Pediatrics in Review_January2011

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Answer Key: 1. C; 2. E; 3. A; 4. E; 5. A; 6. D; 7. E; 8. B; 9. B;10. C

CommentaryThe Pediatrician as Teacher3Lawrence F. Nazarian

ArticlesInfants of Drug-dependent Mothers5Lauren M. Jansson, Martha L. Velez

Inflammatory Bowel Disease14Sarah R. Glick, Ryan S. Carvalho

Visual Diagnosis: Perceived Fevers andBack Pain in a 1-week-old Infant27Delia L. Gold

Focus on Diagnosis: A Primer on D-dimer31Cristyn N. Camet, Donald L. Yee

Pediatrics in the Community:The Haiti Earthquake34Sachin D. Shah, C. Andrew Aligne

Index of SuspicionCase 1: Recurrent Oral Ulcers in an AdolescentCase 2: Visual Impairment in an Autistic ChildCase 3: Fever and Hepatosplenomegaly in an Infant35Case 1: Benjamin Bruins, Howard F. Fine, L. Nandini MoorthyCase 2: Ayesha Jain, Ashok K. Jain, Thomas W. MilliganCase 3: Rinku Patel

In BriefThrombotic Disorders41Michael Roth, Deepa Manwani

Internet-Only ArticlesAbstracts appear on page 26.

Ethics for the Pediatrician:Physician Interaction With thePharmaceutical Industrye1Mark X. Cicero, Michael B. Curi, Mark Mercurio

Delayed Tooth Emergencee4Jeffrey M. Karp

Cover: The artwork on the cover of thismonth’s issue is by one of the winners of our2009 Cover Art Contest, 9-year-old Grace Aof Williamsville, NY. Grace’s pediatrician isBohdan Dejneka, MD.

contentsPediatrics inReview� Vol.32 No.1 January 2011

Editor-in-Chief: Lawrence F. Nazarian, Rochester, NYAssociate Editors: Tina L. Cheng, Baltimore, MD

Joseph A. Zenel, Sioux Falls, SDEditor, In Brief: Henry M. Adam, Bronx, NYConsulting Editor, In Brief: Janet Serwint, Baltimore, MDEditor, Index of Suspicion:

Deepak M. Kamat, Detroit, MIConsulting Editor Online and Multimedia

Projects: Laura Ibsen, Portland, OREditor Emeritus and Founding Editor:

Robert J. Haggerty, Canandaigua, NYManaging Editor: Luann ZanzolaMedical Copy Editor: Deborah K. KuhlmanEditorial Assistants: Sydney Sutherland, Kathleen BernardEditorial Office: Department of Pediatrics

University of RochesterSchool of Medicine & Dentistry601 Elmwood Avenue, Box 777Rochester, NY [email protected]

Editorial BoardHugh D. Allen, Columbus, OHMargie Andreae, Ann Arbor, MIRichard Antaya, New Haven, CTDenise Bratcher, Kansas City, MOGeorge R. Buchanan, Dallas, TXBrian Carter, Nashville, TNJoseph Croffie, Indianapolis, INB. Anne Eberhard, New Hyde Park, NYPhilip Fischer, Rochester, MNRani Gereige, Miami, FLLindsey Grossman, Springfield, MAPatricia Hamilton, London, United Kingdom

Jacob Hen, Bridgeport, CTHal B. Jenson, Springfield, MADonald Lewis, Norfolk, VAGregory Liptak, Syracuse, NYSusan Massengill, Charlotte, NCJennifer Miller, Gainesville, FLBlaise Nemeth, Madison, WIRenata Sanders, Baltimore, MDThomas L. Sato, Milwaukee, WISarah E. Shea, Halifax, Nova ScotiaAndrew Sirotnak, Denver, CONancy D. Spector, Philadelphia, PA

Publisher: American Academy of PediatricsMichael J. Held, Director, Division of Scholarly Journals and Professional Periodicals

Pediatrics in Review�Pediatrics in Review�(ISSN 0191-9601) is owned and controlled by the American Academy ofPediatrics. It is published monthly by the American Academy of Pediatrics, 141Northwest Point Blvd., Elk Grove Village, IL 60007-1098Statements and opinions expressed in Pediatrics in Review� are those of the authorsand not necessarily those of the American Academy of Pediatrics or its Committees.Recommendations included in this publication do not indicate an exclusive courseof treatment or serve as a standard of medical care.Subscription price for 2010 for print and online/online only: AAP Fellow $172/$131; AAP Candidate Fellow $161/$120; Nonmember $215/$167; AlliedHealth or Resident $160/$108. Institutions call for pricing (866-843-2271). Foroverseas delivery, add $95. Current single issue price is $10 domestic, $12international. Replacement issues must be claimed within 6 months from the dateof issue and are limited to three per calendar year.Periodicals postage paid at ARLINGTON HEIGHTS, ILLINOIS and atadditional mailing offices.© AMERICAN ACADEMY OF PEDIATRICS, 2011. All rights reserved. Printedin USA. No part may be duplicated or reproduced without permission of theAmerican Academy of Pediatrics.POSTMASTER: Send address changes to PEDIATRICS IN REVIEW�, AmericanAcademy of Pediatrics Customer Service Center, 141 Northwest Point Blvd., ElkGrove Village, IL 60007-1098.Pediatrics in ReviewPrint Issue Editorial Board DisclosuresThe American Academy of Pediatrics (AAP) Policy on Disclosure of FinancialRelationships and Resolution of Conflicts of Interest for AAP CME Activities isdesigned to ensure quality, objective, balanced, and scientifically rigorous AAP CMEactivities by identifying and resolving all potential conflicts of interest before theconfirmation of service of those in a position to influence and/or control CME content.All individuals in a position to influence and/or control the content of AAP CMEactivities are required to disclose to the AAP and subsequently to learners that theindividual either has no relevant financial relationships or any financial relationships withthe manufacturer(s) of any commercial product(s) and/or provider(s) of commercialservices discussed in CME activities. Commercial interest is defined as any entityproducing, marketing, reselling or distributing health-care goods or services consumedby, or used on, patients.Each of the editorial board members, reviewers, question writers, PREP CoordinatingCommittee members and staff has disclosed, if applicable, that the CME content he/she edits/writes/reviews may include discussion/reference to generic pharmaceuticals,off-label pharmaceutical use, investigational therapies, brand names, and manufacturers.None of the editors, board members, reviewers, question writers, PREP CoordinatingCommittee members, or staff has any relevant financial relationships to disclose, unlessnoted below. The AAP has taken steps to resolve any potential conflicts of interest.Disclosures● Richard Antaya, MD, FAAP, disclosed that he participates in Astellas Pharma, US,

Inc., clinical trials, speaker bureau and advisory board; and that he participates in theNovartis speaker bureau.

● Athos Bousvaros, MD, MPH, FAAP, disclosed that he has research grants from Merckand UCB; and that he is a paid consultant and on the speaker bureau for Millennium.

● David N. Cornfield, MD, FAAP, disclosed that he has National Institutes ofHealth grants.

● Donald W. Lewis, MD, FAAP, disclosed that he is a consultant for and has aresearch grant from Astra Zeneca and Merck; and that he has research grantsfrom Ortho McNeil, Lilly, Bristol-Myers Squibb, GlaxoSmithKline, andBoehringer Ingelheim Pharmaceutical.

● Blaise Nemeth, MD, MS, FAAP, has disclosed he has an unrestrictededucational grant for fellowship from Biomet.

● Janet Serwint, MD, FAAP, disclosed that she receives a research grant fromthe Maternal and Child Health Bureau.

● Richard Sills, MD, FAAP disclosed that he receives a research grant from Novartis.

Pediatrics in Review� is supported, in part, through aneducational grant from Abbott Nutrition, a division ofAbbott Laboratories, Inc.

CME Statements:The American Academy of Pediatrics (AAP) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) toprovide continuing medical education for physicians.The AAP designates this journal-based CME activity for a maximum of 36 AMA PRA Category 1 CreditsTM. Physicians should claim onlythe credit commensurate with the extent of their participation in the activity.This activity is acceptable for a maximum of 36 AAP credits. These credits can be applied toward the AAP CME/CPD* Award availableto Fellows and Candidate Members of the AAP.The American Academy of Physician Assistants accepts AMA PRA Category 1 CreditsTM from organizations accredited by the ACCME.This program is approved for 36 NAPNAP CE contact hours; pharmacology (Rx) contact hours to be determined per the NationalAssociation of Pediatric Nurse Practitioners (NAPNAP) Continuing Education Guidelines.*Continuing Professional DevelopmentHow to complete this activityPediatrics in Review can be accessed and reviewed in print or online at http://pedsinreview.aappublications.org. Learners can claim creditmonthly online or submit their scannable answer sheet for credit upon completion of the 12-month activity. A CME scannable answer sheetfor recording your quiz answers can be found bound in the January 2011 issue. The deadline for submitting the 2011 answer sheet for thisactivity is December 31, 2013. Credit will be recorded in the year in which it is submitted. It is estimated that it will take approximately3 hours to complete each issue. This activity is not considered to have been completed until the learner documents participation in thatactivity to the provider via online submission of answers or submission of the answer sheet. Course evaluations will be requested online andin print.

DOI: 10.1542/pir.32-1-3 2011;32;3-4 Pediatr. Rev.

Lawrence F. Nazarian The Pediatrician as Teacher

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CommentaryThe 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,” andlike all physicians, pediatricians func-tion as teachers in many contexts. Ev-ery time a patient is cared for, someteaching is accomplished, even in abrief visit. When performing healthmaintenance or managing chronic ill-ness, teaching becomes a major com-ponent of care. Patients, parents, andcaregivers are the students (althoughthe complete physician will be learningconstantly from those folks as well).

In a pediatric office, physician part-ners teach and learn from each other,and that type of interchange extends tothe entire health-care team. I acknowl-edge with gratitude the invaluable les-sons I have learned from nurses andnurse practitioners, and I hope I haverepaid in kind. Secretaries, reception-ists, business personnel – we can teachall of them, and their contribution toour education is critical.

Many in our profession have de-voted their careers to teaching, andthose of us in practice who havelearned so much from academic physi-cians, both in our training years andthrough our experiences in the office,are grateful for their dedication andexpertise. However, the practitioner canprovide a great deal of education tostudents and residents if there is asymbiotic relationship with an aca-

demic program. A student can be incor-porated into a busy office schedule,first as an observer, then in a moredirect role. This time-honored appren-ticeship model works well, especially ifthe academic department can provideguidance and follow-up. Office teach-ing also works well for students innursing and physician assistant pro-grams.

Visiting a patient in the hospitaloffers opportunities for conversationswith residents that can be mutuallyeducational, and contributing time toround on the wards can be tremen-dously rewarding. Some of the mostfruitful experiences I have enjoyed havecome from the dual rounding system, inwhich an academic specialist and ageneral pediatrician form a teachingteam in the hospital. The ability tocomplement each other’s perspectivesmakes for a full and balanced learningexperience. Office-based pediatricianscan contribute to conferences andgrand rounds as well, especially whenthe topic involves activities they knowintimately, such as telephone manage-ment or well child care, as well assubjects in which they might have aparticular interest.

The general public can benefit fromthe teaching pediatrician. From ad-dressing a group of nursery schoolteachers and parents to appearing onnational television, we are in a positionto pass along information that is accu-rate and evidence-based. Exerting thisinfluence has become more importantthan ever with the proliferation of in-accurate information in the media, es-pecially on the Internet.

Pediatrics in Review (PIR) has as itsmission to improve the health and wel-

fare of all children by educating pedi-atricians and other clinicians who carefor children. As you are reading thiscommentary, authors are crafting arti-cles, reviewers are critiquing papers,editors are planning and refining mate-rial, and other staff are working inmyriad ways to allow our readers tostay current across the whole spectrumof pediatric medicine. We are gratefulfor all of these contributions, many ofwhich are made on a volunteer basis.We appreciate also the feedback we getfrom readers, which we take seriouslyand on which we follow up.

It is important for readers to knowthat the Accreditation Council for Con-tinuing Medical Education sets stan-dards and establishes criteria for certi-fying organizations that grant credit forcontinuing medical education. TheAmerican Academy of Pediatrics (AAP)adheres to these guidelines, which areupdated constantly, in its role as aneducational institution. Adherence in-volves such activities as identifyinglearning gaps, making specific plans forfilling those gaps, and monitoring theeffects of learning and continuing ed-ucation on competence and actualpractice. Making such measurements isa considerable task, and techniquesvary with the type of education; medi-cal journals are different from single-session workshops and multiday con-ferences. Conflict of interest is anotherfacet of education that is addressed bythese standards. Be assured that allwho are involved in the AAP’s educa-tional efforts are working hard toachieve the highest standards.

We are also on the alert for newmodalities to make our teaching moreeffective. Realizing that social networks

commentary

Pediatrics in Review Vol.32 No.1 January 2011 3. Provided by Health Internetwork on April 20, 2011 http://pedsinreview.aappublications.orgDownloaded from


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 formany of the AAP’s publications as wellas current news for each journal. Besure to check it out! Both PIR andNeoReviews have pages on Facebookthat amplify the ways in which we cancommunicate with our readers, andsuch involvement in networking willonly grow.

We would like to introduce a new

resource that should be of great help inassisting you as a teacher of patientsand parents. The AAP has an online web-site (www.healthychildren.org) thatcontains a wealth of material on abroad range of pediatric topics writtenby experts for the lay public. Pediatricclinicians should familiarize themselveswith this site and direct patients, par-ents, and caregivers to it. Material canbe taken from the site and given out.When appropriate, we link resources onthis site to specific articles published in

the journal, but you can help yourpatients at any time by going to the siteyourself or directing them to it.

Just as the AAP and PIR are workingconstantly to improve the ways inwhich we educate you, we encourageyou to be aware of the importance ofyour role as a teacher and to take stepsthat will enhance this critical function.

Lawrence F. Nazarian, MDEditor-in-Chief

commentary

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Lauren M. Jansson and Martha L. Velez Infants of Drug-dependent Mothers







Infants of Drug-dependent MothersLauren 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.

Objectives After completing this article, readers should be able to:

1. Recognize the effects of maternal substance use on the developing fetus, neonate, andgrowing 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.

IntroductionIn 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 factorfor developmental alterations in infants. Intrauterine substance exposure affects morenewborns than many other common major medical conditions, making the problem of thesubstance-exposed infant an inevitable concern for all pediatricians. Of the 4.3 millioninfants born annually in the United States, between 800,000 and 1 million are born towomen who used drugs during pregnancy; approximately 1 in 9 infants is exposed toalcohol, 1 in 5 is exposed to nicotine, and 1 in 20 is exposed to illegal drugs. Opioid useduring 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, and3.4 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 achild 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%, and1.4%, respectively). (2) Pregnant adolescents represent a special population becauseyoung women ages 15 to 17 years report a higher rate of use of illicit drugs and misuse ofprescription drugs than same-age nonpregnant peers. (3) Even a woman who has decidednot to use substances during a pregnancy may do so inadvertently during the early stagesbefore the pregnancy is recognized.

Initial studies examining specific effects of maternal drug use on the infant did notaccount for the wide spectrum of associated risk factors for birth outcomes, particularlypsychosocial risk factors, or failed to estimate the proportion of risk attributable to apresumed biologic mechanism versus these other factors. For these reasons, the traditionalteratology model has been replaced by a transactional or multiple-risk model in which thepsychoactive substance exposure is considered a marker or risk indicator in a contextualframework to explain the outcome of the prenatally substance-exposed newborn.

Multiple risk and protective factors have been investigated for their roles as mediators ormoderators of the effects of maternal drug use on the developing child. Factors such asamount 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. Medicalcomplications in the neonatal period, such as prematurity and low birthweight (LBW), canaffect 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.

Article fetus and newborn



substance abuse frequently is associated with multiplesocial, psychosocial, behavioral, and biomedical maternaland 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 thepopulation 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 allsubstance-abusing pregnant women have a coexistentaxis 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 frequentcomorbid conditions. Psychotropic medications are pre-scribed for women nearly twice as often as they are formen, and these maternal medications can affect infantfunctioning, as can the disorder for which the medicationis prescribed.

The purpose of this review is to examine the currentand relevant scientific literature regarding the effects ofmaternal substance use on the developing child and thefactors that may serve as mediators and moderators of theeffects of maternal substance use on the child as well asprovide some recommendations for clinicians evaluatingand treating substance-abusing mothers and theirsubstance-exposed infants. The goal is to make cliniciansaware of the severity of the potential effects of maternaldrug use on the developing child, the myriad and largelyindefinable mechanisms by which maternal substance usemay affect the infant, and the importance of early andadequate diagnosis and treatment of the substance-exposed mother-child dyad. Improving the clinical ap-proach to these patients may allay the negative short- andlong-term consequences of maternal drug use on thedeveloping child.

Effects of Maternal Drug Use on theDeveloping FetusResearch on the pediatric effects of maternal drug useposes complex challenges because it often is difficult tomake this correlation accurately, given the multiple bio-logic and psychosocial factors that may act as mediatorsor moderators of the effects of drugs on the infant.Animal models traditionally have been used to defineeffects of in utero substance exposure. However, gener-alizing results from animal studies to humans is ham-pered by differences in timing of brain maturation. Drugsof abuse cross the placenta and may influence early

development through several pathophysiologic path-ways. Their teratologic effects are dependent on theintersection of the exposure, the temporal and regionalemergence of critical developmental processes, and thesensitivity of the developing specific brain structure orneural circuit to the drug. Exposure during the first halfof gestation may affect processes related to cytogenesisand histogenesis, whereas effects during the second halfof gestation may compromise progressive events (eg,brain growth and differentiation) and regressive events(eg, programmed cell death). Alterations of these eventshave the capacity to modify brain development as well asthe ability of the developing brain to recover from injury.(5)

Drugs can affect fetal brain development throughindirect and direct mechanisms. Indirect effects may bedue to variations in maternal physiology and placentalfunctioning. For example, potential indirect mechanismsof nicotine exposure include maternal and fetal undernu-trition caused by smoking-induced anorexia, hypoxiadue to increased carboxyhemoglobin and vasoconstric-tion, placental hypertrophy, and reduced transplacentaltransport of nutrients. Direct effects of the drugs includealterations in the development of neurotransmitter andneuromodulator systems, many of which are presentduring early embryogenesis and have pleiotropic effectson brain development.

Marijuana produces its psychoactive effects through spe-cific brain cannabinoid receptors that regulate multipledevelopmental processes such as neuronal proliferation,migration, differentiation, survival, and synaptogenesis.Methamphetamines are potent sympathomimetic agentsthat exert their action by releasing dopamine and serotonin,blocking monoamine reuptake mechanisms, and inhibitingmonoamine oxidase, resulting in increases in synaptic con-centrations of the neurotransmitters dopamine and norepi-nephrine. Opioids are metabolized into morphine, andmechanisms of action are mediated by opioid, principallymu, receptors. Opioid receptors are present in several areasof the brain, and several mechanisms could be affected byopioid exposure. Morphine can affect migration and sur-vival of neurons in rats (6) and increase apoptosis in humanfetal microglia and neurons. (7)

Fetal programming is a mechanism that has beengaining consideration in linking adverse events occurringin utero and related outcomes (eg, enhanced risk formedical, behavioral, or psychiatric problems) in later life.Fetal programming, originally known as the ‘‘Barker” or‘‘fetal origins hypothesis,” (8) assumes that nongeneticfactors such as unfavorable intrauterine conditions canpermanently organize or imprint physiologic and behav-

fetus and newborn infants of drug-dependent mothers



ioral systems and disrupt normal fetal functioning, whichmay result in later disorders. This mechanism has beenimplicated in the causal pathway underlying long-termdeficits observed in alcohol-exposed offspring. (9)(10)Research in animals and emerging studies in humanssuggest that epigenetic changes in regulatory genes andgrowth-related genes play a significant role in fetal pro-gramming. These epigenetic changes are heritable butreversible 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 bepassed on to progeny.

Based on this theory, maternal substance use couldproduce significant changes in the regulation of variousoffspring genes that may be involved in diverse functionalsystems through epigenetic mechanisms. For example, astudy in mice indicated that maternal cocaine exposureduring the second and third trimesters of gestation re-sulted in multiple alterations in the methylation states ofoffspring DNA with persistent effects, suggesting thatmaternal cocaine use could produce potentially profoundstructural 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 thatmost drugs act through different mechanisms with indi-vidual developmental consequences. In the case of co-caine, the drug crosses the placenta and acts at thepresynaptic level, affecting the fetus by blocking thereuptake of the neurotransmitters dopamine, norepi-nephrine, and serotonin; elevating circulating catechol-amine concentrations; and causing vasoconstriction inthe 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 stressorthat alters fetal programming, changing developmentaltrajectories. (12)

Finally, maternal and fetal genotypes and ecogeneticconsiderations (ie, the concept that the combination of aparticular susceptible genome and drug/toxin exposureis necessary for adverse effects to become apparent) alsomay affect outcome.

Effects of prenatal exposures have been shown to besex-specific. For example, prenatal morphine exposureinduces physiologic and behavioral changes involving thestress response in the adult rat that differ between sexes.(13) Prenatal exposure to alcohol alters hypothalamic-pituitary axis responsivity differently in male and female

offspring in both animals and in humans. (14) Prenatalexposure 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 tomaternal methadone use. (16)

Clinically Observable Effects of In UteroSubstance Exposure on the NewbornRegardless of mechanisms of harm and confounding byother risk factors, it is accepted that neonates exposed tosubstances during pregnancy are at increased risk for avariety of conditions that portend future developmentaland other difficulties. The following are the most widelyrecognized clinical conditions associated with in uterodrug exposure.

Drug-related Adverse Birth OutcomesNearly all drugs of abuse have been associated withdrug-related adverse outcomes such as preterm birth,LBW, and growth restriction. Many substances used bydrug-dependent women can shorten gestation and im-pair fetal growth without resulting in preterm deliveriesor LBW, as traditionally defined.

Neonatal Abstinence Syndrome (NAS)NAS is a group of signs indicating dysfunction of respi-ratory, gastrointestinal, or nervous system regulationthat develops after the cessation of the maternal drugsupply at delivery. Neonatal withdrawal is associatedprimarily 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 inascribing any signs of neonatal withdrawal to any partic-ular substance because algorithms used to define NAS arespecific to neonatal opioid withdrawal, and signs of with-drawal to other substances are likely to be qualitativelyand quantitatively different. Nonopioid substances thathave been described as having specific abstinence syn-dromes generally present with infants exhibiting signsthat are described by the Finnegan Neonatal AbstinenceScoring System. (17) However, most newborns exposedto 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-exposedinfants exist. The infant’s display of NAS can affectmaternal functioning and interaction with the newborn,further compounding the threat to progressive neurode-




velopment. Other factors, such as prematurity, can affectthe course and presentation of NAS. (18)

Neurobehavioral and Regulatory ImpairmentSigns displayed by drug-exposed infants that reflect dif-ficulties in their ability to maintain organized behavioraland physiologic responses to external or internal stimu-lation indicate neurobehavioral and regulatory impair-ment, alternatively labeled homeostatic instability ordysregulation. Frequently observed neurobehavioralproblems of substance-exposed infants include tremors;irritability; difficulty being consoled; hypertonicity; in-creased startle response or exaggerated Moro reflex; andrespiratory, feeding, and sleeping problems. Behavioralassessment of signs of regulatory dysfunction displayedby the substance-exposed infant has been facilitated byusing the Neonatal Intensive Care Unit (NICU) Net-work Neurobehavioral Scale. (19) This scale, developedas a neurobehavioral assessment tool for the at-risk in-fant, is used to evaluate how stressors, such as in uterosubstance exposure, affect infant self-organizing neu-robehavioral capacities. A systematic assessment of theneurobehavioral functioning of the substance-exposedneonate 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 ofconcern that can be used to design an individualized careplan. (20)

Structural ChangesCongenital anomalies have been variably reported foralmost all drugs of abuse. Aside from alcohol, which hasa clearly defined pattern of birth defects, large outcomestudies evaluating the correlation between congenitalanomalies and periconceptional drug use generally findno positive associations. (21) Advances in brain magneticresonance imaging-based methods have identified somealterations of brain structures and patterns of functionalactivation in offspring of mothers who used licit (eg,alcohol and tobacco) and illicit (eg, cocaine, metham-

phetamine, marijuana) drugs during pregnancy. Al-though these findings are limited by the complexities ofseparating the specific effects of each drug from otherconfounding variables and the impracticality of usingsuch methods in the clinical setting, particularly duringthe neonatal period, these methods may advance theunderstanding of the underlying structures affected byprenatal drug exposure to improve diagnosis and provi-sion of therapeutic resources for affected infants, chil-dren, and young adults.

Postnatal Problems due to Environmental orCaregiving Deficiencies

Infant neurodevelopmental or behavioral problems canbe 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 tophysiologic or behavioral signs of dysregulation createdby external or internal stimuli, the caregiver’s actions orinteractive style can impair the recovery of the infant andperpetuate dysregulated responses. This impairment, inturn, can affect basic functions such as feeding, sleeping,and interactive patterns that may contribute to altereddevelopmental trajectories. Neurodevelopmental diffi-culties also can be caused or exacerbated by maternalpsychopathology or postnatal drug use, which may pro-vide the infant with further postnatal passive or activeexposure to substances (eg, secondhand smoke or sub-stances via human milk).

The Effects of Individual Substances on theNeonateAlthough it is difficult to ascribe any particular symptomto any particular substance, because most overlap (Table)and are nonspecific, full appreciation of the complexitiesand clinical status of the exposed neonate requires con-sideration of the effects of individual substances.

Table. Observed Effects of Substance Abuse in the NewbornNicotine Alcohol Marijuana Cocaine Opioids PCP Methamphetamine Benzodiazepines

Prematurity Yes Yes No Yes Yes/No No Yes/No YesLow birthweight Yes Yes No Yes Yes/No No Yes YesNeurobehavioral symptoms Yes Yes Yes Yes Yes Yes Yes YesNAS Yes Yes No No? Yes Yes/No Yes? YesCongenital malformations Yes/No Yes No? Yes/No No Yes Yes? Yes/No

Yes/No�both have been reported, ?�controversial or unclear findings, NAS�neonatal abstinence syndrome, PCP�phencyclidine




NicotineNicotine has been described as a neuroteratogen thatcompromises critical neural pathways in the developingbrain. (22) Nicotine crosses the placenta, and the fetus isexposed to concentrations that are 15% higher than inthe maternal bloodstream. Cigarette use also involvesexposure to substances that interfere with oxygen deliv-ery and use, such as carbon monoxide and hydrogencyanide; these additional factors may participate in theoverall effects of smoking. Nicotine exposure duringgestation includes effects that have been found to berelated to secondhand smoke as well as nicotine replace-ment therapies. (23) Neurobehavioral symptoms de-scribed in exposed neonates include impairment ofarousal, irritability and hyperexcitability, hypertonicity,and tremors. (24)(25)

Reports of sporadic congenital anomalies associatedwith nicotine consist principally of higher incidences oforofacial clefts, neural tube defects, and cryptorchidism,although large-scale studies have found no significantincrease in gross malformations. (26) Prenatallynicotine-exposed infants are at increased risk for pretermbirth and sudden infant death syndrome (27) as well asfetal growth restriction, which has been linked to subse-quent development of both neonatal and adult disease.(28) Dose-dependent LBW has been associated withmaternal smoking. (29) Heavily nicotine-exposed infantshave been described as having withdrawal syndromes.(30)(31)

AlcoholAlcohol exposure during gestation is a significant riskfactor for poor infant outcomes. Alcohol passes throughthe placenta, and the amniotic fluid is a reservoir forethanol, which increases availability of the drug to thefetus. Maternal alcohol use can produce preterm birth,LBW, and fetal alcohol spectrum disorder. Fetal alcoholsyndrome is characterized by specific facial features,growth deficiency, central nervous system abnormalities,behavioral abnormalities, and intellectual disability. (32)A neonatal alcohol withdrawal phenomenon has beendescribed in children born to alcoholic mothers andincludes jitteriness, irritability, seizures, opisthotonus,abdominal distention, (33)(34) excessive mouthingmovements, and reflex abnormalities. (35)

MarijuanaDelta9-tetrahydrocannabinol is the major psychoactiveingredient in cannabis. Cannabis constituents cross theplacenta and are stored in amniotic fluid. Prolonged fetalexposure can result from regular marijuana use. Minor

physical anomalies (ocular hypertelorism and epican-thus) have been reported in heavy users of cannabis, butthere is a lack of a definitive relationship between physicalanomalies and prenatal cannabis exposure in general.Neurobehavioral effects of in utero cannabis exposurerange from mild deficits in visual functioning, height-ened tremors, startling, jitteriness, hypotonia, and leth-argy (36) to difficulties with arousal, regulation, andexcitability. (37) Although shorter gestational periodshave been reported among heavy marijuana users, (38)neither LBW nor preterm birth have generally beenreported.

CocaineCocaine-exposed infants are at risk for preterm birth andLBW. Neurobehavioral signs at birth include jitterinessand tremors, high-pitched cry, irritability, excessive suck,hyperalertness, autonomic instability, (39) hypertonic-ity, and excitability. (40) Congenital anomalies havebeen reported previously in cocaine-exposed infants, butlarger and more recent studies have disputed those find-ings. (39) A dose-response relationship for a negativeassociation with motor and state regulation capabilitieshas been reported. (41)

OpioidsOpioids are narcotic, analgesic substances that havemorphine-like effects and include narcotic pain killers,heroin, and methadone, a synthetic opiate with similarpharmacologic properties to morphine that is used totreat individuals who have opiate addictions. Most stud-ies report increased preterm birth and LBW related toopioid use, although few have controlled for associatedrisk factors. Those that have done so generally report noindependent relationships between opiate use andgrowth parameters. The most notable opioid effect onthe neonate is NAS, which may include tonal problems,tachypnea, feeding and sleeping problems, fever, andseizures among its signs. The tool used most commonlyto evaluate opioid-related NAS is the Finnegan scale.(42) Evaluation of the opioid-exposed newborn usingthis scale is recommended every 3 to 4 hours duringhospitalization, and surveillance should last for severaldays after birth. The scale contains 31 weighted (depend-ing on symptom and severity) items. Opioid agonistpharmacotherapy is recommended for infants who haveFinnegan scores above a threshold level.

PhencyclidineInfants exposed in utero to phencyclidine (PCP) havebeen reported to display dysmorphologic features that




consist of microcephaly (43) and alterations in facialfeatures. (44) Described neurobehavioral symptoms af-ter delivery consist of decreased attention, high-pitchedcry, poor visual tracking, coarse flapping tremors, leth-argy, nystagmus/roving eye movements, poor feeding,and altered newborn reflexes. (43)(45) Although infantsexposed to PCP generally are smaller and have lowergestational ages than nonexposed infants, PCP exposureis not associated with LBW or preterm birth. (46) AnNAS has been described (47) and disputed (48) forPCP-exposed infants.

MethamphetaminesDespite concerns about infants exposed to this drug asrates of usage in the United States increase, there is ageneral dearth of reports involving in utero exposure.Isolated cases of cardiac defects, cleft lip, and biliaryatresia have been reported. (49) Use during pregnancyalso has been associated with increased rates of fetaldistress and growth restriction, (50) resulting in small-for-gestational age size at birth. (50)(51)(52) Metham-phetamine exposure has been associated with pretermbirth, (50) but this linkage has been disputed morerecently. (52) Neurobehavioral patterns of decreasedarousal, increased stress, and poor quality of movement(53) have been described, as has a withdrawal syndromein a few infants (4%). (54)

BenzodiazepinesOne of the most commonly prescribed class of drugsduring pregnancy, despite the absence of completeknowledge of their potential adverse effects, benzodiaz-epines also are commonly abused licit drugs, and expo-sure often is unrecognized due to inconsistent screeningpolicies. Benzodiazepines cross the placenta and accu-mulate in the fetus to varying degrees, depending on thespecific drug and its properties. Withdrawal phenomenahave been reported in exposed infants. Signs includehypoventilation, irritability, hypertonicity, and “floppyinfant syndrome,” particularly after use in late gestation.(55)(56) These symptoms can appear within a few daysto 3 weeks after birth and can last for several months.(57) There has been variable reporting on the relative riskof congenital anomalies in this group of infants. Anincreased risk of orofacial clefts was described in earlycase-control studies and refuted in later cohort studies.(58) Benzodiazepines appear to increase the risk of pre-term birth and LBW. (59)

ManagementThe drug-dependent mother and her infant are a com-plex and highly vulnerable dyad that present a challengeto any clinician. Due to the often multiple negativeexperiences and maladaptive behaviors of the mother andthe frequently confusing constellation of signs and symp-toms of abstinence and neurobehavioral dysregulation ofthe infant, the dyad commonly is “out of sync” or “notbonding.” Thus, they require a caring and well-trainedclinician to ensure a successful neonatal adaptation andprevent the initiation of altered developmental and inter-actional trajectories. Provision of optimal care for the pairinvolves appropriate identification of the maternal sub-stance abuse and other difficulties, careful and frequentobservation of the infant, and delineation of individual-ized care plans for the dyad. Lack of acknowledgment ofthe 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 quietenvironment and gentle handling, swaddling, small andfrequent 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 includeresponses and sensitivities to auditory, tactile, and visualstimuli; motor capabilities; tremors and jitteriness; andstyle of communication, including eye contact, ability tocalm with intervention, ability to signal needs, and signsof stress or abstinence. The infant’s capacities and diffi-culties in each area should be addressed in individual careplans as well as in maternal-infant care.

For infants experiencing significant NAS symptom-atology, pharmacotherapy is warranted. Medicationsused to treat the neurobehavioral symptoms related toprenatal exposure to psychoactive drugs vary widelyamong institutions. The most commonly used first-linemedications for opioid withdrawal are opioids (oral mor-phine solution, tincture of opium) and methadone. (60)A major review advocates opioids as the drug of choicefor neonatal opioid withdrawal. (61) For polydrug-exposed infants, commonly employed medications areopioids, phenobarbital, and methadone. (60) Weight-based versus symptom-based treatment strategies can beemployed, and examples of both have been described.(62)(63) Little empirically based evidence supports the




use of one medication or one treatment strategy over theother, reflecting a paucity of randomized studies in thisarea. At the time of this writing, newer agents for thetreatment of NAS, such as clonidine (64)(65) and bu-prenorphine, (66) are being explored and may have a rolein the management of NAS.

By examining the newborn in the presence of themother and evaluating her perceptions and responses tonewborn 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 othercaregivers can be taught to provide appropriate environ-ments (eg, not over- or understimulating) for the infant.Infants who have significant NAS require medication andprolonged hospitalization. In situations where mothersare able to stay with their infants or visit regularly, thisperiod can be used as a time of prolonged evaluation ofthe 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, andschedules, can provide a basis for improved parentingskills in the mother as the child grows. Maternal satisfac-tion with the diminution of NAS symptoms associatedwith 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 inthe care of the dyad for providing a basis for improvedparenting and infant/child development.

Drug-dependent women also require thoughtful andcareful evaluation because their needs can be as complexas 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 appropriatesubstance abuse treatment that will accept the infant. Forwomen in treatment, conference (after consent) withtreatment counselors to determine ongoing care plans isimportant. Mood disorders or other psychiatric comor-bidity should be evaluated and addressed in ongoingpostpartum care, particularly because women who havedepression are at increased risk for postpartum depres-sion. Postpartum guilt and anxiety, particularly forwomen who have infants experiencing NAS, is common,can interfere with dyadic communication, and must begently addressed and monitored. Prejudicial or punitiveattitudes, negative stereotyping, and conflicting advicehave no place in the care of postpartum drug-dependentwomen because such attitudes only drive them away

from treatment and other beneficial encounters at a timewhen treatment is most needed from those professionalsmost poised to help. Similarly, caregivers of the infantmust refrain from stereotypical or prejudicial attitudestoward the mother. Referral to child protective or other

Summary• Nearly any psychoactive licit or illicit substance

consumed by the pregnant woman is likely to resultin enhanced risk of medical, developmental, andemotional/behavioral disability in the developinginfant/child. These risks can be compounded bybiologic and psychosocial factors associated withmaternal addiction.

• Drug-dependent women do not use substances inisolation and they cannot escape the myriadcomplications of their internal and externalenvironments and the attendant risks to thedeveloping fetus and infant.

• The developmental trajectories of fetuses exposed topsychoactive substances may be altered by manyfactors, including disruption to neuroendocrine andneurotransmitter system development and fetalprogramming via stress hormone changes, resultingin altered set points for physiologic, metabolic, andbehavioral outcomes. (69)

• Epigenetic models of developmental theoryexamining the intersecting influences of genes,physiology, and behavior with the physical, cultural,and social environment as well as other mechanismshave been implicated in the alteration ofdevelopmental trajectories. (5)

• These effects occur through the programming of cellfate and differentiation, in defining ultimate activitylevels of specific functional systems, and inmediating environmental modulation of geneticallybased developmental programs. In this context,maternal substance use during gestation maydirectly or indirectly derail normal development byadversely modifying fetal/neonatal gene expression,resulting in disruption in brain development.

• The consequences of drug exposure can be seen atbirth but sometimes do not emerge until later in lifeand may be produced at doses that are relativelyharmless for adults.

• The role for all clinicians in the comprehensive careof the substance-exposed neonate should includethorough, comprehensive, and individual evaluationof the infant, the mother, and their interaction. Onlythrough a willingness to understand and treat themother who has drug addiction and the exposedinfant as a pair, which may involve the extension ofthe boundaries of pediatric care, can we provideoptimal care for substance-exposed infants, perhapsthe most poorly understood, marginalized, andvulnerable segment of the pediatric population.




monitoring services, when appropriate, may be neces-sary, particularly for women who have positive urinetoxicology screening results that indicate recent drug useat delivery or substance-abusing women not in drugtreatment. However, these services are not warranted formost abstinent and stable methadone-maintainedwomen enrolled in comprehensive substance abuse treat-ment.

Women receiving methadone maintenance may havedifficulties with oversedation in the postpartum perioddue to changing medication needs and pain control andshould be assessed for such reactions by pediatric clini-

cians who are likely to observe them. Communicationwith obstetric and mental health professionals is impor-tant in these cases. Breastfeeding is not contraindicatedfor women receiving methadone maintenance therapybut may not be advised for women relapsing to drug useclose 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 QuizQuiz 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 inutero. They ask for information about how drug exposure affects medical and behavioral issues as childrenmature. 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 associatedwith this infant’s birthweight is:

A. Diazepam.B. Fentanyl.C. Marijuana.D. Oxycodone.E. Phencyclidine.




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 hyperactivityand 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 tospeak 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. Theintrauterine drug exposure most likely associated with these findings is:

A. Alcohol.B. Benzodiazepines.C. Cocaine.D. Marijuana.E. Methamphetamines.





Lauren M. Jansson and Martha L. Velez Infants of Drug-dependent Mothers



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Sarah R. Glick and Ryan S. Carvalho Inflammatory Bowel Disease







Inflammatory Bowel DiseaseSarah R. Glick, MD,*

Ryan S. Carvalho, MD†

Author Disclosure

Drs Glick and

Carvalho have

disclosed no financial

relationships relevant

to this article. This

commentary does


of an unapproved/


commercial

product/device.


1. Develop a differential diagnosis and plan an initial evaluation for the child oradolescent who presents with bloody diarrhea and abdominal pain.

2. Recognize that growth failure and pubertal delay may be an initial presentation ofCrohn disease.

3. List the extraintestinal manifestations of inflammatory bowel disease (IBD).4. Discuss the genetic advances in understanding the pathogenesis of IBD.5. Describe the current treatments for IBD and the common adverse effects.

IntroductionIBD is a complex, multifactorial disease characterized by chronic inflammation in theintestinal tract of a genetically predisposed host. The spectrum of IBD in children primarilyincludes ulcerative colitis (UC) and Crohn disease (CD). With pediatric patients nowaccounting for 20% to 25% of newly diagnosed cases, it is becoming increasingly importantfor pediatricians to recognize the symptoms of IBD. (1) In this review, we discuss theepidemiology, clinical presentation, diagnosis, and complications of IBD, with specificemphasis on growth failure and pubertal delay because these are unique manifestations inchildren. We also describe newer, less invasive diagnostic techniques and current trends inmanagement and advances in the pharmacologic treatment of affected children.

Epidemiology and DemographicsThe epidemiologic patterns of pediatric IBD have evolved over the past few decades, withsignificant increases in both incidence and prevalence. The current incidence is 5 to 11 per100,000 children, with a recent statewide survey from Wisconsin reporting the annualrate 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 from9.5 per 100,000 in 1994 to 11.4 per 100,000 in 2005. Themost significant increases were among the younger agegroups, with the incidence rising 5% annually in childrenyounger than 4 years of age and 7.6% annually in childrenages 5 to 9 years. (3)

The mean age at diagnosis of pediatric IBD in the UnitedStates is 12.5 years, (2) with 20% of children diagnosedbefore the age of 10 years and fewer than 5% diagnosedbefore age 5 years. Males seem overrepresented in new casesof pediatric CD, although an equal number of males andfemales receive a UC diagnosis. (4)

Many risk factors have been associated with IBD, includ-ing family history, ethnicity, and tobacco use. Up to 25% ofchildren who develop IBD have a positive family history ofIBD. (5) Children who have a first-degree relative affectedby either UC or CD have a 10 to 13 times higher risk fordeveloping IBD. (5) Monozygotic twin concordance is ap-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.

Abbreviations

5-ASA: 5-aminosalicylatesCD: Crohn diseaseEN: erythema nodosumESR: erythrocyte sedimentation rateFC: calprotectinFL: lactoferrinIBD: inflammatory bowel diseaseIGF-1: insulin-like growth factor-1MRI: magnetic resonance imagingPG: pyoderma gangrenosumPSC: primary sclerosing cholangitisSNP: single-nucleotide polymorphismTNF: tumor necrosis factorUC: ulcerative colitisVCE: video capsule endoscopy

Article gastrointestinal



cally have shown a higher prevalence of IBD in patientsof European or African descent than in patients of His-panic or Asian descent. (7) Notably, Jewish ancestry(Ashkenazi more than Sephardic) is a significant riskfactor for the development of IBD. However, morerecent pediatric-specific population studies detected nodifferences in IBD frequency between ethnic groups. (2)

The prevalence of IBD is highest in the industrializedworld, including North America, northern Europe, andthe 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 ofdeveloping CD is twice as high as for nonsmokers. (7)Passive exposure to smoking may be influential as well. (8)

GeneticsA genetic predisposition to IBD has been hypothesizedfor decades because of the strong familial pattern ofdisease. Linkage analyses and genome-wide associationstudies 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 recognitionof bacterial peptidoglycans in monocytes, macrophages,gut epithelial cells, and Paneth cells. NOD2 mutationscan impair the degradation of gut bacteria, leading to anaccumulation of bacterial antigens and predisposing tomucosal T-cell activation.

Nearly 40% of white patients who have CD carry oneof these NOD2 SNPs compared with 20% of controls. (9)These allelic variants also have phenotypic implicationsfor those who have CD, with earlier age of onset, stric-turing disease, and ileal involvement occurring morefrequently.

The IBD5 locus on chromosome 5q31 is associatedwith a higher susceptibility toward CD. Patients whohave CD and IBD5 locus polymorphisms may have moreperianal 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 theIBD5 locus with UC.

The IBD3 locus on chromosome 6 contains themajor histocompatibility complex genes, which also maycontribute toward IBD predisposition. The DRB1*1502gene has been associated with UC, and the DRB1*07gene has been associated with CD, particularly in patients

who have ileal disease without a high-risk NOD2 poly-morphism. The DRB1*0103 allele has been linked toUC and colonic CD. Patients who have UC and thisvariant seem to have a greater predisposition towardmore extensive and severe colonic involvement. Therealso seems to be an association between IBD3 locusvariants and the extraintestinal manifestations of uveitisand peripheral arthropathy. (9)

The field of IBD genetics is continuously expanding,but genetic testing is currently limited to research. In thefuture, children who have IBD may undergo genetictesting to quantify disease risk in family members or topredict phenotypic expression.

CausesThe precise causes of IBD remain unknown, but thecurrent understanding involves a genetic predispositioncombined with a dysregulation between the immunesystem and the antigenic environment in the gastrointes-tinal tract, leading to inflammation and damage. (11)The major pathogenic mechanism underlying CD is anexcessive Th1 immune response, whereby CD4� T cellsbecome 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 leadto enhanced uptake of luminal bacteria, causing thenormally protective mucosal immune system to be over-whelmed. This derangement may be a result of toler-ance to luminal antigens, a hyperreactive cell-mediatedimmune system, or specific gene mutations (such asNOD2).

It has been postulated that the unchecked intestinalimmune response to ubiquitous bacterial and entericantigens could lead to the pathologic gross tissue injurycharacteristic of IBD. Activated immune cells secretea variety of soluble mediators of inflammation, includ-ing cytokines (tumor necrosis factor [TNF]-alpha,interferon-gamma, transforming growth factor-beta, andinterleukin-2, -5, -6, -12, and -18), arachidonic acidmetabolites, 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 ofthose who have CD.

The most persuasive argument for a pathogenic roleof enteric flora comes from murine studies of IBD.(14)(15) The gut inflammation seen in mouse models ofIBD depends on the presence of bacterial flora. No singleinfectious agent has been reproducibly associated with

gastrointestinal inflammatory bowel disease



IBD, but several bacterial species, including Salmonella,Helicobacter, toxigenic Escherichia coli, Listeria, andCampylobacter, have been suggested to play a role inpathogenesis. Mycobacterium paratuberculosis has beenstrongly suspected in IBD development. (16) Viral the-ories have been proposed, including the potential formeasles virus to cause a granulomatous vasculitis. (17)Another antigenic hypothesis in the development of IBDincludes 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 PresentationUC and CD can have varied yet overlapping presenta-tions. The cardinal symptoms of UC are diarrhea, rectalbleeding, and abdominal pain. Most children presentwith an insidious history of diarrhea without systemicsigns of fever or weight loss. One third present withmoderate 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 ormore bloody stools per day; more profound anemia andhypoalbuminemia; fever; tachycardia; and a diffusely ten-der or distended abdomen. (19)(20) Children who haveUC may develop symptoms of reflux or dyspepsia asso-ciated with inflammation of the upper gastrointestinaltract. (21)

The classic presentation of ab-dominal pain, diarrhea, and weightloss occurs in most children whohave CD. Abdominal pain typicallyis crampy and can be diffuse or lo-calized to the right lower quadrant.(22) Stools can appear nonbloodyor melanotic or can contain frankred blood. Chronic perianal disease,including tags, fissures, fistulae, andabscesses, may be present. (23) Re-current aphthous-stomatitis can alsosuggest the diagnosis. A decrease inheight velocity may precede overt ab-dominal symptoms by 5 years, andgrowth failure may be the only sign ofillness in 5% of children who receivethe diagnosis of CD. (24) Poor appe-tite, fevers, and iron deficiency ane-mia are also commonly noted at ini-

tial presentation in children who have CD. Decreased bonedensity is seen in 25% of newly diagnosed children, evenbefore initiation of corticosteroid therapy. (25)

Extraintestinal ManifestationsOne third of patients who have IBD develop extra-intestinal manifestations, which may predate the onsetof intestinal symptoms (Table 1). (26) Arthralgias andarthritis are common extraintestinal manifestations ofCD. (26) Arthropathy also occurs in 20% to 25% ofpatients 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 withintestinal disease activity. (27) Ankylosing spondylitisassociated with IBD runs a course independent ofbowel disease activity and may progress to permanentdeformity.

Erythema nodosum (EN) and pyoderma gangreno-sum (PG), although rare, are the most frequent cutane-ous manifestations in IBD. EN occurs more commonlywith CD; is characterized by tender, warm, red nodulesor plaques; and typically is localized to the extensorsurfaces of the lower extremities. PG occurs in fewer than5% of UC patients and often is associated with moreextensive colonic involvement. The lesions may appearinitially as discrete pustules with surrounding erythemaand subsequently extend peripherally, developing into anulceration that has a well-defined border and a deeperythematous-to-violaceous color. PG tends to develop

Table 1. Extraintestinal Manifestations ofInflammatory Bowel Disease

System Extraintestinal manifestations

Skeletal Arthritis, arthralgia, ankylosing spondylitis, digital clubbing(hypertrophic osteoarthropathy), osteopenia, osteoporosis,aseptic necrosis

Cutaneous Erythema nodosum, pyoderma gangrenosum, aphthous ulcers,vesiculopustular eruption, necrotizing vasculitis, metastaticCrohn disease

Ocular Uveitis, episcleritis, corneal ulceration, retinal vascular diseaseHepatic Primary sclerosing cholangitis, bile duct carcinoma, autoimmune

chronic active hepatitis, fatty liver disease, cholelithiasisEndocrine Growth failure, pubertal delayHematologic Autoimmune hemolytic anemia, thrombocytopenic purpura,

thrombocytosis, thrombophlebitis, thromboembolism, arteritisRenal Nephrolithiasis (classically oxalate stones)Cardiac Pericarditis, myocarditis, heart blockPancreatic Acute pancreatitis (Crohn disease > ulcerative colitis)Neurologic Peripheral neuropathy, myelopathy, myasthenia gravis




around sites of trauma and surgical scars. Although theemergence of EN usually follows intestinal disease activ-ity, PG runs an independent course, often necessitatingpotent therapy.

Transient transaminase elevation occurs in some chil-dren who have IBD and may be related to medicationsor disease activity. Persistent elevations suggest the pres-ence of primary sclerosing cholangitis (PSC) or auto-immune hepatitis. PSC is more commonly associatedwith 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 valuesalong with results of cholangiography and liver biopsyhelp confirm the diagnosis. (29)

Nutritional ConsiderationsGrowth failure occurs in 15% to 40% of children whohave IBD and is more frequent in CD than UC. TheZ-score (or standard deviation score) is used as an objec-tive measurement of growth. The mean height Z-scoreat diagnosis of pediatric CD is �0.54, and a delay indiagnosis or presence of jejunal disease is negativelycorrelated with the Z-score. (4) Poor weight gain alsomay precede a diagnosis of IBD. Mean weight Z-score atdiagnosis 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 diagnosisof UC is �0.32, with only 9% of patients falling belowthe 3rd percentile for age. (4)

The cause of growth failure in IBD is multifactorial.Patients often experience abdominal pain and diarrhearelated to eating, leading to food avoidance behaviorsand a decrease in total energy intake. Elevated concen-trations of proinflammatory cytokines contribute to an-orexia and can cause growth hormone resistance, withinhibition of insulin-like growth factor-1 (IGF-1) pro-duction. (30) In CD, active inflammation in the smallintestine can decrease the absorptive surface area, result-ing in a protein-losing enteropathy. Fat malabsorptioncontributes to the general energy-deficient state and maycause deficiencies in fat-soluble vitamins. Disease com-plications such as the presence of internal fistulae, surgi-cal bowel resections, or diverting ostomies can decreasenutrient absorption further.

Differential DiagnosisThe differential diagnosis for a child or adolescent pre-senting with abdominal pain and bloody diarrhea isbroad. Infectious enterocolitis, pseudomembranous

colitis, lymphocytic colitis, eosinophilic enterocolitis,Henoch-Schonlein purpura, and hemolytic-uremic syn-drome should be considered in addition to IBD. Intesti-nal malignancies such as non-Hodgkin lymphoma alsoshould be considered. The periodic fevers syndromes,including TRAPS (TNF receptor-associated periodicsyndrome) and PFAPA (periodic fever, aphthous stoma-titis, pharyngitis, and cervical adenitis), are rare but havesome clinical overlap with IBD. Rheumatologic disor-ders, such as juvenile idiopathic arthritis, ankylosingspondylitis, and systemic lupus erythematosus, sharemany characteristics with pediatric IBD, specifically,weight loss, malaise, recurrent fevers, and joint involve-ment. Finally, intestinal tuberculosis and CD have similarclinical, radiographic, and endoscopic features and canbe remarkably hard to differentiate. Intestinal tuberculo-sis typically involves the ileocolonic region, and the ul-cerative form is most common. A patient who has riskfactors for tuberculosis should have a tuberculin skin testplaced.

DiagnosisA new diagnosis of IBD often is suggested by the clinicalhistory and findings on physical examination (Fig. 1).The history should focus on the nature and duration ofsymptoms; 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 extraintestinalsymptoms (aphthous ulcers, skin lesions, joint pains, eyesymptoms). 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 MaturityRating staging. A complete evaluation includes examin-ing the mouth for aphthous lesions and performing athorough abdominal examination. Physical findings mayinclude abdominal tenderness, right lower quadrant massor 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 areamust be checked for skin tags, fistulae, and fissures.

Nutritional assessment should include measurementsof growth velocity, height and weight Z-scores, and acomparison of absolute height with predicted mid-parental height. A bone age radiograph can be obtainedif there is concern for significant growth delay. A dietaryhistory should be obtained, with calculation of protein,carbohydrate, fat, vitamin, and mineral intake and com-parison to recommended daily values. Serum concentra-




tions of total protein, albumin, vitamin D, and ironshould be measured. Depending on disease location,vitamin B12, folic acid, and micronutrients such as zincalso should be assessed.

Measurements of hemoglobin, platelet count, eryth-rocyte sedimentation rate (ESR), and albumin classicallyshow abnormalities in children who have new-onsetIBD. Anemia is present in approximately 70% of patients,and ESR is elevated in nearly 75% of children who havemoderate-to-severe disease. Only 4% of children whohave moderate or severe IBD have normal test results atthe time of diagnosis compared with 21% of patients whohave mild CD and about 50% of those who have mildUC. (31) Thus, normal values in these domains shouldnot delay further diagnostic evaluation if a high degree ofsuspicion 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 measuredquantitatively in stool samples. (32) These markers are

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 differentiatingchildren 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 populationscreening or as an isolated diagnostic tool is not recom-mended. False-positive results can create unwarrantedanxiety and lead to excessive invasive testing. It should benoted that nearly one third of patients who have a posi-tive serologic panel do not have IBD. Serologic panelsare most useful in children who have indeterminate coli-tis to differentiate CD from UC (Table 2). (34) Higherserologic antibody titers and a greater number of positivemarkers are associated with a more aggressive diseasecourse. (35)(36) Notably, anti-Saccharomyces cerevisiae-positive CD patients are more likely to have perianal diseaseand ileal stricturing disease requiring resection. (37)

Imaging studies play an important role in the diag-nosis of IBD. With CD, a barium upper gastrointestinalradiographic series may demonstrate stenosis, abnormalseparation of bowel loops, and fistula formation. Com-puted tomography scan can assess for intestinal wallthickening and is important in the assessment of urgentcomplications of IBD, such as abscess formation andfistulizing or stricturing disease. Magnetic resonance im-aging (MRI) is beginning to play a larger role in childrenwho have IBD because there is no radiation exposure.MRI has greater than 90% sensitivity and specificity fordetecting CD of the small intestine and has the potentialto distinguish colonic CD from UC because mucosaland full-thickness bowel wall inflammation enhance dif-ferently. (38)(39)

Endoscopy, including esophagogastroduodenoscopyand colonoscopy with biopsy sampling, is the gold stan-dard for diagnosing IBD. Inflammation of the uppergastrointestinal tract can be seen in both UC and CD,although the presence of noncaseating granulomas inthe stomach (versus nonspecific gastritis) is diagnosticof CD.

Endoscopic features of UC include the characteristiccontinuous inflammation beginning in the rectum andextending a variable distance proximally into the largeintestine. A sharp demarcation may exist between normaland diseased colon. The mucosal surface may be ery-thematous and granular, and there can be a loss of thenormal vascular pattern with remarkable friability in areasof endoscope contact (Fig. 2). There may be small ero-sions, patches of exudates, and pseudopolyps. “Patchy”

Figure 1. Evaluation of a patient suspected of having inflam-matory bowel disease (IBD). ESR�erythrocyte sedimentationrate, UGI�upper gastrointestinal, VCE�video capsuleendoscopy




colitis and relative rectal sparing can be consistent withearly disease or partially treated UC. Biopsies may revealcrypt distortion with branching, shortening, or atrophy;there may also be crypt abscesses. Inflammatory changesare limited to the mucosal layer.

Endoscopic features of CD include the characteristicskip lesions, in which areas of inflamed mucosa are in-terspersed with normal-appearing gut. “Cobblestoning”involves linear ulceration, with adjacent swelling givingtissue a cobblestone pattern (Fig. 3). Aphthae, exudates,

and stricturing may be present anywhere from the mouthto the anus, but the rectum typically is spared from grossinflammation. The terminal ileum is classically abnormalon gross inspection, and the ileocecal valve may bestenotic. The characteristic finding on biopsy is noncase-ating granulomas. Inflammation can extend through thefull thickness of the bowel wall.

Wireless video capsule endoscopy (VCE) is an excit-ing modality that can detect small bowel lesions in areasnot accessible to traditional endoscopy. VCE is also

Table 2. Detection of Commercially Available Serologic MarkersSerologic Marker Crohn Disease Ulcerative Colitis Controls

ASCA (anti-Saccharomyces cerevisiae antibody)immunoglobulin A and G

40% to 56% 0% to 7% <5%

ANCA (anti-neutrophil cytoplasmic antibody)histamine 1 protein, DNAase-specific

18% to 24% 60% to 80% <5%

Anti Omp C (outer membrane protein ofEscherichia coli )

25% 6% 3%

Figure 2. A. Normal colonic mucosa and vascularity. B. Colonin a child who has ulcerative colitis, showing continuousinflammation, swelling, loss of vascular markings, and bleeding.

Figure 3. A. Normal terminal ileum with lymphoid nodularity.B. Terminal ileum in a child who has Crohn disease, showinginflammation, cobblestoning, exudates, and bleeding.




helpful in identifying disease recurrence, evaluating anas-tomotic sites, and detecting luminal complications suchas malignancy. The drawbacks of VCE are difficulty withcapsule ingestion in young children and risk of capsuleretention.

TreatmentMedical Management

Immense progress has been made in the medical man-agement of pediatric IBD over the past decade. Theprimary goals of therapy are induction and maintenanceof remission, prevention of disease complications (suchas fistula, stricture, abscess, and cancer), control of post-operative disease recurrence, maintenance of normalgrowth and development, and maximization of qualityof life.

Medications are selected based on the disease loca-tion and severity, the potential for adverse effects, andanticipated 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 addressedmost commonly with oral or intravenous corticosteroids,which inhibit the inflammatory cascade. The goal is touse corticosteroids for as short a period as possible, thenchange to nonsteroidal maintenance therapy. Budes-onide, an oral corticosteroid, is frequently employed inthe treatment of mild-to-moderate CD because it isreleased 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 dependencyoccurs in up to 50% of UC patients and 30% of CDpatients. (40)(41)

For adult patients who have mild-to-moderate UC,5-ASA medications (sulfasalazine, mesalamine, balsala-zide) are effective in inducing and maintaining remissionin 90% of cases. (42) Experience in children suggestssimilar response rates. The exact mechanism of actionremains unknown but may involve decreased leukotrieneproduction or scavenging of reactive oxygen species.A new, once-daily 5-ASA medication, mesalaminedelayed-release tablets, has shown comparable efficacywith the benefit of better compliance. However, the useof 5-ASA medications in CD has become controversialbecause a meta-analysis demonstrated no superiority toplacebo in maintaining remission. (43)

The use of immunomodulators in children who haveIBD has become the standard of care. Fifty percent ofnewly diagnosed children who have UC and 75% of those

who have CD are given immunomodulators within 2years of diagnosis. Immunomodulators such as azathio-prine and 6-mercaptopurine, which interfere with purinebiosynthesis, have demonstrated good tolerance andcan maintain remission in 75% of patients after discon-tinuation of corticosteroids. (44)(45) Because azathio-prine (which is metabolized to 6-mercaptopurine) and6-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 andmay be particularly useful when remission is not achievedwith azathioprine or 6-mercaptopurine or in patientswho experience intolerable adverse effects from thosemedications. (46) Methotrexate inhibits dihydrofolatereductase, an enzyme necessary for folic acid metabolismand thymidine synthesis. The drug is effective at provid-ing short-term symptom control, long-term remission,and steroid withdrawal. (47) Methotrexate usually isdelivered as a weekly subcutaneous injection, and folicacid supplementation is recommended. Other immuno-modulators used infrequently in IBD treatment includetacrolimus and mycophenolate mofetil.

For moderate-to-severe disease, biologic therapy isuseful for induction and maintenance of remission. In-fliximab is a chimeric monoclonal antibody directedagainst the cytokine TNF-alpha that acts by inducingapoptosis of active T lymphocytes. A response rate of upto 90% is achieved in patients who have moderate-to-severe CD, even when disease is refractory to corticoste-roids and immunomodulators. (48) Those children whohave refractory UC previously were treated with cyclo-sporine, but infliximab has become the treatment ofchoice because cyclosporine therapy has a high likelihoodof eventual treatment failure and the need for colectomyin children.

For patients who respond to infliximab, scheduled

Figure 4. Treatment pyramid for ulcerative colitis (UC)and Crohn disease (CD) in children. TPN�total parenteralnutrition, TNF-��tumor necrosis factor-alpha, 6-MP�6-mercaptopurine, 5-ASA�5-aminosalicylates, IV�intravenous




maintenance infusions are continued every 6 to 12 weeks.Gut mucosal healing has been demonstrated followinginfliximab therapy. Infliximab also plays an importantrole in treating fistulizing CD, which typically is moreresistant to conventional therapies, and extraintestinalmanifestations of IBD. PG, vasculitis, uveitis, EN, andarthritis have responded to this therapy.

Infliximab is the only immunomodulator approvedby the United States Food and Drug Administration forchildren who have CD. However, two other anti-TNFagents, adalimumab and certolizumab, appear effica-cious. Response rates are similar to infliximab, but be-cause these antibodies are more fully humanized, allergicreactions may be less common. Adalimumab has shownefficacy 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 hasdemonstrated clinical efficacy in treating children whohave CD. (50) Three cases of progressive multifocalleukoencephalopathy associated with the human JC viruswere described following trials in adults, which has cre-ated concern about its routine use.

Nutritional therapy may be a primary or adjunctivetreatment in CD. Exclusive enteral nutrition from ele-mental or polymeric formulas has been associated withshort-term remission in up to 80% of children, equal tothe response rate from corticosteroids. (51) The mecha-nism involves adequate suppression of bowel inflamma-tion and the induction of mucosalhealing. (51) Improved growth anddevelopment, without the adverseeffects of corticosteroids, makes en-teral nutrition an excellent choicefor first-line therapy in childrenwho have active CD. However,after induction, long-term medica-tions, such as immunomodulators,are necessary to maintain remis-sion. Supplements such as iron, fo-lic acid, calcium, and vitamin D arerequired in certain situations.

Antibiotics have specific indica-tions in IBD treatment. Metronida-zole is used to treat perirectal fistu-las, although recurrence rates arehigh and toxicity (eg, paresthesias)often limit long-term use. (52) Cip-rofloxacin is also useful in fistulatreatment. Both antibiotics are pre-

scribed for treatment of pouchitis following colectomyor ileoanal pouch procedures in UC patients. (53) Rifaxi-min, a nonabsorbed oral antibiotic, has shown benefit insymptom reduction of abdominal pain and diarrhea inchildren who have IBD. (54)

Probiotics have not been shown reproducibly to alterthe natural history of CD, but for children who havenewly diagnosed UC, probiotics are beneficial for main-taining remission when added to standard treatmentregimens. (55) Probiotics are also helpful in the preven-tion and treatment of pouchitis. (56)(57) Safety in IBDpatients is well established.

Significant adverse effects exist for all of the previouslydescribed medications (Table 3). A favorable risk-benefitratio is the goal when considering any therapy. Infliximabis contraindicated in patients who have active tuberculo-sis, opportunistic infection, history of demyelinating dis-ease, malignancy, congestive heart failure, or concurrentserious infection. Immunity to varicella should be as-certained before use of anti-TNF therapy. Recently, anaggressive malignancy, hepatosplenic T-cell lymphoma,has been described in young patients (mostly male) whowere treated with a combination of infliximab and eitherazathioprine or 6-mercaptopurine. (58)

Surgical ManagementDespite improvements in medical strategies, surgerymaintains an important therapeutic role. Indications forsurgery include uncontrolled gastrointestinal bleeding,bowel perforation, obstruction, intractable disease de-

Table 3. Adverse Effects of Medications CommonlyUsed to Treat Inflammatory Bowel Disease

Medication Class Important Adverse Effects

Corticosteroids Cushingoid facies, growth suppression, osteopenia,hypertension, hyperglycemia, acne, cataracts,hypothalamic-pituitary-adrenal axis suppression

5-Aminosalicylates Hypersensitivity reaction, disease exacerbation,headache, diarrhea, rash, pneumonitis, interstitialnephritis

6-Mercaptopurine,azathioprine

Bone marrow suppression, pancreatitis, hepatitis, rash,vasculitis; increased risk of lymphoma

Methotrexate Hepatitis, liver fibrosis, rash, folic acid deficiency,nausea, vomiting, hair loss

Anti-tumor necrosisfactor

Resurgence of tuberculosis, histoplasmosis, varicella,malignancies (including lymphoma), fatallymphoproliferative syndromes, anaphylaxis, serumsickness syndrome, lupuslike syndrome, increased riskof serious infections

Anti-integrin Progressive multifocal leukomalacia




spite standard therapy, and dysplasia. At times, surgicalresection is used to treat growth failure, especially if itallows the discontinuation of corticosteroids.

The surgical procedure of choice in UC is resection ofthe entire colon with ileal pouch-anal anastomosis. Thiscurative procedure can be performed either as a primaryoperation or in a staged approach, depending on thecondition of the patient. Long-term results are excellent,and continence can be achieved in 89% of patients after2 years with creation of a J-pouch reservoir. (59) Themajor complication occurring after ileoanal pull-throughis inflammation of the pouch (pouchitis), which occurs in10% to 40% of children. (60)(61)

In CD, segmental bowel resection is the most com-mon surgery and typically involves removing the diseasedterminal ileum and adjacent inflamed colon. Short seg-ments of bowel that are narrowed from fibrosis can betreated with stricturoplasty. Perirectal disease also maynecessitate surgery.

Adjunctive TherapiesOral nutrition supplements and either nasogastric orgastrostomy feedings may be critically important in ad-dressing chronic undernutrition in children who haveIBD. The administration of adequate calories with theaddition of these supplements can help to reverse growthfailure.

Complementary and alternative medicine approachesare used by up to 40% of patients who have IBD. Toprevent medication interactions and limit undue adverseeffects, these therapies are not routinely recommendedwithout physician consultation.

The need for family education and reassurance cannotbe overemphasized. Adolescents who have IBD mayhave a particularly difficult time because of issues relatedto growth failure, body image (eg, cushingoid featuresand acne from corticosteroids), and social invalidismfrom abdominal pain and diarrhea. Pubertal delay mayalso cause significant anxiety. Recent trials with growthhormone and IGF-1 have shown some promise in im-proving growth.

In general, patient and family counseling and peersupport groups are very helpful.

Prognosis and Disease ComplicationsDisease symptoms recur in up to one third of patients at1 year and more than one half at 2 years after initiationof therapy. Factors that predispose to a relapse of CDinclude the number of previous strictures and the pres-ence of FC or FL in the stool. (62)(63)(64) In UC, asignificant number of patients remain corticosteroid-

dependent after 1 year, and 5% may require colectomy.(40)

Toxic megacolon, although rare in children, occurs inapproximately 5% of adults who have severe UC and maybe 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 fivebloody 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 ofinfliximab in reducing colectomy rates among patientswho have severe colitis.

The risk of colorectal cancer depends on the extentand duration of the disease. (66) The cumulative inci-dence of colorectal cancer in patients who have pancolitisis 5% to 10% after 20 years and 12% to 20% after 30 yearsof disease. Screening is recommended beginning 8 yearsafter diagnosis.

Patients who experience early-onset CD have a lowerfinal adult height compared with predicted mid-parentalheight, with an average height reduction of 2.4 cm.Population studies have not shown a difference in finaladult 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, whichinhibit IGF-1. Abnormally low bone mineral density isfound 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 andmineralization in the growing child, particularly duringpuberty. Dual-energy radiograph absorptiometry scansshould be performed in children who experience growthfailure and prolonged steroid use. (25)(68)(69)

Issues for the General PediatricianChildren and adolescents who have IBD should avoidthe use of nonsteroidal anti-inflammatory drugs (includ-ing ibuprofen) because their routine use can trigger adisease flare, enteropathy, or gastritis. Cautious use ofacetaminophen is suggested for treatment of minor painand fever. The casual use of antibiotics should be limitedin children who have IBD to prevent the risk of C difficilecolitis, which has been associated with increased morbid-ity. Children taking immunosuppressive medications andbiologic therapy should be restricted from live vaccineadministration. 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 pubertalSexual Maturity Rating staging, and annual-to-biannualeye examinations are recommended, even for asymptom-atic children who have IBD.

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Summary• Recent major advances have been made in the

diagnosis and treatment of pediatric IBD, andunderstanding of its pathophysiology continues toevolve.

• The long-term outcome for children who have IBDcontinues to improve with better appreciation ofgenotype-phenotype correlations, earlier diagnosis,and more effective treatments.

• Although the incidence of pediatric IBD appears tobe rising, the future for affected children andadolescents appears promising.




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for moderate to severe Crohn disease in adolescents. J PediatrGastroenterol Nutr. 2007;44:185–19151. Griffiths AM, Ohlsson A, Sherman PM, Sutherland LR. Meta-analysis of enteral nutrition as a primary treatment of active Crohn’sdisease. Gastroenterology. 1995;108:1056–106752. Brandt LJ, Bernstein LH, Boley SJ, Frank MS. Metronidazoletherapy for perineal Crohn’s disease: a follow-up study. Gastroen-terology. 1982;83:383–38753. Sandborn WJ, Pardi DS. Clinical management of pouchitis.Gastroenterology. 2004;127:1809–181454. Muniyappa P, Gulati R, Mohr F, Hupertz V. Use and safety ofrifaximin in children with inflammatory bowel disease. J PediatrGastroenterol Nutr. 2009;49:400–40455. Miele E, Pascarella F, Giannetti E, Quaglietta L, BaldassanoRN, Staiano A. Effect of a probiotic preparation (VSL#3) oninduction and maintenance of remission in children with ulcerativecolitis. Am J Gastroenterol. 2009;104:437–44356. Gionchetti P, Amadini C, Rizzello F, Venturi A, Poggioli G,Campieri M. Diagnosis and treatment of pouchitis. Best Pract ResClin Gastroenterol. 2003;17:75–8757. Gionchetti P, Morselli C, Rizzello F, et al. Management ofpouch dysfunction or pouchitis with an ileoanal pouch. Best PractRes Clin Gastroenterol. 2004;18:993–100658. Thayu M, Markowitz JE, Mamula P, Russo PA, Muinos WI,Baldassano RN. Hepatosplenic T-cell lymphoma in an adolescentpatient after immunomodulator and biologic therapy for Crohndisease. J Pediatr Gastroenterol Nutr. 2005;40:220–22259. Koivusalo A, Pakarinen MP, Rintala RJ. Surgical complicationsin relation to functional outcomes after ileoanal anastomosis inpediatric patients with ulcerative colitis. J Pediatr Surg. 2007;42:290–29560. Stavlo PL, Libsch KD, Rodeberg DA, Moir CR. Pediatric ilealpouch-anal anastomosis: functional outcomes and quality of life.J Pediatr Surg. 2003;38:935–93961. Tilney HS, Constantinides V, Ioannides AS, Tekkis PP, DarziAW, Haddad MJ. Pouch-anal anastomosis vs straight ileoanal anas-tomosis in pediatric patients: a meta-analysis. J Pediatr Surg. 2006;41:1799–180862. Greenstein AJ, Zhang LP, Miller AT, et al. Relationship of thenumber of Crohn’s strictures and strictureplasties to postoperativerecurrence. J Am Coll Surg. 2009;208:1065–107063. McLeod RS, Wolff BG, Steinhart AH, et al. Risk and signifi-cance of endoscopic/radiological evidence of recurrent Crohn’sdisease. Gastroenterology. 1997;113:1823–182764. Lamb CA, Mohiuddin MK, Gicquel J, et al. Faecal calprotectinor lactoferrin can identify postoperative recurrence in Crohn’sdisease. Br J Surg. 2009;96:663–67465. Sheth SG, LaMont JT. Toxic megacolon. Lancet. 1998;351:509–51366. Brostrom O, Lofberg R, Nordenvall B, Ost A, Hellers G. Therisk of colorectal cancer in ulcerative colitis. An epidemiologicstudy. Scand J Gastroenterol. 1987;22:1193–119967. Sawczenko A, Ballinger AB, Savage MO, Sanderson IR. Clin-ical features affecting final adult height in patients with pediatric-onset Crohn’s disease. Pediatrics. 2006;118:124–12968. Harpavat M, Keljo DJ. Perspectives on osteoporosis in pediat-ric inflammatory bowel disease. Curr Gastroenterol Rep. 2003;5:225–23269. Sylvester FA. IBD and skeletal health: children are not smalladults! Inflamm Bowel Dis. 2005;11:1020–1023




PIR QuizQuiz 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 childrenwho 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 activedisease despite 5 months of 6-mercaptopurine therapy and two courses of corticosteroid therapy. Of thefollowing, 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 for2 years and presents today for a health supervision visit. She asks which immunizations she can have inthe 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.





Sarah R. Glick and Ryan S. Carvalho Inflammatory Bowel Disease




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Delia L. Gold Visual Diagnosis: Perceived Fevers and Back Pain in a 1-week-old Infant







Perceived Fevers and Back Pain in a1-week-old Infant

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.

Delia L. Gold, MD*

PresentationA 7-day-old female infant presents to the emergencydepartment with the complaints of perceived back painand subjective fevers. Her mother also describes unex-plained skin color changes to her infant’s back andshoulders. For the past 2 days, the mother had noticedthat her infant was fussy and would cry when her backwas touched. She has no other systemic symptoms, nosick contacts, and no known history of trauma. Themother has no reported history of methicillin-resistantStaphylococcus aureus infection or colonization. This isthe first time the mother has sought medical attentionfor 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. Laborhad 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 andwas admitted directly to the newborn nursery, where shestayed for 3 days. The mother had adequate prenatal careand no serologic evidence of prenatal infections. Of note,because the mother had one prior spontaneous abortion,she had received Rho (D) immune globulin during thispregnancy.

Physical examination reveals an afebrile, irritableinfant. Examination of the skin demonstrates a warm,confluent, blanching, erythematous, and somewhatpurpuric area covering the upper third of her back(Fig. 1). Areas of induration are scattered over thepatient’s upper back and posterior axillae (Fig. 2).Shotty lymphadenopathy is noted in both axillae. Therest of the physical examination findings are unremark-able.

After blood and cerebrospinal fluid specimens forculture are obtained in the emergency department, theinfant is admitted to the infectious disease service forintravenous antibiotic therapy and further evaluation.Results of the initial laboratory examination, consistingof a complete blood cell count, metabolic panel, coagu-lation studies, and cerebrospinal fluid studies, appear tobe unremarkable. A clinical diagnosis is made.

*Department of Pediatrics, Nationwide Children’s Hospital, The Ohio StateUniversity, Columbus, OH.

Figure 1. Warm, confluent, blanching, erythematous, andsomewhat purpuric area covering the upper third of theinfant’s back.

Figure 2. Axillary erythema and induration.

visual diagnosis



Diagnosis: Subcutaneous Fat Necrosisof the NewbornThe clinical diagnosis was based initially on the typicalskin changes associated with subcutaneous fat necrosis ofthe newborn (SCFN) and the risk factors noted in theprenatal and birth history (maternal history of pre-eclampsia and Rh incompatibility, meconium-stainedamniotic fluid, low Apgar scores). The diagnosis ofSCFN subsequently was confirmed by skin biopsy.

The ConditionSCFN is an uncommon, often benign, self-limited pan-niculitis that develops typically in term or postterm new-borns in the first few postnatal weeks, primarily as aconsequence of perinatal stress or complications. SCFNis characterized by erythematous, firm, indurated plaquesor nodules usually located on the back, posterior surfacesof the arms, buttocks, and thighs, rarely involving theface or trunk. The plaques or nodules may becomefluctuant due to liquefaction of fat or firm due to calcifi-cation. The lesions sometimes are painful. Resolution ofthe lesions may result in mild atrophy of the involvedskin.

CauseAlthough SCFN is a rare occurrence, numerous studieshave explored possible causes. In most cases, SCFN isbelieved to result from perinatal complications such asasphyxia, meconium aspiration, seizures, obstetrictrauma, maternal-fetal Rh factor incompatibility, andumbilical cord prolapse. Fetal factors such as sepsis,anemia, thrombocytosis, hypothermia, and a primarydefect 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 frequentlyrecognized causative factors for development of SCFN.

The prevalence of SCFN is increased in infants bornby cesarean section, but some researchers have postu-lated that trauma such as pressure injury experienced in avaginal delivery also can contribute to the developmentof SCFN by causing local ischemia to the affected tissues.The development of SCFN seems to be independent ofthe modalities of delivery, that is, vaginal delivery versuscesarean section. The elevated prevalence of this skindisorder in infants born via cesarean section might berelated to the fetal stress that prompted the urgent sur-gical delivery rather than the mode of delivery.

PathogenesisThe exact pathogenesis of SCFN is unknown but appearsto be related to the relatively higher concentration ofsaturated fatty acids in neonatal fat compared with thehigher proportion of unsaturated fatty acids in adult fat.Saturated fatty acids have a high melting point. Undercold stress, the saturated fat in neonates may solidify andcrystallize, leading to subsequent adipocyte necrosis. It ispostulated that fetal or neonatal distress around the timeof delivery leads to cooling and hypoperfusion of subcu-taneous fat, thereby causing subcutaneous granuloma-tous inflammation and necrosis that results in the char-acteristic skin lesions of SCFN.

DiagnosisThe diagnosis of SCFN usually is suspected from findingson physical examination and the birth history, but thedefinitive diagnosis is based on skin biopsy findings. Theskin biopsy performed on this infant during her hospital-ization yielded results that were consistent with SCFN(Fig. 3). A biopsy specimen of SCFN demonstrates fatnecrosis, abundant histiocytes, and chronic inflammatorygranulomatous formation with multinucleated giantcells. Both giant cells and necrotic adipocytes demon-strate needle-shaped crystals arranged radially.

The differential diagnosis for SCFN primarily includessclerema neonatorum (SN), skin cellulitis, and superficialtrauma. SN is a distinct dermatologic condition seen inneonates that is characterized by hardening of the skin

Figure 3. Biopsy sample of subcutaneous tissue, with originalmagnification of 100x, shows flocculent, crystalline lipidwithin adipocytes (upper half of the image). Prominent acuteinflammation with neutrophilic infiltration is present in thelower half.

visual diagnosis



that can adhere to underlying muscle and bone, causingdifficulties with respiration and feeding. Unlike SCFN,this entity is associated with congenital anomalies andcritical illness. A skin biopsy of SN demonstrates thick-ening of the connective tissue bands supporting thesubcutaneous adipose tissue (Fig. 4) and a sparse inflam-matory infiltrate of lymphocytes, histiocytes, andmultinucleate giant cells, in contrast to the pathologicfindings in SCFN. SN is associated with a poor prognosisbecause it is related to severe clinical illness, usuallyfollowing emergent delivery or surgery.

Associated ComplicationsSCFN generally follows an uncomplicated course, withspontaneous resolution and no medical intervention.However, certain uncommon but serious complicationsrequire investigation: hypercalcemia, hypoglycemia,thrombocytopenia, and hypertriglyceridemia. Hypercal-cemia is the most frequently reported complication ofSCFN, but the exact incidence is unknown. Differenthypotheses for the pathogenesis of hypercalcemia havebeen proposed, including bone resorption stimulated byelevated concentrations of parathyroid hormone or cal-cium release from resolving subcutaneous plaques. Theaccepted, most likely theory proposes that macrophageswithin the granulomas of the fat necrosis produce extra-renal 1,25-dihydroxyvitamin D3, a mechanism similar tothat suggested for other granulomatous disorders, suchas sarcoidosis and tuberculosis, that are associated withhypercalcemia.

Hypoglycemia, thrombocytopenia, and hypertriglyc-eridemia are observed very rarely in SCFN and often haveno clinical consequence. In general, if the initial labora-tory tests do not reveal these metabolic and hematologicabnormalities, the studies do not need to be repeated.Patients who have SCFN and hypercalcemia should havetheir calcium values monitored weekly until the hyper-calcemia resolves or the lesions resolve.

TreatmentSCFN is most often self-limited, with resolution occur-ring within several weeks to 6 months. Usually, nospecific treatment is needed for the lesions; rather, med-ical intervention focuses on possible complications. If thelesions are particularly large and fluctuant, fine-needleaspiration may prevent secondary infection, skin necrosis,and scarring. Although uncommon, hypercalcemia is themost frequently reported complication of SCFN and canbe significant enough to cause seizures, renal failure,nephrolithiasis, cardiac toxicity and arrest, calcium dep-osition in the tissues, and even death. Hypercalcemiausually manifests when the lesions begin to resolve. If anyof the signs of hypercalcemia are present, aggressivemeasures should be taken to correct the electrolyte ab-normality, including intravenous hydration with normalsaline, administration of loop diuretics to decrease thecalcium serum concentration, and dietary restriction ofcalcium and vitamin D. Corticosteroids, calcitonin, andbisphosphonates are alternative treatments that shouldbe considered if the hypercalcemia is severe enough or isrefractory to the previously cited measures.

Because hypercalcemia is a rare yet serious complica-tion of SCFN, the physician should assess serial serumcalcium concentrations. There is no definitive guidelineon the duration of such assessment, but the consensus inthe existing literature is that the serum calcium concen-tration should be checked weekly for 2 to 6 months afterdiagnosis or until the hypercalcemia disappears or thelesions 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 CourseThe infant remained afebrile for the duration of her2-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. Shewas referred to an endocrinologist, and her serum cal-cium was monitored for 1 month, during which time the

Figure 4. Sclerema neonatorum, original magnification 100x.This section of subcutaneous tissue from a 3-day-old infantshows no inflammation and no fat necrosis. The wide connec-tive tissue septum shows separation of collagen due to edema.

visual diagnosis



values returned to the normal range without medicalintervention. The infant’s primary pediatrician and adermatologist followed her progress after hospital dis-charge and documented no further complications andcomplete resolution of the lesions on her back. Thepatient is doing well at age 7 months.

ACKNOWLEDGMENTS. The author would like tothank Jonathan Thackeray, MD, Dwight Powell, MD,and Peter Baker, MD, at Nationwide Children’s Hospitalin Columbus, Ohio, for their helpful input, photographs,and histologic slides.

Suggested ReadingBurden AD, Krafchik BR. Subcutaneous fat necrosis of the new-

born: a review of 11 cases. Pediatr Dermatol. 1999;16:384–387Ladoyanni 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 necrosisof the newborn: a systematic evaluation of risk factors, clinicalmanifestations, complications and outcome of 16 children. Br JDermatol. 2007;156:709–715

Tran JT, Sheth AP. Complications of subcutaneous fat necrosis ofthe newborn: a case report and review of the literature. PediatrDermatol. 2003;20:257–261

Zeb A, Darmstadt GL. Sclerema neonatorum: a review of nomen-clature, clinical presentation, histological features, differentialdiagnoses and management. J Perinatol. 2008;28:453–460

Summary• SCFN of the newborn is an uncommon, benign

disorder typically found in term, otherwise healthyneonates who have experienced perinatal stressorssuch as birth asphyxia, meconium aspiration, cordprolapse, hypothermia, and hypoxemia.

• Maternal factors such as preeclampsia, gestationaldiabetes, and in utero exposure to certainmedications may play roles.

• Physical examination demonstrates firm, indurated,circumscribed, erythematous-to-purplish plaques ornodules, often on the back, shoulders, arms, thighs,or buttocks.

• Prognosis generally is very good, but rarecomplications such as hypercalcemia,thrombocytopenia, hypoglycemia, andhypertriglyceridemia have been reported.

• Hypercalcemia is the most common complicationthat can have potentially lethal effects on the renal,cardiovascular, and neurologic systems. Patients whohave SCFN should have their calcium concentrationsmonitored weekly until the hypercalcemia disappearsor the lesions resolve.

• Signs of hypercalcemia include irritability, lethargy,vomiting, hypotonia, dehydration, and failure tothrive. Parents of newborns who have SCFN shouldbe educated about the signs and symptoms ofhypercalcemia.

visual diagnosis




Delia L. Gold Visual Diagnosis: Perceived Fevers and Back Pain in a 1-week-old Infant




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Cristyn N. Camet and Donald L. Yee Focus on Diagnosis: A Primer on D-dimer







Author Disclosure

Drs Camet and Yee have disclosed no

financial relationships relevant to

this article. This commentary does

not contain a discussion of an



A Primer on D-dimerCristyn N. Camet, MD,* Donald L. Yee,

MD†

IntroductionThe D-dimer antigen is a degrada-tion byproduct of the fibrinolyticprocess (Figure) and is commonlyused as a biomarker in various clinicalsettings such as the evaluation of ve-nous thromboembolism (VTE) anddisseminated intravascular coagula-tion (DIC). Much more literature onand collective experience with use ofthe D-dimer assay exists for adultthan pediatric patients. However,thrombotic complications are be-coming increasingly recognized ininfants and children, and reports onthis assay’s utility in a variety of otherpediatric applications are increasing.This review examines the biochemi-cal basis of D-dimer formation, issuesraised by the varied testing methodsused to measure D-dimer, and thescenarios in which this assay may pro-vide information useful for medicalmanagement.

D-dimer FormationD-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 toform factor XIIIa that, in turn, cata-lyzes formation of covalent bonds be-tween D-domains of the polymerizedfibrin. Finally, during fibrinolysis, plas-minogen is activated to plasmin, whichcleaves the fibrin polymers at specificlocations and releases fibrin degrada-tion products that vary in molecularweight and size but include moietiescontaining the exposed D-dimer anti-

gen. Thus, D-dimer concentrationsare increased under any conditions ofincreased fibrin formation, as with he-mostasis, thrombosis, and tissue repair.

Laboratory ConsiderationsA wide variety of testing methods hasevolved over the years for detection ofthe D-dimer antigen, but the lack ofstandardization among these methodshas been an ongoing source of con-cern. Although all modern commer-cially available assays use monoclonalantibodies specific for the D domainon factor XIIIa-cross-linked fibrin,they are not identical in the preciseepitope (antigenic determinant) thatthey identify. The assays also differ informat, calibration methods, instru-mentation, sensitivity, and specificity.Ideally, only assays that have been val-idated in clinical studies of relevant testpopulations 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 ofsuch validation testing and the relianceon reference ranges provided by stud-ies in adults when there are significantage-related differences in D-dimer val-ues.

A recent study reported a six- toeightfold higher D-dimer referencerange for newborns compared withadults. Although this difference largelyresolves during infancy, subtle differ-ences persist into late childhood. Suchfindings are consistent with the con-cept of “developmental hemostasis”coined by Andrew and associates (1) todescribe the physiologic, age-relatedvariation in concentrations of many co-agulation proteins. However, develop-mental hemostasis places a significantburden on laboratories striving to pro-vide optimal care to pediatric patientsbecause age-related reference ranges

*Pediatric Resident.†Department of Pediatrics, Hematology-OncologySection, Baylor College of Medicine, Houston, TX.

focus on diagnosis



for the specific reagent/analyzer com-bination used in a given laboratorymust be determined for many coagu-lation tests, including the D-dimer as-say. Otherwise, use of reference rangesbased on studies of adults or differentanalyzer systems may lead to inaccu-rate interpretation of test results in pe-diatric patients.

Clinical Uses of D-dimerAntigen AssayThe D-dimer assay is commonly usedin adult patients for assessment ofpossible VTE. In selected adult pa-tient populations, a normal D-dimerresult is as sensitive for the exclusionof VTE as a negative imaging study.Specificity is much lower, however,because a positive D-dimer finding isnot sufficient to diagnose VTE ordictate therapy; it only directs the

clinician toward more diagnosticallyspecific imaging studies. Limited ret-rospective studies in children tend tosupport the assay’s high sensitivity inthis setting but suggest that its spec-ificity for VTE may be even lowerthan in adults (specificity no higherthan 57% among the limited numberof pediatric patients studied).

Other uses of the D-dimer assay inadults include stratifying risk for recur-rent VTE, especially in identifying pa-tients who would benefit from longerduration of anticoagulation therapy.Again, limited studies in children sug-gest that a markedly elevated D-dimervalue is a marker for negative outcomesof VTE, including clot persistence, clotrecurrence, and the long-term compli-cation known as the postthromboticsyndrome (characterized by limb

asymmetry, skin changes, and chronicpain in the most severe cases).

A recent small study suggests a rolefor D-dimer in assessing the prognosisand cause of pediatric arterial ischemicstroke. (2) Strokes of cardioembolicsubtype were associated with signifi-cantly higher D-dimer values thannoncardioembolic subtypes (eg, arte-riopathies), consistent with the con-cept that a hypercoagulable state ismore relevant to the former type ofstroke. If confirmed in larger studies,the ability to distinguish betweenpediatric stroke subtypes could aiddecision-making about the use of anti-thrombotic therapy as well as guidediagnostic approaches for new-onsetchildhood stroke.

D-dimer is commonly used to as-sess for the presence of DIC, whichmay accompany extreme states suchas sepsis, trauma, malignancy, andobstetric emergencies. DIC is char-acterized by continuous intravascularthrombin and fibrin formation thatmay lead to clinical bleeding causedby depletion of coagulation factors.However, the diagnosis of DIC is notbased solely on the D-dimer result,but on a combination of laboratoryvalues, including platelet count, fi-brinogen value, and prothrombintime, in addition to the detection ofmarkers of fibrin formation (such asD-dimer).

The test also has been used toguide decisions about the adequacyof anticoagulation therapy in patientswho have rare thrombotic disorderssuch as severe protein C deficiencybecause a markedly elevated or risingD-dimer value can be a sign of devel-oping VTE or DIC in such patients.

Inflammation and coagulationpathways are intimately linked, lead-ing to D-dimer elevation during in-flammatory disease states. An appli-cation of this association is the use ofD-dimer to monitor outcomes in pa-tients who have systemic juvenile id-

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 degradationproducts of uniform composition. Adapted from Adam SS, Key NS, Greenberg CS.D-dimer antigen: current concepts and future prospects. Blood. 2009;113:2878–2887.

focus on diagnosis



iopathic arthritis (JIA). ElevatedD-dimer values seen in JIA are be-lieved to result from cytokine-induced endothelial activation andare associated with disease activityand poor response to therapy. Persis-tently elevated D-dimer values, de-spite therapy with immune modula-tors, predict a poor outcome forthese patients. D-dimer testing, thus,holds promise as a predictive tool tohelp target more intensive treatmentfor high-risk JIA patients early in thedisease course.

Elevated D-dimer has also beenreported in the setting of other sys-temic vascular diseases such as Ka-wasaki disease, Henoch-Schonleinpurpura, and hemolytic-uremic syn-drome. In such cases, D-dimer valuestend to correlate with disease stage,and it has been suggested thatD-dimer measurement might serveas a prognostic tool for these condi-tions or to help differentiate amongother diagnostic considerations.

Of special relevance to the generalpediatrician, elevated D-dimer con-centrations also have been associatedwith poorer outcomes in pediatricpatients who develop community-acquired pneumonia (CAP). Patientswho have CAP and elevated D-dimerconcentrations may be at higher riskfor developing parapneumonic effu-sion or empyema. Patients who expe-rience these complications may ex-hibit increased coagulation activityand fibrin deposition in the pleuralspace, leading to increased fibrinoly-sis and D-dimer formation. D-dimervalues showed an increasing trendamong groups of patients who hadCAP, pneumonia with effusion, andempyema, respectively, and werehigher than in healthy children.

However, further prospective studiesare required.

Future ConsiderationsD-dimer is a widely available test, andan increasing number of applicationsfor its use within adult medicine areevolving. Although additional valida-tion studies and studies of age-related changes in D-dimer valuesstill need to be performed to allowfor reliable and interpretable resultsfor pediatricians, D-dimer measure-ment holds promise for monitoringof pediatric diseases. Prospectivestudies are required to examine thedynamics of D-dimer plasma concen-trations, such as time to normaliza-tion, so clinicians can interpret whenan abnormal result is suggestive ofsignificant new or ongoing diseaserather than expected recovery froman elevated concentration after sur-gery or a resolving infection.

Additional studies of the utility ofD-dimer measurement in specificclinical situations are required. Can-didate disorders for such study in-clude inflammatory diseases such asother vasculitides and inflammatorybowel disease. Given the link be-tween inflammation and obesity,D-dimer could also prove useful inassessing vascular risk in obese chil-dren, as suggested by a recent study.(3) However, at present, rigorousstudies of D-dimer applications inpediatric medicine are limited. Thus,caution should be exercised in inter-preting D-dimer results in the clinicalcare of pediatric patients because ref-erence ranges, cut-off values, andinterpretation of clinical researchstudies in adults cannot be reliablyextended to children. The D-dimerassay will have only limited utility ingeneral pediatrics until the necessary

prospective clinical validation studiesin children are performed.

References1. Andrew M, Vegh P, Johnston M,Bowker J, Ofosu F, Mitchell L. Maturationof the hemostatic system during childhood.Blood. 1992;80:1998–20052. Bernard TJ, Fenton LZ, Apkon SD, etal. Biomarkers of hypercoagulability andinflammation in childhood-onset arterialischemic stroke. J Pediatr. 2010;156:651–6563. Balagopal P, George D, Sweeten S, et al.Response of fractional synthesis rate (FSR)of fibrinogen, concentration of D-dimerand fibrinolytic balance to physical activity-based intervention in obese children. JThromb Haemost. 2008;6:1296–1303

Suggested ReadingAdam SS, Key NS, Greenberg CS.

D-dimer antigen: current concepts andfuture prospects. Blood. 2009;113:2878–2887

Biss TT, Brandao LR, Kahr WH, Chan AK,Williams S. Clinical probability scoreand D-dimer estimation lack utility inthe diagnosis of childhood pulmonaryembolism. J Thromb Haemost. 2009;7:1633–1638

Bloom BJ, Alario AJ, Miller LC. Persistentelevation of fibrin D-dimer predictslong-term outcome in systemic juvenileidiopathic 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—Impactfor clinical haemostasis laboratories.Thromb Haemost. 2006;95:362–372

Rajpurkar M, Warrier I, Chitlur M, et al.Pulmonary embolism – experience at asingle children’s hospital. Thromb Res.2007;119:699–703

Strouse JJ, Tamma P, Kickler TS, TakemotoCM. D-dimer for the diagnosis of ve-nous thromboembolism in children.Am J Hematol. 2009;84:62–63

focus on diagnosis




Cristyn N. Camet and Donald L. Yee Focus on Diagnosis: A Primer on D-dimer




of_blood_neoplasmshttp://pedsinreview.aappublications.org/cgi/collection/disorders_

Blood/NeoplasmsDisorders of vascular_other_multisystem_disorders

http://pedsinreview.aappublications.org/cgi/collection/collagen_ Collagen Vascular and Other Multisystem Disorders

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DOI: 10.1542/pir.32-1-34 2011;32;34 Pediatr. Rev.

Sachin D. Shah and C. Andrew Aligne Pediatrics in the Community: The Haiti Earthquake







Author Disclosure

Drs Shah and Aligne have disclosed

no financial relationships relevant to

this article. This commentary does

not contain a discussion of an



Disaster relief appeals to our noblestqualities as health-care professionalsand compassionate human beings.The devastation caused by the January2010 earthquake inspired many pedia-tricians to travel to Haiti. One ofthese was Dr Sachin Shah, a veteran ofnumerous 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 operationboasting a 35-bed pediatrics ward thatincluded a fully equipped neonatal in-tensive care unit/pediatric intensivecare unit, a freestanding emergencydepartment, and a separate operatingtent (OR) with two operating theatersstaffed by an orthopedist, neurosur-geon, and pediatric surgeon.

“One of the most memorablechildren I cared for was a 2-year-oldboy with congenital hydrocephalus,likely a consequence of a prenatalinfection,” related Dr Shah. “He pre-sented with fever and severe abdom-inal pain with peritoneal signs. The

The Haiti EarthquakeSachin D. Shah, MD,* C. Andrew Aligne, MD, MPH†

month before, a neurosurgeon atour facility had placed a ventriculo-peritoneal (VP) shunt. A Gram stainof cerebrospinal fluid confirmed ashunt infection, and he was takenback to the OR where the VP shuntwas removed by another neurosur-geon. Three days later, largely be-cause the neurosurgeon was leavingthe next morning, the patient under-went an endoscopic third ventricu-lostomy. Although the care this childreceived was remarkable, it struck mehow little we, in fact, accomplished.His hydrocephalus did not improve,and he was, perhaps, worse off thanbefore our involvement.”

Emergency medical relief servicesare important, and the rescue workers,physicians, nurses, and others whohelped in Haiti did much good. How-ever, one needs to step back and askwhy the devastation from the earth-quake was so enormous. Unfortu-nately, it was just one consequence ofsevere underlying problems. Hence,after all the heroic efforts in Haiti, thehealth situation there still is dismal.The country is a landscape dominatedby the diseases of poverty: malaria, tet-anus, and tuberculosis. Basic sanitationremains an overwhelming need, withmore than 100 people per toilet anddifficult access to clean water. Malnu-trition is common.

The volunteers who seemed to bemaking a lasting impact were thosewho addressed these basic needs withsimple measures such as diphtheria-pertussis-tetanus vaccination or deliv-ery of portable, self-contained out-houses. Global health experts agree onthe need to emphasize simple, cheap,and effective public health preventive

interventions over high-tech rescuecare. In addition, we must favor broad-based grassroots improvements in in-frastructure, education, and economicdevelopment. Successful efforts in var-ious parts of the world show thatprogress is possible.

SECTION EDITOR’S NOTE. It is un-fortunate that overseas medical volun-teer experiences frequently end in thetype of frustration described in thisstory. There is a tendency to think thatthe problems of poor countries are in-surmountable but that their healthneeds can be satisfied by emergencyrelief efforts. Both extremes are inaccu-rate. A recent book called Give a Littleprovides numerous examples of non-profit organizations engaged in effec-tive interventions to reduce povertyand illness both here and abroad. (2)Small contributions to the right orga-nizations can have a huge and lastingimpact.

References1. Project Medishare website. AccessedJuly 2010 at: www.projectmedishare.org2. Smith W. Give a Little. New York, NY:Hyperion; 2009

Suggested ReadingCrump JA, Sugarman J. Ethical consider-

ations for short-term experiences bytrainees 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 TropicalDisease: A Short History of Malaria.Baltimore, Md: Johns Hopkins Uni-versity Press; 2007

*University of Chicago, Chicago, Ill.†University of Rochester, Rochester, NY

pediatrics in the community



DOI: 10.1542/pir.32-1-34 2011;32;34 Pediatr. Rev.

Sachin D. Shah and C. Andrew Aligne Pediatrics in the Community: The Haiti Earthquake




y_carehttp://pedsinreview.aappublications.org/cgi/collection/emergenc

Emergency Carefollowing collection(s): This article, along with others on similar topics, appears in the







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Thomas W. Milligan and Rinku Patel Benjamin Bruins, Howard F. Fine, L. Nandini Moorthy, Ayesha Jain, Ashok K. Jain,

in an InfantVisual Impairment in an Autistic Child • Case 3: Fever and Hepatosplenomegaly

Index of Suspicion • Case 1: Recurrent Oral Ulcers in an Adolescent • Case 2:







The reader is encouraged to writepossible diagnoses for each case beforeturning to the discussion. We invitereaders to contribute case presentationsand discussions. Please inquire first bycontacting Dr. Deepak Kamat [email protected].

Author Disclosure

Drs Bruins, Fine, Moorthy, Jain,Milligan, and Patel and Ms Jain havedisclosed no financial relationshipsrelevant to these cases. Thiscommentary does not contain adiscussion of an unapproved/investigative use of a commercialproduct/device.

Case 1: Recurrent Oral Ulcers in an AdolescentCase 2: Visual Impairment in an Autistic ChildCase 3: Fever and Hepatosplenomegaly in an InfantCase 1 PresentationA 16-year-old African American girlpresents with extremely painful re-current oral ulcers over the past 2months. She reports similar painfululcers of the genital area that havewhitish discharge and intermittentlow-grade fevers. A recent complaintof blurry vision prompted a visit to anophthalmologist, who prescribed eyedrops for “inflammation.” She de-nies sexual activity, drug use, nausea,vomiting, diarrhea, headaches, rash,joint pains, cough, or frequent infec-tions. Her past medical history is un-remarkable, but an older brotherhas human immunodeficiency virus(HIV) infection.

Physical examination reveals a well-developed adolescent girl in no acutedistress. Her vital signs are within age-appropriate limits. She has several well-demarcated aphthous ulcers in herbuccal mucosa and oval ulcers withwhitish discharge over her labia ma-jora. The remainder of the physical ex-amination yields no findings of note.

Laboratory testing reveals normalfindings on a complete metabolicpanel, urinalysis, and serum immuno-globulin and complement assessment.Her Hgb is 11.5 g/dL (115 g/L) andher ESR is elevated at 55 mm/hr. Se-rologic testing reveals negative titersfor herpes simplex virus (HSV) types1 and 2; HIV; cytomegalovirus; Toxo-plasma; and hepatitis A, B, and C.HSV cultures from ulcers as well asgonococcus and Chlamydia DNA andrapid plasma reagin tests are negative.Antinuclear and antidouble-strandedDNA antibodies are negative. How-ever, a test for antiphospholipid anti-bodies is mildly positive to B2 glyco-protein. Biopsy results are consistentwith vulvitis.

A discussion with the patient’sophthalmologist confirms the clinicaldiagnosis and well-known complica-tion.

Case 2 PresentationA 15-year-old Hispanic boy who hasa previous diagnosis of autism pre-sents to the ophthalmology clinicwith a 2-month history of visionproblems. His parents report that hedoes not walk around freely becausehe cannot see, he holds on to walls,and he runs into the furniture. He isno longer able to transcribe wordsfrom the blackboard as he had donepreviously. He has stopped daily ac-tivities such as using the computer.However, he still can use a spoon andfork and dress himself. He has mildphotosensitivity, and he rubs his eyesfrequently. His appetite has re-mained unchanged. His past historyincludes being nonverbal and havingdevelopmental delay, moderate far-sightedness, and bilateral astigma-tism.

He is obese, with a body massindex of 33. During an ophthalmo-logic examination, he is very uncoop-erative. There is no improvement af-ter a slight change is made in hiseyeglass prescription. The ophthal-mologic examination conducted un-der general anesthesia shows normalintraocular pressure on both sidesbut keratinization of the bulbar con-junctiva and cornea bilaterally. Bothcorneas appear cloudy, and punctu-ate corneal staining is noted on bothsides. There is a mild superior pannuspresent in both eyes. Funduscopicexamination shows a normal cup-to-disc ratio on both sides, and the ret-inas appear normal. The cause of his

Frequently Used Abbreviations

ALT: alanine aminotransferaseAST: aspartate aminotransferaseBUN: blood urea nitrogenCBC: complete blood countCNS: central nervous systemCSF: cerebrospinal fluidCT: computed tomographyECG: electrocardiographyED: emergency departmentEEG: electroencephalographyESR: erythrocyte sedimentation rateGI: gastrointestinalGU: genitourinaryHct: hematocritHgb: hemoglobinMRI: magnetic resonance imagingWBC: white blood cell

index of suspicion



suspected disorder is confirmed byblood tests.

Case 3 PresentationA 4-month-old boy presents with3 weeks of intermittent high feversand mild fussiness. He has no othersigns. Initially, he was seen in theED, and screening tests that includedCBC, blood culture, serum electro-lytes, BUN, creatinine, liver en-zymes, and urinalysis and culture allyielded normal results. He wasplaced on antipyretic therapy only.For the next 2 weeks he continued tohave fevers daily, despite taking acet-aminophen. Today his father notesthat the boy’s abdomen also is “morefull” than it used to be.

The boy was born vaginally atterm and has received his 2-monthimmunizations. Past medical andfamily histories have no findings ofnote. He lives at home with hismother and older sister in an oldhouse on a farm in rural central Illi-nois and does not attend child care.

Physical examination reveals avery thin, fussy, yet consolable infantwhose temperature is 39.4°C, respi-rations are 40 breaths/min, heartrate is 130 beats/min, and bloodpressure is 88/48 mm Hg. Abdomi-nal examination shows a firm andsignificantly distended abdomen aswell as hepatosplenomegaly. Theliver edge is palpated just above theright pelvic brim, and the spleen ispalpable 3 cm below the left costalmargin. Findings on the rest of thephysical examination are normal.The patient is hospitalized and re-mains febrile until the diagnosis ismade by additional laboratory evalu-ation.

Case 1 DiscussionThis patient’s clinical presentationwas consistent with Adamantiades-

Behcet disease (BD), and she wasstarted on hydroxychloroquine, pen-toxifylline, and aspirin. In addition,given her age and the possibility ofhigh-risk behaviors, sexually trans-mitted diseases were ruled out. Aftertreatment was started, she developedpanuveitis in the left eye, which didnot resolve when topical corticoste-roids and methotrexate were addedto the regimen. After missing an ap-pointment with the ophthalmolo-gist, she reported progressive wors-ening of vision in the right eye, new-onset paresthesias of the left upperextremity, and ataxia. Emergentophthalmologic examination re-vealed severe retinal vasculitis of theright eye (Figure). Brain MRI andangiography showed subacute infarc-tion of her right medulla and pons,suggestive of small vessel CNS vascu-litis. She received intravenous cyclo-phosphamide and high-dose corti-costeroids as an inpatient, which re-

sulted in significant improvement inher clinical status.

Differential DiagnosisThe differential diagnosis for oraland genital ulcers includes commoninfections with HSV and lympho-granuloma venereum virus as well assyphilis and chancroid. Once sexuallytransmitted diseases are ruled out,BD and Crohn disease are importantconsiderations.

The ConditionThe prevalence of BD is low in theUnited States and is highest in indi-viduals of Middle Eastern and Japa-nese heritage. BD is correlated withthe presence of human leukocyte an-tigen B51. Childhood BD has no sexbias, the age of presentation varies,and it represents 4% to 26% of allcases of BD.

BD is a multisystemic autoim-mune condition characterized by a

Figure. Color fundus photographs of the right eye demonstrate vascular sheathingalong the superotemporal arcade and marked cystoid macular edema. Note theperivascular yellow lipid exudation due to diffuse vasculitis in the mid-peripheralretina. The images are slightly blurred due to anterior segment inflammation, cataract,and vitreous haze.

index of suspicion



classic triad of aphthous stomatitis,genital ulceration, and uveitis. TheInternational Study Group has for-malized clinical criteria requiring atleast three episodes of oral herpeti-form or aphthous ulcerations withina 12-month period observed directlyby a physician or reported by thepatient. In addition, two of the fol-lowing also must be demonstrated:1) recurrent painful genital ulcersthat heal with scarring; 2) ophthal-mic lesions, including anterior orposterior uveitis, hypopyon, or reti-nal vasculitis; 3) skin lesions, includ-ing erythema nodosum-like lesions,pseudofolliculitis, or papulopustularor acneiform lesions; and 4) positiveresults from pathergy skin testing,defined as the formation of a sterileerythematous papule 2 mm in diam-eter or larger that appears 48 hoursfollowing a skin prick with a sharpsterile needle. (1)

The clinical presentation of child-hood BD is variable, and differentorgan systems can be involved. Oralulcers (100%), genital ulcers (33% to96%), 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 anterioruveitis with or without posterior uve-itis, hypopyon, retinitis, papillitis,macular edema, and retinal vasculitis.Because it is a multisystem disease,additional clinical manifestations caninvolve nearly any organ system. GIinvolvement can range from abdom-inal pain to gastric or small bowelulcerations with risk of perforationand can mimic Crohn disease. Pul-monary artery aneurysms with risk ofmassive hemoptysis as well as intersti-tial lung disease are found rarely inpatients who have BD. Neuro-BDpresents commonly as meningoen-cephalitis, but parenchymal lesionscan lead to hemiparesis and cognitivechanges. Arthritis, thrombophlebitis,

and vasculitis are other manifesta-tions of BD. The presence of anticar-diolipin antibodies may be related toretinal vascular disease.

Treatment and PrognosisTreatment is tailored to clinical man-ifestations. Numerous agents areavailable to treat oral and genital ul-cers, including colchicine, pentoxi-fylline, thalidomide, corticosteroids,hydroxychloroquine, and azathio-prine. Uveitis is treated with ocularcorticosteroids (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 thesecomplications and aggressive treat-ment with topical and systemic im-munosuppressive medication (suchas cytotoxic and anti-TNF agents) iscritical to protect visual acuity andminimize long-term ocular and neu-rologic sequelae. A multidisciplinaryapproach involving the pediatrician,rheumatologist, and ophthalmolo-gist is ideal when treating childrenwho have BD.

The prognosis is guarded for chil-dren who present with active diseaseand severe ocular, CNS, and pulmo-nary involvement. Significant ocularinvolvement can result in irreversiblevisual loss leading to permanentblindness, especially when the pa-tient has posterior uveitis with syn-echiae and retinal vasculitis. Devas-tating complications can occur withocclusions and aneurysms of theCNS 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 multisystemdiseases such as BD, it is essential to

perform a comprehensive historyand physical examination, and careshould be coordinated within amultidisciplinary team.

● Once BD is diagnosed, it is criticalto screen for common complica-tions, especially ocular involve-ment.

● In addition to ocular involvement,the patient also can present withvaried CNS findings.

● Untreated systemic disease can bedevastating and warrants promptdiagnosis and treatment.

(Benjamin Bruins, MD, Children’sHospital of Philadelphia, Philadel-phia, PA; Howard F. Fine, MD,MHSC, L. Nandini Moorthy, MD,MS, UMDNJ/RWJ Medical School,New Brunswick, NJ)

Reference1. Criteria for diagnosis of Behcet’s disease:International Study Group for Behcet’s Dis-ease. Lancet. 1990;335:1070–1080

Case 2 DiscussionThe findings of xerophthalmia andkeratomalacia 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’smeals and snacks consisted of Frenchfried potatoes and tortillas and weredevoid of leafy vegetables, fruits, andanimal sources of food. This diet pro-vided him less than 1% of the dailyrecommended dietary allowance(RDA) of vitamin A. There was nohistory 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 withmultivitamins, minerals, and lubri-cant eye drops. Within 1 month, hisvision improved, he lost his photo-sensitivity, and he was no longer rub-bing his eyes. Slitlamp examination

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 saw8-mm targets at 2 feet with glasses.Refraction showed that distance acu-ity (20/600) could not be improvedwith a change in eyeglass prescrip-tion. He was classified as being le-gally blind.

His serum 25-hydroxyvitamin Dconcentration also was severely de-pressed (�7 ng/mL [17.4 nmol/L]), although serum calcium andphosphorus values were normal.A radiograph of the knee revealedmild osteopenia without signs ofrickets. Prothrombin time, serum vi-tamin E concentration, and serumvitamin B12 values were withinnormal range. He was given vitaminD3 (50,000 IU) once a week for12 weeks. At the end of 3 months oftreatment, his serum vitamin A and25-hydroxyvitamin D values hadnormalized. Occupational therapyhelped in expanding his food reper-toire, and he started consuminghamburger patties, fried chicken, sal-ads, oranges, gelatin desserts, andjuices. This improved diet was able tomeet 50% of his vitamin A RDA butwas significantly deficient in vitaminD. He remained on multiple vitaminsupplements.

Vitamin AVitamin A plays two roles in ocularmetabolism: photo transduction andprevention of xerophthalmia. Theretina has two discrete photorecep-tors, the rods and the cones. The rodcells, containing rhodopsin, sensemotion and allow for adaptation todark. The cones contain iodopsinand detect color. The aldehyde formof vitamin A serves as the precursorfor both of these visual pigments. Invitamin A deficiency (VAD), synthe-sis of rhodopsin is decreased, result-ing in night blindness. By promoting

the integrity of lacrimal glands andgoblet cells in the surface epitheliumof the conjunctiva, vitamin A helps inthe production of a healthy tear film.The latter keeps the corneal surfacemoist, preventing ocular dryness andits related complications such as xe-rophthalmia.

Hypovitaminosis A can occur ineither primary or secondary form.A primary form occurs among pa-tients whose diet lacks adequateamounts of fruits, liver, and leafy veg-etables. Secondary causes include fatmalabsorption, disorders associatedwith exocrine pancreatic insuffi-ciency (eg, cystic fibrosis), chroniccholestasis, and abetalipoproteine-mia. Postsurgical causes include bari-atric procedures and short bowel syn-drome.

Clinical Manifestations ofVAD

VAD, although rare in the UnitedStates, is a leading cause of morbidityand mortality, affecting millions ofchildren in resource-poor countries.Approximately 250,000 to 500,000children 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 andmortality in various disease states,such as measles, due to an alteredimmune response.

An initial symptom of hypovita-minosis A, weakened adaptation tothe dark, can evolve to night blind-ness if untreated. Xerophthalmia, an-other clinical feature of VAD, occursdue to keratinization of ocular epi-thelium. The cornea dries, developsscaly layers of cells, and is more sus-ceptible to infections. As diseaseprogresses, the cornea degenerates,turns hazy, and becomes wrinkledand soft (keratomalacia), resulting inirremediable blindness.

Bitot spots, which are superficial,

irregular, or triangular-shaped foamygray patches containing keratinizedepithelial debris, are found on bulbarconjunctiva. In retrospect, the bilat-eral pannus described in this patientmay have been Bitot spots. Otherclinical features of VAD include pooroverall growth, impaired immunity,and susceptibility to infections.

Treatment and Prevention ofVAD

Recognizing the endemic prevalenceof VAD states in resource-poorcountries, the World Health Organi-zation has published age-specificdosing guidelines for prevention andtreatment of VAD. Dietary recom-mendations include dark green leafyvegetables, 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 EatingBehavior

Autism is a developmental disordercharacterized by impairment of com-munication and social interactionalong with stereotypic and repetitivebehaviors. Many children who haveautism have feeding difficulties andlimited food selection related to sen-sory regulatory difficulties, resultingin strong interest in some texturesand taste and complete aversion toothers. Affected children frequentlyare reported as insisting on routinesand playing with food. Fewer than50% of the parents of such childrenreported that their children ate bal-anced diets, and 6% of parents re-ported a poor appetite for most foodsamong their children. Such aberranteating behaviors place some childrenwho have autism at greater risk forboth macronutrient and micronutri-ent deficiencies. Therefore, many nu-

index of suspicion



tritional deficiency states such asscurvy, rickets, blindness, and earlyfailure to thrive have been reportedin these children.

Lessons for the Clinician● Clinicians should be cognizant of

the abnormal eating habits of pa-tients who have autism.

● A comprehensive dietary historyand nutritional assessment mayhelp in recognizing uncommonbut classic vitamin deficiencystates.

● Even those who are overweight orobese 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, CorpusChristi, TX)

Case 3 DiscussionHepatosplenomegaly results from alarge array of conditions and gener-ally occurs because of inappropriatestorage, infiltration, vascular conges-tion, or inflammation. Because theliver plays an important role in me-tabolism, metabolic abnormalitiescan result in storage of glycogen, lip-ids, proteins, and metals in the liverthat cause hepatomegaly. Many ofthese conditions are accompanied byneurologic findings or deterioration,such as developmental delay or sei-zures. Similarly, splenomegaly canresult from metabolic disorders. Inthis patient, an extensive metabolicevaluation yielded negative results.

Hepatosplenomegaly caused byinfiltration is likely due to tumors orconditions such as hemophagocyticsyndromes and extramedullary he-matopoiesis. In this patient, the CBCwas normal. In addition, abdominalultrasonography and a contrast-enhanced CT scan of the abdomen

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 biliaryductal dilatation. The studies alsoshowed an enlarged spleen (8 cm inlength) without any retroperitoneallymphadenopathy or ascitic fluid.

Vascular congestion that results inan enlarged liver can be divided intosuprahepatic (congestive heart fail-ure, hepatic vein thrombosis) and in-trahepatic (veno-occlusive disease,Alagille syndrome) conditions. Theresulting portal hypertension alsocan cause congestive splenomegaly.Vascular congestion was ruled outfor this child because of normal echo-cardiographic findings and normalflow pattern on Doppler abdominalultrasonography.

Inflammatory conditions, whichcommonly cause hepatosplenomegaly,usually are due to infections with vi-ruses, bacteria, fungi, or parasites andtypically present with fever. Othercauses of hepatosplenomegaly due toinflammation are toxins, drugs (non-steroidal anti-inflammatory drugs,isoniazid, propylthiouracil, sulfon-amides), and autoimmune diseases. Inthis patient, repeat CBC, completemetabolic panel, C-reactive protein,and ESR yielded normal results. In ad-dition, blood, urine, and CSF culturesas well as serologic tests for HIV, hep-atitis A, B, and C, Toxoplasma gondii,rubella virus, herpes simplex virus, cy-tomegalovirus, and Ebstein-Barr viruswere negative. A purified protein de-rivative skin test for tuberculosis alsoyielded negative results. Screening im-mune evaluation, including serumconcentrations of immunoglobulinsand immune phenotyping, also hadnormal results. On day 7 of admission,urine was sent for Histoplasma capsu-latum and Blastomyces dermatitidis an-tigens and was positive for both. Basedon clinical and epidemiologic evi-

dence, progressive disseminated his-toplasmosis (PDH) was diagnosed.

The ConditionH capsulatum is a dimorphic fungusfound in the environment as a sapro-phyte mold in mycelial and micro-conidia (aerosolized fungal spore)forms and as yeast in host tissue. Theorganism is found primarily in themidwestern United States, specifi-cally near the Ohio and Mississippiriver valleys. Soil rich with nitrate(from bird droppings or decayedwood) allows the fungus to thrive. Hcapsulatum infection causes symp-toms in fewer than 5% of infectedpeople, with most presenting with aninfluenzalike illness. However, themicroconidia can be inhaled into thealveoli, remain as spores, and lead toreinfection as they germinate andproliferate into the yeast phase. Theyeast cells can gain access to the re-ticuloendothelial system via hilarlymph 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 isknown as PDH.

PDH usually is seen in immuno-compromised individuals, specificallyindividuals who have HIV infec-tion, X-linked hyperimmunoglobulin(Ig)M syndrome, hyper-IgE syn-drome, and common variable immu-nodeficiency, but can occur in healthyyoung children. Positive culture frombone marrow, blood, sputum, or tissueis the gold standard for diagnosis. My-cologic media can take 1 to 6 weeks togrow the organisms. Polysaccharideantigen testing is a rapid and specificmethod for diagnosis and is used tomonitor response to treatment. Be-cause cross-reactions occur with othermycoses, clinical and epidemiologicconsiderations, as with this patient, as-sist in differentiating the infections.

index of suspicion



TreatmentTreatment for PDH involves intrave-nous (IV) amphotericin B, followedby long-term oral itraconazole. Al-though data for children are limited,based on international studies, someexperts recommend IV amphotericinB for 2 to 3 weeks, followed by 3 to 6months of oral itraconazole.

Clinical CourseThis boy received IV amphotericin Bfor 2 weeks, and by the third day, hisfever had subsided. On further inves-tigation, it was found that his fatherhad complained of excess bird drop-pings on his truck 1 month earlierand was forced to cut down the treesin front of the farm. Two other out-

breaks of acute histoplasmosis hadoccurred in the county within thepast 3 years. This patient continuedto do well and was transitioned tooral itraconazole for 6 months. After2 months of therapy, his spleen wasno longer palpable, and the liveredge was within normal limits. Re-peat urine test for H capsulatum an-tigen at that time showed negativeresults.

Lessons for the Clinician● Massive hepatomegaly has a large

differential diagnosis.● Concurrent splenomegaly usually

is explained by involvement of thereticuloendothelial system.

● In areas endemic for certain myco-

ses, failure to consider a fungal in-fection for prolonged fevers maydelay the diagnosis.

● Most patients who develop PDHare immunocompromised, usuallyhaving defects with T-cell-mediated immunity. However,healthy children younger than theage of 2 years who have difficultyclearing the infection do developPDH rarely.

(Rinku Patel, DO, Advocate HopeChildren’s Hospital, Oak Lawn, IL)

To view Suggested Reading lists,for these cases, visit http://pedsinreview.aappublications.org and clickon “Index of Suspicion”.

index of suspicion




Thomas W. Milligan and Rinku Patel Benjamin Bruins, Howard F. Fine, L. Nandini Moorthy, Ayesha Jain, Ashok K. Jain,

in an InfantVisual Impairment in an Autistic Child • Case 3: Fever and Hepatosplenomegaly

Index of Suspicion • Case 1: Recurrent Oral Ulcers in an Adolescent • Case 2:



Supplementary Material

DC1http://pedsinreview.aappublications.org/cgi/content/full/32/1/35/Supplementary material can be found at:







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Michael Roth and Deepa Manwani Thrombotic Disorders







In BriefThrombotic DisordersMichael Roth, MDDeepa Manwani, MDChildren’s Hospital at MontefioreBronx, 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 VenousThromboembolic Disease. Kearon C,Kahn S, Agnelli G, et al. Chest. 2008;133:176S-193S

Antithrombotic Therapy in Neonatesand Children. Monagle P, ChalmersE, Chan A. Chest. 2008;133:887S-968S

Diagnosis and Treatment of Thrombosisin Children: General Principles.Young G. Pediatr Blood Cancer.2006;46:540–546

How I Treat Venous Thrombosis inChildren. Manco-Johnson MJ. Blood.2006;107:21–29

Thrombosis historically has been con-sidered a disorder of older adults, inwhom it has an incidence of 2.5% to5%. In comparison, the overall inci-dence of thrombosis in pediatrics isonly 0.07 per 10,000 children, withneonates and adolescents affectedmost commonly. Advances in pediatriccritical care, with survival of sickerchildren, coupled with the frequent useof central venous lines, have contrib-uted to the growing prevalence ofthrombotic disorders. The incidence of

thrombosis in hospitalized children isreported to be 5.3 per 10,000 children,greatly increased from previous reports,but still 2 logs lower than in adults. Thesmall numbers of patients, as well asthe difficulty of sampling blood, partic-ularly in neonates, have been impedi-ments to pediatric-specific clinicaltrials. As a result, evidence-based treat-ment for thrombotic disorders in child-hood is largely in its infancy. Treatmentfrequently has been extrapolated fromstudies performed in adults, often withdisappointing results. The more recentdevelopment of national and interna-tional registries holds great promise asemerging data reveal potentially impor-tant differences in outcomes in chil-dren.

Hemostasis is a balance betweenthe tendencies to bleed and to clot andresults from an equilibrium betweenprocoagulant and anticoagulant fac-tors. A perturbation in any of thesecomponents can lead to an increasedtendency for thrombosis. The Virchowtriad describes the three broad catego-ries of such disruptions: damaged en-dothelium, interrupted or decreasedblood flow, and abnormalities in bloodcomposition. Damage to the endothe-lium can be caused, for example, bytrauma from a central catheter or frominflammation, as in vasculitis. De-creased blood flow can result fromarrhythmias or from immobilizationleading to stasis. Abnormalities in theblood most commonly result from de-fective or deficient coagulant proteins.Very often these predisposing factors,either inherited or acquired, work inconcert, providing a cumulative risk ofthrombus formation. Acquired risk fac-tors may be transient, such as preg-nancy, surgery, and the presence of a

central catheter. Genetic thrombophiliais obviously longstanding and has im-plications for the health of other familymembers as well. Table 1 provides amore detailed list of potential causes ofthrombophilia.

The signs and symptoms of venousand arterial thrombosis vary by thelocation and extent of vessel occlusion.Many of the acute symptoms of venousthrombosis result from vessel obstruc-tion, stasis, and decreased venous re-turn, leading to pain and swelling distalto the site of obstruction. One third ofvenous thrombotic events in childreninvolve the upper extremities, a signif-icantly higher proportion than in adultsbecause of the disproportionately largernumber of catheter-related thrombosesin children. An obstructing thrombus inthe superior vena cava (SVC) can leadto SVC syndrome, consisting of upperextremity and facial swelling. Sinus ve-nous thromboses often present withheadache, sometimes occurring withadditional neurologic symptoms suchas blurry vision and even seizures.

Arterial thrombi usually presentwith obvious signs of decreased perfu-sion. In the peripheral arteries, pallorand coolness may progress rapidly tocyanosis and tissue necrosis. Cerebralarterial thrombi present dramaticallywith new-onset neurologic deficits.Pulmonary artery thrombi often areasymptomatic 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 leadsto significant morbidity. Approximately10% to 60% of children who havethrombi of the extremity develop post-thrombotic syndrome, a clinical con-

in brief



stellation of symptoms that includespain, swelling, visible collateral veinformation, hyperpigmentation, indura-tion, and stasis ulcers. Similarly, visceralthrombosis can lead to organ dysfunc-tion over the long term.

Definitive diagnosis of thrombosis re-quires appropriate imaging studies and isdependent on the location of the throm-bus. Ultrasonography is the first-lineimaging technique for a deep venousthrombosis of the extremity, especially ofthe lower limb. Echocardiography is usedto view cardiac and proximal vena cavathrombi. Imaging upper extremity throm-bosis can be problematic, and detectionof clots in the proximal veins requireseither computed tomography (CT) scan ormagnetic resonance imaging. Thrombi inthe central nervous system vasculatureare imaged best by magnetic resonanceangiography. No one test is best for

imaging pulmonary emboli. CT angiogra-phy is often the first-line approach forchildren suspected of having pulmonaryemboli (PE). Helical CT frequently is ob-tained in adults at high risk for PE be-cause it has high specificity, and aventilation-perfusion scan often is per-formed in patients at low risk because ofits high negative predictive value.

In addition to imaging, measure-ment of D-dimer has demonstratedutility as a nonspecific marker ofthrombosis. D-dimer is generated fromthe action of naturally occurring fi-brinolytic enzymes on cross-linked fi-brin within the thrombus. A positiveD-dimer test result is worrisome for thepresence of a thrombus but should beconsidered in conjunction with imagingtest results.

Mortality from thrombosis in chil-dren is low compared with that inadults. Most affected children surviveand can be expected to live for decadesfollowing a thrombotic event. Thus, theimpact on long-term morbidity andquality of life is greater in children.Rapid treatment to prevent complica-tions must be balanced carefully withthe risk of bleeding. Anticoagulantsform the mainstay of therapy (Table 2).Unfractionated heparin (UH) or low-molecular weight heparin (LMWH) isused initially for at least 5 to 7 days. Instable patients, therapy is completed byeither continuing LMWH or switchingto warfarin.

Because of its short half-life, UH hasbeen used commonly as the first-lineagent in patients who have a high riskfor bleeding or a need for invasiveprocedures. For the same reason, UHmust be administered as a continuousintravenous infusion. LMWH appears tobe effective, with fewer adverse effectsthan UH, and is being used increasinglyas front-line therapy. LMWH workslargely 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 advantageas an oral agent. The need to crush themedication, which is not available as aliquid preparation, leads to significantdose-to-dose variability, making warfa-rin impractical for use in very youngchildren.

Whereas the anticoagulants blockthe formation of clots, tissue plasmin-ogen activator (TPA) is a thrombolyticagent that promotes clot breakdown byactivating plasminogen to plasmin,thus tipping hemostatic balance in fa-vor of increased fibrinolysis. Systemicthrombolytic therapy should bestrongly considered for clots that havea high risk of morbidity and mortality.The rate of vascular patency followinganticoagulant therapy in children hasbeen reported at 50%; followingthrombolysis, it is greater than 90%.Systemic TPA is effective when admin-istered within 2 weeks of symptomaticclot onset and only partially effectivebeyond 2 weeks. TPA can be deliveredlocally to the site of the thrombus viacatheter-directed administration andhas been effective even in clots thatpersist several months from diagnosis.Contraindications to the use of throm-bolytic agents include active bleeding,recent surgery, and cerebral ischemia orhemorrhage. Surgical thrombectomy isan option for treating life- or limb-threatening thrombi when thrombolysisis contraindicated or has failed.

Antiplatelet agents such as aspirin areused in certain cardiac disorders, arterialischemic stroke, and Kawasaki disease.Several anticoagulant-deficient states,such as antithrombin III deficiency andhomozygous protein C disease, requirespecific protein concentrate replacementtherapy. Adjuvant therapies include fittedcompression stockings, nutritional andexercise 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

Table 1. Causes ofThrombophiliaAcquired Thrombophilia/Risk

Factors

Indwelling catheter, trauma,recent surgery, immobilization,congenital heart disease,prosthetic valves, diabetes,sickle cell anemia,chemotherapy, infection, oralcontraceptives, smoking,dehydration, nephroticsyndrome, inflammatory boweldisease, antiphospholipidsyndrome, elevated factor VIII,malignancy, autoimmunedisease

Genetic Thrombophilia

Protein C deficiency, protein Sdeficiency, antithrombindeficiency, prothrombin 20210mutation, factor V Leidenmutation, elevatedhomocysteine/MTHFR, elevatedlipoprotein A

MTHFR�methylenetetrahydrofolate reduc-tase gene

in brief



factor V Leiden mutation or have anti-thrombin deficiency.

Thromboembolic events in childrenhave increased and are a significantcause of morbidity and mortality. On-going multi-institutional researchshould generate the evidence necessaryfor tailored therapy rather than the“adult-size fits all” approach. Activedebate still centers on whom to test,the timing of testing, and which teststo order for children at risk for throm-bosis. Novel oral anticoagulant agentswith improved safety profiles areneeded and are in development.

Comment: Progress comes at aprice, and with advances in neonataland pediatric critical care, particularlywith the widespread use of centralvenous catheters, we are seeing morethrombotic complications affectingchildren than in the past. However,even with their growing prevalence,thromboses remain relatively uncom-mon in pediatrics. As with so manyother uncommon conditions, the goodnews of rarity spawns the bad newsthat evidence sufficient to guide ther-apy is difficult to gather. Depending ondata from the treatment of adults is not

ideal because we know children aredifferent. The paradigm for dealing withthis frequent problem in pediatrics isprovided by the collaborative effortsthat over the past few decades havetransformed the prognosis for acutelymphoblastic leukemia. We need toencourage as standard procedure thedevelopment of national and interna-tional databases and study protocolsfor the multitude of individually un-common conditions that collectivelyaffect so many children.

Henry Adam, MDEditor, In Brief

Table 2. Commonly Used Anticoagulants and Thrombolytics

AgentMechanism ofAction Pros Cons Monitoring

Unfractionatedheparin (UH)

Binds toantithrombin IIIand acceleratesinhibition ofthrombin andfactor Xa

Rapid onset of action,short half-life, easyreversibility, effectiveantidote (protamine)

Continuous infusion.Risk of bleeding,HIT, osteoporosis

Anti-factor Xa concentration(goal: 0.3 to 0.7) PTT(goal: two to three timesbaseline)

Low-molecularweightheparin

Inhibits factor Xa Long half-life, twice aday subcutaneousadministration(allows for outpatienttreatment), stablepharmacokineticsallows infrequentmonitoring andlowers risk ofbleeding

Subcutaneousinjections.Protamine reversalnot complete, HIT(lower than inUH), osteoporosis

Anti-factor Xa concentration4 hours after second dose(goal: 0.6 to 1.0)

Vitamin Kantagonists(warfarin)

Reduces theconcentrationsof vitamin K-dependent factors:II, VII, IX, and X

Long half-life, oraladministration,effective antidote(vitamin K)

Many food andmedicationinteractions andunpredictableconcentrations,requires frequenttitration

INR (goal: 2 to 3) dependenton indication

Tissueplasminogenactivator

Activatesplasminogen toplasmin, rapidlypromoting clotbreak down

Rapid onset of action,active lytic agent forhigh-risk clots

Higher risk ofbleeding, requiresfrequentmonitoring, onlyadministered ininpatient setting

Monitor clot by serialimaging. D-dimerincreases. Fibrinogendecreases

HIT�heparin-induced thrombocytopenia, INR�international normalized ratio, PTT�partial thromboplastin time

in brief




Michael Roth and Deepa Manwani Thrombotic Disorders




of_blood_neoplasmshttp://pedsinreview.aappublications.org/cgi/collection/disorders_

Disorders of Blood/Neoplasmsfollowing collection(s): This article, along with others on similar topics, appears in the







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DOI: 10.1542/pir.32-1-e1 2011;32;e1-e3 Pediatr. Rev.

Mark X. Cicero, Michael B. Curi and Mark Mercurio Industry

Ethics for the Pediatrician: Physician Interaction With the Pharmaceutical

http://pedsinreview.aappublications.org/cgi/content/full/32/1/e1located on the World Wide Web at:




http://pedsinreview.aappublications.org/cgi/content/full/32/1/e1


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.

Physician Interaction With thePharmaceutical IndustryMark X. Cicero, MD,* Michael B. Curi, MD,† Mark Mercurio, MD§

IntroductionIn the United States, more than 40billion dollars are spent annually indrug research and development. (1)Wholesale pharmaceutical sales to-talled $275 billion in 2008. Pharma-ceuticals are both an indispensabletool and a staggering expense inhealth care. When caring for chil-dren, pediatricians consider a medi-cation’s efficacy, potential adverseeffects, and often whether the child’shealth-care insurance covers the pre-scription. A complex relationshiphas evolved between pharmaceuticalcompanies and pediatricians, withdrug manufacturers historically pro-viding gifts, sponsoring continuingmedical education (CME), and de-livering samples to medical offices.We explore this relationship in lightof recommendations of the AmericanAcademy of Pediatrics (AAP) and theAmerican Board of Pediatrics (ABP)and the ethical conflicts relevant tothis relationship.

Pharmaceutical Industry GiftsFor more than a decade, awareness ofthe influence that industry gifts haveon physician prescribing habits hasbeen increasing. (2) In an oft-citedwork, Steinman and associates (3)found most residents (61%) felt theywere immune to the influence ofpharmaceutical representatives andtheir gifts, but only 16% believedtheir peers were similarly above theinfluence of the drug industry. In

truth, industry gifts may influencebehavior. Such gifts may cause a con-flict of interest with a pediatrician’sfiduciary relationship to the patient.By definition, a fiduciary relationshipis one based on trust, in which thephysician works for the benefit ofthe patient, holding his or her needsas the highest priority.

Professional organizations andthe industry have made attempts toaddress the potential conflicts ofinterest. In 2002, the AmericanMedical Association (AMA) andthe Pharmaceutical Researchers andManufacturers of America (PhRMA)released similar voluntary codes gov-erning gifts and other interactionsbetween pharmaceutical representa-tives and physicians. The 2002 AMAcodes, which were endorsed by theAAP, limited gifts to educationalitems and reminder items of minimalvalue, such as pens and notepads.Further, the code eliminated mone-tary and recreational gifts.

PhRMA published more stringentrestrictions in 2009, (4) no longerallowing reminder items, prohibitingmeals at restaurants, and requiringpharmaceutical representatives to betrained in ethics and legal statutespertaining to interacting with physi-cians. The 2009 guidelines still allowthe meal provision to doctors in of-fices, although feeding physiciansdoes not benefit patients directly.According to PhRMA, The Code at-tempts to ensure that “all interac-tions [between manufacturers andhealth care professionals are] focusedon informing healthcare profession-als about products, providing scien-tific and educational information,

*Assistant Professor of Pediatrics, Yale UniversitySchool of Medicine, New Haven, CT.†Assistant Clinical Professor of Pediatrics, Universityof Connecticut School of Medicine, Farmington, CT.§Associate Professor of Pediatrics, Yale UniversitySchool of Medicine, New Haven, CT.

ethics for the pediatrician

Pediatrics in Review Vol.32 No.1 January 2011 e1. Provided by Health Internetwork on April 20, 2011 http://pedsinreview.aappublications.orgDownloaded from


and supporting medical research andeducation.”

In April 2010, the Council ofMedical Specialty Societies (CMSS),of which the AAP is a member, re-leased a Code For Interactions WithCompanies. (5) This Code elimi-nates all pharmaceutical logos fromconferences, removes all reminderitems, and limits overt pharmaceuti-cal sponsorship of professional con-ferences. Despite these new, volun-tary protections, pediatricians shoulduse caution when pharmaceuticalrepresentatives offer any gifts.

There is evidence that even edu-cational items and meals may inducea sense of obligation in the receiverto the giver. (2)(3)(6) The 2007AAP Committee on Bioethics (COB)statement on professionalism remindspediatricians of the responsibilitiesto children and families as well as tothe medical profession. (7) The COBstates, “Issues of professionalism andthe integrity of the profession as awhole are raised when pediatriciansare the recipients of special market-ing incentives such as gifts . . . fromrepresentatives of the health care in-dustry.” The COB suggests furtherthat acceptable educational giftsshould benefit patients by improvingthe knowledge and skills of the phy-sician. Pediatricians should be awarethat they are subject to influencefrom the pharmaceutical industrywhen they accept gifts, no matterhow small.

ContinuingMedical EducationIn the United States, 44 states re-quire CME to maintain medical li-censure. This requirement ensuresthat physicians maintain a currentknowledge base. The ABP encour-ages pediatricians to “take primaryresponsibility for lifelong learning toimprove knowledge, skills, and prac-

tice performance” as part of mainte-nance of certification in general pedi-atrics. Despite its importance, CMEis an unfunded, sometimes costlymandate.

The pharmaceutical industry spon-sors CME, providing a service topediatricians by defraying the costof seminars and conferences. How-ever, with CME sponsorship comesthe opportunity to influence themessage. For example, an industry-sponsored seminar on atypical pneu-monia may focus subtly on treatmentrather than diagnosis, allowing em-phasis to be placed on a newly re-leased antibiotic. An atypical pneu-monia seminar free from industrysponsorship is potentially more bal-anced. Speakers at CME presenta-tions who have received honorariafrom drug companies disclose the fi-nancial relationship, and it is hopedthat they present unbiased data.However, disclosing conflicts of in-terest may not be sufficient to ensurefreedom from industry-favorable bias.

As a potential protection frombias, third-party agencies known as“medical education and communica-tion companies” (MECCs) oftenprepare the agendas for CME eventsand choose and compensate thespeakers. (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 commitmentto CME, MECCs still receive mostof their compensation from the phar-maceutical industry. Full disclosureof sponsorship is a necessary step inhighlighting potential conflicts ofinterest and endorsed in the CMSSCode. (5) The Code also calls forindependent development of educa-tional programs, free of industry sup-porters. Thus, the role of MECCs ina Code-compliant landscape is un-certain.

Sampling and DetailingAs with most industries, profit is adriving force for the pharmaceut-ical industry. Members of PhRMAmight seek to accomplish this goalby persuading physicians to prescribemore expensive drugs when less costlyalternatives are equally effective. Drugrepresentative office detailing and pro-vision of samples change prescribingpractices. (10)(11) This continuedpresence of detailing and sampling,even after the changes in the PhRMACode, is clear evidence of significantefficacy.

The amount of influence industry-provided samples have on prescrib-ing behavior has been debated. (10)(11)(12) What is the benefit to thepatient in receiving samples? Samplesallow physicians to provide medica-tions to patients when cost otherwisewould be prohibitive. Samples are apart of marketing strategy, but it is anoversimplification to dismiss samplesas only marketing.

Because most physicians’ officesare not provided samples of generic,less-expensive medicines, there is adilemma. Many sample medicines arefor chronic illnesses, a situation thatoffers an avenue for pharmaceuticalcompanies to leverage patients tofill a prescription multiple times, re-couping the initial sample cost manytimes over. Miller and associates (13)reported an increase in prescriptionsfor more costly prescription drugswhen samples were present in an in-ternal medicine practice. However,samples in a doctor’s office do notensure that a patient will use thesampled medicines because much ofprescribing is limited by formularycoverage.

It seems best to seek a physician-pharmaceutical relationship that bene-fits patients long term, rather than pro-viding samples that lead to greaterlong-term expense. Strategies to ac-complish this goal include coupons


e2 Pediatrics in Review Vol.32 No.1 January 2011. Provided by Health Internetwork on April 20, 2011 http://pedsinreview.aappublications.orgDownloaded from


for a recurring discount on prescrip-tion costs, copay vouchers, and whenefficacious, prescribing from the ge-neric formularies present in many re-tail pharmacies.

Internet interactions are a newavenue for detailing and sample pro-vision. Physicians are invited to vir-tual interactions, video lectures, andonline chat rooms to discuss newpharmaceuticals and to request sam-ples. This type of communicationreflects a paradigm shift away fromone-on-one detailing and provision

of samples. These new modalities ofsharing information and connectingphysicians to pharmaceutical compa-nies still should benefit patients pri-marily and directly.

References1. Austin D, Kile J, Moore D, et al. AnnualCost of Pharmaceutical Research and Devel-opment. Washington, DC: CongressionalBudget Office; 2006:3–82. Chren M, Landefeld C, Murray T. Doc-tors, drug companies, and gifts. JAMA.1989;262:3448–3451

3. Steinman MA, Shlipak MG, McPhee SJ.Of principles and pens: attitudes and prac-tices of medicine housestaff toward pharma-ceutical industry promotions. Am J Med.2001;110:74. Pharmaceutical Research and Manufac-turers of America. Code on Interactions WithHealthcare Professionals. Washington, DC:Pharmaceutical Research and Manufactur-ers of America; 2008:5, 125. Council of Medical Specialty Societies.Code for Interactions With Companies. Chi-cago, IL: Council of Medical Specialty So-cieties; 2010:17, 186. Higgins S. Drug representatives: givingyou lunch or stealing your soul? DermatolOnline J. 2007;13:57. Fallat M, Glover J. Professionalism inpediatrics. Pediatrics. 2007;120:e1123–e11338. Cleary J. Industry sponsorship of con-tinuing medical education. JAMA. 2003;290:11509. Peterson E, Overstreet K, Parochka J,Lemon M. Medical education and commu-nication companies involved in CME: anupdated profile. J Contin Educ Health Prof.2008;28:205–21310. Lurk J, DeJong D, Woods T, Knell M,Carroll C. Effects of changes in patient costsharing and drug sample policies on pre-scription drug costs and utilization in asafety-net-provider setting. Am J Health SystPharm. 2004;61:267–27211. Hall K, Tett S, Nissen L. Perceptions ofthe influence of prescription medicine sam-ples on prescribing by family physicians.Med Care. 2006;44:383–38712. Wofford J, Ohl C. Teaching appropri-ate interactions with pharmaceutical com-pany representatives: the impact of an inno-vative workshop on student attitudes. BMCMed Educ. 2005;5:513. Miller D, Mansfield R, Woods J, Wof-ford J, Moran W. The impact of drug sam-ples on prescribing to the uninsured. SouthMed J. 2008;101:888–893

Summary• The ABP professional competencies remind pediatricians of their need to

demonstrate “. . . a responsiveness to the needs of patients and society thatsupersedes self-interest.”

• Physician relationships with the pharmaceutical industry remain complexand continue to evolve.

• If a textbook given as a gift leads to the diagnosis of an uncommon rash,the relationship is beneficial to the patient. If expensive gifts given to apediatrician lead to an increase in health-care costs, the patient’s well-being has been subjugated to the physician’s.

• If a pediatrician’s knowledge is broadened by CME, children benefit, but theauthors believe that presenters should have complete and unbiased controlof what is presented at industry-sponsored CME events.

• If a patient is given a sample of a necessary medication in lieu of goingwithout that necessary medication, the pharmaceutical company haspromoted the child’s health. If samples lead to prescriptions for costliermedication with no significant advantage over other drugs or if thepediatrician receives personal gain from the sampling process, the child’shealth is not the key goal of sampling.

• Two groups, pediatricians and the pharmaceutical industry, have greatpotential to improve the well-being of children. However, when therelationship between the two compromises the decisions of pediatricians orthe quality of care rendered to children, the relationship must be modifiedor ended.





Mark X. Cicero, Michael B. Curi and Mark Mercurio Industry

Ethics for the Pediatrician: Physician Interaction With the Pharmaceutical


http://pedsinreview.aappublications.org/cgi/content/full/32/1/e1including high-resolution figures, can be found at:


diatricianhttp://pedsinreview.aappublications.org/cgi/collection/ethics_pe

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Jeffrey M. Karp Delayed Tooth Emergence

http://pedsinreview.aappublications.org/cgi/content/full/32/1/e4located on the World Wide Web at:






Delayed Tooth EmergenceJeffrey M. Karp, DMD, MS*

Author Disclosure

Dr Karp has disclosed

no financial

relationships relevant

to this article. This

commentary does not


of an unapproved/


commercial product/

device.


1. Recognize abnormalities in tooth emergence timing and order based on oral inspection.2. Discuss local and systemic causes of delayed tooth emergence.3. List treatment modalities available for management of delayed tooth emergence.4. Determine when timely referral to a dentist is necessary.

IntroductionDelayed tooth emergence (DTE) is a clinical term used when exposure of a tooth ormultiple teeth through the oral mucosa is overdue, according to population norms basedon chronologic age. DTE is common in childhood and adolescence, yet it is oftenoverlooked or dismissed in pediatric primary care. Timely screening and recognition ofDTE by clinicians can minimize medical, developmental, functional, and esthetic prob-lems resulting from untreated underlying local and systemic causes. This article providesclinicians with an overview of conditions responsible for DTE in children. Multidisci-plinary care for patients who experience DTE in medical, dental, and surgical settings alsois discussed.

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

Tooth Eruption and EmergenceTooth emergence, the clinical exposure of any part of a tooth through the oral mucosa, isthe culmination of numerous developmental processes occurring within the jaws. Bonycrypts house developing teeth during crown morphogenesis (size and shape) as well as hard

tissue (eg, enamel, dentin) secretion and calcification. Asroot development begins, teeth initiate a physiologic processof vertical eruption through the overlying alveolar bonetoward the oral mucosa. Bone remodeling in the area isnecessary for progression of tooth eruption. Root develop-ment exceeds two thirds of its final length when the alveolarbone crest is reached. The primary dentition undergoes rootresorption, followed by crown exfoliation, to permit emer-gence of permanent incisors, canines, and premolars into theproper position within the dental arch. Permanent molarsdo not replace primary teeth under normal circumstances.Teeth make clinical emergence into the oral cavity when 75%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 MedicalCenter, Rochester, NY.

Abbreviations

DTE: delayed tooth emergenceGE: gingival enlargementHGF: hereditary gingival fibromatosisKCOT: keratocytic odontogenic tumorMPFM: maxillary permanent first molarMx.C.P1: maxillary canine/first premolarNBCCS: nevoid basal cell carcinoma syndromePDC: palatally displaced canineSP: supernumerary premolar

Article ear, nose, throat



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, withhigh heritability scores reported in monozygotic twin stud-ies. As seen in Table 1, tooth emergence and exfoliationtimes are usually presented as ranges of chronologic age toaccount for the previously mentioned factors. Cliniciansshould recognize that teeth that fail to emerge within 12months of the normal range are considered delayed. Inthese cases, referral to a dentist is warranted for furtherclinical and radiographic assessment. Some cases requiresurgical treatment to permit tooth emergence.

Detection of DTEDTE is a nonspecific clinical finding that can occur in alocalized or generalized distribution. Oral inspectioncoupled with history can provide clinicians with substan-tial information to define further the natural history andclinical manifestations of the underlying condition. Oralexamination should consist of evaluation of the alveolarridges as well as the alignment and morphology of theteeth that are present. The size and shape of the alveolarridges can help determine whether DTE is due to abnor-malities in tooth development, eruption, or emergence.

Tooth eruption through alveolar bone causes expansionand fullness of the alveolar ridge. On average, 2 months arerequired for a tooth to progress from causing palpableenlargement of the gingival tissues to overt clinical emer-gence. Palpation of the oral mucosa in the area of eruptingteeth should cause localized tissue blanching if tooth emer-gence is imminent. In addition, redness of the mucosa or aneruption hematoma has been noted to precede tooth emer-gence in more than 30% of cases. Thin, knife-edge alveolarridges suggest the absence of teeth in the area.

The dentition should be inspected systematically forage-appropriate tooth counts (Figs. 1 and 2). Properinspection requires a working knowledge of the differ-ences in tooth morphology among tooth classes andbetween the two dentitions. Tooth counts should beassessed for appropriateness in timing and order. For themost part, the primary dentition adheres to the follow-ing emergence order in each jaw: central incisors, lateralincisors, first molars, canines, and second molars. Al-though published emergence orders are available for thepermanent 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 bysystemic disease do not usually result in changes in the order

Table 1. Tooth Emergence and ExfoliationPRIMARY DENTITION

Mandible Maxilla

Eruption(months)

Exfoliation(years)

Eruption(months)

Exfoliation(years)

Central incisors 5 to 8 6 to 7 6 to 10 7 to 8Lateral incisors 7 to 10 7 to 8 8 to 12 8 to 9Canines 16 to 20 9 to 11 16 to 20 11 to 12First molars 11 to 18 10 to 12 11 to 18 9 to 11Second molars 20 to 30 11 to 13 20 to 30 9 to 12

PERMANENT DENTITION

Mandible Maxilla

Eruption(years)

Root Complete(years)

Eruption(years)

Root Complete(years)

Central incisors 6 to 7 9 to 10 7 to 8 9 to 10Lateral incisors 7 to 8 10 8 to 9 11Canines 9 to 11 12 to 15 11 to 12 12 to 15First premolars 10 to 12 12 to 13 10 to 11 12 to 13Second premolars 11 to 13 12 to 14 10 to 12 12 to 14First molars 5.5 to 7 9 to 10 5.5 to 7 9 to 10Second molars 12 to 14 14 to 16 12 to 14 14 to 16Third molars 17 to 30 18� 17 to 30 18�

Adapted from American Academy of Pediatric Dentistry, Guideline on management of the developing dentition and occlusion in pediatric dentistry. ReferenceManual. 2009;32(6). Copyright © American Dental Association. All rights reserved. Used with permission.

ear, nose, throat delayed tooth emergence



of tooth emergence or exfoliation. In contrast, localizeddisease should be investigated when the order of toothemergence is altered. Three general rules exist for normaltooth development and emergence: 1) anterior teeth withina specific tooth class (eg, first premolars) always precedeposterior 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

antimeres (corresponding teeth on opposite side) usuallyoccurs.

Causes of DTEAnomalies in Tooth Number

Tooth agenesis, one of the most common developmentalanomalies in humans, alters the order of tooth emer-gence. Although missing teeth are noted in only 1% ofchildren in the primary dentition, approximately 30% ofthe general population fails to develop a full complementof primary and permanent teeth. Agenesis of one or morepermanent third molars (wisdom teeth) affects about

Figure 1. Development of the dentition from birth to 6 yearsof age. Reprinted with permission from Logan WHG, KronfeldR. Development of the human jaws and surrounding structuresfrom birth to the age of fifteen years. JADA. 1933;20(3):379–427. Copyright © 1933 American Dental Association. All rightsreserved. Adapted 2010 with permission of the AmericanDental Association. Schour L, Massler M. The development ofhuman 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.

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 structuresfrom birth to the age of fifteen years. JADA. 1933;20(3):379–427. Copyright © 1933 American Dental Association. All rightsreserved. Adapted 2010 with permission of the AmericanDental Association. Schour L, Massler M. The development ofhuman 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.




one in every five people. A recent meta-analysis reportedthe prevalence of dental agenesis, excluding third mo-lars, as 2.5% to 6.9%, depending on the race, sex, andcountry of study. (1) Tooth agenesis is slightly morecommon (1.3:1) in females versus males.

Hypodontia is defined as the absence of up to sixteeth. In more than 80% of patients, one or two teeth aremissing. After the third molars, the mandibular secondpremolars, maxillary lateral incisors, and maxillary secondpremolars are affected most frequently, with a 1.5% to3.1% prevalence rate. Unilateral tooth agenesis is seenmore commonly, except for permanent maxillary lateralincisors (Fig. 3), which have a propensity toward bilateralagenesis.

Only 0.14% of the general population has oligo-dontia, defined as the absence of six or more teeth.Oligodontia following autosomal dominant inheritancepatterns can be indicative of PAX9, MSX1, or AXIN2mutations. Ectodermal dysplasia should be consideredwhen underdeveloped alveolar ridges are seen in theanterior jaws of predentate infants older than 7 monthsof age, when multiple primary teeth are absent, or whenconical incisors are seen (Fig. 4).

Recognition of missing teeth by number and loca-tion along with other physical findings can aid in thediagnosis of numerous genetic diseases (Table 2). Clini-cians should consider abnormal alignment and increasedspacing of teeth as well as localized delays in primarytooth exfoliation as potential clinical manifestations ofhypodontia (Fig. 5). Patients who manifest hypodontiamay warrant consultation with a geneticist to rule outassociated syndromes.

Supernumerary teeth (hyperdontia) developing withthe jaws often delay the eruption and emergence ofpermanent teeth. Hyperdontia is seen in 1.5% to 3.5% of

the general population. More than 80% of cases occur inthe anterior maxilla, and supernumerary teeth presentingat this site can occur singly or in multiples, can havenormal incisor anatomy, can be conical (Fig. 6), or canappear to have cuspal morphology. The teeth can emergeinto the mouth or be inverted within the maxilla. A singlesupernumerary tooth that develops in the primary palatedirectly behind the maxillary central incisors is called amesiodens. These teeth account for more than 50% of allsupernumerary teeth reported in epidemiologic studies.Altered fusion between the medial nasal process and themaxillary facial process during embryogenesis producesthe presence of two maxillary lateral incisors on theaffected side, as is seen occasionally in the general popu-lation and more commonly in children born with isolatedcleft lip and cleft lip and palate.

Maxillary permanent fourth molars or rudimentaryparamolars constitute approximately 18% of all supernu-merary teeth. Supernumerary premolars (SPs), on theother hand, develop in 0.64% of the general population.A 3:1 male-to-female distribution is seen. SPs are themost common type of hyperdontia occurring in themandible. Their development appears to be geneticallycontrolled, although the pattern of inheritance remainsunclear. 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 becomesnecessary when it impedes or deflects age-appropriatetooth eruption and emergence. One in four patients whohas a history of extra teeth in the anterior maxilla later

Figure 3. An 8-year-old white boy who has bilateral agenesisof the maxillary lateral incisors (3) causing a wide diastemabetween the maxillary central incisors. Photograph courtesy ofRyan Walker, DDS.

Figure 4. A 9-year-old white girl who has ectodermal dys-plasia. Agenesis of the permanent maxillary lateral incisorsand all mandibular incisors is seen, and a conical permanentmaxillary central incisor (*) is present. Photograph courtesy ofDavid Levy, DMD MS.




Tab

le2.

Gene

tic

Dise

ases

Wit

hAn

omal

ies

inTo

oth

Num

ber

Cond

ition

Gene

Inhe

ritan

ceDe

ntal

Find

ings

Oth

erFi

ndin

gs

Auto

som

aldo

min

ant

olig

odon

tiaPA

X9AD

Agen

esis

ofpe

rman

ent

mol

ars

Non

edo

cum

ente

dAX

IN2

Perm

anen

tto

oth

agen

esis

acro

ssto

oth

type

sCo

lon

poly

psan

dca

ncer

,cle

ftlip

and

pala

teM

SX1

Agen

esis

ofse

cond

prem

olar

san

dth

irdm

olar

sCl

eft

lipan

dpa

late

Witk

opsy

ndro

me

MSX

1AD

Agen

esis

ofpe

rman

ent

man

dibu

lar

inci

sors

and

seco

ndm

olar

s,m

axill

ary

perm

anen

tca

nine

sN

ailh

ypop

lasi

a(e

spec

ially

toen

ails

)

Van

der

Wou

deIR

F6AD

Perm

anen

tto

oth

agen

esis

,sec

ond

prem

olar

s,m

axill

ary

late

rali

ncis

ors

Clef

tlip

and

pala

te,m

andi

bula

rlip

pits

Dow

nsy

ndro

me

Num

erou

sTr

isom

y21

Agen

esis

ofin

ciso

rsan

dse

cond

prem

olar

s,pe

g-sh

aped

late

rali

ncis

ors,

max

illar

yca

nine

-firs

tpr

emol

artr

ansp

ositi

on

Dysm

orph

icfa

cies

,con

geni

talh

eart

dise

ase,

inte

llect

uald

isab

ility

,leu

kem

ia,t

hyro

iddy

sfun

ctio

n,he

arin

glo

ss,m

axill

ary

hypo

plas

iaEl

lis-v

anCr

evel

dEV

CAD

Toot

hag

enes

is,e

nam

elhy

popl

asia

,mul

tiple

oral

fren

ula,

prem

atur

eex

folia

tion

ofpr

imar

yte

eth

Chon

drod

yspl

asia

,pol

ydac

tyly

,con

geni

talh

eart

defe

cts

Aper

tsy

ndro

me

FGFR

2AD

Perm

anen

tto

oth

agen

esis

Cran

iosy

nost

osis

,max

illar

yhy

popl

asia

,han

dan

omal

ies

Ost

eoge

nesi

sim

perf

ecta

COL1

A1/2

ADH

ypod

ontia

,den

tinog

enes

isim

perf

ecta

Blue

scle

ra,m

ultip

lefr

actu

res

Inci

sor-

prem

olar

hypo

dont

iaUn

know

nAD

Agen

esis

ofla

tera

linc

isor

san

dse

cond

prem

olar

s,ta

urod

ontis

m,e

ctop

icm

axill

ary

cani

nes

Non

edo

cum

ente

d

Hut

chin

son-

Guilf

ord

prog

eria

synd

rom

esLM

NA

Spor

adic

Perm

anen

tto

oth

agen

esis

,ect

opic

erup

tion

ofpe

rman

ent

inci

sors

Prec

ocio

usse

nilit

y,ea

rlyde

ath,

coro

nary

arte

rydi

seas

e,be

aked

nose

,bal

dnes

s,lip

odys

trop

hy,

shor

tst

atur

eH

ypoh

idro

ticec

tode

rmal

dysp

lasi

aED

AXd

Prim

ary

and

perm

anen

tto

oth

agen

esis

,con

ical

inci

sors

,ano

dont

iaDe

fect

ive

hair,

nails

,ski

n;hy

pohi

dros

is;p

oor

hear

ing;

resp

irato

ryin

fect

ions

EDAR

AD,A

RED

ARR

AD,A

RIn

cont

inen

tiapi

gmen

tiIK

K�Xd

Perm

anen

tto

oth

agen

esis

,con

ical

teet

h,de

laye

dex

folia

tion

ofpr

imar

yde

ntiti

onDe

fect

ive

hair,

nails

,eye

s;in

telle

ctua

ldis

abili

ty;

auto

chth

onou

sta

ttoo

ing

NEM

OAg

enes

is,c

onic

alte

eth,

dela

yed

toot

hem

erge

nce

Hyp

ohid

rosi

s,im

mun

odefi

cien

cy

Axen

feld

-Rie

ger

synd

rom

ePI

TX2

ADAg

enes

isof

inci

sors

and

cani

nes,

enam

elhy

popl

asia

,con

ical

teet

hGl

auco

ma,

redu

ndan

tpe

rium

bilic

alsk

in

Oro

faci

al-d

igita

lsyn

drom

ety

pe1

CXO

RF5

XdAg

enes

isof

inci

sors

and

cani

nes

Clef

tpa

late

,han

dan

omal

ies,

inte

llect

uald

isab

ility

Hol

opro

senc

epha

lyN

umer

ous

ADSo

litar

ym

axill

ary

cent

rali

ncis

orSe

izur

es,s

yndr

omic

faci

es,p

rem

axill

ary

agen

esis

,cl

eft

lipan

dpa

late

,hyp

otel

oris

mCl

eido

cran

iald

yspl

asia

RUN

X2AD

Mul

tiple

supe

rnum

erar

yte

eth,

reta

ined

prim

ary

teet

h,im

pact

edpe

rman

ent

teet

hH

ypop

last

icca

lvar

ia,a

bsen

tcl

avic

les,

mid

face

hypo

plas

ia,d

elay

edfo

ntan

elle

clos

ure,

shor

tst

atur

e,sc

olio

sis,

sinu

s/re

spira

tory

infe

ctio

ns,

hear

ing

loss

Gard

ner

synd

rom

eAP

CAD

Supe

rnum

erar

yte

eth,

toot

hag

enes

is,j

awos

teom

as,i

mpa

cted

teet

hGa

stro

inte

stin

alpo

lyps

,mul

tiple

oste

omas

,ski

nan

dso

ft-t

issu

etu

mor

s,ca

ncer

in50

%by

age

30

AD

�au

toso

mal

dom

inan

t,A

R�

auto

som

alre

cess

ive,

Xd�

X-l

inke

d




develops SPs. Moreover, SPs, unlike other supernumer-ary teeth, recur in 8% of patients. Of note, natal andneonatal teeth should be maintained when possible be-cause they not supernumerary in more than 90% of cases.Clinicians who suspect the presence of a supernumerarytooth should refer the child to a dentist for radiographicexamination.

Delayed Dental AgeBiologic delays in dental development generally retardemergence of the primary and permanent dentitions.Delayed dental age has been studied using tooth countsfrom clinical inspection as well as the stage of toothformation on panoramic radiography. As mentioned,DTE using clinical tooth counts is an inexact measure ofdental age due to a host of local factors. Dental age scores

are best determined using radiographic stages of toothformation.

Few studies have focused on the primary dentitionbecause radiography is limited by patient cooperation.However, numerous methods have been proposed toscore dental age using a variety of statistical methodsbased on scores of crown and root formation for thepermanent teeth. The Demirjian method, originallystudied in a French Canadian pediatric population, isused most commonly. (2) This method scores the man-dibular left permanent teeth, excluding the third molars,according to eight developmental stages. More than100 studies have used the Demirjian method and modi-fications of it to compare dental age to the chronologicage of a population. This method, although validatedthrough epidemiologic studies, gives varied results bysex, race, and ethnicity of the population of study. Dentalage scoring using these methods is used commonly inforensics and immigration proceedings for unaccompa-nied minors as a means of age estimation when additionalinformation 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 ofpubertal onset using tooth formation stages. In general,skeletal age delayed by systemic disease or malnutrition isoften two to six times more severe than the delay noted indental age.

Using the Demirjian method and others in conjunc-tion with clinical tooth counts, patients who have a hostof systemic diseases have been found to have delayeddental age. Most studies, however, involve a limited

Figure 5. A 14-year-old African American boy who hashypodontia. The mandibular right second premolar (**) did notdevelop. Clinically, the mandibular right second primary molar(3) shows delayed exfoliation. The permanent third molarscontinue to develop in the jaws (*). Photograph courtesy ofAliakbar Bahreman, DDS, MS.

Figure 6. A conical mesiodens (3) has emerged into theanterior maxilla, causing the permanent maxillary right cen-tral incisor (*) to emerge late and out of position. Surgicalremoval of the mesiodens is recommended. Photograph cour-tesy of Aliakbar Bahreman, DDS, MS.

Figure 7. A 15-year-old Hispanic boy who has delayed exfo-liation of the mandibular right primary molars (3) as well asdelayed emergence of the mandibular left premolars (*). Anage-appropriate set of permanent teeth is present in themaxillary arch. Four supernumerary mandibular premolars,two on each side, are the cause for the delayed emergence ofthe mandibular premolars. Photograph courtesy of AliakbarBahreman, DDS, MS.




number of affected individuals, lending poor statisticalpower. In addition, numerous genetic syndromes haveDTE (also described as delayed tooth eruption) listed asa clinical finding. Case reports and studies involving thesepatients do not usually assess dental age based on radio-graphic parameters.

Nonetheless, oral inspection of children who haveDown syndrome, hypothyroidism, growth hormone de-ficiency, hypopituitarism, and chronic malnutrition oftenresults 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 havedelayed dental age. DTE resulting from delayed dentalage in children who have Down syndrome remains un-treatable. In contrast, growth hormone therapy has beenshown 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 agenormalizes when the child’s term age is used. (4) Simi-larly, children who have enamel and dentin anomaliesdue to X-linked hypophosphatemic rickets do notpresent initially with delayed dental age. They do, how-ever, develop spontaneous dental abscesses due to micro-scopic abnormalities in the mineralized dental tissuesthat allow ingress of microorganisms and pulpal necrosis.Early primary tooth loss due to infection can slow thedental development of the permanent successors andlead to DTE.

Dental CrowdingInsufficient space in the jaws for eruption and emergenceof teeth constitutes the most benign, yet common,

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 insmall jaws, 2) larger-size teeth in normal-size jaws, or 3) acombination of both. Children who have constricted,V-shaped alignment of the teeth are more likely havetooth crowding than those in whom the dental arch isU-shaped. Dental crowding among primary incisors pre-dicts moderate-to-severe crowding in the permanentdentition.

Early tooth loss due to dental caries raises a child’s riskfor dental crowding and delayed emergence of perma-nent teeth. Primary teeth serve as placeholders for theirsuccessors. Premature extraction of primary canines ormolars results in migration of adjacent teeth (Fig. 8), lossof dental arch length and circumference, and shift ofdental midlines toward the side of early tooth loss. Pedi-atric dentists and orthodontists attach appliances to teethadjacent to tooth extraction sites to maintain space forlater permanent tooth emergence.

The presence of supernumerary teeth as well as fusedteeth (Fig. 9) can exacerbate dental crowding. Laterdeveloping teeth can remain unerupted in the jaws or beforced to emerge ectopically when adjacent teeth areimpediments to the normal eruption path. Odontogenicpathology and jaw bone disorders also worsen dentalcrowding through displacement of unerupted andemerged teeth into compact areas of the jaws.

Dental crowding can be alleviated by transverse ex-pansion of the jaws. Posterior retraction of mediallypositioned molars also increases the amount of space forfuture tooth emergence. In some cases, dental crowdingnecessitates the removal (serial extraction) of healthyprimary canines and molars as well as permanent firstpremolars sequentially to allow proper alignment of thepermanent dentition in adolescence and adulthood.Dentists, orthodontists, and oral maxillofacial surgeons

Figure 8. Space loss in the maxillary left quadrant is seenwhen compared with the contralateral side due to earlyextraction of the maxillary left primary molars because ofdental caries. The maxillary permanent first molar (bottomright) has migrated into the space previously occupied by theprimary molars due to the lack of a space maintenanceappliance.

Figure 9. A 6-year-old African American girl who has amaxillary left primary incisor fused (**) to a supernumerarytooth. Photograph courtesy of Aliakbar Bahreman, DDS, MS.




work collaboratively on these cases to obtain optimaltreatment outcomes.

Ectopic Tooth EruptionAbnormalities in the path of tooth eruption also cancause delayed tooth emergence in the permanent denti-tion. The literature suggests that 2% to 6% of childrendemonstrate 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 andpalate, 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 emergesthrough the gingival tissues and uses the posterior sur-face of the primary molar to guide its eruption intofunctional occlusion with teeth in the opposing jaw.Ectopic MPFMs take a medial eruption course, leadingthem under the crown of the second primary molar(Fig. 10). This eruption disturbance, often detected ondental radiographs between 5 and 7 years of age, delaysMPFM emergence and often causes root resorption ofthe primary second molar, with some cases persistinguntil the primary tooth is exfoliated prematurely. Twothirds of ectopic MPFMs self-correct, usually by 7 yearsof age. For the remaining cases, orthodontic manage-ment is necessary to prevent anterior migration of theectopic MPFM and future impaction of the ipsilateralmaxillary second premolar. Clinically, this anomaly canbe detected through premature mobility of the primarysecond molar or mesial angulation of the MPFM, withemergence of the distal (away from midline) cusps only.

PDCs in the maxilla should be suspected in children

older than 9 years of age when alveolar ridge palpationadjacent to the buccal vestibule lacks a canine bulge, aclinical finding suggestive of normal canine eruption.The early manifestations of PDCs can be detected onpanoramic radiography because ectopic maxillary caninesoften appear more horizontal on the film and tend tooverlap the root of the mature ipsilateral lateral incisor.Early extraction of the adjacent maxillary primary caninecorrects the eruption path and spatial orientation ofPDCs in almost 70% of cases. PDCs are associated withother dental anomalies (small-size maxillary permanentlateral incisors, infraocclusion of primary molars, andenamel hypoplasia) that can be detected by cliniciansthrough oral inspection. Delayed exfoliation of the ipsi-lateral maxillary primary canine or asymmetric anteriorpalatal enlargement with or without primary canine loss(Fig. 11) are late clinical manifestations of PDCs. If leftuntreated, ectopic eruption of the maxillary canine leadsto tooth impaction in the hard palate. Surgical toothexposure, 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 toothemergence in many cases. This abnormality of dentalposition occurs more frequently in the maxilla than themandible. Maxillary canine/first premolar (Mx.C.P1)transposition cases (Fig. 12) occur most commonly, witha prevalence of 0.25%. Based on a review of 143 cases,Mx.C.P1 transposition appears to be polygenic, with apropensity for occurrence in females. (5) A higher prev-alence of Mx.C.P1 transposition is seen among childrenwho have Down syndrome. Clinically, agenesis of theipsilateral lateral incisor is common. Twenty-seven per-cent of published Mx.C.P1 cases occur bilaterally.

Figure 10. The maxillary permanent first molars (*) are erupt-ing in an ectopic position under the crowns of the maxillaryprimary second molars. Root resorption of the primary secondmolars is also occurring. Photograph courtesy of AliakbarBahreman, DDS, MS.

Figure 11. Asymmetric expansion of the anterior palate (3).The maxillary primary canine on the ipsilateral side (*) hasbeen exfoliated. This clinical presentation is indicative of anuntreated palatally displaced canine. Photograph courtesy ofAliakbar Bahreman, DDS, MS.




Early permanent tooth loss due to dental caries ortrauma as well as traumatic displacement of developing,unerupted teeth within the jaws accounts for most othercases of transposition in the maxilla, including canine/lateral incisor, canine/first molar, lateral incisor/centralincisor, and canine/central incisor patterns. Mandib-ular canine/lateral incisor transposition, identified in0.03% of dental patients, often is seen in conjunctionwith permanent third molar agenesis, suggestive of ge-netic influences. Transposition cases, if recognized earlyenough, usually can be managed effectively with inter-ceptive orthodontics without surgery.

Delayed Exfoliation of Primary TeethDelayed exfoliation of primary teeth is intimately associ-ated with delayed root development and eruption oftheir permanent successors. As a result, permanent toothagenesis or delayed dental maturity typically results indelayed exfoliation of primary teeth according to chro-nologic age. In these cases, the timing of primary toothroot resorption is appropriate from a biologic standpoint.In contrast, primary tooth exfoliation is considered bio-logically delayed when the primary tooth remains in placedespite permanent tooth root length greater than 75% ofits expected final length.

Primary teeth that appear biologically ready for exfo-liation are common in primary care. These teeth areusually retained in soft tissue or interlocked betweenadjacent teeth, limiting their ability to be removed athome. Children also tend to delay tooth removal if they

feel that pain is likely. Timely extraction of over-retainedprimary teeth is indicated if maxillary permanent incisorswill 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 teethultimately causes exfoliation of their predecessors, followedby anterior repositioning of the permanent incisors withinthe 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 reachthe normal occlusal plane) are reported to occur in 5% ofthe general population. These teeth often appear to beankylosed on clinical examination because they are im-mobile to palpation and tend to be submerged in thegingival tissues compared with continually erupting ad-jacent teeth (Fig. 14). Nonetheless, infraoccluded pri-mary molars usually exfoliate within 1 year of the normalrange as long as the permanent tooth successor is presentwith adequate root formation.

Infraoccluded primary molars can become surgicalproblems if the crowns of the adjacent teeth are allowedto migrate over top of them. In addition, alveolar bonelevels surrounding the adjacent teeth can approximatethe crown of the infraoccluded molar, leading to im-

Figure 12. Maxillary permanent left canine with left firstpremolar transposition. In this case, reshaping of the teethwith dental composite restorations can permit normal func-tion and satisfactory esthetics. Photograph courtesy of Aliak-bar Bahreman, DDS, MS.

Figure 13. The maxillary primary central incisors are delayedin exfoliation. They are forcing the maxillary permanentcentral incisors to erupt in the anterior palate. When the childoccludes his teeth, the maxillary permanent central incisorsare behind (crossbite) the mandibular incisors (3). Orthodon-tic correction of this condition becomes necessary. Photo-graph courtesy of Aliakbar Bahreman, DDS, MS.




paired exfoliation and delayed premolar emergence (Fig.15). Close monitoring of infraoccluded primary molarsby dentists is recommended to avoid these complications.

TraumaTooth development, eruption, and emergence can bealtered by dental or maxillofacial trauma in infancy orchildhood. Trauma to developing primary teeth is rela-tively rare. Extreme root curvature (aka dilaceration) anderuption failure of maxillary incisors have been reported

as sequelae of traumatic laryngoscopy and prolongedendotracheal intubation in infancy. Clinicians also mayencounter children who have emigrated from EasternAfrica and appear to have DTE of the primary canines orother adjacent teeth on clinical inspection (Fig. 16). Thisfinding is consistent with the practice of ebinyo, in whichtribal healers remove these teeth in infancy to preventor treat high fevers, vomiting, or diarrhea in the child.Damage, displacement, or extraction of adjacent primaryand permanent teeth also can be seen.

Mandibular fractures due to falls, motor vehicle crashes,or child abuse can disturb teeth developing along the lineof fracture. Infection and inadvertent placement of platesand screws during jaw fixation also jeopardizes adjacentdeveloping teeth. Similarly, children born with microgna-thia (eg, Pierre Robin sequence, Goldenhar syndrome)who require mandibular distraction osteogenesis to preventlong-term tracheostomy can have permanent molar toothgerms displaced or destroyed during mandibular osteot-omy and placement of the internal distraction device. Pro-phylactic enucleation of tooth germs in planned sites ofdistractor pins is advocated by some surgeons to improvebone volume and treatment outcomes.

Intrusion of primary incisors into the dental alveoluscommonly results in developmental changes to theirpermanent 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, ortooth germ displacement are possible sequelae. Reim-

Figure 15. A 12-year-old white boy who has infraoccludedmaxillary second primary molars (*). The adjacent teeth haveerupted over the top of the infraoccluded teeth, causing themto become impacted in the jaw. This condition impedes themaxillary second premolars from erupting into the mouth.Photograph courtesy of Aliakbar Bahreman, DDS, MS.

Figure 14. The mandibular left primary first molar is infra-occluded. The adjacent teeth continue to erupt while itremains stationary, creating the clinical appearance of a toothsubmerging into the gingiva. Photograph courtesy of AliakbarBahreman, DDS, MS.

Figure 16. A 6-year-old boy born in Uganda presents withmalformed mandibular primary canines (*) and missing max-illary primary canines (�). His history corroborates that canineextirpation was completed before emigration from Uganda.Photograph courtesy of Terry Farquhar, RN, DDS.




plantation of avulsed primary incisors after trauma pre-disposes them to delayed tooth exfoliation because de-struction of the periodontal ligament apparatus andankylosis between the alveolar bone and the tooth’s rootoften occur. In these cases, ectopic permanent incisoreruption occurs along with rotation of adjacent teeth(Fig. 17). This problem is seen infrequently becausedentists and first responders at accident sites are educatedto avoid replantation of avulsed primary teeth.

Jaw Bone PathologyTooth development and emergence often are affected byjaw pathology. In some cases, dental abnormalities occuras a result of inadequate bone remodeling, and in otherdisorders, displacement of developing teeth is caused byexpanding jaw lesions.

Children who have infantile osteopetrosis experiencemarked delays in tooth emergence as well as tooth agenesisand enamel hypoplasia. These clinical manifestations aredirectly related to osteoclast dysfunction. Stem cell rescue ofthose who have osteopetrosis can restitute normal tootheruption and emergence of the permanent dentition.

Various types of osteogenesis imperfecta present withdental developmental anomalies. Delayed tooth emergenceis seen in 20% of patients who have osteogenesis imperfectatype III. Ectopic tooth eruption is another common findingin affected individuals. Bisphosphonate therapy used in themanagement of osteogenesis imperfecta can cause delayedtooth emergence of 1.6 years relative to matched controls.

To date, bisphosphonate therapy has not been associatedwith osteonecrosis of the jaws, as is reported in adult pa-tients using these medications.

McCune-Albright syndrome is a sporadic multisystemdisease characterized by polyostotic fibrous dysplasia, cafeau lait hyperpigmentation, and precocious puberty. Cranio-facial forms of fibrous dysplasia result in progressive facial,palatal, and jaw asymmetries. The maxilla is affected morecommonly than the mandible, with a ground-glass appear-ance of the lesion noted through panoramic radiography orcomputed tomography scans. Oligodontia as well as toothimpaction, displacement, and rotations are common inaffected patients.

Jaw osteomas and supernumerary teeth often are thefirst manifestations of Gardner syndrome in puberty. Earlyrecognition is necessary to permit monitoring of gastroin-testinal polyps because malignant transformation occurs in50% of patients by age 30.

Permanent teeth often fail to erupt in patients born withcleidocranial dysplasia because the teeth lack secondarycementum. Extraction of primary teeth that have failed toexfoliate normally does not promote eruption of their per-manent successors. In addition, supernumerary teeth canimpede tooth emergence. Surgical exposure of uneruptedteeth followed by orthodontic traction has limited success.Oral rehabilitation for these patients often centers on jawreconstruction and the use of dental prostheses.

Cherubism is a rare autosomal dominant disease thataffects the jaws. The condition is characterized by bilateralexpansion of the posterior mandible and, in some cases,the maxilla and facial bones. Bony expansion of the jawscauses the individual to have a “chubby cheeked,” cherubicappearance. The osseous lesions are usually multilocularradiolucencies affecting the angles and ascending rami ofthe mandible. They are histologically defined by multinu-cleated giant cells in a loose fibrous stroma. The lesions tendto increase in size until puberty, after which lesion stabiliza-tion or even regression is noted. Bilateral expansion of theselesions causes marked displacement of developing andemerged teeth. Failure of tooth eruption due to severedental crowding and malocclusion is common. Watchfulmonitoring is the usual course of action unless expansionprogresses rapidly.

Odontogenic Cysts and TumorsEpithelial-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 ofthe follicle around the crown of an unerupted tooth,comprise approximately 20% of all odontogenic cysts.

Figure 17. A 9-year-old African American girl who hasdelayed exfoliation of the maxillary right primary centralincisor (#). This tooth is discolored due to dental trauma. Herpermanent incisor emergence order is affected. Extraction ofthe over-retained primary incisor is indicated. Photographcourtesy of Aliakbar Bahreman, DDS, MS.




Mandibular third molars, followed by maxillary perma-nent canines (Fig. 18), are affected most commonly.Dentigerous cysts around supernumerary teeth andodontomas also are seen frequently. Usually, the lesionshould measure at least 3 to 4 mm in diameter onradiograph to be called a dentigerous cyst rather than avariation in normal follicular anatomy. These lesions arefound more often in the second decade, with the highestprevalence noted in white patients. Dentigerous cysts cangrow very large and have a tendency to displace the involvedtooth within the jaw (Fig. 19). Treatment of these lesionsinvolves either marsupialization or enucleation of the cystwith or without removal of the unerupted tooth. Recur-rence is rare after complete removal of the cyst.

Keratocytic odontogenic tumors (KCOTs), previouslyknown as odontogenic keratocysts, have been reported toaccount for 2% of all oral biopsies performed in childrenyounger than 16 years of age, according to retrospectivereview of a United States dental school biopsy service. (6)

KCOTs are aggressive tumors that have a marked tendencyfor development in the posterior body and ascending ramusof the mandible. An unerupted tooth is involved in 25% to40% of cases, mimicking a dentigerous cyst. KCOTs havethin, 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 bonegrafting may be necessary.

The presence of multiple KCOTs warrants furthertesting 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 cellcarcinomas, hyperkeratosis of the palms and soles, skele-tal abnormalities, intracranial ectopic calcifications, andfacial dysmorphia. NBCCS is caused by mutations in thePTCH1 gene. It is transmitted as an autosomal dominanttrait and is reported in fewer than 1 in 57,000 individu-als, with a 1:1 male-to-female ratio. Multidisciplinarycare by dental professionals, pediatricians, dermatolo-gists, and neurologists is recommended.

Ameloblastomas have been described as the mostclinically significant odontogenic tumor. They arise fromcells of odontogenic epithelial origin. Multicystic lesionsare seen most commonly across the lifespan. However,only 8.7% to 15% of all ameloblastomas in Westerncountries develop in the pediatric population. Fifty per-cent of unicystic intraosseous ameloblastomas are diag-nosed in the second decade of life. Most of these tumorsdevelop as asymptomatic lesions in the posterior mandi-

Figure 19. A 17-year-old white girl who presents with painlessswelling of the mandibular left posterior jaw has age-appropriatedentition on clinical examination. On panoramic radiography, alarge unilocular radiolucency is seen along with marked displace-ment of the unerupted third molar. Histopathologic examinationconfirmed the lesion to be a dentigerous cyst.

Figure 18. A 13-year-old white girl presents with delayedexfoliation of the maxillary right primary canine (*). On dentalradiography, a large unilocular cyst is present around thecrown of the unerupted permanent canine. Histopathologicexamination reveals a dentigerous cyst.




ble. An unerupted third molar as well as teeth adjacentto it often can become involved. These tumors resemblecysts on surgical exposure. As such, they usually aretreated by enucleation with curettage. Recurrence ratesranging from 10% to 20% are seen. Block resection canbecome 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. Theydevelop in both jaws, with greater prevalence in themaxilla. They are equally distributed between both sexes.Two types, compound and complex, are seen. Com-pound odontomas are well-circumscribed masses of tinyteeth of various numbers. The teeth are usually cone-shaped and have normal delineation of tooth layers.Complex odontomas are similar but do not have orga-nized dental structures. They are easily removed by enu-cleation and do not recur. Fifty-five percent of them arediagnosed when delayed permanent tooth emergence ordelayed exfoliation of a primary tooth is seen.

More than 20 other types of odontogenic cysts andtumors can develop in the jaws. Histopathologic exami-nation is necessary to discriminate these lesions, includ-ing identification of specific odontogenic elements andmineralized tissue. If left untreated, odontogenic diseasecan cause displacement and mobility of teeth, delayedtooth emergence, root resorption, pain, jaw swelling,and paresthesia. Large cystic lesions in the posteriormandible can lead to pathologic jaw fractures.

Gingival EnlargementsThe gingiva and oral mucosa provide the last barrier totooth emergence when sufficient space is present in thedental arch. Under normal circumstances, reduced enamelepithelium of erupting teeth fuses with the oral mucosa,permitting emergence of the dentition. Gingival remodel-ing also is necessary for emergence and continued tootheruption over time. A variety of genetic and environmentalconditions active in the gingival tissues can preclude eitherlocalized or generalized tooth emergence.

Tooth emergence can be delayed when the gingivaltissue becomes scarred as a result of oral trauma (Fig. 20).Eruption cysts can form over emerging teeth when fluidextravasation occurs between the tooth crown and theoverlying gingival tissues. These conditions are usually self-limiting with time and optimal oral hygiene. If persistenceof the lesions affects normal emergence and alignment ofadjacent teeth, surgical excision may become necessary.

Drug-induced gingival enlargement (GE) in severe casescan impair tooth emergence. Drug-induced GE is charac-

terized by proliferation of connective tissue extracellularmatrix in response to gingival drug metabolism. Phenytoin,nifedipine, and cyclosporine are the most common catalystsof the condition. Poor oral hygiene exacerbates GEthrough inflammatory mechanisms. The anterior gingivaltissues are involved more frequently. Males tend to be moreseverely affected for poorly understood reasons. The use ofmultiple anticonvulsant medications in addition to phenyt-oin increases the severity of phenytoin-induced GE. Addi-

Figure 20. An 8-year-old white boy who has a history of traumato the maxillary anterior teeth presents with delayed emergenceof the maxillary permanent right central and lateral incisors. Thecontralateral permanent incisors are already present. The outlineof the unerupted teeth can be seen within the gingiva. Surgicalexposure was necessary to permit tooth emergence.

Figure 21. An 8-year-old African American boy who hashereditary gingival fibromatosis. Marked gingival enlargementwith delayed tooth emergence can be seen. Surgical resectionof the gingiva is necessary to permit tooth emergence.Photograph courtesy of Paul Romano, DDS, MS.




tive effects are seen when nifedipine and cyclosporine areused in organ transplant patients. Cyclosporine also hasbeen implicated in the development of oral eruption cystsin select cases. Tacrolimus, another immunosuppressiveagent, has not been found to cause GE after organ andhematopoietic stem cell transplantation. In fact, some clini-cians believe that substitution of cyclosporine with tacroli-mus can reverse GE in these patients. Surgical managementof GE through gingival resection may become necessary ifmastication, speech, and esthetics become problematic.

Hereditary gingival fibromatosis (HGF) is a rare con-dition affecting 1 in 350,000 individuals that has no sexpredilection. Clinically, HGF affects the emergence ofthe permanent teeth. The clinical manifestations of HGFvary, with malpositioned teeth, delayed exfoliation ofprimary teeth, delayed emergence of permanent teeth,malocclusion, and open lip posture seen (Fig. 21). HGFis usually managed through optimal oral hygiene prac-tices and surgical resection if esthetics and function arecompromised.

References1. Polder BJ, Van’t Hof MA, Van der Linden FPGM, Kuijpers-Jagtman AM. A meta-analysis of the prevalence of dental agenesis inpermanent teeth. Community Dent Oral Epidemiol. 2004;32:217–2262. Demirjian A, Goldstein H, Tanner JM. A new system of dentalage assessment. Hum Biol. 1973;45:211–2273. Krekmanova L, Carlstedt-Duke J, Dahllof MC. Dental maturityin children of short stature—a two-year longitudinal study ofgrowth hormone substitution. Acta Odontol Scand. 1999;57:93–964. Paulsson L, Bondemark L, Soderfeldt B. A systematic review ofthe consequences of premature birth on palatal morphology, dentalocclusion, tooth-crown dimensions, and tooth maturity and erup-tion. Angle Orthod. 2004;74:269–2795. Peck S, Peck L. Classification of maxillary tooth transpositions.Am J Orthod Dentofac Orthop. 1995;107:505–5176. Shah SK, Le MC, Carpenter WM. Retrospective review ofpediatric oral lesions from a dental school biopsy service. PediatrDent. 2009;31:14–19

Suggested ReadingAmerican Academy of Pediatric Dentistry. Guideline on manage-

ment of the developing dentition and occlusion in pediatricdentistry. Reference Manual. 2009;32(6). Accessed August2009 at: http://www.aapd.org/media/Policies_Guidelines/G_DevelopDentition.pdf

Bailleul-Forestier I, Berdal A, Vinckier F, et al. The genetic basisof inherited anomalies of the teeth. Part 2: syndromes withsignificant dental involvement. Eur J Med Genet. 2008;51:383–408

Bailleul-Forestier I, Molla M, Verloes A, Berdal A. The genetic basisof inherited anomalies of the teeth: Part 1: clinical and molecularaspects of non-syndromic dental disorders. Eur J Med Genet.2008;51:273–291

Frank CA. Treatment options for impacted teeth. JADA. 2000;131:623–632

Huber KL, Suri L, Taneja P. Eruption disturbances of the maxillaryincisors: a literature review. J Clin Pediatr Dent. 2008;32:221–230

Slootweg PJ. Lesions of the jaws. Histopathology. 2009;54:401–418

Summary• The presence of DTE, a commonly overlooked finding

in primary care, signals abnormalities in toothformation, eruption, or emergence.

• DTE often occurs through benign acquired processessuch as tooth loss due to dental caries or tooth-jawsize discrepancy. However, the detection of DTE isimportant because early identification can minimizethe comorbidity associated with systemic disease,genetic syndromes, or odontogenic pathology.

• Pediatricians can reduce the burden of care relatedto DTE through appropriate history taking and oralinspection during health supervision visits.

• Children awaiting emergence of teeth for more than12 months beyond normal chronologic ranges orthose who experience localized alterations in thenormal emergence order should be referred to adentist for further evaluation.





Jeffrey M. Karp Delayed Tooth Emergence


http://pedsinreview.aappublications.org/cgi/content/full/32/1/e4including high-resolution figures, can be found at:


y_carehttp://pedsinreview.aappublications.org/cgi/collection/emergenc

Emergency Care throat_disordershttp://pedsinreview.aappublications.org/cgi/collection/ear_nose_

Ear, Nose and Throat Disorders dysmorphologyhttp://pedsinreview.aappublications.org/cgi/collection/genetics_

Genetics/Dysmorphologyfollowing collection(s): This article, along with others on similar topics, appears in the







http://pedsinreview.aappublications.org/cgi/collection/genetics_dysmorphology

http://pedsinreview.aappublications.org/cgi/collection/ear_nose_throat_disorders

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Pediatrics in Review_January2011