. The goal is to make clinicians
aware of the severity of the potential effects of maternal
drug use on the developing child, the myriad and largely
indefinable mechanisms by which maternal substance use
may affect the infant, and the importance of early and
adequate diagnosis and treatment of the substance-
exposed mother-child dyad. Improving the clinical ap-
proach to these patients may allay the negative short- and
long-term consequences of maternal drug use on the
developing child.
Effects of Maternal Drug Use on the
Developing Fetus
Research on the pediatric effects of maternal drug use
poses complex challenges because it often is difficult to
make this correlation accurately, given the multiple bio-
logic and psychosocial factors that may act as mediators
or moderators of the effects of drugs on the infant.
Animal models traditionally have been used to define
effects of in utero substance exposure. However, gener-
alizing results from animal studies to humans is ham-
pered by differences in timing of brain maturation. Drugs
of abuse cross the placenta and may influence early
6 Pediatrics in Review Vol.32 No.1 January 2011
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development through several pathophysiologic path-
ways. Their teratologic effects are dependent on the
intersection of the exposure, the temporal and regional
emergence of critical developmental processes, and the
sensitivity of the developing specific brain structure or
neural circuit to the drug. Exposure during the first half
of gestation may affect processes related to cytogenesis
and histogenesis, whereas effects during the second half
of gestation may compromise progressive events (eg,
brain growth and differentiation) and regressive events
(eg, programmed cell death). Alterations of these events
have the capacity to modify brain development as well as
the ability of the developing brain to recover from injury.
(5)
Drugs can affect fetal brain development through
indirect and direct mechanisms. Indirect effects may be
due to variations in maternal physiology and placental
functioning. For example, potential indirect mechanisms
of nicotine exposure include maternal and fetal undernu-
trition caused by smoking-induced anorexia, hypoxia
due to increased carboxyhemoglobin and vasoconstric-
tion, placental hypertrophy, and reduced transplacental
transport of nutrients. Direct effects of the drugs include
alterations in the development of neurotransmitter and
neuromodulator systems, many of which are present
during early embryogenesis and have pleiotropic effects
on brain development.
Marijuana produces its psychoactive effects through spe-
cific brain cannabinoid receptors that regulate multiple
developmental processes such as neuronal proliferation,
migration, differentiation, survival, and synaptogenesis.
Methamphetamines are potent sympathomimetic agents
that exert their action by releasing dopamine and serotonin,
blocking monoamine reuptake mechanisms, and inhibiting
monoamine oxidase, resulting in increases in synaptic con-
centrations of the neurotransmitters dopamine and norepi-
nephrine. Opioids are metabolized into morphine, and
mechanisms of action are mediated by opioid, principally
mu, receptors. Opioid receptors are present in several areas
of the brain, and several mechanisms could be affected by
opioid exposure. Morphine can affect migration and sur-
vival of neurons in rats (6) and increase apoptosis in human
fetal microglia and neurons. (7)
Fetal programming is a mechanism that has been
gaining consideration in linking adverse events occurring
in utero and related outcomes (eg, enhanced risk for
medical, behavioral, or psychiatric problems) in later life.
Fetal programming, originally known as the ‘‘Barker” or
‘‘fetal origins hypothesis,” (8) assumes that nongenetic
factors such as unfavorable intrauterine conditions can
permanently organize or imprint physiologic and behav-

ioral systems and disrupt normal fetal functioning, which
may result in later disorders. This mechanism has been
implicated in the causal pathway underlying long-term
deficits observed in alcohol-exposed offspring. (9)(10)
Research in animals and emerging studies in humans
suggest that epigenetic changes in regulatory genes and
growth-related genes play a significant role in fetal pro-
gramming. These epigenetic changes are heritable but
reversible alterations in gene expression caused by mech-
anisms other than changes in DNA sequence. It is be-
lieved that epigenetic changes can persist through mul-
tiple cell divisions and cell differentiation and even be
passed on to progeny.
Based on this theory, maternal substance use could
produce significant changes in the regulation of various
offspring genes that may be involved in diverse functional
systems through epigenetic mechanisms. For example, a
study in mice indicated that maternal cocaine exposure
during the second and third trimesters of gestation re-
sulted in multiple alterations in the methylation states of
offspring DNA with persistent effects, suggesting that
maternal cocaine use could produce potentially profound
structural and functional modifications in the epi-
genomic programs. (11)
How these potential mechanisms contribute individ-
ually and collectively to altered brain growth and matu-
ration has not been well established, but it is known that
most drugs act through different mechanisms with indi-
vidual developmental consequences. In the case of co-
caine, the drug crosses the placenta and acts at the
presynaptic level, affecting the fetus by blocking the
reuptake of the neurotransmitters dopamine, norepi-
nephrine, and serotonin; elevating circulating catechol-
amine concentrations; and causing vasoconstriction in
the fetoplacental unit. Cocaine affects neuronal forma-
tion and proliferation and disrupts neuronal migration,
resulting in changes to cortical architecture. In addition,
cocaine has been implicated as an intrauterine stressor
that alters fetal programming, changing developmental
trajectories. (12)
Finally, maternal and fetal genotypes and ecogenetic
considerations (ie, the concept that the combination of a
particular susceptible genome and drug/toxin exposure
is necessary for adverse effects to become apparent) also
may affect outcome.
Effects of prenatal exposures have been shown to be
sex-specific. For example, prenatal morphine exposure
induces physiologic and behavioral changes involving the
stress response in the adult rat that differ between sexes.
(13) Prenatal exposure to alcohol alters hypothalamic-
pituitary axis responsivity differently in male and female
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fetus and newborn infants of drug-dependent mothers
offspring in both animals and in humans. (14) Prenatal
exposure to cigarettes increases the risk for developmen-
tal psychopathology in human boys but not girls. (15)
Male infants have been found to be more vulnerable to
maternal methadone use. (16)
Clinically Observable Effects of In Utero
Substance Exposure on the Newborn
Regardless of mechanisms of harm and confounding by
other risk factors, it is accepted that neonates exposed to
substances during pregnancy are at increased risk for a
variety of conditions that portend future developmental
and other difficulties. The following are the most widely
recognized clinical conditions associated with in utero
drug exposure.
Drug-related Adverse Birth Outcomes
Nearly all drugs of abuse have been associated with
drug-related adverse outcomes such as preterm birth,
LBW, and growth restriction. Many substances used by
drug-dependent women can shorten gestation and im-
pair fetal growth without resulting in preterm deliveries
or LBW, as traditionally defined.
Neonatal Abstinence Syndrome (NAS)
NAS is a group of signs indicating dysfunction of respi-
ratory, gastrointestinal, or nervous system regulation
that develops after the cessation of the maternal drug
supply at delivery. Neonatal withdrawal is associated
primarily with opiates, sedative-hypnotics, and alcohol,
but most psychoactive drugs used during pregnancy,
including antidepressants, antipsychotics, and nicotine,
can produce “withdrawal-like symptoms” in the new-
born. Other than for opioids, there are difficulties in
ascribing any signs of neonatal withdrawal to any partic-
ular substance because algorithms used to define NAS are
specific to neonatal opioid withdrawal, and signs of with-
drawal to other substances are likely to be qualitatively
and quantitatively different. Nonopioid substances that
have been described as having specific abstinence syn-
dromes generally present with infants exhibiting signs
that are described by the Finnegan Neonatal Abstinence
Scoring System. (17) However, most newborns exposed
to these substances do not reach cut-off values for phar-
macologic treatment and may have symptoms not in-
cluded in the Finnegan Scoring System. In addition,
generally no specific treatments for nonopioid-exposed
infants exist. The infant’s display of NAS can affect
maternal functioning and interaction with the newborn,
further compounding the threat to progressive neurode-
Pediatrics in Review Vol.32 No.1 January 2011 7
fetus and newborn infants of drug-dependent mothers
velopment. Other factors, such as prematurity, can affect
the course and presentation of NAS. (18)
Neurobehavioral and Regulatory Impairment
Signs displayed by drug-exposed infants that reflect dif-
ficulties in their ability to maintain organized behavioral
and physiologic responses to external or internal stimu-
lation indicate neurobehavioral and regulatory impair-
ment, alternatively labeled homeostatic instability or
dysregulation. Frequently observed neurobehavioral
problems of substance-exposed infants include tremors;
irritability; difficulty being consoled; hypertonicity; in-
creased startle response or exaggerated Moro reflex; and
respiratory, feeding, and sleeping problems. Behavioral
assessment of signs of regulatory dysfunction displayed
by the substance-exposed infant has been facilitated by
using the Neonatal Intensive Care Unit (NICU) Net-
work Neurobehavioral Scale. (19) This scale, developed
as a neurobehavioral assessment tool for the at-risk in-
fant, is used to evaluate how stressors, such as in utero
substance exposure, affect infant self-organizing neu-
robehavioral capacities. A systematic assessment of the
neurobehavioral functioning of the substance-exposed
neonate in the domains of state control regulation, mo-
tor and tone functioning, reactivity to sensory stimula-
tion, and autonomic signs of stress, can define areas of
concern that can be used to design an individualized care
plan. (20)
Structural Changes
Congenital anomalies have been variably reported for
almost all drugs of abuse. Aside from alcohol, which has
a clearly defined pattern of birth defects, large outcome
studies evaluating the correlation between congenital
anomalies and periconceptional drug use generally find
no positive associations. (21) Advances in brain magnetic
resonance imaging-based methods have identified some
alterations of brain structures and patterns of functional
activation in offspring of mothers who used licit (eg,
alcohol and tobacco) and illicit (eg, cocaine, metham-
Table. Observed Effects of Substance Abuse in the Newborn
Nicotine Alcohol Marijuana Cocaine Opioids PCP
Prematurity Yes Yes No
Low birthweight Yes Yes No
Neurobehavioral symptoms Yes Yes Yes
NAS Yes Yes No
Congenital malformations Yes/No Yes No?
Yes/No⫽both have been reported, ?⫽controversial or unclear findings, NAS⫽neonatal abstinence syndrome, PCP⫽phencyclidine
8 Pediatrics in Review Vol.32 No.1 January 2011
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phetamine, marijuana) drugs during pregnancy. Al-
though these findings are limited by the complexities of
separating the specific effects of each drug from other
confounding variables and the impracticality of using
such methods in the clinical setting, particularly during
the neonatal period, these methods may advance the
understanding of the underlying structures affected by
prenatal drug exposure to improve diagnosis and provi-
sion of therapeutic resources for affected infants, chil-
dren, and young adults.
Postnatal Problems due to Environmental or
Caregiving Deficiencies
Infant neurodevelopmental or behavioral problems can
be created by an overstimulating or insensitive environ-
ment or a caregiver’s style of interaction. When caregiv-
ers are not trained or able to interpret and respond to
physiologic or behavioral signs of dysregulation created
by external or internal stimuli, the caregiver’s actions or
interactive style can impair the recovery of the infant and
perpetuate dysregulated responses. This impairment, in
turn, can affect basic functions such as feeding, sleeping,
and interactive patterns that may contribute to altered
developmental trajectories. Neurodevelopmental diffi-
culties also can be caused or exacerbated by maternal
psychopathology or postnatal drug use, which may pro-
vide the infant with further postnatal passive or active
exposure to substances (eg, secondhand smoke or sub-
stances via human milk).
The Effects of Individual Substances on the
Neonate
Although it is difficult to ascribe any particular symptom
to any particular substance, because most overlap (Table)
and are nonspecific, full appreciation of the complexities
and clinical status of the exposed neonate requires con-
sideration of the effects of individual substances.
Methamphetamine Benzodiazepines
Yes Yes/No No Yes/No Yes
Yes Yes/No No Yes Yes
Yes Yes Yes Yes Yes
No? Yes Yes/No Yes? Yes
Yes/No No Yes Yes? Yes/No

Nicotine
Nicotine has been described as a neuroteratogen that
compromises critical neural pathways in the developing
brain. (22) Nicotine crosses the placenta, and the fetus is
exposed to concentrations that are 15% higher than in
the maternal bloodstream. Cigarette use also involves
exposure to substances that interfere with oxygen deliv-
ery and use, such as carbon monoxide and hydrogen
cyanide; these additional factors may participate in the
overall effects of smoking. Nicotine exposure during
gestation includes effects that have been found to be
related to secondhand smoke as well as nicotine replace-
ment therapies. (23) Neurobehavioral symptoms de-
scribed in exposed neonates include impairment of
arousal, irritability and hyperexcitability, hypertonicity,
and tremors. (24)(25)
Reports of sporadic congenital anomalies associated
with nicotine consist principally of higher incidences of
orofacial clefts, neural tube defects, and cryptorchidism,
although large-scale studies have found no significant
increase in gross malformations. (26) Prenatally
nicotine-exposed infants are at increased risk for preterm
birth and sudden infant death syndrome (27) as well as
fetal growth restriction, which has been linked to subse-
quent development of both neonatal and adult disease.
(28) Dose-dependent LBW has been associated with
maternal smoking. (29) Heavily nicotine-exposed infants
have been described as having withdrawal syndromes.
(30)(31)
Alcohol
Alcohol exposure during gestation is a significant risk
factor for poor infant outcomes. Alcohol passes through
the placenta, and the amniotic fluid is a reservoir for
ethanol, which increases availability of the drug to the
fetus. Maternal alcohol use can produce preterm birth,
LBW, and fetal alcohol spectrum disorder. Fetal alcohol
syndrome is characterized by specific facial features,
growth deficiency, central nervous system abnormalities,
behavioral abnormalities, and intellectual disability. (32)
A neonatal alcohol withdrawal phenomenon has been
described in children born to alcoholic mothers and
includes jitteriness, irritability, seizures, opisthotonus,
abdominal distention, (33)(34) excessive mouthing
movements, and reflex abnormalities. (35)
Marijuana
Delta9-tetrahydrocannabinol is the major psychoactive
ingredient in cannabis. Cannabis constituents cross the
placenta and are stored in amniotic fluid. Prolonged fetal
exposure can result from regular marijuana use. Minor
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fetus and newborn infants of drug-dependent mothers
physical anomalies (ocular hypertelorism and epican-
thus) have been reported in heavy users of cannabis, but
there is a lack of a definitive relationship between physical
anomalies and prenatal cannabis exposure in general.
Neurobehavioral effects of in utero cannabis exposure
range from mild deficits in visual functioning, height-
ened tremors, startling, jitteriness, hypotonia, and leth-
argy (36) to difficulties with arousal, regulation, and
excitability. (37) Although shorter gestational periods
have been reported among heavy marijuana users, (38)
neither LBW nor preterm birth have generally been
reported.
Cocaine
Cocaine-exposed infants are at risk for preterm birth and
LBW. Neurobehavioral signs at birth include jitteriness
and tremors, high-pitched cry, irritability, excessive suck,
hyperalertness, autonomic instability, (39) hypertonic-
ity, and excitability. (40) Congenital anomalies have
been reported previously in cocaine-exposed infants, but
larger and more recent studies have disputed those find-
ings. (39) A dose-response relationship for a negative
association with motor and state regulation capabilities
has been reported. (41)
Opioids
Opioids are narcotic, analgesic substances that have
morphine-like effects and include narcotic pain killers,
heroin, and methadone, a synthetic opiate with similar
pharmacologic properties to morphine that is used to
treat individuals who have opiate addictions. Most stud-
ies report increased preterm birth and LBW related to
opioid use, although few have controlled for associated
risk factors. Those that have done so generally report no
independent relationships between opiate use and
growth parameters. The most notable opioid effect on
the neonate is NAS, which may include tonal problems,
tachypnea, feeding and sleeping problems, fever, and
seizures among its signs. The tool used most commonly
to evaluate opioid-related NAS is the Finnegan scale.
(42) Evaluation of the opioid-exposed newborn using
this scale is recommended every 3 to 4 hours during
hospitalization, and surveillance should last for several
days after birth. The scale contains 31 weighted (depend-
ing on symptom and severity) items. Opioid agonist
pharmacotherapy is recommended for infants who have
Finnegan scores above a threshold level.
Phencyclidine
Infants exposed in utero to phencyclidine (PCP) have
been reported to display dysmorphologic features that
Pediatrics in Review Vol.32 No.1 January 2011 9
fetus and newborn infants of drug-dependent mothers
consist of microcephaly (43) and alterations in facial
features. (44) Described neurobehavioral symptoms af-
ter delivery consist of decreased attention, high-pitched
cry, poor visual tracking, coarse flapping tremors, leth-
argy, nystagmus/roving eye movements, poor feeding,
and altered newborn reflexes. (43)(45) Although infants
exposed to PCP generally are smaller and have lower
gestational ages than nonexposed infants, PCP exposure
is not associated with LBW or preterm birth. (46) An
NAS has been described (47) and disputed (48) for
PCP-exposed infants.
Methamphetamines
Despite concerns about infants exposed to this drug as
rates of usage in the United States increase, there is a
general dearth of reports involving in utero exposure.
Isolated cases of cardiac defects, cleft lip, and biliary
atresia have been reported. (49) Use during pregnancy
also has been associated with increased rates of fetal
distress and growth restriction, (50) resulting in small-
for-gestational age size at birth. (50)(51)(52) Metham-
phetamine exposure has been associated with preterm
birth, (50) but this linkage has been disputed more
recently. (52) Neurobehavioral patterns of decreased
arousal, increased stress, and poor quality of movement
(53) have been described, as has a withdrawal syndrome
in a few infants (4%). (54)
Benzodiazepines
One of the most commonly prescribed class of drugs
during pregnancy, despite the absence of complete
knowledge of their potential adverse effects, benzodiaz-
epines also are commonly abused licit drugs, and expo-
sure often is unrecognized due to inconsistent screening
policies. Benzodiazepines cross the placenta and accu-
mulate in the fetus to varying degrees, depending on the
specific drug and its properties. Withdrawal phenomena
have been reported in exposed infants. Signs include
hypoventilation, irritability, hypertonicity, and “floppy
infant syndrome,” particularly after use in late gestation.
(55)(56) These symptoms can appear within a few days
to 3 weeks after birth and can last for several months.
(57) There has been variable reporting on the relative risk
of congenital anomalies in this group of infants. An
increased risk of orofacial clefts was described in early
case-control studies and refuted in later cohort studies.
(58) Benzodiazepines appear to increase the risk of pre-
term birth and LBW. (59)
10 Pediatrics in Review Vol.32 No.1 January 2011
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Management
The drug-dependent mother and her infant are a com-
plex and highly vulnerable dyad that present a challenge
to any clinician. Due to the often multiple negative
experiences and maladaptive behaviors of the mother and
the frequently confusing constellation of signs and symp-
toms of abstinence and neurobehavioral dysregulation of
the infant, the dyad commonly is “out of sync” or “not
bonding.” Thus, they require a caring and well-trained
clinician to ensure a successful neonatal adaptation and
prevent the initiation of altered developmental and inter-
actional trajectories. Provision of optimal care for the pair
involves appropriate identification of the maternal sub-
stance abuse and other difficulties, careful and frequent
observation of the infant, and delineation of individual-
ized care plans for the dyad. Lack of acknowledgment of
the maternal addiction and its implications for the new-
born, usually stemming from lack of knowledge of ad-
dictions in general or lack of available resources postdis-
charge, can affect the prognosis for the dyad negatively.
All substance-exposed infants should receive support-
ive care and evaluation for signs and symptoms of evolv-
ing NAS and other regulatory problems. Standard sup-
portive care for the exposed infant should include a quiet
environment and gentle handling, swaddling, small and
frequent feedings, and pacifier use. The individual func-
tioning of each infant should be assessed thoroughly,
evaluating the ability to regulate sleep/awake states;
autonomic, sensory, motor, and interactive capacities;
and displayed behaviors. Important behaviors include
responses and sensitivities to auditory, tactile, and visual
stimuli; motor capabilities; tremors and jitteriness; and
style of communication, including eye contact, ability to
calm with intervention, ability to signal needs, and signs
of stress or abstinence. The infant’s capacities and diffi-
culties in each area should be addressed in individual care
plans as well as in maternal-infant care.
For infants experiencing significant NAS symptom-
atology, pharmacotherapy is warranted. Medications
used to treat the neurobehavioral symptoms related to
prenatal exposure to psychoactive drugs vary widely
among institutions. The most commonly used first-line
medications for opioid withdrawal are opioids (oral mor-
phine solution, tincture of opium) and methadone. (60)
A major review advocates opioids as the drug of choice
for neonatal opioid withdrawal. (61) For polydrug-
exposed infants, commonly employed medications are
opioids, phenobarbital, and methadone. (60) Weight-
based versus symptom-based treatment strategies can be
employed, and examples of both have been described.
(62)(63) Little empirically based evidence supports the

use of one medication or one treatment strategy over the
other, reflecting a paucity of randomized studies in this
area. At the time of this writing, newer agents for the
treatment of NAS, such as clonidine (64)(65) and bu-
prenorphine, (66) are being explored and may have a role
in the management of NAS.
By examining the newborn in the presence of the
mother and evaluating her perceptions and responses to
newborn signaling, the clinician can assess and demon-
strate the infant’s physiologic competencies and weak-
nesses while simultaneously evaluating maternal respon-
siveness and comprehension. Mothers and other
caregivers can be taught to provide appropriate environ-
ments (eg, not over- or understimulating) for the infant.
Infants who have significant NAS require medication and
prolonged hospitalization. In situations where mothers
are able to stay with their infants or visit regularly, this
period can be used as a time of prolonged evaluation of
the dyad and an opportunity to provide ongoing parent-
ing support and instruction. Teaching of simple con-
cepts, such as the importance of infant sleep, cueing, and
schedules, can provide a basis for improved parenting
skills in the mother as the child grows. Maternal satisfac-
tion with the diminution of NAS symptoms associated
with her handling can allay some guilt and depression.
Interventions for the drug-dependent mother and ex-
posed infant have been described (67) and are useful in
the care of the dyad for providing a basis for improved
parenting and infant/child development.
Drug-dependent women also require thoughtful and
careful evaluation because their needs can be as complex
as their difficulties. Evaluation for mood or other psychi-
atric disorders, emotional availability to the newborn,
violence exposure, community support systems, and his-
tory of previous pregnancy outcomes is necessary. Addic-
tion is a chronic disorder and must be addressed as such;
all drug-using women should be referred to appropriate
substance abuse treatment that will accept the infant. For
women in treatment, conference (after consent) with
treatment counselors to determine ongoing care plans is
important. Mood disorders or other psychiatric comor-
bidity should be evaluated and addressed in ongoing
postpartum care, particularly because women who have
depression are at increased risk for postpartum depres-
sion. Postpartum guilt and anxiety, particularly for
women who have infants experiencing NAS, is common,
can interfere with dyadic communication, and must be
gently addressed and monitored. Prejudicial or punitive
attitudes, negative stereotyping, and conflicting advice
have no place in the care of postpartum drug-dependent
women because such attitudes only drive them away
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fetus and newborn infants of drug-dependent mothers
Summary
• Nearly any psychoactive licit or illicit substance
consumed by the pregnant woman is likely to result
in enhanced risk of medical, developmental, and
emotional/behavioral disability in the developing
infant/child. These risks can be compounded by
biologic and psychosocial factors associated with
maternal addiction.
• Drug-dependent women do not use substances in
isolation and they cannot escape the myriad
complications of their internal and external
environments and the attendant risks to the
developing fetus and infant.
• The developmental trajectories of fetuses exposed to
psychoactive substances may be altered by many
factors, including disruption to neuroendocrine and
neurotransmitter system development and fetal
programming via stress hormone changes, resulting
in altered set points for physiologic, metabolic, and
behavioral outcomes. (69)
• Epigenetic models of developmental theory
examining the intersecting influences of genes,
physiology, and behavior with the physical, cultural,
and social environment as well as other mechanisms
have been implicated in the alteration of
developmental trajectories. (5)
• These effects occur through the programming of cell
fate and differentiation, in defining ultimate activity
levels of specific functional systems, and in
mediating environmental modulation of genetically
based developmental programs. In this context,
maternal substance use during gestation may
directly or indirectly derail normal development by
adversely modifying fetal/neonatal gene expression,
resulting in disruption in brain development.
• The consequences of drug exposure can be seen at
birth but sometimes do not emerge until later in life
and may be produced at doses that are relatively
harmless for adults.
• The role for all clinicians in the comprehensive care
of the substance-exposed neonate should include
thorough, comprehensive, and individual evaluation
of the infant, the mother, and their interaction. Only
through a willingness to understand and treat the
mother who has drug addiction and the exposed
infant as a pair, which may involve the extension of
the boundaries of pediatric care, can we provide
optimal care for substance-exposed infants, perhaps
the most poorly understood, marginalized, and
vulnerable segment of the pediatric population.
from treatment and other beneficial encounters at a time
when treatment is most needed from those professionals
most poised to help. Similarly, caregivers of the infant
must refrain from stereotypical or prejudicial attitudes
toward the mother. Referral to child protective or other
Pediatrics in Review Vol.32 No.1 January 2011 11
fetus and newborn infants of drug-dependent mothers

monitoring services, when appropriate, may be neces-
sary, particularly for women who have positive urine
toxicology screening results that indicate recent drug use
at delivery or substance-abusing women not in drug
treatment. However, these services are not warranted for
most abstinent and stable methadone-maintained
women enrolled in comprehensive substance abuse treat-
ment.
Women receiving methadone maintenance may have
difficulties with oversedation in the postpartum period
due to changing medication needs and pain control and
should be assessed for such reactions by pediatric clini-
cians who are likely to observe them. Communication
with obstetric and mental health professionals is impor-
tant in these cases. Breastfeeding is not contraindicated
for women receiving methadone maintenance therapy
but may not be advised for women relapsing to drug use
close to term, women not in substance abuse treatment,
or women experiencing difficulties in maintaining sobri-
ety in an outpatient setting. Each woman desiring lacta-
tion must be evaluated individually. (68)
To view references for this article, visit http://
pedsinreview.aappublications.org and click on this ar-
ticle title.

PIR Quiz
Quiz also available online at http://pedsinreview.aappublications.org.

1. You are seeing a family who is considering adopting a newborn boy who has been exposed to drugs in
utero. They ask for information about how drug exposure affects medical and behavioral issues as children
mature. Your best response is that:
A. Drug exposure effects manifest through physiologic rather than genetic mechanisms.
B. Drug exposure in the third trimester is the most detrimental to long-term outcome.
C. Effects of drug exposure in utero generally are the product of polydrug exposures and factors related to
substance use.
D. There is a common mechanism by which drugs exert their intrauterine effects.
E. There is no difference in effects of drug exposure based on the sex of the fetus.

2. You are seeing a newborn in the nursery whose mother took prescribed benzodiazepines during pregnancy.
One likely manifestation of benzodiazepine exposure in this baby is:
A. Cardiac defects.
B. Elevated bilirubin concentrations.
C. Hyperventilation.
D. Large-for-gestational age birthweight.
E. Withdrawal symptoms lasting for several months.

3. An infant was born at term with birthweight 2.1 kg. The most likely intrauterine drug exposure associated
with this infant’s birthweight is:
A. Diazepam.
B. Fentanyl.
C. Marijuana.
D. Oxycodone.
E. Phencyclidine.

12 Pediatrics in Review Vol.32 No.1 January 2011

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 fetus and newborn infants of drug-dependent mothers

4. An infant in the newborn nursery has tremors, poor feeding, and increased tone and is not easily consoled.
An associated symptom of neonatal abstinence syndrome that might manifest in this infant is:
A. Cardiac arrest.
B. Hyperbilirubinemia.
C. Hypothermia.
D. Hypotonia.
E. Seizure.

5. A 3-year-old boy has been asked to leave several child care settings because of his extreme hyperactivity
and inattention. His birth weight was 2.3 kg. His growth parameters show height at the 20th percentile,
weight at the 10th percentile, and head circumference less than the 3rd percentile. He is just beginning to
speak a few words, and his mother relates that his developmental skills are similar to the skills of his 18-
month-old brother. Magnetic resonance imaging of his brain shows absent corpus callosum. The
intrauterine drug exposure most likely associated with these findings is:
A. Alcohol.
B. Benzodiazepines.
C. Cocaine.
D. Marijuana.
E. Methamphetamines.

Pediatrics in Review Vol.32 No.1 January 2011 13

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 Infants of Drug-dependent Mothers
Lauren M. Jansson and Martha L. Velez
Pediatr. Rev. 2011;32;5-13
DOI: 10.1542/pir.32-1-5

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 Inflammatory Bowel Disease
Sarah R. Glick and Ryan S. Carvalho
Pediatr. Rev. 2011;32;14-25
DOI: 10.1542/pir.32-1-14

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Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
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Article gastrointestinal

Inflammatory Bowel Disease

Sarah R. Glick, MD,*
Objectives After completing this article, readers should be able to:
Ryan S. Carvalho, MD†
1. Develop a differential diagnosis and plan an initial evaluation for the child or
adolescent who presents with bloody diarrhea and abdominal pain.
Author Disclosure 2. Recognize that growth failure and pubertal delay may be an initial presentation of
Drs Glick and Crohn disease.
Carvalho have 3. List the extraintestinal manifestations of inflammatory bowel disease (IBD).
disclosed no financial 4. Discuss the genetic advances in understanding the pathogenesis of IBD.
relationships relevant 5. Describe the current treatments for IBD and the common adverse effects.
to this article. This
commentary does
contain a discussion
Introduction
IBD is a complex, multifactorial disease characterized by chronic inflammation in the
of an unapproved/
intestinal tract of a genetically predisposed host. The spectrum of IBD in children primarily
investigative use of a includes ulcerative colitis (UC) and Crohn disease (CD). With pediatric patients now
commercial accounting for 20% to 25% of newly diagnosed cases, it is becoming increasingly important
product/device. for pediatricians to recognize the symptoms of IBD. (1) In this review, we discuss the
epidemiology, clinical presentation, diagnosis, and complications of IBD, with specific
emphasis on growth failure and pubertal delay because these are unique manifestations in
children. We also describe newer, less invasive diagnostic techniques and current trends in
management and advances in the pharmacologic treatment of affected children.

Epidemiology and Demographics

The epidemiologic patterns of pediatric IBD have evolved over the past few decades, with
significant increases in both incidence and prevalence. The current incidence is 5 to 11 per
100,000 children, with a recent statewide survey from Wisconsin reporting the annual
rate of diagnosis as 4.56 per 100,000 for CD and 2.14 per 100,000 for UC. (2) Canadian
studies have reported an acceleration in new diagnoses from
9.5 per 100,000 in 1994 to 11.4 per 100,000 in 2005. The
most significant increases were among the younger age
Abbreviations groups, with the incidence rising 5% annually in children
5-ASA: 5-aminosalicylates younger than 4 years of age and 7.6% annually in children
CD: Crohn disease ages 5 to 9 years. (3)
EN: erythema nodosum The mean age at diagnosis of pediatric IBD in the United
ESR: erythrocyte sedimentation rate States is 12.5 years, (2) with 20% of children diagnosed
FC: calprotectin before the age of 10 years and fewer than 5% diagnosed
FL: lactoferrin before age 5 years. Males seem overrepresented in new cases
IBD: inflammatory bowel disease of pediatric CD, although an equal number of males and
IGF-1: insulin-like growth factor-1 females receive a UC diagnosis. (4)
MRI: magnetic resonance imaging Many risk factors have been associated with IBD, includ-
PG: pyoderma gangrenosum ing family history, ethnicity, and tobacco use. Up to 25% of
PSC: primary sclerosing cholangitis children who develop IBD have a positive family history of
SNP: single-nucleotide polymorphism IBD. (5) Children who have a first-degree relative affected
TNF: tumor necrosis factor by either UC or CD have a 10 to 13 times higher risk for
UC: ulcerative colitis developing IBD. (5) Monozygotic twin concordance is ap-
VCE: video capsule endoscopy proximately 50% for CD and nearly 20% for UC. (6)
In the United States, population-based studies histori-

*Wright State University Boonshoft School of Medicine, Children’s Medical Center of Dayton, Dayton OH.
†
The Ohio State University College of Medicine, Nationwide Children’s Hospital, Columbus, OH.

14 Pediatrics in Review Vol.32 No.1 January 2011

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cally have shown a higher prevalence of IBD in patients
of European or African descent than in patients of His-
panic or Asian descent. (7) Notably, Jewish ancestry
(Ashkenazi more than Sephardic) is a significant risk
factor for the development of IBD. However, more
recent pediatric-specific population studies detected no
differences in IBD frequency between ethnic groups. (2)
The prevalence of IBD is highest in the industrialized
world, including North America, northern Europe, and
the United Kingdom. However, with progressive mod-
ernization, the prevalence is now increasing in the devel-
oping world. Tobacco use is linked closely with an in-
creased risk of IBD. In smokers, the probability of
developing CD is twice as high as for nonsmokers. (7)
Passive exposure to smoking may be influential as well. (8)
Genetics
A genetic predisposition to IBD has been hypothesized
for decades because of the strong familial pattern of
disease. Linkage analyses and genome-wide association
studies have identified numerous IBD candidate genes.
Many share a connection to the immune, inflammatory,
or bacterial recognition pathways, which are fundamen-
tal mechanisms in the pathogenesis of IBD.
In 2001, the NOD2/CARD15 gene, located on chro-
mosome 16q in the IBD1 susceptibility locus, was asso-
ciated with CD. Three high-risk single nucleotide poly-
morphisms (SNPs) are suggested to alter recognition
of bacterial peptidoglycans in monocytes, macrophages,
gut epithelial cells, and Paneth cells. NOD2 mutations
can impair the degradation of gut bacteria, leading to an
accumulation of bacterial antigens and predisposing to
mucosal T-cell activation.
Nearly 40% of white patients who have CD carry one
of these NOD2 SNPs compared with 20% of controls. (9)
These allelic variants also have phenotypic implications
for those who have CD, with earlier age of onset, stric-
turing disease, and ileal involvement occurring more
frequently.
The IBD5 locus on chromosome 5q31 is associated
with a higher susceptibility toward CD. Patients who
have CD and IBD5 locus polymorphisms may have more
perianal disease, colonic disease, and importantly in pe-
diatric patients, decreased weight and height at diagno-
sis. (10) There also has been a weak association of the
IBD5 locus with UC.
The IBD3 locus on chromosome 6 contains the
major histocompatibility complex genes, which also may
contribute toward IBD predisposition. The DRB1*1502
gene has been associated with UC, and the DRB1*07
gene has been associated with CD, particularly in patients
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gastrointestinal inflammatory bowel disease
who have ileal disease without a high-risk NOD2 poly-
morphism. The DRB1*0103 allele has been linked to
UC and colonic CD. Patients who have UC and this
variant seem to have a greater predisposition toward
more extensive and severe colonic involvement. There
also seems to be an association between IBD3 locus
variants and the extraintestinal manifestations of uveitis
and peripheral arthropathy. (9)
The field of IBD genetics is continuously expanding,
but genetic testing is currently limited to research. In the
future, children who have IBD may undergo genetic
testing to quantify disease risk in family members or to
predict phenotypic expression.
Causes
The precise causes of IBD remain unknown, but the
current understanding involves a genetic predisposition
combined with a dysregulation between the immune
system and the antigenic environment in the gastrointes-
tinal tract, leading to inflammation and damage. (11)
The major pathogenic mechanism underlying CD is an
excessive Th1 immune response, whereby CD4⫹ T cells
become upregulated and markedly resistant to apoptosis.
(12) An excessive Th2 immune response has been impli-
cated in patients who have UC. (13)
Defective gastrointestinal mucosal integrity may lead
to enhanced uptake of luminal bacteria, causing the
normally protective mucosal immune system to be over-
whelmed. This derangement may be a result of toler-
ance to luminal antigens, a hyperreactive cell-mediated
immune system, or specific gene mutations (such as
NOD2).
It has been postulated that the unchecked intestinal
immune response to ubiquitous bacterial and enteric
antigens could lead to the pathologic gross tissue injury
characteristic of IBD. Activated immune cells secrete
a variety of soluble mediators of inflammation, includ-
ing cytokines (tumor necrosis factor [TNF]-alpha,
interferon-gamma, transforming growth factor-beta, and
interleukin-2, -5, -6, -12, and -18), arachidonic acid
metabolites, reactive oxygen intermediates, streptolysins,
and growth factors. (12) Activated neutrophils and mac-
rophages may also release metalloproteinases, which di-
gest collagen in the lamina propria and basement mem-
brane and are markedly elevated in the fistulous tracts of
those who have CD.
The most persuasive argument for a pathogenic role
of enteric flora comes from murine studies of IBD.
(14)(15) The gut inflammation seen in mouse models of
IBD depends on the presence of bacterial flora. No single
infectious agent has been reproducibly associated with
Pediatrics in Review Vol.32 No.1 January 2011 15
gastrointestinal inflammatory bowel disease
IBD, but several bacterial species, including Salmonella,
Helicobacter, toxigenic Escherichia coli, Listeria, and
Campylobacter, have been suggested to play a role in
pathogenesis. Mycobacterium paratuberculosis has been
strongly suspected in IBD development. (16) Viral the-
ories have been proposed, including the potential for
measles virus to cause a granulomatous vasculitis. (17)
Another antigenic hypothesis in the development of IBD
includes the phenomenon of dysbiosis, which is an al-
tered balance between protective bacteria, such as Lacto-
bacillus and Bifidobacterium, and aggressive organisms,
including Bacteroides, Enterococcus, and invasive E coli.
(18)
Clinical Presentation
UC and CD can have varied yet overlapping presenta-
tions. The cardinal symptoms of UC are diarrhea, rectal
bleeding, and abdominal pain. Most children present
with an insidious history of diarrhea without systemic
signs of fever or weight loss. One third present with
moderate symptoms, including hematochezia, abdomi-
nal cramping associated with fecal urgency, malaise, low-
grade or intermittent fevers, anorexia with weight loss,
mild anemia, and hypoalbuminemia. Only 10% of pa-
tients present with severe colitis, characterized by five or
more bloody stools per day; more profound anemia and
hypoalbuminemia; fever; tachycardia; and a diffusely ten-
der or distended abdomen. (19)(20) Children who have
UC may develop symptoms of reflux or dyspepsia asso-
ciated with inflammation of the upper gastrointestinal
tract. (21)
The classic presentation of ab-
dominal pain, diarrhea, and weight Table 1. Extraintestinal Manifestations of
loss occurs in most children who
have CD. Abdominal pain typically Inflammatory Bowel Disease
is crampy and can be diffuse or lo- System
calized to the right lower quadrant.
(22) Stools can appear nonbloody Skeletal
or melanotic or can contain frank
red blood. Chronic perianal disease, Cutaneous
including tags, fissures, fistulae, and
abscesses, may be present. (23) Re-
current aphthous-stomatitis can also Ocular
Hepatic
suggest the diagnosis. A decrease in
height velocity may precede overt ab- Endocrine
dominal symptoms by 5 years, and Hematologic
growth failure may be the only sign of
illness in 5% of children who receive Renal
Cardiac
the diagnosis of CD. (24) Poor appe-
Pancreatic
tite, fevers, and iron deficiency ane- Neurologic
mia are also commonly noted at ini-
16 Pediatrics in Review Vol.32 No.1 January 2011
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tial presentation in children who have CD. Decreased bone
density is seen in 25% of newly diagnosed children, even
before initiation of corticosteroid therapy. (25)
Extraintestinal Manifestations
One third of patients who have IBD develop extra-
intestinal manifestations, which may predate the onset
of intestinal symptoms (Table 1). (26) Arthralgias and
arthritis are common extraintestinal manifestations of
CD. (26) Arthropathy also occurs in 20% to 25% of
patients who have UC and may be the presenting symp-
tom. Large joints, such as the knee, ankle, hip, and wrist,
typically are involved. A polyarticular arthropathy in-
volves more than five joints; a pauciarticular form in-
volves fewer joints and its disease course correlates with
intestinal disease activity. (27) Ankylosing spondylitis
associated with IBD runs a course independent of
bowel disease activity and may progress to permanent
deformity.
Erythema nodosum (EN) and pyoderma gangreno-
sum (PG), although rare, are the most frequent cutane-
ous manifestations in IBD. EN occurs more commonly
with CD; is characterized by tender, warm, red nodules
or plaques; and typically is localized to the extensor
surfaces of the lower extremities. PG occurs in fewer than
5% of UC patients and often is associated with more
extensive colonic involvement. The lesions may appear
initially as discrete pustules with surrounding erythema
and subsequently extend peripherally, developing into an
ulceration that has a well-defined border and a deep
erythematous-to-violaceous color. PG tends to develop
Extraintestinal manifestations
Arthritis, arthralgia, ankylosing spondylitis, digital clubbing
(hypertrophic osteoarthropathy), osteopenia, osteoporosis,
aseptic necrosis
Erythema nodosum, pyoderma gangrenosum, aphthous ulcers,
vesiculopustular eruption, necrotizing vasculitis, metastatic
Crohn disease
Uveitis, episcleritis, corneal ulceration, retinal vascular disease
Primary sclerosing cholangitis, bile duct carcinoma, autoimmune
chronic active hepatitis, fatty liver disease, cholelithiasis
Growth failure, pubertal delay
Autoimmune hemolytic anemia, thrombocytopenic purpura,
thrombocytosis, thrombophlebitis, thromboembolism, arteritis
Nephrolithiasis (classically oxalate stones)
Pericarditis, myocarditis, heart block
Acute pancreatitis (Crohn disease > ulcerative colitis)
Peripheral neuropathy, myelopathy, myasthenia gravis

around sites of trauma and surgical scars. Although the
emergence of EN usually follows intestinal disease activ-
ity, PG runs an independent course, often necessitating
potent therapy.
Transient transaminase elevation occurs in some chil-
dren who have IBD and may be related to medications
or disease activity. Persistent elevations suggest the pres-
ence of primary sclerosing cholangitis (PSC) or auto-
immune hepatitis. PSC is more commonly associated
with UC and can predate the onset of intestinal symp-
toms in 50% of patients. (28) Typical symptoms in-
clude chronic fatigue, anorexia, pruritus, and jaundice,
although children may be asymptomatic. Elevated gamma-
glutamyltranspeptidase and alkaline phosphatase values
along with results of cholangiography and liver biopsy
help confirm the diagnosis. (29)
Nutritional Considerations
Growth failure occurs in 15% to 40% of children who
have IBD and is more frequent in CD than UC. The
Z-score (or standard deviation score) is used as an objec-
tive measurement of growth. The mean height Z-score
at diagnosis of pediatric CD is ⫺0.54, and a delay in
diagnosis or presence of jejunal disease is negatively
correlated with the Z-score. (4) Poor weight gain also
may precede a diagnosis of IBD. Mean weight Z-score at
diagnosis of pediatric CD is ⫺1.06, with almost 30%
of patients having weight Z-scores below the 3rd per-
centile. In comparison, mean weight Z-score at diagnosis
of UC is ⫺0.32, with only 9% of patients falling below
the 3rd percentile for age. (4)
The cause of growth failure in IBD is multifactorial.
Patients often experience abdominal pain and diarrhea
related to eating, leading to food avoidance behaviors
and a decrease in total energy intake. Elevated concen-
trations of proinflammatory cytokines contribute to an-
orexia and can cause growth hormone resistance, with
inhibition of insulin-like growth factor-1 (IGF-1) pro-
duction. (30) In CD, active inflammation in the small
intestine can decrease the absorptive surface area, result-
ing in a protein-losing enteropathy. Fat malabsorption
contributes to the general energy-deficient state and may
cause deficiencies in fat-soluble vitamins. Disease com-
plications such as the presence of internal fistulae, surgi-
cal bowel resections, or diverting ostomies can decrease
nutrient absorption further.
Differential Diagnosis
The differential diagnosis for a child or adolescent pre-
senting with abdominal pain and bloody diarrhea is
broad. Infectious enterocolitis, pseudomembranous
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gastrointestinal inflammatory bowel disease
colitis, lymphocytic colitis, eosinophilic enterocolitis,
Henoch-Schönlein purpura, and hemolytic-uremic syn-
drome should be considered in addition to IBD. Intesti-
nal malignancies such as non-Hodgkin lymphoma also
should be considered. The periodic fevers syndromes,
including TRAPS (TNF receptor-associated periodic
syndrome) and PFAPA (periodic fever, aphthous stoma-
titis, pharyngitis, and cervical adenitis), are rare but have
some clinical overlap with IBD. Rheumatologic disor-
ders, such as juvenile idiopathic arthritis, ankylosing
spondylitis, and systemic lupus erythematosus, share
many characteristics with pediatric IBD, specifically,
weight loss, malaise, recurrent fevers, and joint involve-
ment. Finally, intestinal tuberculosis and CD have similar
clinical, radiographic, and endoscopic features and can
be remarkably hard to differentiate. Intestinal tuberculo-
sis typically involves the ileocolonic region, and the ul-
cerative form is most common. A patient who has risk
factors for tuberculosis should have a tuberculin skin test
placed.
Diagnosis
A new diagnosis of IBD often is suggested by the clinical
history and findings on physical examination (Fig. 1).
The history should focus on the nature and duration of
symptoms; location and quality of abdominal symptoms;
frequency and consistency of bowel movements; pres-
ence of blood in stools; urgency, tenesmus, and night-
time awakening for bowel movements; and perianal,
systemic (weight loss, fevers, fatigue), and extraintestinal
symptoms (aphthous ulcers, skin lesions, joint pains, eye
symptoms). A family history of IBD is of critical impor-
tance.
The physical examination should include measure-
ments of height and weight as well as Sexual Maturity
Rating staging. A complete evaluation includes examin-
ing the mouth for aphthous lesions and performing a
thorough abdominal examination. Physical findings may
include abdominal tenderness, right lower quadrant mass
or fullness, pallor, and digital clubbing. A benign abdom-
inal examination does not exclude the diagnosis of IBD.
A rectal examination is mandatory, and the perianal area
must be checked for skin tags, fistulae, and fissures.
Nutritional assessment should include measurements
of growth velocity, height and weight Z-scores, and a
comparison of absolute height with predicted mid-
parental height. A bone age radiograph can be obtained
if there is concern for significant growth delay. A dietary
history should be obtained, with calculation of protein,
carbohydrate, fat, vitamin, and mineral intake and com-
parison to recommended daily values. Serum concentra-
Pediatrics in Review Vol.32 No.1 January 2011 17
gastrointestinal inflammatory bowel disease
Figure 1. Evaluation of a patient suspected of having inflam-
matory bowel disease (IBD). ESRⴝerythrocyte sedimentation
rate, UGIⴝupper gastrointestinal, VCEⴝvideo capsule
endoscopy
tions of total protein, albumin, vitamin D, and iron
should be measured. Depending on disease location,
vitamin B12, folic acid, and micronutrients such as zinc
also should be assessed.
Measurements of hemoglobin, platelet count, eryth-
rocyte sedimentation rate (ESR), and albumin classically
show abnormalities in children who have new-onset
IBD. Anemia is present in approximately 70% of patients,
and ESR is elevated in nearly 75% of children who have
moderate-to-severe disease. Only 4% of children who
have moderate or severe IBD have normal test results at
the time of diagnosis compared with 21% of patients who
have mild CD and about 50% of those who have mild
UC. (31) Thus, normal values in these domains should
not delay further diagnostic evaluation if a high degree of
suspicion for IBD exists.
An infectious cause should be excluded before diag-
nosing IBD. Screening stool studies should include:
culture for Salmonella, Shigella, E coli, Campylobacter,
and Yersinia; examination for Giardia and Cryptospo-
ridium; and an assay for Clostridium difficile cytotoxin.
If there is a history of immigration or overseas travel,
stool should be checked for Entamoeba histolytica.
Fecal markers, such as calprotectin (FC) and lacto-
ferrin (FL), are released by neutrophils that have mi-
grated into the intestinal wall and can be measured
quantitatively in stool samples. (32) These markers are
18 Pediatrics in Review Vol.32 No.1 January 2011
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used as noninvasive markers of gut inflammation. Al-
though conditions other than IBD, such as infections,
can cause inflammation and thus elevate these markers,
measurement of FC and FL has a role in differentiating
children who have IBD from those who have non-
inflammatory gastrointestinal conditions, such as irrita-
ble bowel syndrome. (33)
The use of IBD serologic panels for population
screening or as an isolated diagnostic tool is not recom-
mended. False-positive results can create unwarranted
anxiety and lead to excessive invasive testing. It should be
noted that nearly one third of patients who have a posi-
tive serologic panel do not have IBD. Serologic panels
are most useful in children who have indeterminate coli-
tis to differentiate CD from UC (Table 2). (34) Higher
serologic antibody titers and a greater number of positive
markers are associated with a more aggressive disease
course. (35)(36) Notably, anti-Saccharomyces cerevisiae-
positive CD patients are more likely to have perianal disease
and ileal stricturing disease requiring resection. (37)
Imaging studies play an important role in the diag-
nosis of IBD. With CD, a barium upper gastrointestinal
radiographic series may demonstrate stenosis, abnormal
separation of bowel loops, and fistula formation. Com-
puted tomography scan can assess for intestinal wall
thickening and is important in the assessment of urgent
complications of IBD, such as abscess formation and
fistulizing or stricturing disease. Magnetic resonance im-
aging (MRI) is beginning to play a larger role in children
who have IBD because there is no radiation exposure.
MRI has greater than 90% sensitivity and specificity for
detecting CD of the small intestine and has the potential
to distinguish colonic CD from UC because mucosal
and full-thickness bowel wall inflammation enhance dif-
ferently. (38)(39)
Endoscopy, including esophagogastroduodenoscopy
and colonoscopy with biopsy sampling, is the gold stan-
dard for diagnosing IBD. Inflammation of the upper
gastrointestinal tract can be seen in both UC and CD,
although the presence of noncaseating granulomas in
the stomach (versus nonspecific gastritis) is diagnostic
of CD.
Endoscopic features of UC include the characteristic
continuous inflammation beginning in the rectum and
extending a variable distance proximally into the large
intestine. A sharp demarcation may exist between normal
and diseased colon. The mucosal surface may be ery-
thematous and granular, and there can be a loss of the
normal vascular pattern with remarkable friability in areas
of endoscope contact (Fig. 2). There may be small ero-
sions, patches of exudates, and pseudopolyps. “Patchy”
 gastrointestinal inflammatory bowel disease

Table 2. Detection of Commercially Available Serologic Markers

Serologic Marker Crohn Disease Ulcerative Colitis Controls
ASCA (anti-Saccharomyces cerevisiae antibody) 40% to 56% 0% to 7% <5%
immunoglobulin A and G
ANCA (anti-neutrophil cytoplasmic antibody) 18% to 24% 60% to 80% <5%
histamine 1 protein, DNAase-specific
Anti Omp C (outer membrane protein of 25% 6% 3%
Escherichia coli )

colitis and relative rectal sparing can be consistent with
early disease or partially treated UC. Biopsies may reveal
crypt distortion with branching, shortening, or atrophy;
there may also be crypt abscesses. Inflammatory changes
are limited to the mucosal layer.
Endoscopic features of CD include the characteristic
skip lesions, in which areas of inflamed mucosa are in-
terspersed with normal-appearing gut. “Cobblestoning”
involves linear ulceration, with adjacent swelling giving
tissue a cobblestone pattern (Fig. 3). Aphthae, exudates,
and stricturing may be present anywhere from the mouth
to the anus, but the rectum typically is spared from gross
inflammation. The terminal ileum is classically abnormal
on gross inspection, and the ileocecal valve may be
stenotic. The characteristic finding on biopsy is noncase-
ating granulomas. Inflammation can extend through the
full thickness of the bowel wall.
Wireless video capsule endoscopy (VCE) is an excit-
ing modality that can detect small bowel lesions in areas
not accessible to traditional endoscopy. VCE is also

Figure 2. A. Normal colonic mucosa and vascularity. B. Colon Figure 3. A. Normal terminal ileum with lymphoid nodularity.
in a child who has ulcerative colitis, showing continuous B. Terminal ileum in a child who has Crohn disease, showing
inflammation, swelling, loss of vascular markings, and bleeding. inflammation, cobblestoning, exudates, and bleeding.

Pediatrics in Review Vol.32 No.1 January 2011 19

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gastrointestinal inflammatory bowel disease
helpful in identifying disease recurrence, evaluating anas-
tomotic sites, and detecting luminal complications such
as malignancy. The drawbacks of VCE are difficulty with
capsule ingestion in young children and risk of capsule
retention.
Treatment
Medical Management
Immense progress has been made in the medical man-
agement of pediatric IBD over the past decade. The
primary goals of therapy are induction and maintenance
of remission, prevention of disease complications (such
as fistula, stricture, abscess, and cancer), control of post-
operative disease recurrence, maintenance of normal
growth and development, and maximization of quality
of life.
Medications are selected based on the disease loca-
tion and severity, the potential for adverse effects, and
anticipated compliance. Current IBD medications in-
clude corticosteroids, 5-aminosalicylates (5-ASA), im-
munomodulators, biologic agents, antibiotics, and pro-
biotics (Fig. 4).
Moderate-to-severe symptoms initially are addressed
most commonly with oral or intravenous corticosteroids,
which inhibit the inflammatory cascade. The goal is to
use corticosteroids for as short a period as possible, then
change to nonsteroidal maintenance therapy. Budes-
onide, an oral corticosteroid, is frequently employed in
the treatment of mild-to-moderate CD because it is
released in the distal small bowel and proximal colon,
common sites of inflammation. Acute response to corti-
costeroids is excellent, with 80% of IBD patients show-
ing improvement, although corticosteroid dependency
occurs in up to 50% of UC patients and 30% of CD
patients. (40)(41)
For adult patients who have mild-to-moderate UC,
5-ASA medications (sulfasalazine, mesalamine, balsala-
zide) are effective in inducing and maintaining remission
in 90% of cases. (42) Experience in children suggests
similar response rates. The exact mechanism of action
remains unknown but may involve decreased leukotriene
production or scavenging of reactive oxygen species.
A new, once-daily 5-ASA medication, mesalamine
delayed-release tablets, has shown comparable efficacy
with the benefit of better compliance. However, the use
of 5-ASA medications in CD has become controversial
because a meta-analysis demonstrated no superiority to
placebo in maintaining remission. (43)
The use of immunomodulators in children who have
IBD has become the standard of care. Fifty percent of
newly diagnosed children who have UC and 75% of those
20 Pediatrics in Review Vol.32 No.1 January 2011
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Figure 4. Treatment pyramid for ulcerative colitis (UC)
and Crohn disease (CD) in children. TPNⴝtotal parenteral
nutrition, TNF-␣ⴝtumor necrosis factor-alpha, 6-MPⴝ6-
mercaptopurine, 5-ASAⴝ5-aminosalicylates, IVⴝintravenous
who have CD are given immunomodulators within 2
years of diagnosis. Immunomodulators such as azathio-
prine and 6-mercaptopurine, which interfere with purine
biosynthesis, have demonstrated good tolerance and
can maintain remission in 75% of patients after discon-
tinuation of corticosteroids. (44)(45) Because azathio-
prine (which is metabolized to 6-mercaptopurine) and
6-mercaptopurine require 3 to 6 months to take effect,
these medications often are started soon after diagnosis.
Methotrexate is used in children who have CD and
may be particularly useful when remission is not achieved
with azathioprine or 6-mercaptopurine or in patients
who experience intolerable adverse effects from those
medications. (46) Methotrexate inhibits dihydrofolate
reductase, an enzyme necessary for folic acid metabolism
and thymidine synthesis. The drug is effective at provid-
ing short-term symptom control, long-term remission,
and steroid withdrawal. (47) Methotrexate usually is
delivered as a weekly subcutaneous injection, and folic
acid supplementation is recommended. Other immuno-
modulators used infrequently in IBD treatment include
tacrolimus and mycophenolate mofetil.
For moderate-to-severe disease, biologic therapy is
useful for induction and maintenance of remission. In-
fliximab is a chimeric monoclonal antibody directed
against the cytokine TNF-alpha that acts by inducing
apoptosis of active T lymphocytes. A response rate of up
to 90% is achieved in patients who have moderate-to-
severe CD, even when disease is refractory to corticoste-
roids and immunomodulators. (48) Those children who
have refractory UC previously were treated with cyclo-
sporine, but infliximab has become the treatment of
choice because cyclosporine therapy has a high likelihood
of eventual treatment failure and the need for colectomy
in children.
For patients who respond to infliximab, scheduled

maintenance infusions are continued every 6 to 12 weeks.
Gut mucosal healing has been demonstrated following
infliximab therapy. Infliximab also plays an important
role in treating fistulizing CD, which typically is more
resistant to conventional therapies, and extraintestinal
manifestations of IBD. PG, vasculitis, uveitis, EN, and
arthritis have responded to this therapy.
Infliximab is the only immunomodulator approved
by the United States Food and Drug Administration for
children who have CD. However, two other anti-TNF
agents, adalimumab and certolizumab, appear effica-
cious. Response rates are similar to infliximab, but be-
cause these antibodies are more fully humanized, allergic
reactions may be less common. Adalimumab has shown
efficacy in children who are intolerant or become unre-
sponsive to infliximab. (49)
Natalizumab (anti-alpha 4 integrin) inhibits the ad-
hesion, migration, and activation of monocytes, macro-
phages, and lymphocytes in a variety of tissues and has
demonstrated clinical efficacy in treating children who
have CD. (50) Three cases of progressive multifocal
leukoencephalopathy associated with the human JC virus
were described following trials in adults, which has cre-
ated concern about its routine use.
Nutritional therapy may be a primary or adjunctive
treatment in CD. Exclusive enteral nutrition from ele-
mental or polymeric formulas has been associated with
short-term remission in up to 80% of children, equal to
the response rate from corticosteroids. (51) The mecha-
nism involves adequate suppression of bowel inflamma-
tion and the induction of mucosal
healing. (51) Improved growth and
development, without the adverse Table 3. Adverse Effects of Medications Commonly
effects of corticosteroids, makes en-
teral nutrition an excellent choice Used to Treat Inflammatory Bowel Disease
for first-line therapy in children Medication Class
who have active CD. However,
after induction, long-term medica- Corticosteroids
tions, such as immunomodulators,
are necessary to maintain remis- 5-Aminosalicylates
sion. Supplements such as iron, fo-
lic acid, calcium, and vitamin D are
required in certain situations. 6-Mercaptopurine,
azathioprine
Antibiotics have specific indica-
Methotrexate
tions in IBD treatment. Metronida-
zole is used to treat perirectal fistu- Anti-tumor necrosis
las, although recurrence rates are factor
high and toxicity (eg, paresthesias)
often limit long-term use. (52) Cip-
rofloxacin is also useful in fistula Anti-integrin
treatment. Both antibiotics are pre-
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gastrointestinal inflammatory bowel disease
scribed for treatment of pouchitis following colectomy
or ileoanal pouch procedures in UC patients. (53) Rifaxi-
min, a nonabsorbed oral antibiotic, has shown benefit in
symptom reduction of abdominal pain and diarrhea in
children who have IBD. (54)
Probiotics have not been shown reproducibly to alter
the natural history of CD, but for children who have
newly diagnosed UC, probiotics are beneficial for main-
taining remission when added to standard treatment
regimens. (55) Probiotics are also helpful in the preven-
tion and treatment of pouchitis. (56)(57) Safety in IBD
patients is well established.
Significant adverse effects exist for all of the previously
described medications (Table 3). A favorable risk-benefit
ratio is the goal when considering any therapy. Infliximab
is contraindicated in patients who have active tuberculo-
sis, opportunistic infection, history of demyelinating dis-
ease, malignancy, congestive heart failure, or concurrent
serious infection. Immunity to varicella should be as-
certained before use of anti-TNF therapy. Recently, an
aggressive malignancy, hepatosplenic T-cell lymphoma,
has been described in young patients (mostly male) who
were treated with a combination of infliximab and either
azathioprine or 6-mercaptopurine. (58)
Surgical Management
Despite improvements in medical strategies, surgery
maintains an important therapeutic role. Indications for
surgery include uncontrolled gastrointestinal bleeding,
bowel perforation, obstruction, intractable disease de-
Important Adverse Effects
Cushingoid facies, growth suppression, osteopenia,
hypertension, hyperglycemia, acne, cataracts,
hypothalamic-pituitary-adrenal axis suppression
Hypersensitivity reaction, disease exacerbation,
headache, diarrhea, rash, pneumonitis, interstitial
nephritis
Bone marrow suppression, pancreatitis, hepatitis, rash,
vasculitis; increased risk of lymphoma
Hepatitis, liver fibrosis, rash, folic acid deficiency,
nausea, vomiting, hair loss
Resurgence of tuberculosis, histoplasmosis, varicella,
malignancies (including lymphoma), fatal
lymphoproliferative syndromes, anaphylaxis, serum
sickness syndrome, lupuslike syndrome, increased risk
of serious infections
Progressive multifocal leukomalacia
Pediatrics in Review Vol.32 No.1 January 2011 21
gastrointestinal inflammatory bowel disease
spite standard therapy, and dysplasia. At times, surgical
resection is used to treat growth failure, especially if it
allows the discontinuation of corticosteroids.
The surgical procedure of choice in UC is resection of
the entire colon with ileal pouch-anal anastomosis. This
curative procedure can be performed either as a primary
operation or in a staged approach, depending on the
condition of the patient. Long-term results are excellent,
and continence can be achieved in 89% of patients after
2 years with creation of a J-pouch reservoir. (59) The
major complication occurring after ileoanal pull-through
is inflammation of the pouch (pouchitis), which occurs in
10% to 40% of children. (60)(61)
In CD, segmental bowel resection is the most com-
mon surgery and typically involves removing the diseased
terminal ileum and adjacent inflamed colon. Short seg-
ments of bowel that are narrowed from fibrosis can be
treated with stricturoplasty. Perirectal disease also may
necessitate surgery.
Adjunctive Therapies
Oral nutrition supplements and either nasogastric or
gastrostomy feedings may be critically important in ad-
dressing chronic undernutrition in children who have
IBD. The administration of adequate calories with the
addition of these supplements can help to reverse growth
failure.
Complementary and alternative medicine approaches
are used by up to 40% of patients who have IBD. To
prevent medication interactions and limit undue adverse
effects, these therapies are not routinely recommended
without physician consultation.
The need for family education and reassurance cannot
be overemphasized. Adolescents who have IBD may
have a particularly difficult time because of issues related
to growth failure, body image (eg, cushingoid features
and acne from corticosteroids), and social invalidism
from abdominal pain and diarrhea. Pubertal delay may
also cause significant anxiety. Recent trials with growth
hormone and IGF-1 have shown some promise in im-
proving growth.
In general, patient and family counseling and peer
support groups are very helpful.
Prognosis and Disease Complications
Disease symptoms recur in up to one third of patients at
1 year and more than one half at 2 years after initiation
of therapy. Factors that predispose to a relapse of CD
include the number of previous strictures and the pres-
ence of FC or FL in the stool. (62)(63)(64) In UC, a
significant number of patients remain corticosteroid-
22 Pediatrics in Review Vol.32 No.1 January 2011
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dependent after 1 year, and 5% may require colectomy.
(40)
Toxic megacolon, although rare in children, occurs in
approximately 5% of adults who have severe UC and may
be triggered by hypokalemia or opiate use. Colonic per-
foration may occur and colectomy may become neces-
sary. (65) Patients who have severe colitis (more than five
bloody stools per day, fever, hypoalbuminemia, anemia)
require hospitalization, bowel rest with parenteral nutri-
tion support, intravenous corticosteroids, and very care-
ful monitoring. Anecdotal experience supports the use of
infliximab in reducing colectomy rates among patients
who have severe colitis.
The risk of colorectal cancer depends on the extent
and duration of the disease. (66) The cumulative inci-
dence of colorectal cancer in patients who have pancolitis
is 5% to 10% after 20 years and 12% to 20% after 30 years
of disease. Screening is recommended beginning 8 years
after diagnosis.
Patients who experience early-onset CD have a lower
final adult height compared with predicted mid-parental
height, with an average height reduction of 2.4 cm.
Population studies have not shown a difference in final
adult height in pediatric patients who have UC. (67)
Osteopenia and osteoporosis can occur because of vita-
min D deficiency, corticosteroid use, and high concen-
trations of circulating inflammatory cytokines, which
inhibit IGF-1. Abnormally low bone mineral density is
found in nearly 50% of patients who have IBD. Maintain-
ing disease remission, avoiding corticosteroids, exercis-
ing, and ensuring adequate calcium and vitamin D in-
take are imperative to optimize bone development and
mineralization in the growing child, particularly during
puberty. Dual-energy radiograph absorptiometry scans
should be performed in children who experience growth
failure and prolonged steroid use. (25)(68)(69)
Issues for the General Pediatrician
Children and adolescents who have IBD should avoid
the use of nonsteroidal anti-inflammatory drugs (includ-
ing ibuprofen) because their routine use can trigger a
disease flare, enteropathy, or gastritis. Cautious use of
acetaminophen is suggested for treatment of minor pain
and fever. The casual use of antibiotics should be limited
in children who have IBD to prevent the risk of C difficile
colitis, which has been associated with increased morbid-
ity. Children taking immunosuppressive medications and
biologic therapy should be restricted from live vaccine
administration. With administration of inactivated vac-
cines, seroconversion is not always obtained if immuno-
suppressive therapy is being used concomitantly. Mea-

surement of growth velocity, evaluation of pubertal
Sexual Maturity Rating staging, and annual-to-biannual
eye examinations are recommended, even for asymptom-
atic children who have IBD.
Summary
• Recent major advances have been made in the
diagnosis and treatment of pediatric IBD, and
understanding of its pathophysiology continues to
evolve.
• The long-term outcome for children who have IBD
continues to improve with better appreciation of
genotype-phenotype correlations, earlier diagnosis,
and more effective treatments.
• Although the incidence of pediatric IBD appears to
be rising, the future for affected children and
adolescents appears promising.
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 gastrointestinal inflammatory bowel disease

PIR Quiz
Quiz also available online at http://pedsinreview.aappublications.org.

6. Which of the following symptoms or signs is seen in children who have Crohn disease, but not in children
who have ulcerative colitis?
A. Anemia.
B. Arthritis.
C. Loose stools.
D. Perianal fistula.
E. Weight loss.

7. Which of the following infections can mimic the intestinal inflammation of Crohn disease?
A. Epstein-Barr virus.
B. Herpes simplex virus-1.
C. Measles virus.
D. Rotavirus.
E. Tuberculosis.

8. Which of the following tests is the “gold standard” for diagnosis of IBD?
A. Abdominal computed tomography scan.
B. Endoscopy and colonoscopy with biopsy.
C. Fecal lactoferrin.
D. Serologic panel.
E. Wireless capsule endoscopy.

9. A 15-year-old boy received the diagnosis of Crohn disease of the colon 6 months ago. He has had active
disease despite 5 months of 6-mercaptopurine therapy and two courses of corticosteroid therapy. Of the
following, which medication is most likely to induce remission?
A. Azathioprine.
B. Infliximab.
C. Mesalamine.
D. Metronidazole.
E. Rifaximin.

10. An adolescent girl who has ulcerative colitis has been successfully maintained on 6-mercaptopurine for
2 years and presents today for a health supervision visit. She asks which immunizations she can have in
the future. Which of the following vaccines is contraindicated?
A. Human papillomavirus vaccine.
B. Influenza vaccine.
C. Measles, mumps, and rubella vaccine.
D. Pneumococcal vaccine.
E. Tetanus toxoid.

Pediatrics in Review Vol.32 No.1 January 2011 25

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 Inflammatory Bowel Disease
Sarah R. Glick and Ryan S. Carvalho
Pediatr. Rev. 2011;32;14-25
DOI: 10.1542/pir.32-1-14

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 Visual Diagnosis: Perceived Fevers and Back Pain in a 1-week-old Infant
Delia L. Gold
Pediatr. Rev. 2011;32;27-30
DOI: 10.1542/pir.32-1-27

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located on the World Wide Web at:
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Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned,
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Perceived Fevers and Back Pain in a
1-week-old Infant
Figure 1. Warm, confluent, blanching, erythematous, and
somewhat purpuric area covering the upper third of the
infant’s back.
Figure 2. Axillary erythema and induration.
Author Disclosure
Dr Gold has disclosed no financial relationships relevant to
this case. This commentary does not contain a discussion of
an unapproved/investigative use of a commercial
product/device.
*Department of Pediatrics, Nationwide Children’s Hospital, The Ohio State
University, Columbus, OH.
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visual diagnosis
Delia L. Gold, MD*
Presentation
A 7-day-old female infant presents to the emergency
department with the complaints of perceived back pain
and subjective fevers. Her mother also describes unex-
plained skin color changes to her infant’s back and
shoulders. For the past 2 days, the mother had noticed
that her infant was fussy and would cry when her back
was touched. She has no other systemic symptoms, no
sick contacts, and no known history of trauma. The
mother has no reported history of methicillin-resistant
Staphylococcus aureus infection or colonization. This is
the first time the mother has sought medical attention
for her baby since discharge from the newborn nurs-
ery.
The child was born by vacuum-assisted vaginal deliv-
ery at 39 weeks’ gestation and weighed 3.8 kg. Labor
had been induced because of maternal preeclampsia.
Meconium-stained amniotic fluid was present on deliv-
ery. Apgar scores were 3 and 8 at 1 and 5 minutes,
respectively. The infant did not require resuscitation and
was admitted directly to the newborn nursery, where she
stayed for 3 days. The mother had adequate prenatal care
and no serologic evidence of prenatal infections. Of note,
because the mother had one prior spontaneous abortion,
she had received Rho (D) immune globulin during this
pregnancy.
Physical examination reveals an afebrile, irritable
infant. Examination of the skin demonstrates a warm,
confluent, blanching, erythematous, and somewhat
purpuric area covering the upper third of her back
(Fig. 1). Areas of induration are scattered over the
patient’s upper back and posterior axillae (Fig. 2).
Shotty lymphadenopathy is noted in both axillae. The
rest of the physical examination findings are unremark-
able.
After blood and cerebrospinal fluid specimens for
culture are obtained in the emergency department, the
infant is admitted to the infectious disease service for
intravenous antibiotic therapy and further evaluation.
Results of the initial laboratory examination, consisting
of a complete blood cell count, metabolic panel, coagu-
lation studies, and cerebrospinal fluid studies, appear to
be unremarkable. A clinical diagnosis is made.
Pediatrics in Review Vol.32 No.1 January 2011 27
visual diagnosis

Diagnosis: Subcutaneous Fat Necrosis Pathogenesis

of the Newborn The exact pathogenesis of SCFN is unknown but appears
The clinical diagnosis was based initially on the typical to be related to the relatively higher concentration of
skin changes associated with subcutaneous fat necrosis of saturated fatty acids in neonatal fat compared with the
the newborn (SCFN) and the risk factors noted in the higher proportion of unsaturated fatty acids in adult fat.
prenatal and birth history (maternal history of pre- Saturated fatty acids have a high melting point. Under
eclampsia and Rh incompatibility, meconium-stained cold stress, the saturated fat in neonates may solidify and
amniotic fluid, low Apgar scores). The diagnosis of crystallize, leading to subsequent adipocyte necrosis. It is
SCFN subsequently was confirmed by skin biopsy. postulated that fetal or neonatal distress around the time
of delivery leads to cooling and hypoperfusion of subcu-
taneous fat, thereby causing subcutaneous granuloma-
The Condition tous inflammation and necrosis that results in the char-
SCFN is an uncommon, often benign, self-limited pan- acteristic skin lesions of SCFN.
niculitis that develops typically in term or postterm new-
borns in the first few postnatal weeks, primarily as a
Diagnosis
consequence of perinatal stress or complications. SCFN
The diagnosis of SCFN usually is suspected from findings
is characterized by erythematous, firm, indurated plaques
on physical examination and the birth history, but the
or nodules usually located on the back, posterior surfaces
definitive diagnosis is based on skin biopsy findings. The
of the arms, buttocks, and thighs, rarely involving the
skin biopsy performed on this infant during her hospital-
face or trunk. The plaques or nodules may become
ization yielded results that were consistent with SCFN
fluctuant due to liquefaction of fat or firm due to calcifi-
(Fig. 3). A biopsy specimen of SCFN demonstrates fat
cation. The lesions sometimes are painful. Resolution of
necrosis, abundant histiocytes, and chronic inflammatory
the lesions may result in mild atrophy of the involved
granulomatous formation with multinucleated giant
skin.
cells. Both giant cells and necrotic adipocytes demon-
strate needle-shaped crystals arranged radially.
The differential diagnosis for SCFN primarily includes
Cause
sclerema neonatorum (SN), skin cellulitis, and superficial
Although SCFN is a rare occurrence, numerous studies
trauma. SN is a distinct dermatologic condition seen in
have explored possible causes. In most cases, SCFN is
neonates that is characterized by hardening of the skin
believed to result from perinatal complications such as
asphyxia, meconium aspiration, seizures, obstetric
trauma, maternal-fetal Rh factor incompatibility, and
umbilical cord prolapse. Fetal factors such as sepsis,
anemia, thrombocytosis, hypothermia, and a primary
defect in subcutaneous fat may play a causative role.
Maternal factors such as gestational diabetes, preeclamp-
sia, or maternal exposure to cocaine or calcium antago-
nists also may play a part. Perinatal asphyxia and meco-
nium aspiration seem to be the most frequently
recognized causative factors for development of SCFN.
The prevalence of SCFN is increased in infants born
by cesarean section, but some researchers have postu-
lated that trauma such as pressure injury experienced in a
vaginal delivery also can contribute to the development
of SCFN by causing local ischemia to the affected tissues.
The development of SCFN seems to be independent of
the modalities of delivery, that is, vaginal delivery versus Figure 3. Biopsy sample of subcutaneous tissue, with original
cesarean section. The elevated prevalence of this skin magnification of 100x, shows flocculent, crystalline lipid
disorder in infants born via cesarean section might be within adipocytes (upper half of the image). Prominent acute
related to the fetal stress that prompted the urgent sur- inflammation with neutrophilic infiltration is present in the
gical delivery rather than the mode of delivery. lower half.

28 Pediatrics in Review Vol.32 No.1 January 2011

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Figure 4. Sclerema neonatorum, original magnification 100x.
This section of subcutaneous tissue from a 3-day-old infant
shows no inflammation and no fat necrosis. The wide connec-
tive tissue septum shows separation of collagen due to edema.
that can adhere to underlying muscle and bone, causing
difficulties with respiration and feeding. Unlike SCFN,
this entity is associated with congenital anomalies and
critical illness. A skin biopsy of SN demonstrates thick-
ening of the connective tissue bands supporting the
subcutaneous adipose tissue (Fig. 4) and a sparse inflam-
matory infiltrate of lymphocytes, histiocytes, and
multinucleate giant cells, in contrast to the pathologic
findings in SCFN. SN is associated with a poor prognosis
because it is related to severe clinical illness, usually
following emergent delivery or surgery.
Associated Complications
SCFN generally follows an uncomplicated course, with
spontaneous resolution and no medical intervention.
However, certain uncommon but serious complications
require investigation: hypercalcemia, hypoglycemia,
thrombocytopenia, and hypertriglyceridemia. Hypercal-
cemia is the most frequently reported complication of
SCFN, but the exact incidence is unknown. Different
hypotheses for the pathogenesis of hypercalcemia have
been proposed, including bone resorption stimulated by
elevated concentrations of parathyroid hormone or cal-
cium release from resolving subcutaneous plaques. The
accepted, most likely theory proposes that macrophages
within the granulomas of the fat necrosis produce extra-
renal 1,25-dihydroxyvitamin D3, a mechanism similar to
that suggested for other granulomatous disorders, such
as sarcoidosis and tuberculosis, that are associated with
hypercalcemia.
Downloaded from http://pedsinreview.aappublications.org. Provided by Health Internetwork on April 20, 2011
visual diagnosis
Hypoglycemia, thrombocytopenia, and hypertriglyc-
eridemia are observed very rarely in SCFN and often have
no clinical consequence. In general, if the initial labora-
tory tests do not reveal these metabolic and hematologic
abnormalities, the studies do not need to be repeated.
Patients who have SCFN and hypercalcemia should have
their calcium values monitored weekly until the hyper-
calcemia resolves or the lesions resolve.
Treatment
SCFN is most often self-limited, with resolution occur-
ring within several weeks to 6 months. Usually, no
specific treatment is needed for the lesions; rather, med-
ical intervention focuses on possible complications. If the
lesions are particularly large and fluctuant, fine-needle
aspiration may prevent secondary infection, skin necrosis,
and scarring. Although uncommon, hypercalcemia is the
most frequently reported complication of SCFN and can
be significant enough to cause seizures, renal failure,
nephrolithiasis, cardiac toxicity and arrest, calcium dep-
osition in the tissues, and even death. Hypercalcemia
usually manifests when the lesions begin to resolve. If any
of the signs of hypercalcemia are present, aggressive
measures should be taken to correct the electrolyte ab-
normality, including intravenous hydration with normal
saline, administration of loop diuretics to decrease the
calcium serum concentration, and dietary restriction of
calcium and vitamin D. Corticosteroids, calcitonin, and
bisphosphonates are alternative treatments that should
be considered if the hypercalcemia is severe enough or is
refractory to the previously cited measures.
Because hypercalcemia is a rare yet serious complica-
tion of SCFN, the physician should assess serial serum
calcium concentrations. There is no definitive guideline
on the duration of such assessment, but the consensus in
the existing literature is that the serum calcium concen-
tration should be checked weekly for 2 to 6 months after
diagnosis or until the hypercalcemia disappears or the
lesions resolve. The frequency of such tests can be deter-
mined by the severity of the SCFN, the degree of hyper-
calcemia, and the presence or absence of symptoms.
Patient Course
The infant remained afebrile for the duration of her
2-day hospitalization, and she was acting well and feed-
ing appropriately before discharge. Cultures of urine,
blood, and cerebrospinal fluid yielded negative results,
and antibiotic therapy was discontinued. The infant ex-
perienced mild hypercalcemia after discharge home. She
was referred to an endocrinologist, and her serum cal-
cium was monitored for 1 month, during which time the
Pediatrics in Review Vol.32 No.1 January 2011 29
visual diagnosis
Summary
• SCFN of the newborn is an uncommon, benign
disorder typically found in term, otherwise healthy
neonates who have experienced perinatal stressors
such as birth asphyxia, meconium aspiration, cord
prolapse, hypothermia, and hypoxemia.
• Maternal factors such as preeclampsia, gestational
diabetes, and in utero exposure to certain
medications may play roles.
• Physical examination demonstrates firm, indurated,
circumscribed, erythematous-to-purplish plaques or
nodules, often on the back, shoulders, arms, thighs,
or buttocks.
• Prognosis generally is very good, but rare
complications such as hypercalcemia,
thrombocytopenia, hypoglycemia, and
hypertriglyceridemia have been reported.
• Hypercalcemia is the most common complication
that can have potentially lethal effects on the renal,
cardiovascular, and neurologic systems. Patients who
have SCFN should have their calcium concentrations
monitored weekly until the hypercalcemia disappears
or the lesions resolve.
• Signs of hypercalcemia include irritability, lethargy,
vomiting, hypotonia, dehydration, and failure to
thrive. Parents of newborns who have SCFN should
be educated about the signs and symptoms of
hypercalcemia.
30 Pediatrics in Review Vol.32 No.1 January 2011
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values returned to the normal range without medical
intervention. The infant’s primary pediatrician and a
dermatologist followed her progress after hospital dis-
charge and documented no further complications and
complete resolution of the lesions on her back. The
patient is doing well at age 7 months.
ACKNOWLEDGMENTS. The author would like to
thank Jonathan Thackeray, MD, Dwight Powell, MD,
and Peter Baker, MD, at Nationwide Children’s Hospital
in Columbus, Ohio, for their helpful input, photographs,
and histologic slides.
Suggested Reading
Burden AD, Krafchik BR. Subcutaneous fat necrosis of the new-
born: a review of 11 cases. Pediatr Dermatol. 1999;16:384 –387
Ladoyanni E, Moss C, Brown RM, Ogboli M. Subcutaneous fat
necrosis in a newborn associated with asymptomatic and uncom-
plicated hypercalcemia. Pediatr Dermatol. 2009;26:217–219
Mahe E, Girszyn N, Hadj-Rabia S, et al. Subcutaneous fat necrosis
of the newborn: a systematic evaluation of risk factors, clinical
manifestations, complications and outcome of 16 children. Br J
Dermatol. 2007;156:709 –715
Tran JT, Sheth AP. Complications of subcutaneous fat necrosis of
the newborn: a case report and review of the literature. Pediatr
Dermatol. 2003;20:257–261
Zeb A, Darmstadt GL. Sclerema neonatorum: a review of nomen-
clature, clinical presentation, histological features, differential
diagnoses and management. J Perinatol. 2008;28:453– 460
 Visual Diagnosis: Perceived Fevers and Back Pain in a 1-week-old Infant
Delia L. Gold
Pediatr. Rev. 2011;32;27-30
DOI: 10.1542/pir.32-1-27

Updated Information including high-resolution figures, can be found at:

& Services http://pedsinreview.aappublications.org/cgi/content/full/32/1/27
Subspecialty Collections This article, along with others on similar topics, appears in the
following collection(s):
Fetus and Newborn Infant
http://pedsinreview.aappublications.org/cgi/collection/fetus_new
born_infant Skin Disorders
http://pedsinreview.aappublications.org/cgi/collection/skin_disor
ders
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tables) or in its entirety can be found online at:
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 Focus on Diagnosis: A Primer on D-dimer
Cristyn N. Camet and Donald L. Yee
Pediatr. Rev. 2011;32;31-33
DOI: 10.1542/pir.32-1-31

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/cgi/content/full/32/1/31

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2011 by the American Academy of
Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.

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Author Disclosure
Drs Camet and Yee have 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.
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A Primer on D-dimer
Cristyn N. Camet, MD,* Donald L. Yee,
MD†
Introduction
The D-dimer antigen is a degrada-
tion byproduct of the fibrinolytic
process (Figure) and is commonly
used as a biomarker in various clinical
settings such as the evaluation of ve-
nous thromboembolism (VTE) and
disseminated intravascular coagula-
tion (DIC). Much more literature on
and collective experience with use of
the D-dimer assay exists for adult
than pediatric patients. However,
thrombotic complications are be-
coming increasingly recognized in
infants and children, and reports on
this assay’s utility in a variety of other
pediatric applications are increasing.
This review examines the biochemi-
cal basis of D-dimer formation, issues
raised by the varied testing methods
used to measure D-dimer, and the
scenarios in which this assay may pro-
vide information useful for medical
management.
D-dimer Formation
D-dimer formation begins with cleav-
age of fibrinogen molecules by acti-
vated thrombin into fibrin monomers,
which then polymerize. Thrombin ac-
tivates fibrin-bound factor XIII to
form factor XIIIa that, in turn, cata-
lyzes formation of covalent bonds be-
tween D-domains of the polymerized
fibrin. Finally, during fibrinolysis, plas-
minogen is activated to plasmin, which
cleaves the fibrin polymers at specific
locations and releases fibrin degrada-
tion products that vary in molecular
weight and size but include moieties
containing the exposed D-dimer anti-
*Pediatric Resident.
†
Department of Pediatrics, Hematology-Oncology
Section, Baylor College of Medicine, Houston, TX.
focus on diagnosis
gen. Thus, D-dimer concentrations
are increased under any conditions of
increased fibrin formation, as with he-
mostasis, thrombosis, and tissue repair.
Laboratory Considerations
A wide variety of testing methods has
evolved over the years for detection of
the D-dimer antigen, but the lack of
standardization among these methods
has been an ongoing source of con-
cern. Although all modern commer-
cially available assays use monoclonal
antibodies specific for the D domain
on factor XIIIa-cross-linked fibrin,
they are not identical in the precise
epitope (antigenic determinant) that
they identify. The assays also differ in
format, calibration methods, instru-
mentation, sensitivity, and specificity.
Ideally, only assays that have been val-
idated in clinical studies of relevant test
populations and for which specific cut-
off values have been reliably deter-
mined should be used. Unfortunately,
this requirement is especially problem-
atic in pediatrics due to the paucity of
such validation testing and the reliance
on reference ranges provided by stud-
ies in adults when there are significant
age-related differences in D-dimer val-
ues.
A recent study reported a six- to
eightfold higher D-dimer reference
range for newborns compared with
adults. Although this difference largely
resolves during infancy, subtle differ-
ences persist into late childhood. Such
findings are consistent with the con-
cept of “developmental hemostasis”
coined by Andrew and associates (1) to
describe the physiologic, age-related
variation in concentrations of many co-
agulation proteins. However, develop-
mental hemostasis places a significant
burden on laboratories striving to pro-
vide optimal care to pediatric patients
because age-related reference ranges
Pediatrics in Review Vol.32 No.1 January 2011 31
focus on diagnosis

asymmetry, skin changes, and chronic

Figure. Sequential process of fibrinogen cleavage, fibrin polymerization, cross-linking,
and fibrinolysis that leads to degradation products containing the D-dimer antigen.
This diagram is simplified by depicting only a single fibrin strand and degradation
products of uniform composition. Adapted from Adam SS, Key NS, Greenberg CS.
D-dimer antigen: current concepts and future prospects. Blood. 2009;113:2878 –
2887.
for the specific reagent/analyzer com-
bination used in a given laboratory
must be determined for many coagu-
lation tests, including the D-dimer as-
say. Otherwise, use of reference ranges
based on studies of adults or different
analyzer systems may lead to inaccu-
rate interpretation of test results in pe-
diatric patients.
Clinical Uses of D-dimer
Antigen Assay
The D-dimer assay is commonly used
in adult patients for assessment of
possible VTE. In selected adult pa-
tient populations, a normal D-dimer
result is as sensitive for the exclusion
of VTE as a negative imaging study.
Specificity is much lower, however,
because a positive D-dimer finding is
not sufficient to diagnose VTE or
dictate therapy; it only directs the
clinician toward more diagnostically
specific imaging studies. Limited ret-
rospective studies in children tend to
support the assay’s high sensitivity in
this setting but suggest that its spec-
ificity for VTE may be even lower
than in adults (specificity no higher
than 57% among the limited number
of pediatric patients studied).
Other uses of the D-dimer assay in
adults include stratifying risk for recur-
rent VTE, especially in identifying pa-
tients who would benefit from longer
duration of anticoagulation therapy.
Again, limited studies in children sug-
gest that a markedly elevated D-dimer
value is a marker for negative outcomes
of VTE, including clot persistence, clot
recurrence, and the long-term compli-
cation known as the postthrombotic
syndrome (characterized by limb
pain in the most severe cases).
A recent small study suggests a role
for D-dimer in assessing the prognosis
and cause of pediatric arterial ischemic
stroke. (2) Strokes of cardioembolic
subtype were associated with signifi-
cantly higher D-dimer values than
noncardioembolic subtypes (eg, arte-
riopathies), consistent with the con-
cept that a hypercoagulable state is
more relevant to the former type of
stroke. If confirmed in larger studies,
the ability to distinguish between
pediatric stroke subtypes could aid
decision-making about the use of anti-
thrombotic therapy as well as guide
diagnostic approaches for new-onset
childhood stroke.
D-dimer is commonly used to as-
sess for the presence of DIC, which
may accompany extreme states such
as sepsis, trauma, malignancy, and
obstetric emergencies. DIC is char-
acterized by continuous intravascular
thrombin and fibrin formation that
may lead to clinical bleeding caused
by depletion of coagulation factors.
However, the diagnosis of DIC is not
based solely on the D-dimer result,
but on a combination of laboratory
values, including platelet count, fi-
brinogen value, and prothrombin
time, in addition to the detection of
markers of fibrin formation (such as
D-dimer).
The test also has been used to
guide decisions about the adequacy
of anticoagulation therapy in patients
who have rare thrombotic disorders
such as severe protein C deficiency
because a markedly elevated or rising
D-dimer value can be a sign of devel-
oping VTE or DIC in such patients.
Inflammation and coagulation
pathways are intimately linked, lead-
ing to D-dimer elevation during in-
flammatory disease states. An appli-
cation of this association is the use of
D-dimer to monitor outcomes in pa-
tients who have systemic juvenile id-

32 Pediatrics in Review Vol.32 No.1 January 2011

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iopathic arthritis (JIA). Elevated
D-dimer values seen in JIA are be-
lieved to result from cytokine-
induced endothelial activation and
are associated with disease activity
and poor response to therapy. Persis-
tently elevated D-dimer values, de-
spite therapy with immune modula-
tors, predict a poor outcome for
these patients. D-dimer testing, thus,
holds promise as a predictive tool to
help target more intensive treatment
for high-risk JIA patients early in the
disease course.
Elevated D-dimer has also been
reported in the setting of other sys-
temic vascular diseases such as Ka-
wasaki disease, Henoch-Schönlein
purpura, and hemolytic-uremic syn-
drome. In such cases, D-dimer values
tend to correlate with disease stage,
and it has been suggested that
D-dimer measurement might serve
as a prognostic tool for these condi-
tions or to help differentiate among
other diagnostic considerations.
Of special relevance to the general
pediatrician, elevated D-dimer con-
centrations also have been associated
with poorer outcomes in pediatric
patients who develop community-
acquired pneumonia (CAP). Patients
who have CAP and elevated D-dimer
concentrations may be at higher risk
for developing parapneumonic effu-
sion or empyema. Patients who expe-
rience these complications may ex-
hibit increased coagulation activity
and fibrin deposition in the pleural
space, leading to increased fibrinoly-
sis and D-dimer formation. D-dimer
values showed an increasing trend
among groups of patients who had
CAP, pneumonia with effusion, and
empyema, respectively, and were
higher than in healthy children.
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However, further prospective studies
are required.
Future Considerations
D-dimer is a widely available test, and
an increasing number of applications
for its use within adult medicine are
evolving. Although additional valida-
tion studies and studies of age-
related changes in D-dimer values
still need to be performed to allow
for reliable and interpretable results
for pediatricians, D-dimer measure-
ment holds promise for monitoring
of pediatric diseases. Prospective
studies are required to examine the
dynamics of D-dimer plasma concen-
trations, such as time to normaliza-
tion, so clinicians can interpret when
an abnormal result is suggestive of
significant new or ongoing disease
rather than expected recovery from
an elevated concentration after sur-
gery or a resolving infection.
Additional studies of the utility of
D-dimer measurement in specific
clinical situations are required. Can-
didate disorders for such study in-
clude inflammatory diseases such as
other vasculitides and inflammatory
bowel disease. Given the link be-
tween inflammation and obesity,
D-dimer could also prove useful in
assessing vascular risk in obese chil-
dren, as suggested by a recent study.
(3) However, at present, rigorous
studies of D-dimer applications in
pediatric medicine are limited. Thus,
caution should be exercised in inter-
preting D-dimer results in the clinical
care of pediatric patients because ref-
erence ranges, cut-off values, and
interpretation of clinical research
studies in adults cannot be reliably
extended to children. The D-dimer
assay will have only limited utility in
general pediatrics until the necessary
focus on diagnosis
prospective clinical validation studies
in children are performed.
References
1. Andrew M, Vegh P, Johnston M,
Bowker J, Ofosu F, Mitchell L. Maturation
of the hemostatic system during childhood.
Blood. 1992;80:1998 –2005
2. Bernard TJ, Fenton LZ, Apkon SD, et
al. Biomarkers of hypercoagulability and
inflammation in childhood-onset arterial
ischemic stroke. J Pediatr. 2010;156:
651– 656
3. Balagopal P, George D, Sweeten S, et al.
Response of fractional synthesis rate (FSR)
of fibrinogen, concentration of D-dimer
and fibrinolytic balance to physical activity-
based intervention in obese children. J
Thromb Haemost. 2008;6:1296 –1303
Suggested Reading
Adam SS, Key NS, Greenberg CS.
D-dimer antigen: current concepts and
future prospects. Blood. 2009;113:
2878 –2887
Biss TT, Brandão LR, Kahr WH, Chan AK,
Williams S. Clinical probability score
and D-dimer estimation lack utility in
the diagnosis of childhood pulmonary
embolism. J Thromb Haemost. 2009;7:
1633–1638
Bloom BJ, Alario AJ, Miller LC. Persistent
elevation of fibrin D-dimer predicts
long-term outcome in systemic juvenile
idiopathic arthritis. J Rheumatol. 2009;
36:422– 426
Michelin E, Snijders D, Conte S, et al. Pro-
coagulant activity in children with com-
munity acquired pneumonia, pleural ef-
fusion and empyema. Pediatr Pulmonol.
2008;43:472– 475
Monagle P, Barnes C, Ignjatovic V, et al.
Developmental haemostasis—Impact
for clinical haemostasis laboratories.
Thromb Haemost. 2006;95:362–372
Rajpurkar M, Warrier I, Chitlur M, et al.
Pulmonary embolism – experience at a
single children’s hospital. Thromb Res.
2007;119:699 –703
Strouse JJ, Tamma P, Kickler TS, Takemoto
CM. D-dimer for the diagnosis of ve-
nous thromboembolism in children.
Am J Hematol. 2009;84:62– 63
Pediatrics in Review Vol.32 No.1 January 2011 33
 Focus on Diagnosis: A Primer on D-dimer
Cristyn N. Camet and Donald L. Yee
Pediatr. Rev. 2011;32;31-33
DOI: 10.1542/pir.32-1-31

Updated Information including high-resolution figures, can be found at:

& Services http://pedsinreview.aappublications.org/cgi/content/full/32/1/31
Subspecialty Collections This article, along with others on similar topics, appears in the
following collection(s):
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vascular_other_multisystem_disorders Disorders of
Blood/Neoplasms
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of_blood_neoplasms
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 Pediatrics in the Community: The Haiti Earthquake
Sachin D. Shah and C. Andrew Aligne
Pediatr. Rev. 2011;32;34
DOI: 10.1542/pir.32-1-34

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/cgi/content/full/32/1/34

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2011 by the American Academy of
Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.

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pediatrics in the community
Author Disclosure
Drs Shah and Aligne have 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.
Disaster relief appeals to our noblest
qualities as health-care professionals
and compassionate human beings.
The devastation caused by the January
2010 earthquake inspired many pedia-
tricians to travel to Haiti. One of
these was Dr Sachin Shah, a veteran of
numerous international health experi-
ences, who spent a week in Port-au-
Prince helping to staff a field hospital.
This facility, run by Project Medishare,
(1) was a sophisticated operation
boasting a 35-bed pediatrics ward that
included a fully equipped neonatal in-
tensive care unit/pediatric intensive
care unit, a freestanding emergency
department, and a separate operating
tent (OR) with two operating theaters
staffed by an orthopedist, neurosur-
geon, and pediatric surgeon.
“One of the most memorable
children I cared for was a 2-year-old
boy with congenital hydrocephalus,
likely a consequence of a prenatal
infection,” related Dr Shah. “He pre-
sented with fever and severe abdom-
inal pain with peritoneal signs. The
*University of Chicago, Chicago, Ill.
†
University of Rochester, Rochester, NY
34 Pediatrics in Review Vol.32 No.1 January 2011
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The Haiti Earthquake
Sachin D. Shah, MD,* C. Andrew Aligne, MD, MPH†
month before, a neurosurgeon at
our facility had placed a ventriculo-
peritoneal (VP) shunt. A Gram stain
of cerebrospinal fluid confirmed a
shunt infection, and he was taken
back to the OR where the VP shunt
was removed by another neurosur-
geon. Three days later, largely be-
cause the neurosurgeon was leaving
the next morning, the patient under-
went an endoscopic third ventricu-
lostomy. Although the care this child
received was remarkable, it struck me
how little we, in fact, accomplished.
His hydrocephalus did not improve,
and he was, perhaps, worse off than
before our involvement.”
Emergency medical relief services
are important, and the rescue workers,
physicians, nurses, and others who
helped in Haiti did much good. How-
ever, one needs to step back and ask
why the devastation from the earth-
quake was so enormous. Unfortu-
nately, it was just one consequence of
severe underlying problems. Hence,
after all the heroic efforts in Haiti, the
health situation there still is dismal.
The country is a landscape dominated
by the diseases of poverty: malaria, tet-
anus, and tuberculosis. Basic sanitation
remains an overwhelming need, with
more than 100 people per toilet and
difficult access to clean water. Malnu-
trition is common.
The volunteers who seemed to be
making a lasting impact were those
who addressed these basic needs with
simple measures such as diphtheria-
pertussis-tetanus vaccination or deliv-
ery of portable, self-contained out-
houses. Global health experts agree on
the need to emphasize simple, cheap,
and effective public health preventive
interventions over high-tech rescue
care. In addition, we must favor broad-
based grassroots improvements in in-
frastructure, education, and economic
development. Successful efforts in var-
ious parts of the world show that
progress is possible.
SECTION EDITOR’S NOTE. It is un-
fortunate that overseas medical volun-
teer experiences frequently end in the
type of frustration described in this
story. There is a tendency to think that
the problems of poor countries are in-
surmountable but that their health
needs can be satisfied by emergency
relief efforts. Both extremes are inaccu-
rate. A recent book called Give a Little
provides numerous examples of non-
profit organizations engaged in effec-
tive interventions to reduce poverty
and illness both here and abroad. (2)
Small contributions to the right orga-
nizations can have a huge and lasting
impact.
References
1. Project Medishare website. Accessed
July 2010 at: www.projectmedishare.org
2. Smith W. Give a Little. New York, NY:
Hyperion; 2009
Suggested Reading
Crump JA, Sugarman J. Ethical consider-
ations for short-term experiences by
trainees in global health. JAMA. 2008;
300:1456 –1458
Hilts PJ. Rx for Survival. New York, NY:
Penguin Books; 2005
Packard RM. The Making of a Tropical
Disease: A Short History of Malaria.
Baltimore, Md: Johns Hopkins Uni-
versity Press; 2007
 Pediatrics in the Community: The Haiti Earthquake
Sachin D. Shah and C. Andrew Aligne
Pediatr. Rev. 2011;32;34
DOI: 10.1542/pir.32-1-34

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 Index of Suspicion • Case 1: Recurrent Oral Ulcers in an Adolescent • Case 2:
Visual Impairment in an Autistic Child • Case 3: Fever and Hepatosplenomegaly
in an Infant
Benjamin Bruins, Howard F. Fine, L. Nandini Moorthy, Ayesha Jain, Ashok K. Jain,
Thomas W. Milligan and Rinku Patel
Pediatr. Rev. 2011;32;35-40
DOI: 10.1542/pir.32-1-35

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located on the World Wide Web at:
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Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned,
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 index of suspicion

Case 1: Recurrent Oral Ulcers in an Adolescent

Case 2: Visual Impairment in an Autistic Child
Case 3: Fever and Hepatosplenomegaly in an Infant
Case 1 Presentation A discussion with the patient’s
A 16-year-old African American girl ophthalmologist confirms the clinical
presents with extremely painful re- diagnosis and well-known complica-
current oral ulcers over the past 2 tion.
months. She reports similar painful
ulcers of the genital area that have
The reader is encouraged to write
possible diagnoses for each case before whitish discharge and intermittent Case 2 Presentation
turning to the discussion. We invite low-grade fevers. A recent complaint A 15-year-old Hispanic boy who has
readers to contribute case presentations of blurry vision prompted a visit to an a previous diagnosis of autism pre-
and discussions. Please inquire first by ophthalmologist, who prescribed eye
contacting Dr. Deepak Kamat at sents to the ophthalmology clinic
drops for “inflammation.” She de- with a 2-month history of vision
dkamat@med.wayne.edu.
nies sexual activity, drug use, nausea, problems. His parents report that he
vomiting, diarrhea, headaches, rash, does not walk around freely because
joint pains, cough, or frequent infec- he cannot see, he holds on to walls,
Author Disclosure tions. Her past medical history is un- and he runs into the furniture. He is
remarkable, but an older brother no longer able to transcribe words
Drs Bruins, Fine, Moorthy, Jain,
has human immunodeficiency virus from the blackboard as he had done
Milligan, and Patel and Ms Jain have
(HIV) infection. previously. He has stopped daily ac-
disclosed no financial relationships
relevant to these cases. This
Physical examination reveals a well- tivities such as using the computer.
commentary does not contain a developed adolescent girl in no acute However, he still can use a spoon and
discussion of an unapproved/ distress. Her vital signs are within age- fork and dress himself. He has mild
investigative use of a commercial appropriate limits. She has several well- photosensitivity, and he rubs his eyes
product/device. demarcated aphthous ulcers in her frequently. His appetite has re-
buccal mucosa and oval ulcers with mained unchanged. His past history
whitish discharge over her labia ma- includes being nonverbal and having
jora. The remainder of the physical ex- developmental delay, moderate far-
amination yields no findings of note. sightedness, and bilateral astigma-
Frequently Used Abbreviations Laboratory testing reveals normal tism.
ALT: alanine aminotransferase findings on a complete metabolic He is obese, with a body mass
AST: aspartate aminotransferase panel, urinalysis, and serum immuno- index of 33. During an ophthalmo-
BUN: blood urea nitrogen globulin and complement assessment. logic examination, he is very uncoop-
CBC: complete blood count Her Hgb is 11.5 g/dL (115 g/L) and erative. There is no improvement af-
CNS: central nervous system her ESR is elevated at 55 mm/hr. Se- ter a slight change is made in his
CSF: cerebrospinal fluid rologic testing reveals negative titers eyeglass prescription. The ophthal-
CT: computed tomography for herpes simplex virus (HSV) types mologic examination conducted un-
ECG: electrocardiography 1 and 2; HIV; cytomegalovirus; Toxo- der general anesthesia shows normal
ED: emergency department plasma; and hepatitis A, B, and C. intraocular pressure on both sides
EEG: electroencephalography HSV cultures from ulcers as well as but keratinization of the bulbar con-
ESR: erythrocyte sedimentation rate gonococcus and Chlamydia DNA and junctiva and cornea bilaterally. Both
GI: gastrointestinal rapid plasma reagin tests are negative. corneas appear cloudy, and punctu-
GU: genitourinary Antinuclear and antidouble-stranded ate corneal staining is noted on both
Hct: hematocrit DNA antibodies are negative. How- sides. There is a mild superior pannus
Hgb: hemoglobin ever, a test for antiphospholipid anti- present in both eyes. Funduscopic
MRI: magnetic resonance imaging bodies is mildly positive to B2 glyco- examination shows a normal cup-to-
WBC: white blood cell protein. Biopsy results are consistent disc ratio on both sides, and the ret-
with vulvitis. inas appear normal. The cause of his

Pediatrics in Review Vol.32 No.1 January 2011 35

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index of suspicion

suspected disorder is confirmed by Behçet disease (BD), and she was sulted in significant improvement in
blood tests. started on hydroxychloroquine, pen- her clinical status.
toxifylline, and aspirin. In addition,
given her age and the possibility of Differential Diagnosis
Case 3 Presentation high-risk behaviors, sexually trans- The differential diagnosis for oral
A 4-month-old boy presents with mitted diseases were ruled out. After and genital ulcers includes common
3 weeks of intermittent high fevers treatment was started, she developed infections with HSV and lympho-
and mild fussiness. He has no other panuveitis in the left eye, which did granuloma venereum virus as well as
signs. Initially, he was seen in the not resolve when topical corticoste- syphilis and chancroid. Once sexually
ED, and screening tests that included roids and methotrexate were added transmitted diseases are ruled out,
CBC, blood culture, serum electro- to the regimen. After missing an ap- BD and Crohn disease are important
lytes, BUN, creatinine, liver en- pointment with the ophthalmolo- considerations.
zymes, and urinalysis and culture all gist, she reported progressive wors-
yielded normal results. He was ening of vision in the right eye, new- The Condition
placed on antipyretic therapy only. onset paresthesias of the left upper The prevalence of BD is low in the
For the next 2 weeks he continued to extremity, and ataxia. Emergent United States and is highest in indi-
have fevers daily, despite taking acet- ophthalmologic examination re- viduals of Middle Eastern and Japa-
aminophen. Today his father notes vealed severe retinal vasculitis of the nese heritage. BD is correlated with
that the boy’s abdomen also is “more right eye (Figure). Brain MRI and the presence of human leukocyte an-
full” than it used to be. angiography showed subacute infarc- tigen B51. Childhood BD has no sex
The boy was born vaginally at tion of her right medulla and pons, bias, the age of presentation varies,
term and has received his 2-month suggestive of small vessel CNS vascu- and it represents 4% to 26% of all
immunizations. Past medical and litis. She received intravenous cyclo- cases of BD.
family histories have no findings of phosphamide and high-dose corti- BD is a multisystemic autoim-
note. He lives at home with his costeroids as an inpatient, which re- mune condition characterized by a
mother and older sister in an old
house on a farm in rural central Illi-
nois and does not attend child care.
Physical examination reveals a
very thin, fussy, yet consolable infant
whose temperature is 39.4°C, respi-
rations are 40 breaths/min, heart
rate is 130 beats/min, and blood
pressure is 88/48 mm Hg. Abdomi-
nal examination shows a firm and
significantly distended abdomen as
well as hepatosplenomegaly. The
liver edge is palpated just above the
right pelvic brim, and the spleen is
palpable 3 cm below the left costal
margin. Findings on the rest of the
physical examination are normal.
The patient is hospitalized and re-
mains febrile until the diagnosis is
made by additional laboratory evalu-
ation.
Figure. Color fundus photographs of the right eye demonstrate vascular sheathing
along the superotemporal arcade and marked cystoid macular edema. Note the
Case 1 Discussion perivascular yellow lipid exudation due to diffuse vasculitis in the mid-peripheral
This patient’s clinical presentation retina. The images are slightly blurred due to anterior segment inflammation, cataract,
was consistent with Adamantiades- and vitreous haze.

36 Pediatrics in Review Vol.32 No.1 January 2011

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classic triad of aphthous stomatitis,
genital ulceration, and uveitis. The
International Study Group has for-
malized clinical criteria requiring at
least three episodes of oral herpeti-
form or aphthous ulcerations within
a 12-month period observed directly
by a physician or reported by the
patient. In addition, two of the fol-
lowing also must be demonstrated:
1) recurrent painful genital ulcers
that heal with scarring; 2) ophthal-
mic lesions, including anterior or
posterior uveitis, hypopyon, or reti-
nal vasculitis; 3) skin lesions, includ-
ing erythema nodosum-like lesions,
pseudofolliculitis, or papulopustular
or acneiform lesions; and 4) positive
results from pathergy skin testing,
defined as the formation of a sterile
erythematous papule 2 mm in diam-
eter or larger that appears 48 hours
following a skin prick with a sharp
sterile needle. (1)
The clinical presentation of child-
hood BD is variable, and different
organ systems can be involved. Oral
ulcers (100%), genital ulcers (33% to
96%), skin lesions (35% to 100%),
and ophthalmic lesions (27% to 92%)
are common findings at presenta-
tion. The ophthalmic findings in-
clude recurrent or persistent anterior
uveitis with or without posterior uve-
itis, hypopyon, retinitis, papillitis,
macular edema, and retinal vasculitis.
Because it is a multisystem disease,
additional clinical manifestations can
involve nearly any organ system. GI
involvement can range from abdom-
inal pain to gastric or small bowel
ulcerations with risk of perforation
and can mimic Crohn disease. Pul-
monary artery aneurysms with risk of
massive hemoptysis as well as intersti-
tial lung disease are found rarely in
patients who have BD. Neuro-BD
presents commonly as meningoen-
cephalitis, but parenchymal lesions
can lead to hemiparesis and cognitive
changes. Arthritis, thrombophlebitis,
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and vasculitis are other manifesta-
tions of BD. The presence of anticar-
diolipin antibodies may be related to
retinal vascular disease.
Treatment and Prognosis
Treatment is tailored to clinical man-
ifestations. Numerous agents are
available to treat oral and genital ul-
cers, including colchicine, pentoxi-
fylline, thalidomide, corticosteroids,
hydroxychloroquine, and azathio-
prine. Uveitis is treated with ocular
corticosteroids (with or without sys-
temic corticosteroids), methotrex-
ate, and anti-tumor necrosis factor
(TNF) agents. Retinal and CNS vas-
culitis often present therapeutic chal-
lenges. Early recognition of these
complications and aggressive treat-
ment with topical and systemic im-
munosuppressive medication (such
as cytotoxic and anti-TNF agents) is
critical to protect visual acuity and
minimize long-term ocular and neu-
rologic sequelae. A multidisciplinary
approach involving the pediatrician,
rheumatologist, and ophthalmolo-
gist is ideal when treating children
who have BD.
The prognosis is guarded for chil-
dren who present with active disease
and severe ocular, CNS, and pulmo-
nary involvement. Significant ocular
involvement can result in irreversible
visual loss leading to permanent
blindness, especially when the pa-
tient has posterior uveitis with syn-
echiae and retinal vasculitis. Devas-
tating complications can occur with
occlusions and aneurysms of the
CNS and cardiac and pulmonary vas-
culature.
Lessons for the Clinician
● BD presents challenges to the pe-
diatrician in establishing early diag-
nosis.
● For patients who have multisystem
diseases such as BD, it is essential to
index of suspicion
perform a comprehensive history
and physical examination, and care
should be coordinated within a
multidisciplinary team.
● Once BD is diagnosed, it is critical
to screen for common complica-
tions, especially ocular involve-
ment.
● In addition to ocular involvement,
the patient also can present with
varied CNS findings.
● Untreated systemic disease can be
devastating and warrants prompt
diagnosis and treatment.
(Benjamin Bruins, MD, Children’s
Hospital of Philadelphia, Philadel-
phia, PA; Howard F. Fine, MD,
MHSC, L. Nandini Moorthy, MD,
MS, UMDNJ/RWJ Medical School,
New Brunswick, NJ)
Reference
1. Criteria for diagnosis of Behçet’s disease:
International Study Group for Behçet’s Dis-
ease. Lancet. 1990;335:1070 –1080
Case 2 Discussion
The findings of xerophthalmia and
keratomalacia in this patient are char-
acteristic of hypovitaminosis A. Vita-
min A was undetectable in the serum,
confirming the cause of the eye find-
ings. A dietary history revealed ab-
normal eating habits. The boy’s
meals and snacks consisted of French
fried potatoes and tortillas and were
devoid of leafy vegetables, fruits, and
animal sources of food. This diet pro-
vided him less than 1% of the daily
recommended dietary allowance
(RDA) of vitamin A. There was no
history or laboratory evidence to sug-
gest fat malabsorption. He was pre-
scribed a 10,000-IU vitamin A cap-
sule daily for 60 days along with
multivitamins, minerals, and lubri-
cant eye drops. Within 1 month, his
vision improved, he lost his photo-
sensitivity, and he was no longer rub-
bing his eyes. Slitlamp examination
Pediatrics in Review Vol.32 No.1 January 2011 37
index of suspicion
showed clear corneas without stain-
ing. He could identify red, blue,
green, and yellow colors. Visual acu-
ity testing suggested that he saw
8-mm targets at 2 feet with glasses.
Refraction showed that distance acu-
ity (20/600) could not be improved
with a change in eyeglass prescrip-
tion. He was classified as being le-
gally blind.
His serum 25-hydroxyvitamin D
concentration also was severely de-
pressed (⬍7 ng/mL [17.4 nmol/
L]), although serum calcium and
phosphorus values were normal.
A radiograph of the knee revealed
mild osteopenia without signs of
rickets. Prothrombin time, serum vi-
tamin E concentration, and serum
vitamin B12 values were within
normal range. He was given vitamin
D3 (50,000 IU) once a week for
12 weeks. At the end of 3 months of
treatment, his serum vitamin A and
25-hydroxyvitamin D values had
normalized. Occupational therapy
helped in expanding his food reper-
toire, and he started consuming
hamburger patties, fried chicken, sal-
ads, oranges, gelatin desserts, and
juices. This improved diet was able to
meet 50% of his vitamin A RDA but
was significantly deficient in vitamin
D. He remained on multiple vitamin
supplements.
Vitamin A
Vitamin A plays two roles in ocular
metabolism: photo transduction and
prevention of xerophthalmia. The
retina has two discrete photorecep-
tors, the rods and the cones. The rod
cells, containing rhodopsin, sense
motion and allow for adaptation to
dark. The cones contain iodopsin
and detect color. The aldehyde form
of vitamin A serves as the precursor
for both of these visual pigments. In
vitamin A deficiency (VAD), synthe-
sis of rhodopsin is decreased, result-
ing in night blindness. By promoting
38 Pediatrics in Review Vol.32 No.1 January 2011
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the integrity of lacrimal glands and
goblet cells in the surface epithelium
of the conjunctiva, vitamin A helps in
the production of a healthy tear film.
The latter keeps the corneal surface
moist, preventing ocular dryness and
its related complications such as xe-
rophthalmia.
Hypovitaminosis A can occur in
either primary or secondary form.
A primary form occurs among pa-
tients whose diet lacks adequate
amounts of fruits, liver, and leafy veg-
etables. Secondary causes include fat
malabsorption, disorders associated
with exocrine pancreatic insuffi-
ciency (eg, cystic fibrosis), chronic
cholestasis, and abetalipoproteine-
mia. Postsurgical causes include bari-
atric procedures and short bowel syn-
drome.
Clinical Manifestations of
VAD
VAD, although rare in the United
States, is a leading cause of morbidity
and mortality, affecting millions of
children in resource-poor countries.
Approximately 250,000 to 500,000
children in developing countries be-
come blind each year due to VAD,
with the highest prevalence in South-
east Asia and Africa. VAD is associ-
ated with increased morbidity and
mortality in various disease states,
such as measles, due to an altered
immune response.
An initial symptom of hypovita-
minosis A, weakened adaptation to
the dark, can evolve to night blind-
ness if untreated. Xerophthalmia, an-
other clinical feature of VAD, occurs
due to keratinization of ocular epi-
thelium. The cornea dries, develops
scaly layers of cells, and is more sus-
ceptible to infections. As disease
progresses, the cornea degenerates,
turns hazy, and becomes wrinkled
and soft (keratomalacia), resulting in
irremediable blindness.
Bitot spots, which are superficial,
irregular, or triangular-shaped foamy
gray patches containing keratinized
epithelial debris, are found on bulbar
conjunctiva. In retrospect, the bilat-
eral pannus described in this patient
may have been Bitot spots. Other
clinical features of VAD include poor
overall growth, impaired immunity,
and susceptibility to infections.
Treatment and Prevention of
VAD
Recognizing the endemic prevalence
of VAD states in resource-poor
countries, the World Health Organi-
zation has published age-specific
dosing guidelines for prevention and
treatment of VAD. Dietary recom-
mendations include dark green leafy
vegetables, carrots, sweet potatoes,
and brightly colored fruits. Liver,
beef, chicken, fortified milk, and ce-
reals are other sources of vitamin A.
If adequate intake cannot be assured,
supplemental vitamin should be pro-
vided.
Autism and Altered Eating
Behavior
Autism is a developmental disorder
characterized by impairment of com-
munication and social interaction
along with stereotypic and repetitive
behaviors. Many children who have
autism have feeding difficulties and
limited food selection related to sen-
sory regulatory difficulties, resulting
in strong interest in some textures
and taste and complete aversion to
others. Affected children frequently
are reported as insisting on routines
and playing with food. Fewer than
50% of the parents of such children
reported that their children ate bal-
anced diets, and 6% of parents re-
ported a poor appetite for most foods
among their children. Such aberrant
eating behaviors place some children
who have autism at greater risk for
both macronutrient and micronutri-
ent deficiencies. Therefore, many nu-

tritional deficiency states such as
scurvy, rickets, blindness, and early
failure to thrive have been reported
in these children.
Lessons for the Clinician
● Clinicians should be cognizant of
the abnormal eating habits of pa-
tients who have autism.
● A comprehensive dietary history
and nutritional assessment may
help in recognizing uncommon
but classic vitamin deficiency
states.
● Even those who are overweight or
obese can have micronutrient defi-
ciencies.
(Ayesha Jain, Texas A&M University,
College Station, TX; Ashok K. Jain,
MD, and Thomas W. Milligan, MD,
Driscoll Children’s Hospital, Corpus
Christi, TX)
Case 3 Discussion
Hepatosplenomegaly results from a
large array of conditions and gener-
ally occurs because of inappropriate
storage, infiltration, vascular conges-
tion, or inflammation. Because the
liver plays an important role in me-
tabolism, metabolic abnormalities
can result in storage of glycogen, lip-
ids, proteins, and metals in the liver
that cause hepatomegaly. Many of
these conditions are accompanied by
neurologic findings or deterioration,
such as developmental delay or sei-
zures. Similarly, splenomegaly can
result from metabolic disorders. In
this patient, an extensive metabolic
evaluation yielded negative results.
Hepatosplenomegaly caused by
infiltration is likely due to tumors or
conditions such as hemophagocytic
syndromes and extramedullary he-
matopoiesis. In this patient, the CBC
was normal. In addition, abdominal
ultrasonography and a contrast-
enhanced CT scan of the abdomen
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and pelvis revealed an enlarged liver
(9 cm in length) that had normal echo-
genicity and lacked any intra- or extra-
hepatic masses or cysts as well as biliary
ductal dilatation. The studies also
showed an enlarged spleen (8 cm in
length) without any retroperitoneal
lymphadenopathy or ascitic fluid.
Vascular congestion that results in
an enlarged liver can be divided into
suprahepatic (congestive heart fail-
ure, hepatic vein thrombosis) and in-
trahepatic (veno-occlusive disease,
Alagille syndrome) conditions. The
resulting portal hypertension also
can cause congestive splenomegaly.
Vascular congestion was ruled out
for this child because of normal echo-
cardiographic findings and normal
flow pattern on Doppler abdominal
ultrasonography.
Inflammatory conditions, which
commonly cause hepatosplenomegaly,
usually are due to infections with vi-
ruses, bacteria, fungi, or parasites and
typically present with fever. Other
causes of hepatosplenomegaly due to
inflammation are toxins, drugs (non-
steroidal anti-inflammatory drugs,
isoniazid, propylthiouracil, sulfon-
amides), and autoimmune diseases. In
this patient, repeat CBC, complete
metabolic panel, C-reactive protein,
and ESR yielded normal results. In ad-
dition, blood, urine, and CSF cultures
as well as serologic tests for HIV, hep-
atitis A, B, and C, Toxoplasma gondii,
rubella virus, herpes simplex virus, cy-
tomegalovirus, and Ebstein-Barr virus
were negative. A purified protein de-
rivative skin test for tuberculosis also
yielded negative results. Screening im-
mune evaluation, including serum
concentrations of immunoglobulins
and immune phenotyping, also had
normal results. On day 7 of admission,
urine was sent for Histoplasma capsu-
latum and Blastomyces dermatitidis an-
tigens and was positive for both. Based
on clinical and epidemiologic evi-
index of suspicion
dence, progressive disseminated his-
toplasmosis (PDH) was diagnosed.
The Condition
H capsulatum is a dimorphic fungus
found in the environment as a sapro-
phyte mold in mycelial and micro-
conidia (aerosolized fungal spore)
forms and as yeast in host tissue. The
organism is found primarily in the
midwestern United States, specifi-
cally near the Ohio and Mississippi
river valleys. Soil rich with nitrate
(from bird droppings or decayed
wood) allows the fungus to thrive. H
capsulatum infection causes symp-
toms in fewer than 5% of infected
people, with most presenting with an
influenzalike illness. However, the
microconidia can be inhaled into the
alveoli, remain as spores, and lead to
reinfection as they germinate and
proliferate into the yeast phase. The
yeast cells can gain access to the re-
ticuloendothelial system via hilar
lymph nodes and, thus, have the po-
tential to seed any part of the body,
particularly the GI system, skin, adre-
nals, and CNS. This rare phenome-
non occurs in 10% of cases and is
known as PDH.
PDH usually is seen in immuno-
compromised individuals, specifically
individuals who have HIV infec-
tion, X-linked hyperimmunoglobulin
(Ig)M syndrome, hyper-IgE syn-
drome, and common variable immu-
nodeficiency, but can occur in healthy
young children. Positive culture from
bone marrow, blood, sputum, or tissue
is the gold standard for diagnosis. My-
cologic media can take 1 to 6 weeks to
grow the organisms. Polysaccharide
antigen testing is a rapid and specific
method for diagnosis and is used to
monitor response to treatment. Be-
cause cross-reactions occur with other
mycoses, clinical and epidemiologic
considerations, as with this patient, as-
sist in differentiating the infections.
Pediatrics in Review Vol.32 No.1 January 2011 39
index of suspicion
Treatment
Treatment for PDH involves intrave-
nous (IV) amphotericin B, followed
by long-term oral itraconazole. Al-
though data for children are limited,
based on international studies, some
experts recommend IV amphotericin
B for 2 to 3 weeks, followed by 3 to 6
months of oral itraconazole.
Clinical Course
This boy received IV amphotericin B
for 2 weeks, and by the third day, his
fever had subsided. On further inves-
tigation, it was found that his father
had complained of excess bird drop-
pings on his truck 1 month earlier
and was forced to cut down the trees
in front of the farm. Two other out-
40 Pediatrics in Review Vol.32 No.1 January 2011
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breaks of acute histoplasmosis had
occurred in the county within the
past 3 years. This patient continued
to do well and was transitioned to
oral itraconazole for 6 months. After
2 months of therapy, his spleen was
no longer palpable, and the liver
edge was within normal limits. Re-
peat urine test for H capsulatum an-
tigen at that time showed negative
results.
Lessons for the Clinician
● Massive hepatomegaly has a large
differential diagnosis.
● Concurrent splenomegaly usually
is explained by involvement of the
reticuloendothelial system.
● In areas endemic for certain myco-
ses, failure to consider a fungal in-
fection for prolonged fevers may
delay the diagnosis.
● Most patients who develop PDH
are immunocompromised, usually
having defects with T-cell-
mediated immunity. However,
healthy children younger than the
age of 2 years who have difficulty
clearing the infection do develop
PDH rarely.
(Rinku Patel, DO, Advocate Hope
Children’s Hospital, Oak Lawn, IL)
To view Suggested Reading lists,
for these cases, visit http://pedsin
review.aappublications.org and click
on “Index of Suspicion”.
 Index of Suspicion • Case 1: Recurrent Oral Ulcers in an Adolescent • Case 2:
Visual Impairment in an Autistic Child • Case 3: Fever and Hepatosplenomegaly
in an Infant
Benjamin Bruins, Howard F. Fine, L. Nandini Moorthy, Ayesha Jain, Ashok K. Jain,
Thomas W. Milligan and Rinku Patel
Pediatr. Rev. 2011;32;35-40
DOI: 10.1542/pir.32-1-35

Updated Information including high-resolution figures, can be found at:

& Services http://pedsinreview.aappublications.org/cgi/content/full/32/1/35
Supplementary Material Supplementary material can be found at:
http://pedsinreview.aappublications.org/cgi/content/full/32/1/35/
DC1
Permissions & Licensing Information about reproducing this article in parts (figures,
tables) or in its entirety can be found online at:
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 Thrombotic Disorders
Michael Roth and Deepa Manwani
Pediatr. Rev. 2011;32;41-43
DOI: 10.1542/pir.32-1-41

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/cgi/content/full/32/1/41

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2011 by the American Academy of
Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.

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In Brief
Thrombotic Disorders
Michael Roth, MD
Deepa Manwani, MD
Children’s Hospital at Montefiore
Bronx, NY
Author Disclosure
Drs Roth, Manwani, and Adam have
not disclosed any financial
relationships relevant to this In Brief.
This commentary does not contain a
discussion of an unapproved/
investigative use of a commercial
product/device.
Antithrombotic Therapy for Venous
Thromboembolic Disease. Kearon C,
Kahn S, Agnelli G, et al. Chest. 2008;
133:176S-193S
Antithrombotic Therapy in Neonates
and Children. Monagle P, Chalmers
E, Chan A. Chest. 2008;133:887S-
968S
Diagnosis and Treatment of Thrombosis
in Children: General Principles.
Young G. Pediatr Blood Cancer.
2006;46:540 –546
How I Treat Venous Thrombosis in
Children. Manco-Johnson MJ. Blood.
2006;107:21–29
Thrombosis historically has been con-
sidered a disorder of older adults, in
whom it has an incidence of 2.5% to
5%. In comparison, the overall inci-
dence of thrombosis in pediatrics is
only 0.07 per 10,000 children, with
neonates and adolescents affected
most commonly. Advances in pediatric
critical care, with survival of sicker
children, coupled with the frequent use
of central venous lines, have contrib-
uted to the growing prevalence of
thrombotic disorders. The incidence of
Downloaded from http://pedsinreview.aappublications.org. Provided by Health Internetwork on April 20, 2011
thrombosis in hospitalized children is
reported to be 5.3 per 10,000 children,
greatly increased from previous reports,
but still 2 logs lower than in adults. The
small numbers of patients, as well as
the difficulty of sampling blood, partic-
ularly in neonates, have been impedi-
ments to pediatric-specific clinical
trials. As a result, evidence-based treat-
ment for thrombotic disorders in child-
hood is largely in its infancy. Treatment
frequently has been extrapolated from
studies performed in adults, often with
disappointing results. The more recent
development of national and interna-
tional registries holds great promise as
emerging data reveal potentially impor-
tant differences in outcomes in chil-
dren.
Hemostasis is a balance between
the tendencies to bleed and to clot and
results from an equilibrium between
procoagulant and anticoagulant fac-
tors. A perturbation in any of these
components can lead to an increased
tendency for thrombosis. The Virchow
triad describes the three broad catego-
ries of such disruptions: damaged en-
dothelium, interrupted or decreased
blood flow, and abnormalities in blood
composition. Damage to the endothe-
lium can be caused, for example, by
trauma from a central catheter or from
inflammation, as in vasculitis. De-
creased blood flow can result from
arrhythmias or from immobilization
leading to stasis. Abnormalities in the
blood most commonly result from de-
fective or deficient coagulant proteins.
Very often these predisposing factors,
either inherited or acquired, work in
concert, providing a cumulative risk of
thrombus formation. Acquired risk fac-
tors may be transient, such as preg-
nancy, surgery, and the presence of a
in brief
central catheter. Genetic thrombophilia
is obviously longstanding and has im-
plications for the health of other family
members as well. Table 1 provides a
more detailed list of potential causes of
thrombophilia.
The signs and symptoms of venous
and arterial thrombosis vary by the
location and extent of vessel occlusion.
Many of the acute symptoms of venous
thrombosis result from vessel obstruc-
tion, stasis, and decreased venous re-
turn, leading to pain and swelling distal
to the site of obstruction. One third of
venous thrombotic events in children
involve the upper extremities, a signif-
icantly higher proportion than in adults
because of the disproportionately larger
number of catheter-related thromboses
in children. An obstructing thrombus in
the superior vena cava (SVC) can lead
to SVC syndrome, consisting of upper
extremity and facial swelling. Sinus ve-
nous thromboses often present with
headache, sometimes occurring with
additional neurologic symptoms such
as blurry vision and even seizures.
Arterial thrombi usually present
with obvious signs of decreased perfu-
sion. In the peripheral arteries, pallor
and coolness may progress rapidly to
cyanosis and tissue necrosis. Cerebral
arterial thrombi present dramatically
with new-onset neurologic deficits.
Pulmonary artery thrombi often are
asymptomatic but can lead to hypoxia,
tachypnea, pleuritic chest pain, respira-
tory failure, and circulatory collapse,
depending on size and location.
Venous hypertension from chroni-
cally obstructed and refluxed flow leads
to significant morbidity. Approximately
10% to 60% of children who have
thrombi of the extremity develop post-
thrombotic syndrome, a clinical con-
Pediatrics in Review Vol.32 No.1 January 2011 41
in brief
Causes of
Table 1.
Thrombophilia
Acquired Thrombophilia/Risk
Factors
Indwelling catheter, trauma,
recent surgery, immobilization,
congenital heart disease,
prosthetic valves, diabetes,
sickle cell anemia,
chemotherapy, infection, oral
contraceptives, smoking,
dehydration, nephrotic
syndrome, inflammatory bowel
disease, antiphospholipid
syndrome, elevated factor VIII,
malignancy, autoimmune
disease
Genetic Thrombophilia
Protein C deficiency, protein S
deficiency, antithrombin
deficiency, prothrombin 20210
mutation, factor V Leiden
mutation, elevated
homocysteine/MTHFR, elevated
lipoprotein A
MTHFR⫽methylenetetrahydrofolate reduc-
tase gene
stellation of symptoms that includes
pain, swelling, visible collateral vein
formation, hyperpigmentation, indura-
tion, and stasis ulcers. Similarly, visceral
thrombosis can lead to organ dysfunc-
tion over the long term.
Definitive diagnosis of thrombosis re-
quires appropriate imaging studies and is
dependent on the location of the throm-
bus. Ultrasonography is the first-line
imaging technique for a deep venous
thrombosis of the extremity, especially of
the lower limb. Echocardiography is used
to view cardiac and proximal vena cava
thrombi. Imaging upper extremity throm-
bosis can be problematic, and detection
of clots in the proximal veins requires
either computed tomography (CT) scan or
magnetic resonance imaging. Thrombi in
the central nervous system vasculature
are imaged best by magnetic resonance
angiography. No one test is best for
42 Pediatrics in Review Vol.32 No.1 January 2011
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imaging pulmonary emboli. CT angiogra-
phy is often the first-line approach for
children suspected of having pulmonary
emboli (PE). Helical CT frequently is ob-
tained in adults at high risk for PE be-
cause it has high specificity, and a
ventilation-perfusion scan often is per-
formed in patients at low risk because of
its high negative predictive value.
In addition to imaging, measure-
ment of D-dimer has demonstrated
utility as a nonspecific marker of
thrombosis. D-dimer is generated from
the action of naturally occurring fi-
brinolytic enzymes on cross-linked fi-
brin within the thrombus. A positive
D-dimer test result is worrisome for the
presence of a thrombus but should be
considered in conjunction with imaging
test results.
Mortality from thrombosis in chil-
dren is low compared with that in
adults. Most affected children survive
and can be expected to live for decades
following a thrombotic event. Thus, the
impact on long-term morbidity and
quality of life is greater in children.
Rapid treatment to prevent complica-
tions must be balanced carefully with
the risk of bleeding. Anticoagulants
form the mainstay of therapy (Table 2).
Unfractionated heparin (UH) or low-
molecular weight heparin (LMWH) is
used initially for at least 5 to 7 days. In
stable patients, therapy is completed by
either continuing LMWH or switching
to warfarin.
Because of its short half-life, UH has
been used commonly as the first-line
agent in patients who have a high risk
for bleeding or a need for invasive
procedures. For the same reason, UH
must be administered as a continuous
intravenous infusion. LMWH appears to
be effective, with fewer adverse effects
than UH, and is being used increasingly
as front-line therapy. LMWH works
largely by inhibiting factor Xa, so dos-
ing must be titrated to anti-Xa activity,
not to the activated partial thrombo-
plastin time. Warfarin, a vitamin K an-
tagonist, requires very frequent moni-
toring, which may offset its advantage
as an oral agent. The need to crush the
medication, which is not available as a
liquid preparation, leads to significant
dose-to-dose variability, making warfa-
rin impractical for use in very young
children.
Whereas the anticoagulants block
the formation of clots, tissue plasmin-
ogen activator (TPA) is a thrombolytic
agent that promotes clot breakdown by
activating plasminogen to plasmin,
thus tipping hemostatic balance in fa-
vor of increased fibrinolysis. Systemic
thrombolytic therapy should be
strongly considered for clots that have
a high risk of morbidity and mortality.
The rate of vascular patency following
anticoagulant therapy in children has
been reported at 50%; following
thrombolysis, it is greater than 90%.
Systemic TPA is effective when admin-
istered within 2 weeks of symptomatic
clot onset and only partially effective
beyond 2 weeks. TPA can be delivered
locally to the site of the thrombus via
catheter-directed administration and
has been effective even in clots that
persist several months from diagnosis.
Contraindications to the use of throm-
bolytic agents include active bleeding,
recent surgery, and cerebral ischemia or
hemorrhage. Surgical thrombectomy is
an option for treating life- or limb-
threatening thrombi when thrombolysis
is contraindicated or has failed.
Antiplatelet agents such as aspirin are
used in certain cardiac disorders, arterial
ischemic stroke, and Kawasaki disease.
Several anticoagulant-deficient states,
such as antithrombin III deficiency and
homozygous protein C disease, require
specific protein concentrate replacement
therapy. Adjuvant therapies include fitted
compression stockings, nutritional and
exercise counseling to reduce obesity,
and adequate control of comorbid condi-
tions. Estrogen-containing oral contra-
ceptives should be avoided in at-risk pa-
tients, especially those who carry the
 in brief

Table 2. Commonly Used Anticoagulants and Thrombolytics

Mechanism of
Agent Action Pros Cons Monitoring
Unfractionated Binds to Rapid onset of action, Continuous infusion. Anti-factor Xa concentration
heparin (UH) antithrombin III short half-life, easy Risk of bleeding, (goal: 0.3 to 0.7) PTT
and accelerates reversibility, effective HIT, osteoporosis (goal: two to three times
inhibition of antidote (protamine) baseline)
thrombin and
factor Xa
Low-molecular Inhibits factor Xa Long half-life, twice a Subcutaneous Anti-factor Xa concentration
weight day subcutaneous injections. 4 hours after second dose
heparin administration Protamine reversal (goal: 0.6 to 1.0)
(allows for outpatient not complete, HIT
treatment), stable (lower than in
pharmacokinetics UH), osteoporosis
allows infrequent
monitoring and
lowers risk of
bleeding
Vitamin K Reduces the Long half-life, oral Many food and INR (goal: 2 to 3) dependent
antagonists concentrations administration, medication on indication
(warfarin) of vitamin K- effective antidote interactions and
dependent factors: (vitamin K) unpredictable
II, VII, IX, and X concentrations,
requires frequent
titration
Tissue Activates Rapid onset of action, Higher risk of Monitor clot by serial
plasminogen plasminogen to active lytic agent for bleeding, requires imaging. D-dimer
activator plasmin, rapidly high-risk clots frequent increases. Fibrinogen
promoting clot monitoring, only decreases
break down administered in
inpatient setting
HIT⫽heparin-induced thrombocytopenia, INR⫽international normalized ratio, PTT⫽partial thromboplastin time

factor V Leiden mutation or have anti-
thrombin deficiency.
Thromboembolic events in children
have increased and are a significant
cause of morbidity and mortality. On-
going multi-institutional research
should generate the evidence necessary
for tailored therapy rather than the
“adult-size fits all” approach. Active
debate still centers on whom to test,
the timing of testing, and which tests
to order for children at risk for throm-
bosis. Novel oral anticoagulant agents
with improved safety profiles are
needed and are in development.
Comment: Progress comes at a
price, and with advances in neonatal
and pediatric critical care, particularly
with the widespread use of central
venous catheters, we are seeing more
thrombotic complications affecting
children than in the past. However,
even with their growing prevalence,
thromboses remain relatively uncom-
mon in pediatrics. As with so many
other uncommon conditions, the good
news of rarity spawns the bad news
that evidence sufficient to guide ther-
apy is difficult to gather. Depending on
data from the treatment of adults is not
ideal because we know children are
different. The paradigm for dealing with
this frequent problem in pediatrics is
provided by the collaborative efforts
that over the past few decades have
transformed the prognosis for acute
lymphoblastic leukemia. We need to
encourage as standard procedure the
development of national and interna-
tional databases and study protocols
for the multitude of individually un-
common conditions that collectively
affect so many children.
Henry Adam, MD
Editor, In Brief

Pediatrics in Review Vol.32 No.1 January 2011 43

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 Thrombotic Disorders
Michael Roth and Deepa Manwani
Pediatr. Rev. 2011;32;41-43
DOI: 10.1542/pir.32-1-41

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 Ethics for the Pediatrician: Physician Interaction With the Pharmaceutical
Industry
Mark X. Cicero, Michael B. Curi and Mark Mercurio
Pediatr. Rev. 2011;32;e1-e3
DOI: 10.1542/pir.32-1-e1

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/cgi/content/full/32/1/e1

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2011 by the American Academy of
Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.

Downloaded from http://pedsinreview.aappublications.org. Provided by Health Internetwork on April 20, 2011


Author Disclosure
Drs Cicero, Curi, and Mercurio have
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.
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Physician Interaction With the
Pharmaceutical Industry
Mark X. Cicero, MD,* Michael B. Curi, MD,† Mark Mercurio, MD§
Introduction
In the United States, more than 40
billion dollars are spent annually in
drug research and development. (1)
Wholesale pharmaceutical sales to-
talled $275 billion in 2008. Pharma-
ceuticals are both an indispensable
tool and a staggering expense in
health care. When caring for chil-
dren, pediatricians consider a medi-
cation’s efficacy, potential adverse
effects, and often whether the child’s
health-care insurance covers the pre-
scription. A complex relationship
has evolved between pharmaceutical
companies and pediatricians, with
drug manufacturers historically pro-
viding gifts, sponsoring continuing
medical education (CME), and de-
livering samples to medical offices.
We explore this relationship in light
of recommendations of the American
Academy of Pediatrics (AAP) and the
American Board of Pediatrics (ABP)
and the ethical conflicts relevant to
this relationship.
Pharmaceutical Industry Gifts
For more than a decade, awareness of
the influence that industry gifts have
on physician prescribing habits has
been increasing. (2) In an oft-cited
work, Steinman and associates (3)
found most residents (61%) felt they
were immune to the influence of
pharmaceutical representatives and
their gifts, but only 16% believed
their peers were similarly above the
influence of the drug industry. In
*Assistant Professor of Pediatrics, Yale University
School of Medicine, New Haven, CT.
†
Assistant Clinical Professor of Pediatrics, University
of Connecticut School of Medicine, Farmington, CT.
§
Associate Professor of Pediatrics, Yale University
School of Medicine, New Haven, CT.
ethics for the pediatrician
truth, industry gifts may influence
behavior. Such gifts may cause a con-
flict of interest with a pediatrician’s
fiduciary relationship to the patient.
By definition, a fiduciary relationship
is one based on trust, in which the
physician works for the benefit of
the patient, holding his or her needs
as the highest priority.
Professional organizations and
the industry have made attempts to
address the potential conflicts of
interest. In 2002, the American
Medical Association (AMA) and
the Pharmaceutical Researchers and
Manufacturers of America (PhRMA)
released similar voluntary codes gov-
erning gifts and other interactions
between pharmaceutical representa-
tives and physicians. The 2002 AMA
codes, which were endorsed by the
AAP, limited gifts to educational
items and reminder items of minimal
value, such as pens and notepads.
Further, the code eliminated mone-
tary and recreational gifts.
PhRMA published more stringent
restrictions in 2009, (4) no longer
allowing reminder items, prohibiting
meals at restaurants, and requiring
pharmaceutical representatives to be
trained in ethics and legal statutes
pertaining to interacting with physi-
cians. The 2009 guidelines still allow
the meal provision to doctors in of-
fices, although feeding physicians
does not benefit patients directly.
According to PhRMA, The Code at-
tempts to ensure that “all interac-
tions [between manufacturers and
health care professionals are] focused
on informing healthcare profession-
als about products, providing scien-
tific and educational information,
Pediatrics in Review Vol.32 No.1 January 2011 e1
ethics for the pediatrician
and supporting medical research and
education.”
In April 2010, the Council of
Medical Specialty Societies (CMSS),
of which the AAP is a member, re-
leased a Code For Interactions With
Companies. (5) This Code elimi-
nates all pharmaceutical logos from
conferences, removes all reminder
items, and limits overt pharmaceuti-
cal sponsorship of professional con-
ferences. Despite these new, volun-
tary protections, pediatricians should
use caution when pharmaceutical
representatives offer any gifts.
There is evidence that even edu-
cational items and meals may induce
a sense of obligation in the receiver
to the giver. (2)(3)(6) The 2007
AAP Committee on Bioethics (COB)
statement on professionalism reminds
pediatricians of the responsibilities
to children and families as well as to
the medical profession. (7) The COB
states, “Issues of professionalism and
the integrity of the profession as a
whole are raised when pediatricians
are the recipients of special market-
ing incentives such as gifts . . . from
representatives of the health care in-
dustry.” The COB suggests further
that acceptable educational gifts
should benefit patients by improving
the knowledge and skills of the phy-
sician. Pediatricians should be aware
that they are subject to influence
from the pharmaceutical industry
when they accept gifts, no matter
how small.
Continuing
Medical Education
In the United States, 44 states re-
quire CME to maintain medical li-
censure. This requirement ensures
that physicians maintain a current
knowledge base. The ABP encour-
ages pediatricians to “take primary
responsibility for lifelong learning to
improve knowledge, skills, and prac-
e2 Pediatrics in Review Vol.32 No.1 January 2011
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tice performance” as part of mainte-
nance of certification in general pedi-
atrics. Despite its importance, CME
is an unfunded, sometimes costly
mandate.
The pharmaceutical industry spon-
sors CME, providing a service to
pediatricians by defraying the cost
of seminars and conferences. How-
ever, with CME sponsorship comes
the opportunity to influence the
message. For example, an industry-
sponsored seminar on atypical pneu-
monia may focus subtly on treatment
rather than diagnosis, allowing em-
phasis to be placed on a newly re-
leased antibiotic. An atypical pneu-
monia seminar free from industry
sponsorship is potentially more bal-
anced. Speakers at CME presenta-
tions who have received honoraria
from drug companies disclose the fi-
nancial relationship, and it is hoped
that they present unbiased data.
However, disclosing conflicts of in-
terest may not be sufficient to ensure
freedom from industry-favorable bias.
As a potential protection from
bias, third-party agencies known as
“medical education and communica-
tion companies” (MECCs) often
prepare the agendas for CME events
and choose and compensate the
speakers. (8) Due to criticism of serv-
ing both educational and promo-
tional roles, most MECCs now re-
port an exclusive focus on educa-
tion. (9) Despite this commitment
to CME, MECCs still receive most
of their compensation from the phar-
maceutical industry. Full disclosure
of sponsorship is a necessary step in
highlighting potential conflicts of
interest and endorsed in the CMSS
Code. (5) The Code also calls for
independent development of educa-
tional programs, free of industry sup-
porters. Thus, the role of MECCs in
a Code-compliant landscape is un-
certain.
Sampling and Detailing
As with most industries, profit is a
driving force for the pharmaceut-
ical industry. Members of PhRMA
might seek to accomplish this goal
by persuading physicians to prescribe
more expensive drugs when less costly
alternatives are equally effective. Drug
representative office detailing and pro-
vision of samples change prescribing
practices. (10)(11) This continued
presence of detailing and sampling,
even after the changes in the PhRMA
Code, is clear evidence of significant
efficacy.
The amount of influence industry-
provided samples have on prescrib-
ing behavior has been debated. (10)
(11)(12) What is the benefit to the
patient in receiving samples? Samples
allow physicians to provide medica-
tions to patients when cost otherwise
would be prohibitive. Samples are a
part of marketing strategy, but it is an
oversimplification to dismiss samples
as only marketing.
Because most physicians’ offices
are not provided samples of generic,
less-expensive medicines, there is a
dilemma. Many sample medicines are
for chronic illnesses, a situation that
offers an avenue for pharmaceutical
companies to leverage patients to
fill a prescription multiple times, re-
couping the initial sample cost many
times over. Miller and associates (13)
reported an increase in prescriptions
for more costly prescription drugs
when samples were present in an in-
ternal medicine practice. However,
samples in a doctor’s office do not
ensure that a patient will use the
sampled medicines because much of
prescribing is limited by formulary
coverage.
It seems best to seek a physician-
pharmaceutical relationship that bene-
fits patients long term, rather than pro-
viding samples that lead to greater
long-term expense. Strategies to ac-
complish this goal include coupons
 ethics for the pediatrician

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turers of America. Code on Interactions With
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 Ethics for the Pediatrician: Physician Interaction With the Pharmaceutical
Industry
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 Delayed Tooth Emergence
Jeffrey M. Karp
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Article ear, nose, throat

Delayed Tooth Emergence

Jeffrey M. Karp, DMD, MS*
Objectives After completing this article, readers should be able to:

1. Recognize abnormalities in tooth emergence timing and order based on oral inspection.
Author Disclosure 2. Discuss local and systemic causes of delayed tooth emergence.
Dr Karp has disclosed 3. List treatment modalities available for management of delayed tooth emergence.
no financial 4. Determine when timely referral to a dentist is necessary.
relationships relevant
to this article. This
Introduction
commentary does not
Delayed tooth emergence (DTE) is a clinical term used when exposure of a tooth or
contain a discussion multiple teeth through the oral mucosa is overdue, according to population norms based
of an unapproved/ on chronologic age. DTE is common in childhood and adolescence, yet it is often
investigative use of a overlooked or dismissed in pediatric primary care. Timely screening and recognition of
commercial product/ DTE by clinicians can minimize medical, developmental, functional, and esthetic prob-
device. lems resulting from untreated underlying local and systemic causes. This article provides
clinicians with an overview of conditions responsible for DTE in children. Multidisci-
plinary care for patients who experience DTE in medical, dental, and surgical settings also
is discussed.

Odontogenesis
Human teeth develop through a series of complex, reciprocal interactions between the oral
epithelium and migrating cranial neural crest ectomesenchymal cells of the first branchial
arch. This process is tightly regulated by more than 300 genes expressed temporospatially
within the jaws. Dental patterning of the primary and permanent dentition is expressed
in three dimensions, exerting morphogenetic controls over tooth number, position, size,
and shape. In the end, the normal primary dentition consists of three tooth classes (four
incisors, two canines, four molars) in each jaw, for a total of 20 teeth. Thirty-two teeth
distributed among four tooth classes (8 incisors, 4 canines, 8 premolars, 12 molars)
comprise the permanent dentition.

Tooth Eruption and Emergence

Tooth emergence, the clinical exposure of any part of a tooth through the oral mucosa, is
the culmination of numerous developmental processes occurring within the jaws. Bony
crypts house developing teeth during crown morphogenesis (size and shape) as well as hard
tissue (eg, enamel, dentin) secretion and calcification. As
root development begins, teeth initiate a physiologic process
of vertical eruption through the overlying alveolar bone
Abbreviations toward the oral mucosa. Bone remodeling in the area is
DTE: delayed tooth emergence necessary for progression of tooth eruption. Root develop-
GE: gingival enlargement ment exceeds two thirds of its final length when the alveolar
HGF: hereditary gingival fibromatosis bone crest is reached. The primary dentition undergoes root
KCOT: keratocytic odontogenic tumor resorption, followed by crown exfoliation, to permit emer-
MPFM: maxillary permanent first molar gence of permanent incisors, canines, and premolars into the
Mx.C.P1: maxillary canine/first premolar proper position within the dental arch. Permanent molars
NBCCS: nevoid basal cell carcinoma syndrome do not replace primary teeth under normal circumstances.
PDC: palatally displaced canine Teeth make clinical emergence into the oral cavity when 75%
SP: supernumerary premolar of their roots’ length is achieved.
Numerous population studies conducted worldwide over

*Assistant Professor, Division of Pediatric Dentistry, Departments of Dentistry and Pediatrics, University of Rochester Medical
Center, Rochester, NY.

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 ear, nose, throat delayed tooth emergence

the past 100 years report marked variation in dental chro-
nology based on race, ethnicity, and sex as well as environ-
mental factors. Tooth development, eruption, and emer-
gence in healthy mouths are genetically controlled, with
high heritability scores reported in monozygotic twin stud-
ies. As seen in Table 1, tooth emergence and exfoliation
times are usually presented as ranges of chronologic age to
account for the previously mentioned factors. Clinicians
should recognize that teeth that fail to emerge within 12
months of the normal range are considered delayed. In
these cases, referral to a dentist is warranted for further
clinical and radiographic assessment. Some cases require
surgical treatment to permit tooth emergence.
Detection of DTE
DTE is a nonspecific clinical finding that can occur in a
localized or generalized distribution. Oral inspection
coupled with history can provide clinicians with substan-
tial information to define further the natural history and
clinical manifestations of the underlying condition. Oral
examination should consist of evaluation of the alveolar
ridges as well as the alignment and morphology of the
teeth that are present. The size and shape of the alveolar
ridges can help determine whether DTE is due to abnor-
malities in tooth development, eruption, or emergence.
Tooth eruption through alveolar bone causes expansion
and fullness of the alveolar ridge. On average, 2 months are
required for a tooth to progress from causing palpable
enlargement of the gingival tissues to overt clinical emer-
gence. Palpation of the oral mucosa in the area of erupting
teeth should cause localized tissue blanching if tooth emer-
gence is imminent. In addition, redness of the mucosa or an
eruption hematoma has been noted to precede tooth emer-
gence in more than 30% of cases. Thin, knife-edge alveolar
ridges suggest the absence of teeth in the area.
The dentition should be inspected systematically for
age-appropriate tooth counts (Figs. 1 and 2). Proper
inspection requires a working knowledge of the differ-
ences in tooth morphology among tooth classes and
between the two dentitions. Tooth counts should be
assessed for appropriateness in timing and order. For the
most part, the primary dentition adheres to the follow-
ing emergence order in each jaw: central incisors, lateral
incisors, first molars, canines, and second molars. Al-
though published emergence orders are available for the
permanent dentition, clinicians observe countless varia-
tions in order as a result of numerous genetic, anatomic,
and environmental influences.
Generalized timing delays in tooth emergence caused by
systemic disease do not usually result in changes in the order

Table 1. Tooth Emergence and Exfoliation

PRIMARY DENTITION
Mandible Maxilla
Eruption Exfoliation Eruption Exfoliation
(months) (years) (months) (years)
Central incisors 5 to 8 6 to 7 6 to 10 7 to 8
Lateral incisors 7 to 10 7 to 8 8 to 12 8 to 9
Canines 16 to 20 9 to 11 16 to 20 11 to 12
First molars 11 to 18 10 to 12 11 to 18 9 to 11
Second molars 20 to 30 11 to 13 20 to 30 9 to 12
PERMANENT DENTITION
Mandible Maxilla
Eruption Root Complete Eruption Root Complete
(years) (years) (years) (years)
Central incisors 6 to 7 9 to 10 7 to 8 9 to 10
Lateral incisors 7 to 8 10 8 to 9 11
Canines 9 to 11 12 to 15 11 to 12 12 to 15
First premolars 10 to 12 12 to 13 10 to 11 12 to 13
Second premolars 11 to 13 12 to 14 10 to 12 12 to 14
First molars 5.5 to 7 9 to 10 5.5 to 7 9 to 10
Second molars 12 to 14 14 to 16 12 to 14 14 to 16
Third molars 17 to 30 18ⴙ 17 to 30 18ⴙ
Adapted from American Academy of Pediatric Dentistry, Guideline on management of the developing dentition and occlusion in pediatric dentistry. Reference
Manual. 2009;32(6). Copyright © American Dental Association. All rights reserved. Used with permission.

Pediatrics in Review Vol.32 No.1 January 2011 e5

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ear, nose, throat delayed tooth emergence
Figure 1. Development of the dentition from birth to 6 years
of age. Reprinted with permission from Logan WHG, Kronfeld
R. Development of the human jaws and surrounding structures
from birth to the age of fifteen years. JADA. 1933;20(3):379 –
427. Copyright © 1933 American Dental Association. All rights
reserved. Adapted 2010 with permission of the American
Dental Association. Schour L, Massler M. The development of
human dentition. JADA. 1941;28(7):1153–1160. Copyright
© 1941 American Dental Association. All rights reserved.
Adapted 2010 with permission of the American Dental Asso-
ciation.
of tooth emergence or exfoliation. In contrast, localized
disease should be investigated when the order of tooth
emergence is altered. Three general rules exist for normal
tooth development and emergence: 1) anterior teeth within
a specific tooth class (eg, first premolars) always precede
posterior teeth within the same class (eg, second premo-
lars), 2) mandibular teeth emerge earlier than their maxil-
lary counterparts, and 3) symmetric emergence of tooth
e6 Pediatrics in Review Vol.32 No.1 January 2011
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Figure 2. Development of the dentition from age 7 to adult-
hood. Reprinted with permission from Logan WHG, Kronfeld R.
Development of the human jaws and surrounding structures
from birth to the age of fifteen years. JADA. 1933;20(3):379 –
427. Copyright © 1933 American Dental Association. All rights
reserved. Adapted 2010 with permission of the American
Dental Association. Schour L, Massler M. The development of
human dentition. JADA. 1941;28(7):1153–1160. Copyright
© 1941 American Dental Association. All rights reserved.
Adapted 2010 with permission of the American Dental Asso-
ciation.
antimeres (corresponding teeth on opposite side) usually
occurs.
Causes of DTE
Anomalies in Tooth Number
Tooth agenesis, one of the most common developmental
anomalies in humans, alters the order of tooth emer-
gence. Although missing teeth are noted in only 1% of
children in the primary dentition, approximately 30% of
the general population fails to develop a full complement
of primary and permanent teeth. Agenesis of one or more
permanent third molars (wisdom teeth) affects about

Figure 3. An 8-year-old white boy who has bilateral agenesis
of the maxillary lateral incisors (3) causing a wide diastema
between the maxillary central incisors. Photograph courtesy of
Ryan Walker, DDS.
one in every five people. A recent meta-analysis reported
the prevalence of dental agenesis, excluding third mo-
lars, as 2.5% to 6.9%, depending on the race, sex, and
country of study. (1) Tooth agenesis is slightly more
common (1.3:1) in females versus males.
Hypodontia is defined as the absence of up to six
teeth. In more than 80% of patients, one or two teeth are
missing. After the third molars, the mandibular second
premolars, maxillary lateral incisors, and maxillary second
premolars are affected most frequently, with a 1.5% to
3.1% prevalence rate. Unilateral tooth agenesis is seen
more commonly, except for permanent maxillary lateral
incisors (Fig. 3), which have a propensity toward bilateral
agenesis.
Only 0.14% of the general population has oligo-
dontia, defined as the absence of six or more teeth.
Oligodontia following autosomal dominant inheritance
patterns can be indicative of PAX9, MSX1, or AXIN2
mutations. Ectodermal dysplasia should be considered
when underdeveloped alveolar ridges are seen in the
anterior jaws of predentate infants older than 7 months
of age, when multiple primary teeth are absent, or when
conical incisors are seen (Fig. 4).
Recognition of missing teeth by number and loca-
tion along with other physical findings can aid in the
diagnosis of numerous genetic diseases (Table 2). Clini-
cians should consider abnormal alignment and increased
spacing of teeth as well as localized delays in primary
tooth exfoliation as potential clinical manifestations of
hypodontia (Fig. 5). Patients who manifest hypodontia
may warrant consultation with a geneticist to rule out
associated syndromes.
Supernumerary teeth (hyperdontia) developing with
the jaws often delay the eruption and emergence of
permanent teeth. Hyperdontia is seen in 1.5% to 3.5% of
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ear, nose, throat delayed tooth emergence
Figure 4. A 9-year-old white girl who has ectodermal dys-
plasia. Agenesis of the permanent maxillary lateral incisors
and all mandibular incisors is seen, and a conical permanent
maxillary central incisor (*) is present. Photograph courtesy of
David Levy, DMD MS.
the general population. More than 80% of cases occur in
the anterior maxilla, and supernumerary teeth presenting
at this site can occur singly or in multiples, can have
normal incisor anatomy, can be conical (Fig. 6), or can
appear to have cuspal morphology. The teeth can emerge
into the mouth or be inverted within the maxilla. A single
supernumerary tooth that develops in the primary palate
directly behind the maxillary central incisors is called a
mesiodens. These teeth account for more than 50% of all
supernumerary teeth reported in epidemiologic studies.
Altered fusion between the medial nasal process and the
maxillary facial process during embryogenesis produces
the presence of two maxillary lateral incisors on the
affected side, as is seen occasionally in the general popu-
lation and more commonly in children born with isolated
cleft lip and cleft lip and palate.
Maxillary permanent fourth molars or rudimentary
paramolars constitute approximately 18% of all supernu-
merary teeth. Supernumerary premolars (SPs), on the
other hand, develop in 0.64% of the general population.
A 3:1 male-to-female distribution is seen. SPs are the
most common type of hyperdontia occurring in the
mandible. Their development appears to be genetically
controlled, although the pattern of inheritance remains
unclear. These teeth usually have normal premolar anat-
omy. Five out of every six SPs fail to emerge clinically,
and they can cause impaction of adjacent teeth (Fig. 7).
They are often incidental findings on panoramic radio-
graphs in adolescence. Many can develop after the emer-
gence of age-appropriate premolars.
Surgical removal of a supernumerary tooth becomes
necessary when it impedes or deflects age-appropriate
tooth eruption and emergence. One in four patients who
has a history of extra teeth in the anterior maxilla later
Pediatrics in Review Vol.32 No.1 January 2011 e7
 Table 2. Genetic Diseases With Anomalies in Tooth Number
Condition
Autosomal dominant
oligodontia
Witkop syndrome
Van der Woude
Down syndrome
e8 Pediatrics in Review Vol.32 No.1 January 2011
Ellis-van Creveld
Apert syndrome
Osteogenesis imperfecta
Incisor-premolar
hypodontia
Hutchinson-Guilford
progeria syndromes
Hypohidrotic ectodermal
dysplasia
Incontinentia pigmenti
Axenfeld-Rieger syndrome
Orofacial-digital syndrome
type 1
Holoprosencephaly
Cleidocranial dysplasia
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Gardner syndrome
AD⫽autosomal dominant, AR⫽autosomal recessive, Xd⫽X-linked
Gene Inheritance Dental Findings Other Findings
PAX9 AD Agenesis of permanent molars None documented
ear, nose, throat
AXIN2 Permanent tooth agenesis across tooth types Colon polyps and cancer, cleft lip and palate
MSX1 Agenesis of second premolars and third molars Cleft lip and palate
MSX1 AD Agenesis of permanent mandibular incisors and Nail hypoplasia (especially toenails)
second molars, maxillary permanent canines
IRF6 AD Permanent tooth agenesis, second premolars, Cleft lip and palate, mandibular lip pits
maxillary lateral incisors
Numerous Trisomy 21 Agenesis of incisors and second premolars, peg- Dysmorphic facies, congenital heart disease,
shaped lateral incisors, maxillary canine-first intellectual disability, leukemia, thyroid
premolar transposition dysfunction, hearing loss, maxillary hypoplasia
delayed tooth emergence
EVC AD Tooth agenesis, enamel hypoplasia, multiple oral Chondrodysplasia, polydactyly, congenital heart
frenula, premature exfoliation of primary defects
teeth
FGFR2 AD Permanent tooth agenesis Craniosynostosis, maxillary hypoplasia, hand
anomalies
COL1A1/2 AD Hypodontia, dentinogenesis imperfecta Blue sclera, multiple fractures
Unknown AD Agenesis of lateral incisors and second None documented
premolars, taurodontism, ectopic maxillary
canines
LMNA Sporadic Permanent tooth agenesis, ectopic eruption of Precocious senility, early death, coronary artery
permanent incisors disease, beaked nose, baldness, lipodystrophy,
short stature
EDA Xd Primary and permanent tooth agenesis, conical Defective hair, nails, skin; hypohidrosis; poor
EDAR AD, AR incisors, anodontia hearing; respiratory infections
EDARR AD, AR
IKK␥ Xd Permanent tooth agenesis, conical teeth, delayed Defective hair, nails, eyes; intellectual disability;
exfoliation of primary dentition autochthonous tattooing
NEMO Agenesis, conical teeth, delayed tooth Hypohidrosis, immunodeficiency
emergence
PITX2 AD Agenesis of incisors and canines, enamel Glaucoma, redundant periumbilical skin
hypoplasia, conical teeth
CXORF5 Xd Agenesis of incisors and canines Cleft palate, hand anomalies, intellectual disability
Numerous AD Solitary maxillary central incisor Seizures, syndromic facies, premaxillary agenesis,
cleft lip and palate, hypotelorism
RUNX2 AD Multiple supernumerary teeth, retained primary Hypoplastic calvaria, absent clavicles, midface
teeth, impacted permanent teeth hypoplasia, delayed fontanelle closure, short
stature, scoliosis, sinus/respiratory infections,
hearing loss
APC AD Supernumerary teeth, tooth agenesis, jaw Gastrointestinal polyps, multiple osteomas, skin and
osteomas, impacted teeth soft-tissue tumors, cancer in 50% by age 30

Figure 5. A 14-year-old African American boy who has
hypodontia. The mandibular right second premolar (**) did not
develop. Clinically, the mandibular right second primary molar
(3) shows delayed exfoliation. The permanent third molars
continue to develop in the jaws (*). Photograph courtesy of
Aliakbar Bahreman, DDS, MS.
develops SPs. Moreover, SPs, unlike other supernumer-
ary teeth, recur in 8% of patients. Of note, natal and
neonatal teeth should be maintained when possible be-
cause they not supernumerary in more than 90% of cases.
Clinicians who suspect the presence of a supernumerary
tooth should refer the child to a dentist for radiographic
examination.
Delayed Dental Age
Biologic delays in dental development generally retard
emergence of the primary and permanent dentitions.
Delayed dental age has been studied using tooth counts
from clinical inspection as well as the stage of tooth
formation on panoramic radiography. As mentioned,
DTE using clinical tooth counts is an inexact measure of
dental age due to a host of local factors. Dental age scores
Figure 6. A conical mesiodens (3) has emerged into the
anterior maxilla, causing the permanent maxillary right cen-
tral incisor (*) to emerge late and out of position. Surgical
removal of the mesiodens is recommended. Photograph cour-
tesy of Aliakbar Bahreman, DDS, MS.
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ear, nose, throat delayed tooth emergence
Figure 7. A 15-year-old Hispanic boy who has delayed exfo-
liation of the mandibular right primary molars (3) as well as
delayed emergence of the mandibular left premolars (*). An
age-appropriate set of permanent teeth is present in the
maxillary arch. Four supernumerary mandibular premolars,
two on each side, are the cause for the delayed emergence of
the mandibular premolars. Photograph courtesy of Aliakbar
Bahreman, DDS, MS.
are best determined using radiographic stages of tooth
formation.
Few studies have focused on the primary dentition
because radiography is limited by patient cooperation.
However, numerous methods have been proposed to
score dental age using a variety of statistical methods
based on scores of crown and root formation for the
permanent teeth. The Demirjian method, originally
studied in a French Canadian pediatric population, is
used most commonly. (2) This method scores the man-
dibular left permanent teeth, excluding the third molars,
according to eight developmental stages. More than
100 studies have used the Demirjian method and modi-
fications of it to compare dental age to the chronologic
age of a population. This method, although validated
through epidemiologic studies, gives varied results by
sex, race, and ethnicity of the population of study. Dental
age scoring using these methods is used commonly in
forensics and immigration proceedings for unaccompa-
nied minors as a means of age estimation when additional
information is not available.
Dental age does not consistently correlate with skele-
tal age and the timing of puberty. However, the mandib-
ular canine has been shown to be the best indicator of
pubertal onset using tooth formation stages. In general,
skeletal age delayed by systemic disease or malnutrition is
often two to six times more severe than the delay noted in
dental age.
Using the Demirjian method and others in conjunc-
tion with clinical tooth counts, patients who have a host
of systemic diseases have been found to have delayed
dental age. Most studies, however, involve a limited
Pediatrics in Review Vol.32 No.1 January 2011 e9
ear, nose, throat delayed tooth emergence
number of affected individuals, lending poor statistical
power. In addition, numerous genetic syndromes have
DTE (also described as delayed tooth eruption) listed as
a clinical finding. Case reports and studies involving these
patients do not usually assess dental age based on radio-
graphic parameters.
Nonetheless, oral inspection of children who have
Down syndrome, hypothyroidism, growth hormone de-
ficiency, hypopituitarism, and chronic malnutrition often
results in a finding of DTE. In small case-control studies,
patients who have hypodontia and those who have pala-
tally displaced canines (PDCs) are also noted to have
delayed dental age. DTE resulting from delayed dental
age in children who have Down syndrome remains un-
treatable. In contrast, growth hormone therapy has been
shown in preliminary studies to accelerate dental matu-
ration and improve the timing of tooth emergence. (3)
Although preterm birth has been associated with de-
layed dental age according to chronologic age, dental age
normalizes when the child’s term age is used. (4) Simi-
larly, children who have enamel and dentin anomalies
due to X-linked hypophosphatemic rickets do not
present initially with delayed dental age. They do, how-
ever, develop spontaneous dental abscesses due to micro-
scopic abnormalities in the mineralized dental tissues
that allow ingress of microorganisms and pulpal necrosis.
Early primary tooth loss due to infection can slow the
dental development of the permanent successors and
lead to DTE.
Dental Crowding
Insufficient space in the jaws for eruption and emergence
of teeth constitutes the most benign, yet common,
Figure 8. Space loss in the maxillary left quadrant is seen
when compared with the contralateral side due to early
extraction of the maxillary left primary molars because of
dental caries. The maxillary permanent first molar (bottom
right) has migrated into the space previously occupied by the
primary molars due to the lack of a space maintenance
appliance.
e10 Pediatrics in Review Vol.32 No.1 January 2011
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source of DTE in children. A tooth-to-jaw size discrep-
ancy is often responsible for dental crowding. This dis-
harmony occurs as a result of: 1) normal-size teeth in
small jaws, 2) larger-size teeth in normal-size jaws, or 3) a
combination of both. Children who have constricted,
V-shaped alignment of the teeth are more likely have
tooth crowding than those in whom the dental arch is
U-shaped. Dental crowding among primary incisors pre-
dicts moderate-to-severe crowding in the permanent
dentition.
Early tooth loss due to dental caries raises a child’s risk
for dental crowding and delayed emergence of perma-
nent teeth. Primary teeth serve as placeholders for their
successors. Premature extraction of primary canines or
molars results in migration of adjacent teeth (Fig. 8), loss
of dental arch length and circumference, and shift of
dental midlines toward the side of early tooth loss. Pedi-
atric dentists and orthodontists attach appliances to teeth
adjacent to tooth extraction sites to maintain space for
later permanent tooth emergence.
The presence of supernumerary teeth as well as fused
teeth (Fig. 9) can exacerbate dental crowding. Later
developing teeth can remain unerupted in the jaws or be
forced to emerge ectopically when adjacent teeth are
impediments to the normal eruption path. Odontogenic
pathology and jaw bone disorders also worsen dental
crowding through displacement of unerupted and
emerged teeth into compact areas of the jaws.
Dental crowding can be alleviated by transverse ex-
pansion of the jaws. Posterior retraction of medially
positioned molars also increases the amount of space for
future tooth emergence. In some cases, dental crowding
necessitates the removal (serial extraction) of healthy
primary canines and molars as well as permanent first
premolars sequentially to allow proper alignment of the
permanent dentition in adolescence and adulthood.
Dentists, orthodontists, and oral maxillofacial surgeons
Figure 9. A 6-year-old African American girl who has a
maxillary left primary incisor fused (**) to a supernumerary
tooth. Photograph courtesy of Aliakbar Bahreman, DDS, MS.

work collaboratively on these cases to obtain optimal
treatment outcomes.
Ectopic Tooth Eruption
Abnormalities in the path of tooth eruption also can
cause delayed tooth emergence in the permanent denti-
tion. The literature suggests that 2% to 6% of children
demonstrate ectopic tooth eruption. The maxillary per-
manent first molars and canines are affected most com-
monly. The prevalence of ectopic eruption is substan-
tially higher (⬎20%) in children born with cleft lip and
palate, likely due to genetic and anatomic differences.
Under normal circumstances, the maxillary perma-
nent first molar (MPFM) follows an eruption path pos-
terior to the maxillary second primary molar. It emerges
through the gingival tissues and uses the posterior sur-
face of the primary molar to guide its eruption into
functional occlusion with teeth in the opposing jaw.
Ectopic MPFMs take a medial eruption course, leading
them under the crown of the second primary molar
(Fig. 10). This eruption disturbance, often detected on
dental radiographs between 5 and 7 years of age, delays
MPFM emergence and often causes root resorption of
the primary second molar, with some cases persisting
until the primary tooth is exfoliated prematurely. Two
thirds of ectopic MPFMs self-correct, usually by 7 years
of age. For the remaining cases, orthodontic manage-
ment is necessary to prevent anterior migration of the
ectopic MPFM and future impaction of the ipsilateral
maxillary second premolar. Clinically, this anomaly can
be detected through premature mobility of the primary
second molar or mesial angulation of the MPFM, with
emergence of the distal (away from midline) cusps only.
PDCs in the maxilla should be suspected in children
Figure 10. The maxillary permanent first molars (*) are erupt-
ing in an ectopic position under the crowns of the maxillary
primary second molars. Root resorption of the primary second
molars is also occurring. Photograph courtesy of Aliakbar
Bahreman, DDS, MS.
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ear, nose, throat delayed tooth emergence
Figure 11. Asymmetric expansion of the anterior palate (3).
The maxillary primary canine on the ipsilateral side (*) has
been exfoliated. This clinical presentation is indicative of an
untreated palatally displaced canine. Photograph courtesy of
Aliakbar Bahreman, DDS, MS.
older than 9 years of age when alveolar ridge palpation
adjacent to the buccal vestibule lacks a canine bulge, a
clinical finding suggestive of normal canine eruption.
The early manifestations of PDCs can be detected on
panoramic radiography because ectopic maxillary canines
often appear more horizontal on the film and tend to
overlap the root of the mature ipsilateral lateral incisor.
Early extraction of the adjacent maxillary primary canine
corrects the eruption path and spatial orientation of
PDCs in almost 70% of cases. PDCs are associated with
other dental anomalies (small-size maxillary permanent
lateral incisors, infraocclusion of primary molars, and
enamel hypoplasia) that can be detected by clinicians
through oral inspection. Delayed exfoliation of the ipsi-
lateral maxillary primary canine or asymmetric anterior
palatal enlargement with or without primary canine loss
(Fig. 11) are late clinical manifestations of PDCs. If left
untreated, ectopic eruption of the maxillary canine leads
to tooth impaction in the hard palate. Surgical tooth
exposure, forced orthodontic traction, and space regain-
ing in the maxillary anterior segment through fixed orth-
odontic appliances (braces) becomes necessary.
Tooth transposition also results in delayed tooth
emergence in many cases. This abnormality of dental
position occurs more frequently in the maxilla than the
mandible. Maxillary canine/first premolar (Mx.C.P1)
transposition cases (Fig. 12) occur most commonly, with
a prevalence of 0.25%. Based on a review of 143 cases,
Mx.C.P1 transposition appears to be polygenic, with a
propensity for occurrence in females. (5) A higher prev-
alence of Mx.C.P1 transposition is seen among children
who have Down syndrome. Clinically, agenesis of the
ipsilateral lateral incisor is common. Twenty-seven per-
cent of published Mx.C.P1 cases occur bilaterally.
Pediatrics in Review Vol.32 No.1 January 2011 e11
ear, nose, throat delayed tooth emergence
Figure 12. Maxillary permanent left canine with left first
premolar transposition. In this case, reshaping of the teeth
with dental composite restorations can permit normal func-
tion and satisfactory esthetics. Photograph courtesy of Aliak-
bar Bahreman, DDS, MS.
Early permanent tooth loss due to dental caries or
trauma as well as traumatic displacement of developing,
unerupted teeth within the jaws accounts for most other
cases of transposition in the maxilla, including canine/
lateral incisor, canine/first molar, lateral incisor/central
incisor, and canine/central incisor patterns. Mandib-
ular canine/lateral incisor transposition, identified in
0.03% of dental patients, often is seen in conjunction
with permanent third molar agenesis, suggestive of ge-
netic influences. Transposition cases, if recognized early
enough, usually can be managed effectively with inter-
ceptive orthodontics without surgery.
Delayed Exfoliation of Primary Teeth
Delayed exfoliation of primary teeth is intimately associ-
ated with delayed root development and eruption of
their permanent successors. As a result, permanent tooth
agenesis or delayed dental maturity typically results in
delayed exfoliation of primary teeth according to chro-
nologic age. In these cases, the timing of primary tooth
root resorption is appropriate from a biologic standpoint.
In contrast, primary tooth exfoliation is considered bio-
logically delayed when the primary tooth remains in place
despite permanent tooth root length greater than 75% of
its expected final length.
Primary teeth that appear biologically ready for exfo-
liation are common in primary care. These teeth are
usually retained in soft tissue or interlocked between
adjacent teeth, limiting their ability to be removed at
home. Children also tend to delay tooth removal if they
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Figure 13. The maxillary primary central incisors are delayed
in exfoliation. They are forcing the maxillary permanent
central incisors to erupt in the anterior palate. When the child
occludes his teeth, the maxillary permanent central incisors
are behind (crossbite) the mandibular incisors (3). Orthodon-
tic correction of this condition becomes necessary. Photo-
graph courtesy of Aliakbar Bahreman, DDS, MS.
feel that pain is likely. Timely extraction of over-retained
primary teeth is indicated if maxillary permanent incisors
will be deflected palatally and malocclusion such as ante-
rior crossbite (Fig. 13) is likely to occur.
Soft-tissue infection is another indication for tooth ex-
traction when food becomes impacted under the exfoliat-
ing primary tooth. Lingual emergence of mandibular per-
manent incisors is common but rarely a cause for concern.
In these cases, further emergence of the permanent teeth
ultimately causes exfoliation of their predecessors, followed
by anterior repositioning of the permanent incisors within
the dental arch by tongue pressure. Extraction of over-
retained mandibular primary incisors is needed more fre-
quently in cases of severe dental crowding.
Infraoccluded primary molars (teeth that fail to reach
the normal occlusal plane) are reported to occur in 5% of
the general population. These teeth often appear to be
ankylosed on clinical examination because they are im-
mobile to palpation and tend to be submerged in the
gingival tissues compared with continually erupting ad-
jacent teeth (Fig. 14). Nonetheless, infraoccluded pri-
mary molars usually exfoliate within 1 year of the normal
range as long as the permanent tooth successor is present
with adequate root formation.
Infraoccluded primary molars can become surgical
problems if the crowns of the adjacent teeth are allowed
to migrate over top of them. In addition, alveolar bone
levels surrounding the adjacent teeth can approximate
the crown of the infraoccluded molar, leading to im-

Figure 14. The mandibular left primary first molar is infra-
occluded. The adjacent teeth continue to erupt while it
remains stationary, creating the clinical appearance of a tooth
submerging into the gingiva. Photograph courtesy of Aliakbar
Bahreman, DDS, MS.
paired exfoliation and delayed premolar emergence (Fig.
15). Close monitoring of infraoccluded primary molars
by dentists is recommended to avoid these complications.
Trauma
Tooth development, eruption, and emergence can be
altered by dental or maxillofacial trauma in infancy or
childhood. Trauma to developing primary teeth is rela-
tively rare. Extreme root curvature (aka dilaceration) and
eruption failure of maxillary incisors have been reported
Figure 15. A 12-year-old white boy who has infraoccluded
maxillary second primary molars (*). The adjacent teeth have
erupted over the top of the infraoccluded teeth, causing them
to become impacted in the jaw. This condition impedes the
maxillary second premolars from erupting into the mouth.
Photograph courtesy of Aliakbar Bahreman, DDS, MS.
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ear, nose, throat delayed tooth emergence
Figure 16. A 6-year-old boy born in Uganda presents with
malformed mandibular primary canines (*) and missing max-
illary primary canines (ⴙ). His history corroborates that canine
extirpation was completed before emigration from Uganda.
Photograph courtesy of Terry Farquhar, RN, DDS.
as sequelae of traumatic laryngoscopy and prolonged
endotracheal intubation in infancy. Clinicians also may
encounter children who have emigrated from Eastern
Africa and appear to have DTE of the primary canines or
other adjacent teeth on clinical inspection (Fig. 16). This
finding is consistent with the practice of ebinyo, in which
tribal healers remove these teeth in infancy to prevent
or treat high fevers, vomiting, or diarrhea in the child.
Damage, displacement, or extraction of adjacent primary
and permanent teeth also can be seen.
Mandibular fractures due to falls, motor vehicle crashes,
or child abuse can disturb teeth developing along the line
of fracture. Infection and inadvertent placement of plates
and screws during jaw fixation also jeopardizes adjacent
developing teeth. Similarly, children born with microgna-
thia (eg, Pierre Robin sequence, Goldenhar syndrome)
who require mandibular distraction osteogenesis to prevent
long-term tracheostomy can have permanent molar tooth
germs displaced or destroyed during mandibular osteot-
omy and placement of the internal distraction device. Pro-
phylactic enucleation of tooth germs in planned sites of
distractor pins is advocated by some surgeons to improve
bone volume and treatment outcomes.
Intrusion of primary incisors into the dental alveolus
commonly results in developmental changes to their
permanent successors. The amount of internal displace-
ment and direction of primary tooth displacement cou-
pled with the age of the child aid clinicians in deter-
mining whether enamel hypoplasia, root dilaceration, or
tooth germ displacement are possible sequelae. Reim-
Pediatrics in Review Vol.32 No.1 January 2011 e13
ear, nose, throat delayed tooth emergence
Figure 17. A 9-year-old African American girl who has
delayed exfoliation of the maxillary right primary central
incisor (#). This tooth is discolored due to dental trauma. Her
permanent incisor emergence order is affected. Extraction of
the over-retained primary incisor is indicated. Photograph
courtesy of Aliakbar Bahreman, DDS, MS.
plantation of avulsed primary incisors after trauma pre-
disposes them to delayed tooth exfoliation because de-
struction of the periodontal ligament apparatus and
ankylosis between the alveolar bone and the tooth’s root
often occur. In these cases, ectopic permanent incisor
eruption occurs along with rotation of adjacent teeth
(Fig. 17). This problem is seen infrequently because
dentists and first responders at accident sites are educated
to avoid replantation of avulsed primary teeth.
Jaw Bone Pathology
Tooth development and emergence often are affected by
jaw pathology. In some cases, dental abnormalities occur
as a result of inadequate bone remodeling, and in other
disorders, displacement of developing teeth is caused by
expanding jaw lesions.
Children who have infantile osteopetrosis experience
marked delays in tooth emergence as well as tooth agenesis
and enamel hypoplasia. These clinical manifestations are
directly related to osteoclast dysfunction. Stem cell rescue of
those who have osteopetrosis can restitute normal tooth
eruption and emergence of the permanent dentition.
Various types of osteogenesis imperfecta present with
dental developmental anomalies. Delayed tooth emergence
is seen in 20% of patients who have osteogenesis imperfecta
type III. Ectopic tooth eruption is another common finding
in affected individuals. Bisphosphonate therapy used in the
management of osteogenesis imperfecta can cause delayed
tooth emergence of 1.6 years relative to matched controls.
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To date, bisphosphonate therapy has not been associated
with osteonecrosis of the jaws, as is reported in adult pa-
tients using these medications.
McCune-Albright syndrome is a sporadic multisystem
disease characterized by polyostotic fibrous dysplasia, café
au lait hyperpigmentation, and precocious puberty. Cranio-
facial forms of fibrous dysplasia result in progressive facial,
palatal, and jaw asymmetries. The maxilla is affected more
commonly than the mandible, with a ground-glass appear-
ance of the lesion noted through panoramic radiography or
computed tomography scans. Oligodontia as well as tooth
impaction, displacement, and rotations are common in
affected patients.
Jaw osteomas and supernumerary teeth often are the
first manifestations of Gardner syndrome in puberty. Early
recognition is necessary to permit monitoring of gastroin-
testinal polyps because malignant transformation occurs in
50% of patients by age 30.
Permanent teeth often fail to erupt in patients born with
cleidocranial dysplasia because the teeth lack secondary
cementum. Extraction of primary teeth that have failed to
exfoliate normally does not promote eruption of their per-
manent successors. In addition, supernumerary teeth can
impede tooth emergence. Surgical exposure of unerupted
teeth followed by orthodontic traction has limited success.
Oral rehabilitation for these patients often centers on jaw
reconstruction and the use of dental prostheses.
Cherubism is a rare autosomal dominant disease that
affects the jaws. The condition is characterized by bilateral
expansion of the posterior mandible and, in some cases,
the maxilla and facial bones. Bony expansion of the jaws
causes the individual to have a “chubby cheeked,” cherubic
appearance. The osseous lesions are usually multilocular
radiolucencies affecting the angles and ascending rami of
the mandible. They are histologically defined by multinu-
cleated giant cells in a loose fibrous stroma. The lesions tend
to increase in size until puberty, after which lesion stabiliza-
tion or even regression is noted. Bilateral expansion of these
lesions causes marked displacement of developing and
emerged teeth. Failure of tooth eruption due to severe
dental crowding and malocclusion is common. Watchful
monitoring is the usual course of action unless expansion
progresses rapidly.
Odontogenic Cysts and Tumors
Epithelial-lined jaw cysts derived from odontogenic epi-
thelium commonly impair eruption of developing teeth,
producing alterations in tooth emergence timing or or-
der. Dentigerous cysts, originating from a separation of
the follicle around the crown of an unerupted tooth,
comprise approximately 20% of all odontogenic cysts.

Figure 18. A 13-year-old white girl presents with delayed
exfoliation of the maxillary right primary canine (*). On dental
radiography, a large unilocular cyst is present around the
crown of the unerupted permanent canine. Histopathologic
examination reveals a dentigerous cyst.
Mandibular third molars, followed by maxillary perma-
nent canines (Fig. 18), are affected most commonly.
Dentigerous cysts around supernumerary teeth and
odontomas also are seen frequently. Usually, the lesion
should measure at least 3 to 4 mm in diameter on
radiograph to be called a dentigerous cyst rather than a
variation in normal follicular anatomy. These lesions are
found more often in the second decade, with the highest
prevalence noted in white patients. Dentigerous cysts can
grow very large and have a tendency to displace the involved
tooth within the jaw (Fig. 19). Treatment of these lesions
involves either marsupialization or enucleation of the cyst
with or without removal of the unerupted tooth. Recur-
rence is rare after complete removal of the cyst.
Keratocytic odontogenic tumors (KCOTs), previously
known as odontogenic keratocysts, have been reported to
account for 2% of all oral biopsies performed in children
younger than 16 years of age, according to retrospective
review of a United States dental school biopsy service. (6)
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ear, nose, throat delayed tooth emergence
Figure 19. A 17-year-old white girl who presents with painless
swelling of the mandibular left posterior jaw has age-appropriate
dentition on clinical examination. On panoramic radiography, a
large unilocular radiolucency is seen along with marked displace-
ment of the unerupted third molar. Histopathologic examination
confirmed the lesion to be a dentigerous cyst.
KCOTs are aggressive tumors that have a marked tendency
for development in the posterior body and ascending ramus
of the mandible. An unerupted tooth is involved in 25% to
40% of cases, mimicking a dentigerous cyst. KCOTs have
thin, friable walls that make complete enucleation and thor-
ough curettage difficult. As a result, recurrence is common.
In locally aggressive cases, jaw resection followed by bone
grafting may be necessary.
The presence of multiple KCOTs warrants further
testing for nevoid basal cell carcinoma syndrome
(NBCCS). Gorlin syndrome, as it also is called, is char-
acterized by multiple KCOTs as well as multiple basal cell
carcinomas, hyperkeratosis of the palms and soles, skele-
tal abnormalities, intracranial ectopic calcifications, and
facial dysmorphia. NBCCS is caused by mutations in the
PTCH1 gene. It is transmitted as an autosomal dominant
trait and is reported in fewer than 1 in 57,000 individu-
als, with a 1:1 male-to-female ratio. Multidisciplinary
care by dental professionals, pediatricians, dermatolo-
gists, and neurologists is recommended.
Ameloblastomas have been described as the most
clinically significant odontogenic tumor. They arise from
cells of odontogenic epithelial origin. Multicystic lesions
are seen most commonly across the lifespan. However,
only 8.7% to 15% of all ameloblastomas in Western
countries develop in the pediatric population. Fifty per-
cent of unicystic intraosseous ameloblastomas are diag-
nosed in the second decade of life. Most of these tumors
develop as asymptomatic lesions in the posterior mandi-
Pediatrics in Review Vol.32 No.1 January 2011 e15
ear, nose, throat delayed tooth emergence

ble. An unerupted third molar as well as teeth adjacent

to it often can become involved. These tumors resemble
cysts on surgical exposure. As such, they usually are
treated by enucleation with curettage. Recurrence rates
ranging from 10% to 20% are seen. Block resection can
become necessary in select cases. On very rare occasions,
ameloblastomas act as malignant tumors, with hematog-
enous spread of metastatic disease.
Odontomas are the most common odontogenic tu-
mors, accounting for approximately 30% of lesions. They
develop in both jaws, with greater prevalence in the
maxilla. They are equally distributed between both sexes.
Two types, compound and complex, are seen. Com-
pound odontomas are well-circumscribed masses of tiny
teeth of various numbers. The teeth are usually cone-
Figure 20. An 8-year-old white boy who has a history of trauma
shaped and have normal delineation of tooth layers.
to the maxillary anterior teeth presents with delayed emergence
Complex odontomas are similar but do not have orga- of the maxillary permanent right central and lateral incisors. The
nized dental structures. They are easily removed by enu- contralateral permanent incisors are already present. The outline
cleation and do not recur. Fifty-five percent of them are of the unerupted teeth can be seen within the gingiva. Surgical
diagnosed when delayed permanent tooth emergence or exposure was necessary to permit tooth emergence.
delayed exfoliation of a primary tooth is seen.
More than 20 other types of odontogenic cysts and
terized by proliferation of connective tissue extracellular
tumors can develop in the jaws. Histopathologic exami-
matrix in response to gingival drug metabolism. Phenytoin,
nation is necessary to discriminate these lesions, includ-
nifedipine, and cyclosporine are the most common catalysts
ing identification of specific odontogenic elements and
of the condition. Poor oral hygiene exacerbates GE
mineralized tissue. If left untreated, odontogenic disease
through inflammatory mechanisms. The anterior gingival
can cause displacement and mobility of teeth, delayed
tissues are involved more frequently. Males tend to be more
tooth emergence, root resorption, pain, jaw swelling,
severely affected for poorly understood reasons. The use of
and paresthesia. Large cystic lesions in the posterior
multiple anticonvulsant medications in addition to phenyt-
mandible can lead to pathologic jaw fractures.
oin increases the severity of phenytoin-induced GE. Addi-
Gingival Enlargements
The gingiva and oral mucosa provide the last barrier to
tooth emergence when sufficient space is present in the
dental arch. Under normal circumstances, reduced enamel
epithelium of erupting teeth fuses with the oral mucosa,
permitting emergence of the dentition. Gingival remodel-
ing also is necessary for emergence and continued tooth
eruption over time. A variety of genetic and environmental
conditions active in the gingival tissues can preclude either
localized or generalized tooth emergence.
Tooth emergence can be delayed when the gingival
tissue becomes scarred as a result of oral trauma (Fig. 20).
Eruption cysts can form over emerging teeth when fluid
extravasation occurs between the tooth crown and the
overlying gingival tissues. These conditions are usually self-
limiting with time and optimal oral hygiene. If persistence Figure 21. An 8-year-old African American boy who has
of the lesions affects normal emergence and alignment of hereditary gingival fibromatosis. Marked gingival enlargement
adjacent teeth, surgical excision may become necessary. with delayed tooth emergence can be seen. Surgical resection
Drug-induced gingival enlargement (GE) in severe cases of the gingiva is necessary to permit tooth emergence.
can impair tooth emergence. Drug-induced GE is charac- Photograph courtesy of Paul Romano, DDS, MS.

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tive effects are seen when nifedipine and cyclosporine are
used in organ transplant patients. Cyclosporine also has
been implicated in the development of oral eruption cysts
in select cases. Tacrolimus, another immunosuppressive
agent, has not been found to cause GE after organ and
hematopoietic stem cell transplantation. In fact, some clini-
cians believe that substitution of cyclosporine with tacroli-
mus can reverse GE in these patients. Surgical management
of GE through gingival resection may become necessary if
mastication, speech, and esthetics become problematic.
Hereditary gingival fibromatosis (HGF) is a rare con-
dition affecting 1 in 350,000 individuals that has no sex
predilection. Clinically, HGF affects the emergence of
the permanent teeth. The clinical manifestations of HGF
vary, with malpositioned teeth, delayed exfoliation of
primary teeth, delayed emergence of permanent teeth,
malocclusion, and open lip posture seen (Fig. 21). HGF
is usually managed through optimal oral hygiene prac-
tices and surgical resection if esthetics and function are
compromised.
Summary
• The presence of DTE, a commonly overlooked finding
in primary care, signals abnormalities in tooth
formation, eruption, or emergence.
• DTE often occurs through benign acquired processes
such as tooth loss due to dental caries or tooth-jaw
size discrepancy. However, the detection of DTE is
important because early identification can minimize
the comorbidity associated with systemic disease,
genetic syndromes, or odontogenic pathology.
• Pediatricians can reduce the burden of care related
to DTE through appropriate history taking and oral
inspection during health supervision visits.
• Children awaiting emergence of teeth for more than
12 months beyond normal chronologic ranges or
those who experience localized alterations in the
normal emergence order should be referred to a
dentist for further evaluation.
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ear, nose, throat delayed tooth emergence
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Pediatrics in Review Vol.32 No.1 January 2011 e17
 Delayed Tooth Emergence
Jeffrey M. Karp
Pediatr. Rev. 2011;32;e4-e17
DOI: 10.1542/pir.32-1-e4

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