10 Pediatrics in Review_October2011

Answer Key: 1. A; 2. D; 3. A; 4. D; 5. D; 6. D; 7. A; 8. E; 9. E; 10. D;11. A; 12. A; 13. C; 14. E; 15. D; 16. D; 17. E; 18. D; 19. C; 20. D; 21. C

ArticlesThe Role of the Pediatrician in PreventingCongenital Malformations411Robert L. Brent

Group A Streptococcal Infections423Debra M. Langlois, Margie Andreae

Unintentional Injuries in Pediatrics431Karen Judy

Anxiety and Separation Disorders440Alexa L. Bagnell

Index of SuspicionCase 1: Voiding Difficulty in a 10-year-oldCase 2: Seizure-like Activity Precipitated by Loud Noise

in a 2-year-oldCase 3: Purplish-brown, Shiny Upper Extremity Lesion and

Stiff Hand in a 9-year-old447Case 1: Henry M. Rosevear, Andrew J. Lightfoot,

Charles R. PowellCase 2: Pedro Weisleder, Jorge VidaurreCase 3: Nathan Lehman, L. Nandini Moorthy

In BriefMedia Role in Violence andthe Dynamics of Bullying453Patrick Brown, Cheryl Tierney

Correction454Online-Only ArticleAbstract appears on page 455.Visual Diagnosis: Respiratory Distress:A Great Masqueradere95Catherine Kier, Rula Balluz, Vikash Modi, Latha Chandran

Cover: The artwork on the cover of thismonth’s issue is by one of the winners ofour 2009 Cover Art Contest, 8-year-oldRobbie D. of Downingtown, PA. Robbie’spediatricians are Bradley Dyer, MD, andRobert Duncheskie, MD.

NOTE: Beginning in January 2012,learners will only be able to take Pedi-atrics in Review quizzes and claim creditonline. No paper answer form will beprinted in the journal.

contentsPediatrics inReview� Vol.32 No.10 October 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: Kathleen Bernard, Erin CarlsonEditorial 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 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 KingdomJacob Hen, Bridgeport, CTJeffrey D. Hord, Akron, OH

Hal B. Jenson, Kalamazoo, MIDonald Lewis, Norfolk, VAGregory Liptak, Syracuse, NYMichael Macknin, Cleveland, OHSusan Massengill, Charlotte, NCJennifer Miller, Gainesville, FLBlaise Nemeth, Madison, WIMobeen Rathore, Jacksonville, FLRenata 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 2011 for print and online/online only: AAP Fellow $177/$135; Nonmember $222/$172; Allied Health or Resident $165/$111.Institutions call for pricing (866-843-2271). For overseas delivery, add $109.Current single issue price is $10 domestic, $12 international. Replacement issuesmust be claimed within 6 months from the date of issue and are limited to threeper calendar year. Periodicals postage paid at ARLINGTON HEIGHTS,ILLINOIS and at additional 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.

● Brian Carter, MD, FAAP, disclosed that he participates in the MedImmune speakerbureau.

● 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.

● Mobeen Rathore, MD, FAAP, disclosed that he is a consultant and on the speakerbureaus for GSK, Medimmune, Merck, Novartis, and Pfizer.

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

Laboratories.

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 Development

How 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.

The Role of the Pediatrician in PreventingCongenital MalformationsRobert L. Brent, MD, PhD,

DSc (Hon)*

Author Disclosure

Dr Brent has disclosed

no financial

relationships relevant

to this article. This

commentary does not

contain a discussion

of an unapproved/

investigative use of a

commercial

product/device.

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

1. Review the discoveries and advances in teratology, genetics, toxicology, and clinicalteratology counseling in the past 50 years.

2. Explain the changes that have occurred in some basic principles of teratology.3. List the drugs, chemicals, infections, and other environmental agents that may harm

the developing embryo.4. Explain how congenital malformations can be prevented and how to manage

pregnancies in which the embryo has a congenital malformation.5. Delineate the principles involved in evaluating the risks and effects of environmental

toxicants and know how to evaluate the potential risks of a specific exposure.6. Discuss how to evaluate whether a child’s congenital malformation is caused by an

environmental exposure or other mechanism.

IntroductionDuring the first half of the 20th century, the field of teratology (the study of birth defects)was represented sparsely in the medical literature. Pediatricians who graduated frommedical school in the 1950s were taught that the correct number of human chromosomeswas 48, until the number was reported accurately as 46 by Tijo and Levan in 1956. (1)Gregg had described the teratogenicity of rubella virus infection during pregnancy in1941. (2) The teratogenic risk of the folic acid antagonists (aminopterin) was establishedin humans, (3)(4) and experimental studies indicated that nutritional deficiencies couldproduce congenital malformations (CMs) in animals. (5)(6)(7)

In the 1950s, teratologists were aware that only a small percentage of birth defects werecaused by drugs, chemicals, and physical agents. (5) By 2007, further informationconfirmed the viewpoint that birth defects caused by drugs, chemicals, and physical agentsaccount for a small but significant percentage of total birth defects (Table 1). (6)(7)(8)(9)However, avoiding teratogenic drugs and chemicals or reducing teratogenic maternaldisease states has a major impact on an individual pregnancy and family.

Reproductive problems encompass a multiplicity of diseases, including sterility, infer-tility, spontaneous abortion (miscarriage), stillbirth, congenital malformations (due toenvironmental or hereditary causes), fetal growth restriction, and prematurity. (6)(7)(8)(9) Because these clinical problems occur commonly in the general population,environmental causes are not always easy to corroborate (Table 2). Severe CMs occur in 3%of births.

According to the Centers for Disease Control and Prevention (CDC), severe CMsinclude those birth defects that cause death, hospitalization, or intellectual disability;necessitate significant or repeated surgical procedures; are disfiguring; or interfere withphysical performance. Each year in the United States, 120,000 infants are born withsevere birth defects. Genetic diseases occur in approximately 11% of births. Spontaneousmutations account for less than 2% to 3% of genetic diseases (Table 1). Therefore,mutations induced from preconception exposures to environmental mutagens aredifficult endpoints to document (Table 2). Birth defects account for 440,000 deathsamong children each year in developing nations, representing 3.7% of the deaths inchildren. In the United States, 25% of infant deaths are due to lethal CMs.

*Alfred I. duPont Hospital for Children, Jefferson Medical College, Wilmington, DE.

Article genetics

Pediatrics in Review Vol.32 No.10 October 2011 411 at Health Internetwork on October 2, 2011http://pedsinreview.aappublications.org/Downloaded from

http://pedsinreview.aappublications.org/

Pediatricians and pediatric subspecialists cannot ig-nore the medical problems associated with CMs becausethey are the leading cause of death in infancy (1 to 12months of age). (6)(7) They are the fifth leading cause ofdeath from disease in the entire population and areresponsible for a large number of hospitalizations. Al-though clinicians who care for pregnant women play avery important role in the effort to prevent CMs, pedia-tricians also can contribute to the preventive effort andcounseling of families in their practices who have a childborn with a CM.

Advances in Teratology and Genetics Duringthe Last Half of the 20th CenturyDuring the past 50 years, substantial discoveries andadvances have been made in teratology, genetics, toxi-cology, and clinical teratology counseling (Table 3). Thenumber of genetic diseases catalogued in the post-WorldWar II period was approximately 1,500. (10)(11) In theyear 2006, the Human Genome Project identified morethan 6,000 single-gene genetic abnormalities, many ofwhich manifest as CMs. (12) Also, a large number ofchromosome abnormalities and complex or polygenicgenetic diseases involve multiple genetic loci (eg, diabe-tes and obesity).

The field of prenatal diagnosis,using ultrasonography, karyotyp-ing, biochemical studies, and mo-lecular biology studies, has ex-panded the ability to diagnoseanatomic malformations, metabolicdiseases, and genetic diseases in theembryo and to determine the causeof many birth defects that previ-ously were listed in the unknowncategory (Tables 1 and 2). The abil-ity to determine the cause of achild’s birth defect has improved, aswell as the ability to inform thefamily about the risk of recurrence.(11)(13)(14)(15)(16)(17)(18)

The topic of interruption ofpregnancy is controversial in manycountries and continues to be de-bated both politically and ethically,but it offers the opportunity toeliminate nonviable or severely mal-formed embryos early in preg-nancy. Physicians should under-stand that the family makes thedecision on how to manage preg-

nancies affected with serious abnormalities; the physi-cian’s role is as an educator who defines the problem andprognosis. Nature frequently preempts politics and eth-ics, with most early spontaneous abortions occurring inembryos that have either karyotype abnormalities orserious anatomic malformations. Another reason thatinterruption of pregnancy is controversial is because theprocedure does not prevent CMs; rather, it eliminatesseverely malformed embryos very early in pregnancy.Abnormal pregnancies can be diagnosed early in gesta-tion through maternal serum biochemical markers, andultrasonography, amniocentesis, and chorionic villoussampling can aid in the diagnosis of very serious or fatalabnormalities early in pregnancy.

Discovery of new teratogens, such as the angiotensin-converting enzyme inhibitors and misoprostol, havetaught clinicians to be prepared to accept new principlesin teratology that are discovered when new teratogensare identified that do not follow the “old” rules, such asthe belief that severe anatomic CMs can be induced onlyduring early organogenesis. (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) Microcephaly, intellectualdisability, growth restriction, and vascular disruptivephenomena can be induced by embryotoxic exposures inthe second and third trimesters (Table 4).

Table 1. Reproductive and Developmental EffectsCondition Frequency

Immunologically and clinically diagnosed spontaneousabortions per million conceptions (20% have lethalmalformations or chromosome abnormalities thatcause spontaneous abortion before the first monthof gestation [first missed menstrual period])

350,000

Clinically recognized spontaneous abortions permillion clinically recognized pregnancies

150,000

Spontaneous abortion after the first missed menstrualperiod

Genetic diseases per million births 110,000Multifactorial or polygenic genetic environmental

interactions90,000

Dominantly inherited disease 10,000Autosomal recessive and sex-linked genetic disease 1,200Cytogenetic (chromosomal abnormalities) 5,000New mutations in the developing ova or sperm

before conception3,000

Major malformations (genetic, unknown, environmental) 30,000Prematurity (Ireland, 55,000; United States, 124,000) 69,000Fetal growth restriction 30,000Stillbirths (>20 wk) 4,000 to 20,900Infertility 7% of couples

Modified from Brent. (7)

genetics preventing congenital malformations

412 Pediatrics in Review Vol.32 No.10 October 2011

at Health Internetwork on October 2, 2011http://pedsinreview.aappublications.org/Downloaded from


Environmental Causes of Developmental andReproductive EffectsObstetricians and perinatologists obviously must be fa-miliar with drugs, chemicals, infections, and other envi-ronmental agents (Table 4) that may harm the develop-ing embryos of their pregnant patients, but this an area ofimportance to pediatricians as well. A comprehensivetextbook chapter on the environmental causes of birthdefects may be helpful to pediatricians who wish to havemore extensive information about teratogenic agents.(14) Pediatricians may encounter several specific situa-tions related to birth defects:

● Because teenagers under the care of a pediatriciando get pregnant, it is important to consider thepossibility of pregnancy when prescribing medica-tions for teenage patients. In particular, the admin-istration of retinoids (isotretinoin), anticonvul-sants, and vaccines may place the pediatrician atlegal risk. (31)

● Some of pediatric patients have CMs or other de-velopmental effects and the parents may ask thepediatrician about the cause of their child’s medicalproblems. The pediatrician should be prepared toanswer the questions or refer the family to a clinicalteratologist or geneticist.

● The pediatrician may attend adelivery of a malformed childand subsequently be involvedin litigation as a fact witness ordefendant.

● Mothers of pediatric patientsmay become pregnant andask their child’s pediatricianabout the risk of medications,immunizations, or other envi-ronmental exposures that maybe prescribed during preg-nancy.

● Pediatricians should encour-age teenagers to receive thehuman papillomavirus vaccineand encourage all women ofreproductive age to take 400�g of folic acid and 6 �g ofvitamin B-12 each day to re-duce the risk of neural tubedefects. (15)

Pediatricians have a multitude ofeducational aids to assist in theirevaluations, including consulta-tions with clinical teratologists

and geneticists, the medical literature, OMIM (theweb site for the Online Mendelian Inheritance of Mansupported by the National Institutes of Health) (11)and TERIS (the web site of the Teratogen InformationServices located at the University of Washington),(17) and publications that review the field of CMs.(12)(13)(14)(16)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)

Prevention of Congenital Malformations andManagement of Affected PregnanciesSome of the discoveries pertaining to the causes of inutero developmental problems have been translated intopreventive measures (Table 5) The implementation of allof these measures could reduce the prevalence of birthdefects and other developmental problems. The Centersfor Disease Control and Prevention (CDC) has initiateda campaign to emphasize that some birth defects canbe prevented. (32) A fact sheet from this campaign ispublished in the online version of this article (see datasupplement). The National Academy of Sciences haspublished a report addressing the problem of reducingbirth defects in developing nations. (33) Individual tera-tologists have been attempting to accomplish this goalfor years with regard to the prevention of neural tube

Table 2. Causes of Congenital MalformationsObserved During the First Year After Birth

Suspected CausePercent ofTotal

Unknown 65PolygenicMultifactorial (gene-environment interactions)Spontaneous errors of developmentSynergistic interactions of teratogens?

Genetic 15 to 25Autosomal and sex-linked inherited genetic diseaseCytogenetic (chromosomal abnormalities)New mutations

Environmental 10Maternal conditions: alcoholism, diabetes, endocrinopathies,

phenylketonuria, smoking and nicotine, starvation,nutritional deficits

4

Infectious agents: rubella, toxoplasmosis, syphilis, herpes simplex,cytomegalovirus, varicella-zoster, Venezuelan equine encephalitis,parvovirus B19

3

Mechanical problems (deformations): amniotic band constrictions,umbilical cord constraint, disparity in uterine size and uterinecontents

1 to 2

Chemicals, prescription drugs, high-dose ionizing radiation,hyperthermia

2 to 3

Modified from Brent. (7)




defects (NTDs) through folic acid supplementation.(15)(34)(35)(36)(37)(38)(39)(40)

Folic AcidFolic acid supplementation of grain was recommendedfollowing the 1991 publication of the controlled studyperformed by the Medical Research Council that dem-onstrated that folic acid could prevent NTDs. (35) Basedon this and other publications, the United States Foodand Drug Administration (FDA) recommended that fo-lic acid be added to grains, and the grain industry com-plied. Although only 50% of the amount recommendedby the Institute of Medicine was added to the grainsupply, the incidence of NTDs was reduced. Proponentsof doubling the amount of folic acid in the grains claimedthat all the preventable NTDs were not being prevented.(15)(36)(37)(38)(39)(40) The situation is worse in therest of the world because only 10% of the world’s popu-lation is receiving additional folic acid in the grain supply,which suggests that 90% of the populations in the devel-oping nations are not receiving adequate amounts offolic acid. Only a small proportion of women take 400 �gof folic acid and 6 to 8 �g of vitamin B-12 in a multivi-tamin each day. Because of inadequate supplementationof grains, especially corn meal, even in the United States,

a significant proportion of the pop-ulation is not receiving adequatefolic acid and vitamin B-12 toprevent all folic acid-preventableNTDs.

Tens of thousands of childrenare born each year with folic acid-preventable NTDs. The UnitedStates spends $200,000,000 eachyear to eradicate poliomyelitisthrough an excellent program ofpolio immunization, and frequentepidemiologic monitoring of theincidence of poliomyelitis providesdata on the changing incidence ofthe disease (personal communica-tion, G.P. Oakley Jr, 2010). Theprogram has reduced the incidenceof polio to 1,000 cases per year.Polio may never be eliminated be-cause of subclinical infections andthe possibility of new mutatedstrains, in contrast with smallpox.The CDC has been provided with abudget of $5,000,000 for the pre-vention of the approximate 200,000

folic acid-preventable NTDs worldwide. Thus, the UnitedStates is spending $200,000 for each case of polio pre-vented and $25 for each NTD case prevented.

Iodine DeficienciesIodine deficiency as a cause of intellectual disability andgoiter was recognized by a Swiss physician almost 200years ago, (41) but the Swiss Academy rejected thefindings. One hundred years elapsed before iodine defi-ciency as a clinical entity was supported by other scien-tists. (41) In many parts of the world, the soil is deficientin iodine, and goiters, hypothyroidism, and cretinismhave been endemic. (42)(43) In 2007, the World HealthOrganization estimated that 2 billion individuals hadinsufficient iodine intake. Iodine deficiency is consideredthe single greatest preventable cause of intellectual dis-ability. These problems were reduced or eliminated inthe United States with the addition of sodium iodide tosalt, referred to as “iodized salt.” However, iodide defi-ciency may return to the United States with the emphasison reducing salt intake to reduce the incidence of hyper-tension, especially if restaurants and prepared food prod-uct manufacturers also reduce the amount of salt in theirproducts. The FDA and some pharmaceutical companiesare considering the addition of potassium iodide or so-

Table 3. Advances in Teratology, MolecularBiology, Epidemiology, Clinical Teratology,and Genetics• Correct number of chromosomes: 46 (1)• Karyotyping and the discovery of chromosomal diseases• Advances in molecular biology• Development of the principles of teratology• Improvement in the techniques of counseling parents about causes and risks• Increasing number of identified genetic diseases that are responsible for

congenital malformations and developmental problems• Continuing discovery of new teratogens (3 in 1950 to more than 52 in 2008)• Invention and application of computed tomography scans, magnetic resonance

imaging, and diagnostic ultrasonography• Development and implementation of the administration of rubella vaccination• Folic acid supplementation to wheat grains and the prevention of folic acid-

preventable neural tube defects• Creation of the Online Mendelian Inheritance in Man program on the internet

for diagnosing genetic diseases (10)(11)• Introduction of fetal therapy and accompanying controversies• Improvement in the control and management of diabetes during pregnancy• The Human Genome Project (12)• Determination of the vulnerability of the embryo at different stages of

development• Fetal therapy and intervention based on the wishes of the parents after

thorough discussion of the risks and benefits





Table 4. Environmental Agents or Milieus That May Increase the Risk orBe Associated With an Increased Risk of Reproductive orDevelopmental EffectsAgents

• Alcohol (ethyl alcohol)• Aminopterin, methotrexate• Androgens• Angiotensin-converting enzyme inhibitors• Angiotensin II receptor blocker (sartans)• Antidepressants (selective serotonin reuptake inhibitors)• Antituberculosis therapy• Caffeine• Carbamazepine• Cocaine• Cobalt used in hematinic vitamin preparation• Coumarin derivatives• Cyclophosphamide• Diethylstilbestrol• Diphenylhydantoin• Lithium carbonate (salts)• Methimazole• Minoxidil• Misoprostol• Mycophenolate mofetil• Penicillamine (D-penicillamine)• Phenobarbital• Progestational drugs• Retinoids administered systemically (isotretinoin,

etretinate)• Retinoids administered topically• Streptomycin• Tetracyclines• Thalidomide• Trimethoprim• Valproic acid• Vitamin D

Procedures

• Chorionic villous sampling• Insulin shock therapy• Methylene blue intrauterine instillation• Radiation: radioactive isotopes (radionuclides)• Radiation: external diagnostic or therapeutic ionizing

radiation• Ultrasonography

Environmental Exposures• Carbon monoxide (maternal) poisoning• Electromagnetic fields• Environmental chemicals (eg, dioxin, Agent Orange,

phthalates, bisphenol A)• Lead• Methyl and ethyl mercury “poisoning”• Polychlorinated biphenyls• Smoking tobacco and absorption of nicotine and

other products contained in tobacco• Toluene and gasoline inhalation addiction

Environmental Conditions• Diabetes• Endocrinopathy• Hyperthermia• Folic acid and vitamin B-12 (risk of deficiency)• Iodide deficiency• Phenylketonuria (maternal)• Mechanical problems in utero• Nutritional deprivation• Obesity• Thyroid hypofunction (iodine deficiency,

I-131 administration, antithyroid drugs)• Vitamin A excess and deficiency

Infectious Diseases• Fetal infections• Cytomegalovirus• Herpes simplex 1 and 2• Human immunodeficiency virus• Parvovirus B19• Rubella virus• Rubella vaccine• Syphilis• Toxoplasma• Varicella-zoster• Venezuelan equine virus encephalitis

Reproductive or developmental effects include congenital malformations, miscarriage, growth restriction, and neurobehavioral effects. Published articlesaddressing these reproductive or developmental agents can be found on the TERIS web site, (17) which provides the risk estimate for each agent and thequality of the available literature. Other drugs, chemicals, and environmental situations (eg, obesity) that may affect the embryo/fetus can be obtained fromthe TERIS web site and Shepard (now on the TERIS web site).




dium iodide to multivitamin preparations. Young infantsshould ingest 40 �g/day of iodine, and women require150 �g/day during pregnancy. (44)

Down SyndromeThe incidence of Down syndrome in the United Stateshas increased significantly since 1980. In 1980, the prev-alence was 0.99 per 1,000 births, with 3,579 affectednewborns in the United States. In 2003, the prevalenceof Down syndrome was 1.5 per 1,000 births, with 6,134affected newborns, reflecting a 71% increase in numbersand 52% increase in prevalence. (45) In 1980, 4.57%births were in women older than 35 years. In 2003,14.04% of births occurred in women older than 35 years.The increase in pregnancies in older women related towomen postponing marriage and pregnancy for educa-tion or professional reasons make this a difficult problemto solve.

Clinical EvaluationThe physician responding to the question, “What causedmy child’s birth defect?” should perform the same schol-

arly analysis required for a differ-ential diagnosis of any compli-cated clinical problem. If themother of a malformed infant hadsome type of exposure duringpregnancy, such as a diagnosticradiologic examination or medi-cation, the consulting physicianshould not support or suggest thepossibility of a causal relationshipbefore performing a completeevaluation. Similarly, if a pregnantwoman who has not yet deliveredhad some type of exposure duringpregnancy, the consulting physi-cian should not support or sug-gest the possibility that the fetus isat increased risk before perform-ing a complete evaluation.

Many articles and books can as-sist the physician with the clinicalevaluation, although general pedi-atric training programs do not usu-ally prepare generalists to performsophisticated genetic or teratologycounseling. (11)(24)(25)(26)(27)(28)(29)(30) In addition to per-forming the usual history and

physical evaluation, the physician must obtain infor-mation about the nature, magnitude, and timing ofthe exposure. The physical examination should in-clude descriptive and quantitative information aboutthe physical characteristics of the child. Althoughsome growth measurements are routine, many mea-surements used by specialized counselors are not partof the usual physical examination, such as palpebralfissure size, ear length, intercanthal distances, totalheight-to-trunk ratio, and many other findings. Im-portant physical variations in facial, hand, and footstructure as well as other anatomic structures may besuggestive of known syndromes, either teratologic orgenetic.

Evaluating the Potential Risks ofEnvironmental ExposureMost consultations involving pregnancy exposures con-clude that the exposure does not change the reproduc-tive risks in that pregnancy. In many instances, the avail-able information is so vague that the counselor cannotreach a definitive conclusion about the magnitude of the

Table 5. Prevention of Congenital Malformationand Perinatal Disease1. Rubella vaccination2. Folic acid (400 �g/day), vitamin B-12 supplementation (6 �g/day)3. Supplementation of iodine to deficient populations4. Diagnosis and management of maternal hypothyroidism5. Meticulous diabetic control and eventually the prevention or cure of diabetes6. Obesity control (reduces the risk of birth defects and decreases the risk of

developing diabetes)7. Human immunodeficiency virus screening and treatment8. Vaccination with group B Streptococcus vaccine9. Maternal phenylalanine management for phenylketonuria

10. Management or discontinuation of oral anticoagulants, anticonvulsants,retinoids, thalidomide, and all known teratogens

11. Recognition that that new teratogens can be represented in the next newdrug or chemical: angiotensin-converting enzyme inhibitors, angiotensin IIreceptor blockers, mycophenolate

12. Cessation of maternal smoking and alcohol ingestion13. Immunization against known teratogenic infections (botulin toxin vaccine for

the pregnant mother to prevent infant botulism)14. Reducing the incidence of multiple births following in vitro fertilization15. Counseling older women and men about the increased risk of Down syndrome

and other genetically determined diseases in older couples contemplatingpregnancy

16. Screening for chromosome abnormalities and genetic disease: amniocentesis,chorionic villous sampling, maternal serum monitoring, and ultrasonographicmonitoring to diagnose identifiable genetic diseases, karyotype abnormalities,and serious birth defects to inform the parents about their risks and options





risk. Information that is necessary for this evaluationincludes:

● What was the nature of the exposure?● Is the exposure agent identifiable? If the agent is iden-

tifiable, has it been identified definitively as a reproduc-tive toxin causing a recognized constellation of malfor-mations or other reproductive effects?

● When did the exposure occur during embryonic andfetal development?

● If the agent is known to produce reproductive toxiceffects, was the exposure above or below the thresholdfor these effects?

● Were there other significant environmental exposuresor medical problems during the pregnancy?

● Is this a wanted pregnancy or is the family ambivalentabout carrying this baby to term?

● What is the medical and reproductive history of themother with regard to previous pregnancies and thereproductive history of the family lineage?

Teratology PrinciplesA number of important clinical rules are important whendetermining the cause of a patient’s congenital malfor-mations. (6)(7)(9)(14)

● No teratogenic agent should be described qualitativelyas a teratogen because a teratogenic exposure includesnot only the agent, but also the dose and the time inpregnancy when the exposure has the potential forcausing CMs and other developmental effects.

● Even agents that have been demonstrated to result inmalformations cannot produce every type of malfor-mation. Known teratogens may be implicated pre-sumptively by the spectrum of malformations theyproduce (the syndrome that describes the clinical man-ifestations of the teratogenic agent). However, differ-ent teratogenic agents may affect the fetus with asimilar spectrum of malformations, thus preventing thephysician from providing the family with a definitivediagnosis. Some teratogenic syndromes mimic geneticsyndromes, such as thalidomide effects mimickingHolt-Oran syndrome. It is easier to exclude an agent asa cause of birth defects than to conclude definitivelythat it was responsible for birth defects because of theexistence of genocopies of some teratogenic syn-dromes.

● The dose is a crucial component when evaluating therisk of exposures. Teratogenic agents follow a toxico-logic dose-response curve, which means that each tera-togen has a threshold dose, below which there is no risk

of teratogenesis, no matter when in pregnancy theexposure occurred.

● The evaluation of a child born with CMs cannot beperformed adequately unless it is approached with thesame scholarship and intensity as the evaluation of anyother complicated medical problem.

● Each physician must recognize the consequences ofproviding erroneous information on reproductiverisks to pregnant women exposed to drugs andchemicals during pregnancy or alleging that a child’smalformations are due to an environmental agentwithout performing a complete and scholarly evalu-ation.

● Reproductive problems alarm the public, the press,and some scientists to a greater degree than mostother diseases. In fact, severely malformed childrenare disquieting to clinicians, especially those inexpe-rienced in dealing with these problems. No physicianis comfortable informing a family that their child wasborn without arms and legs. The objective evalua-tion of environmental causes of reproductive dis-eases is clouded by the emotional climate that sur-rounds these diseases, resulting in the expression ofpartisan positions that either diminish or magnify theenvironmental risks. Such nonobjective opinions canbe expressed by scientists, the public, or the press.(31) Every physician must be aware of the emotion-ally charged situation when a family has a child bornwith a birth defect.

Environmental Exposures Occurring DuringPregnancyAfter obtaining all this information, the counselor is in aposition to provide the family with an estimate of thereproductive risks of the exposure. Following are someexamples of consultations that have been referred to ourclinical teratology service:

Patient 1. A 33-year-old mother of two was diagnosedwith breast cancer, and her only treatment was radiationtherapy to the left breast. She had a very good prognosisbecause the disease was only in the breast and there were nopositive axillary lymph nodes. She underwent 6 weeks ofradiation therapy. In the third week of therapy, it wasdetermined that she was 8 weeks postconception. The oncol-ogist and radiation therapist suggested that the pregnancyshould be interrupted. The woman continued her radiationtherapy to her breast but refused the interruption of herpregnancy and requested another opinion. The radiationtherapist informed our office that the mother was receiving2.25 Gy/day to her left breast. The health physicist calcu-lated the fetal exposure to be 0.017 Gy for each therapy




session, which indicated that the fetus would receive 0.425Gy (42.5 rads) during 25 radiation sessions over a period of5 weeks. The mother asked to speak with the physiciandirectly because she wanted the answers to several questions:1) “Could the child be malformed?” Answer: The fetus hada 3% risk of malformation and a 15% of miscarriagebecause that is the background risk for all women. The riskswould not be increased by the radiation exposure because ofthe protracted exposure over a 5-week period. 2) “Could thechild have growth restriction?” Answer: Approximately 4%to 10% of children experience growth restriction, and it isunlikely that the protracted radiation exposure would havea marked effect on growth, but it is possible. 3) “Could mychild be normal?” There is a greater than 90% chance thatthe child will be normal. This mother told her physiciansthat she was not interrupting the pregnancy. She delivereda 6 lb 11oz boy who was physically healthy after a carefulevaluation.

Patient 2. A 34-year-old pregnant laboratory workerdropped and broke a reaction vessel containing a mixtureof chemical reagents. After cleaning the floor with papertowels, she became concerned about the potential harmfuleffects of the exposure. She was in the sixth week of herpregnancy, which means that the embryo was in the periodof organogenesis. The chemicals in the spill were tetrahydro-furan (70%,) pyridine (20%), and iodine (1%). It was notpossible to estimate the quantitative exposure to the agents,but the laboratory worker experienced no symptoms from theexposure. The pregnancy was planned and wanted. Al-though iodine can interfere with thyroid development, theexposure in this situation would be inconsequential becausethe thyroid gland is not yet present in the fetus. The othertwo compounds have not been evaluated in epidemiologicstudies of pregnant women. No other exposure to reproduc-tive toxins occurred in this pregnancy, and the familyhistory for CMs was negative. The woman was advised thatthis exposure was very unlikely to increase her teratogenicrisk because the exposures to the embryo would be extremelylow. She was also told that she still faced the backgroundrisks for birth defects and miscarriage. Therefore, her repro-ductive risks should be the same as the risks for the generalpopulation. The infant was healthy at birth and weighed3,170 g.

Patient 3. A 26-year-old woman was in an automo-bile crash in her tenth week of pregnancy and sustained asevere concussion. Although she did not convulse postin-jury, the treating neurosurgeon prescribed 300 mg ofdiphenylhydantoin during her first 24 hours in the hos-pital. She recovered from the injury without any se-quelae, but her primary physician was concerned that shehad received an anticonvulsant associated with a tera-

togenic syndrome. No other exposure to reproductivetoxins occurred in this pregnancy, and the family historyfor CMs was negative, except for an uncle who was bornwith neurofibromatosis. The primary physician requesteda consultation about the teratogenic risk. Although di-phenylhydantoin administered chronically throughoutpregnancy has been associated with a low incidence ofcharacteristic facial dysmorphogenesis, reduced menta-tion, cleft palate, and digital hypoplasia, no data indi-cate that 1 day of therapy would cause any of the featuresof this syndrome. Furthermore, the lip and palate havecompleted their development by the 10th week of gesta-tion. The mother chose to continue her wanted pregnancyand delivered a healthy 3,370-g boy at term.

Patient 4. A 25-year-old woman was seen in the emer-gency service of her local hospital because of nausea, vomit-ing, and diarrhea. She had just returned from a cruise onwhich a number of the passengers became ill with similarsymptoms. The emergency department physician ordered apregnancy test followed by a radiograph of the abdomenbecause there was evidence of peritoneal irritation. Resultsof both studies were negative. However, 1 week later, thewoman missed her menstrual period, and 2 weeks later, herpregnancy test was positive. Her obstetrician was concernedbecause she had been exposed to a radiologic procedure at atime when she was pregnant and referred her for counselingafter obtaining ultrasonography that indicated that theembryo was approximately 7 days postconception at the timeof the radiologic examination. The patient advised thecounselor that she was ambivalent about the pregnancybecause of the “dangers” of the radiographs to her embryo.The estimated exposure to the embryo was less than 500mrad (0.005 Sv), which is far below the exposure known toaffect the developing embryo. Further, the embryo was ex-posed during the first 2 weeks postconception (all or noneperiod), a time that is less likely to increase the risk ofteratogenesis, even if the exposure had been much higher.After evaluation of the family history and after she receivedcounseling about the risks of the radiograph, the prospectivemother decided to continue the pregnancy. She delivered a3,150-g healthy baby.

Evaluating the Cause of a CongenitalMalformation

Patient 5. A mother of a 30-year-old man born in theAzores in 1960 who had congenital absence of the rightleg below the knee had pursued compensation for her sonbecause she was certain that she must have receivedthalidomide during her pregnancy. The German man-ufacturer of thalidomide refused compensation, claim-ing that thalidomide had never been distributed in the





Azores. The mother fervently believed that thalidomidewas responsible for her son’s malformations and asked fora further opinion. Review of the radiographs of his hipsand legs and reports of his complete evaluation per-formed at the local hospital in the Azores revealed noother stigmata of thalidomide embryopathy (preaxiallimb defects, phocomelia, facial hemangioma, ear mal-formations, deafness, crocodile tears, ventricular septaldefect, intestinal or gall bladder atresia, kidney malfor-mations). Most importantly, his limb malformationswere not of the thalidomide type. He had a unilateralcongenital amputation, with no digital remnants at theend of the limb. His pelvis girdle was completely normal,which would be unusual in a thalidomide-malformedlimb. Finally, his limb defect involved only one leg; theother leg was completely normal, a finding that is veryunusual in a true thalidomide embryopathy. The youngman had a congenital amputation, probably due tovascular disruption, cause unknown. Known causes ofvascular disruptive malformations are placental emboli,cocaine or misoprostol exposure, and chorionic villoussampling.

Patient 6. A family claimed that the antinausea med-ication bendectin, taken by the mother of a malformed boy,was responsible for her son’s congenital limb reductiondefects. The mother took the medication after the period oflimb organogenesis, but some limb malformations can beproduced by environmental insults later in pregnancy. Themalformation was unaccompanied by any other dysmor-phogenetic effects. The boy’s malformation was the classicsplit-hand, split-foot syndrome, which is inherited domi-nantly. In a significant portion of cases, this malformationis due to a new mutation. Because neither parent mani-fested the malformation, the logical conclusion was thata new mutation had occurred in the sex cell of one of theparents. Therefore, the risk of this malformation occur-ring in the offspring of this boy would be 50%. Bendectinobviously was not responsible for this child’s malforma-tions. In spite of the obvious genetic cause of the mal-formed child’s birth defects, a legal suit was filed, and ajury decided that bendectin was not responsible for thechild’s birth defects.

Patient 7. A woman visited the emergency depart-ment of a university hospital complaining of severe lowerabdominal pain. An obstetric resident saw her becauseshe informed the staff that she had experienced a previousectopic pregnancy that necessitated the removal of oneovary and tube. A pregnancy test was positive, and shewas scheduled to return to the obstetric clinic in 1 week.At that time, her chorionic gonadotropin assessment wasrepeated and had not changed from its previous value.

Without performing ultrasonography, ectopic pregnancywas diagnosed. To preserve the patient’s reproductivepotential, it was decided to treat the ectopic pregnancywith methotrexate rather than remove the remainingtube and ovary. Following the administration of metho-trexate, the patient was sent home, but a laboratoryreport subsequently was received that indicated that thegonadotropin value had increased fivefold; the labora-tory report received earlier in the day was a copy of theoriginal report performed a week earlier. The patientwas called back to the hospital, and ultrasonographyrevealed a normally implanted embryo. The senior ob-stetric staff counseled the mother that the baby was atincreased risk for CMs because of the exposure. Thepatient refused to abort the pregnancy. The obstetricdepartment offered to provide care for the pregnancyand delivery that included serial ultrasonography. At28 weeks’ gestation, the patient went into labor anddelivered a liveborn preterm infant. During infancy,hydrocephalus, developmental delay, and spastic cerebralpalsy were diagnosed. The family filed a lawsuit againstthe doctors and the university hospital. The attorneyrepresenting the child requested an evaluation of theallegation that the child’s abnormalities were due to theadministration of the methotrexate. Methotrexate hasbeen reported to cause growth restriction, microcephaly,developmental delay, and hydrocephalus but not prema-turity. Review of the records revealed that ultrasonogra-phy performed 1 week before the preterm delivery showedno evidence of hydrocephalus and that the birthweightwas appropriate for the gestational stage. The exposure tomethotrexate was not responsible for the serious problemsin this infant; the hydrocephalus and neurologic symp-toms were due to an intracranial hemorrhage in thepostnatal period as a complication of the prematurity.

As these case reports indicate, determining the repro-ductive risks of an exposure during pregnancy or thecause of a child’s CM is not a simple process. It involvesa careful analysis of the medical and scientific literaturepertaining to the reproductive toxic effects of exogenousagents in humans and animals as well as an evaluation ofthe exposure and biologic plausibility of an increased riskor a causal connection between the exposure and achild’s CM. Evaluation must include a careful physicalexamination in addition to a review of the scientificliterature pertaining to genetic and environmental causesof the malformations in question. Abridged counseling,based on superficial and incomplete analyses, is a disser-vice to the family.




References1. Tijo JH, Levan A. The chromosome number of man. Hereditas.1956;42:1–62. Gregg NM. Congenital cataract following German measles inthe mother. Trans Ophthalmol Soc Aust. 1941;3:35–463. Thiersch JB. Therapeutic abortions with a folic acid antagonist,

4-aminopteroylglutamic acid (4-amino P.G.A.) administered by theoral route. Am J Obstet Gynecol. 1952;63:1298–13044. Warkany J, Beautry PH, Horstein S. Attempted abortion withaminopterin (4-aminopteroylglutamic acid). Am J Dis Child. 1959;97:274–2815. Wilson JG. Environment and Birth Defects. New York. NY:Academic Press; 19736. Brent RL, Beckman DA. Prescribed drugs, therapeutic agents,and fetal teratogenesis. In: Reese EA, Hobbins JC, eds. Medicine ofthe Fetus and Mother. 2nd ed. Philadelphia, PA: Lippincott-RavenPublishers; 1999:289–3137. Brent RL. The pediatrician’s role in dealing with these complexclinical problems caused by a multiplicity of environmental andgenetic factors. Pediatrics. 2004;113:957–9688. Brent RL. Ionizing radiation. In: Queenan JT, Hobbins JC,Spong CY, eds. Protocols in High Risk Pregnancy. 5th ed. Oxford,UK: Blackwell Publishing Ltd: 2010:21–329. Beckman DA, Fawcett LB, Brent RL. Developmental toxicity.In: Massaro EJ, ed. Handbook of Human Toxicology. New York, NY:CRC Press; 1997:1007–108410. McKusick VA. Mendelian Inheritance in Man: Catalogs ofAutosomal Dominant, Autosomal Recessive, and X-linked Phento-types. Edition 1. Baltimore, MD: Johns Hopkins University Press;196611. OMIM. Online Mendalian Inheritance of Man. Accessed April2011 at: http://www.ncbi.nlm.nih.gov/omim12. Human Genome Project. Accessed April 2011 at: www.genomics.energy.gov13. Brent RL. The complexities of solving the problem of humanmalformations. In: Sever JL, Brent RL, eds. Teratogen Update:Environmentally Induced Birth Defect Risks. New York, NY: Alan R.Liss; 1986:189–19714. Brent RL. Environmental causes of human congenital malfor-mations: the physician’s role in dealing with these complex clinicalproblems caused by environmental and genetic factors. In: Studd J,Tan SL, Chervenak FA, eds. Progress in Obstetrics and Gynecology18. Edinburgh, Scotland: Elsevier Ltd; 2008:61–8415. Brent RL, Oakley GP Jr, Mattison DR. The unnecessaryepidemic of folic acid–preventable spina bifida and anencephaly.Pediatrics. 2000;106:825–82716. Jones KL. Smith’s Recognizable Patterns of Human Malforma-tions. 5th edition. Philadelphia, PA: WB Saunders Co; 199417. TERIS. Accessed April 2011 at: http://apps.medical.washington.edu/teris/teris1a.aspx18. Aase JM. Diagnostic Dysmorphology. New York, NY: PlenumMedical Book Co; 199019. Miller RW. Effects of prenatal exposure to ionizing radiation.Health Physics. 1990;59:57–6120. Miller RW. Discussion: Severe mental retardation and canceramong atomic bomb survivors exposed in utero. National Councilon Radiation Protection and Measurements Bethesda, MD. Tera-tology. 1999;59:234–23521. Miller RW, Mulvihill JJ. Small head size after atomic irradia-tion. Teratology. 1976;14:355–35822. Otake M, Schull WJ. In utero exposure to A-bomb radiationand mental retardation: a reassessment. Br J Radiol. 1984;57:409–41423. Rugh R, Duhamel L, Skaredoff L. Relation of embryonic andfetal X-irradiation to life-time average weights and tumor incidencein mice. Proc Soc Exp Biol Med. 1966;121:714–718

Summary• The development of new knowledge and new

diagnostic techniques and technology as well as thesophistication of epidemiology studies andmaturation of the fields of clinical genetics andclinical teratology have revolutionized the field ofreproductive and developmental biology.

• Advances have enabled physicians and scientists todetermine the causes of developmentalabnormalities and, therefore, discover methods ofprevention. The process of evaluation is based onthe knowledge base developed over the past 50years.

• Although genetic abnormalities are responsible for asignificant proportion of reproductive anddevelopmental deleterious effects, a largerproportion of these effects are due to unknowncauses.

• Environmental causes are less frequent, althoughmany of the environmental effects as well as manyof the genetic effects can be prevented throughgenetic counseling and preconceptual planning.Effective treatment and amelioration ofdevelopmental effects also have improved.

• More than 50 environmental drugs, chemicals,maternal diseases, infections, nutritionalabnormalities, and physical agents can affectreproduction deleteriously and result in CMs.Theoretically, all these causes are preventable.

• Throughout the developing world, the addition offolic acid and iodine could prevent tens ofthousands of birth defects and developmentalabnormalities.

• In the United States, the opportunity for preventioncan be introduced at the population level and byaddressing individual patients’ clinical problems.

• If a mother of a malformed infant had some type ofexposure during pregnancy, such as a diagnosticradiologic examination or medication, the consultingphysician should not support or suggest thepossibility of a causal relationship before performinga complete evaluation. If a pregnant woman whohas not yet delivered had some type of exposureduring pregnancy, the consulting physician shouldnot support or suggest the possibility that the fetusis at increased risk before performing a completeevaluation. (11)(25)(26)(27)(28)(29)(30)

• Every patient deserves a complete, scholarlyevaluation that uses the basic principles ofteratology and risk analysis. (13)(14)24)





24. Brent RL. Congenital malformation case reports: the editor’sand reviewer’s dilemma. Am J Med Genet. 1993;47:872–87425. Friedman JM, Polifka JE. Teratogenic Effects of Drugs: A Re-source for Physicians. 2nd ed. Baltimore, MD: Johns Hopkins Uni-versity Press; 2000:79326. Scialli AR, Lione A, Padget GKB, eds. Reproductive Effects ofChemical, Physical and Biologic Agents; Reprotox. Baltimore, MD:The Johns Hopkins University Press; 199527. Sever JL, Brent RL, eds. Teratogen Update: EnvironmentallyInduced Birth Defect Risks, New York, NY: Alan R. Liss; 1986:1–24828. Shepard TH. Catalogue of Teratogenic Agents. 8th ed. Balti-more, MD: The Johns Hopkins University Press; 1995 (now onTERIS web site)29. Schardein JL. Chemically Induced Birth Defects. 3rd ed. NewYork, NY: Marcel Dekker, Inc; 200030. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy andLactation. 3rd ed. Baltimore, MD: Williams & Wilkins;. 1990;502–50831. Brent RL. The irresponsible expert witness: a failure of bio-medical graduate education and professional accountability. Pedi-atrics. 1982;70:754–76232. Centers for Disease Control and Prevention. Pregnancy. Ac-cessed April 2011 at: www.cdc.gov/pregnancy33. Adetokunbo L, Stoll B, Alisjahbana A, et al. Reducing birthdefects: meeting the challenge in the developing world. ConsensusReport of the Institute of Medicine (IOM) of the National Academy ofSciences. November 4, 200334. Smithells RW, Sheppard S, Schorah CJ, et al. Apparent preven-tion of neural tube defects by periconceptional vitamin supplemen-tation. Arch Dis Child. 1981;56:911–91835. MRC Vitamin Study Research Group. Prevention of neuraltube defects: results of the Medical Research Council VitaminStudy. Lancet. 1991;338:131–137

36. Oakley GP Jr. Let’s increase folic acid fortification and includevitamin B-12. Am J Clin Nutr. 1997;65:1889–189037. Berry RJ, Li Z, Erickson JD, et al. Prevention of neural tubedefects with folic acid in China. China-U.S. Collaborative Projectfor Neural Tube Defect Prevention. N Engl J Med. 1999;341:1485–149038. Brent RL, Oakley GP Jr. Commentary: triumph and/or trag-edy: the present FDA program of enriching grains with folic acid.Pediatrics. 2006;117:930–93239. Brent RL, Oakley GP Jr. Further efforts to reduce the inci-dence of neural tube defects [letter to the editor]. Pediatrics.2007;119:225–22640. Johnston R Jr. Will increasing folic acid in fortified grainproducts further reduce neural tube defects without causing harm?:consideration of the evidence. Pediatr Res. 2008;63:2–841. Zimmerman, MB. Research on iodine deficiency and goiter inthe 19th and early 20th centuries. J Nutr. 2008;138:2060–206342. Santiago-Fernandez P, Torres-Barahona R, Muela-Martinez JA, et al. Intelligence quotient and iodine intake: across-sectional study in children. J Clin Endocrinol Metab. 2004;89:3851–385743. Zimmerman MB, Wegmuller R, Zeder C, Chaouki N, Torre-sani T. Rapid relapse of thyroid dysfunction and goiter in school-age children after discontinuation of salt iodization. Am J ClinNutr. 2004;79:642–64544. Leung AM, Pearce EN, Braverman LE. Iodine content ofprenatal multivitamins in the United States. N Engl J Med. 2009;360:939–94045. Cocchi G, Gualdi S, Bower C, et al. International trends ofDown syndrome 1993–2004: births in relation to maternal age andterminations of pregnancies. Birth Defects Res (Part A). 2010;88:474–479




PIR QuizQuiz also available online at http://pedsinreview.aappublications.org.NOTE: Beginning in January 2012, learners will only be able to take Pediatrics in Review quizzes and claim creditonline. No paper answer form will be printed in the journal.

1. One of the principal advances in teratology over the past five decades is the discovery that:

A. Exposure to teratogenic agents late in the second trimester may mar fetal development.B. Most congenital malformations can be explained by exposure to teratogens.C. Teratogenic syndromes cannot be confused with genetic mimics.D. The effects of exposure to a teratogenic are independent of timing.E. The effects of teratogenic agents are independent of dose.

2. Which of the following is a drug that has established teratogenic potential?

A. Amlodipine.B. Clonidine.C. Hydrochlorothiazide.D. Misoprostrol.E. Metoproterenol.

3. Neural tube defects can be prevented best by assuring adequate folic acid and vitamin B-12 intake:

A. Before pregnancy.B. In pregnant women who have a family history of neural tube defects.C. No later than the beginning of the second trimester.D. Throughout the third trimester.E. Upon diagnosis of pregnancy.

4. A fetus was exposed to radiation via radiotherapy of the mother’s breast cancer over a 5-week periodbeginning at the 8th week of gestation. The infant at term is most likely to be:

A. Deformed.B. Large for age but otherwise normal.C. Malformed.D. Normal in all respects.E. Small for age but otherwise normal.

5. An embryo was exposed at 7 days of gestation to radiation when the mother received a single abdominalflat plate radiographic study to evaluate severe abdominal tenderness. The infant at term is most likely tobe:

A. Deformed.B. Large for age but otherwise normal.C. Malformed.D. Normal in all respects.E. Small for age but otherwise normal.





The following material is available online only for “The Role of the Pediatrician in Preventing Congenital Malforma-tions.”

Things You Need To Know About Birth Defects

4. Did you know that some birth defects can be diagnosed before birth?

Fact: Tests like an ultrasound and amniocentesis can detect birth defects such as spina bifida, heart defects, or Down syndrome before a baby is born. Prenatal care and screening are important because early diagnosis allows families to make decisions and plan for the future.

5. Did you know that birth defects can greatly affect the finances not only of the families involved, but of everyone?

Fact: In the United States, birth defects have accounted for over 139,000 hospital stays during a single year, resulting in $2.5 billion in hospital costs alone. Families and the government share the burden of these costs. Additional costs due to lost wages or

occupational limitations can affect families as well.

1. Did you know that birth defects are common?

Fact: Birth defects affect 1 in 33 babies every year and cause 1 in 5 infant deaths. For many babies born with a birth defect, there is no family history of the condition.

2. Did you know that a woman should take folic acid during her teens and throughout her life?

Fact: Because half of all pregnancies in the United States are not planned, all women who can become pregnant should take a vitamin with folic acid every day. Folic acid helps a baby’s brain and spine develop very early in the first month of pregnancy when a woman might not know she is pregnant.

3. Did you know that many birth defects are diagnosed after a baby leaves the hospital?

Fact: Many birth defects are not found immediately at birth. A birth defect can affect how the body looks, how it works, or both. Some birth defects like cleft lip or spina bifida are easy to see. Others, like heart defects, are not.

Thiings You NThii Y




6. Did you know that birth defects can be caused by many different things, not just genetics?

Fact: The cause of most birth defects is unknown. Use of cigarettes, alcohol, and other drugs, taking of some medicines; and exposure to chemicals and infectious diseases during pregnancy have been linked to birth defects. Researchers are studying the role of these factors, as well as genetics, as causes of birth defects.

7. Did you know that some birth defects can be prevented?

Fact: A woman can take some important steps before and during pregnancy to help prevent birth defects. She can take folic acid; have regular medical checkups; make sure medical conditions, such as diabetes, are under control; have tests for infectious diseases and get necessary vaccinations; and not use cigarettes, alcohol, or other drugs.

8. Did you know there are ways a pregnant woman can keep her unborn baby safe from infections?

Fact: The best way to keep an unborn baby safe from infections is for a pregnant woman to wash her hands often, especially after using the bathroom; touching raw meat, uncooked eggs, or unwashed vegetables; handling pets; gardening; or caring for small children.

To find out more about birth defects and healthy pregnancies, please visit the Centers for Disease Control and Prevention website

www.cdc. gov/pregnancy or call your state or local health department.

This fact sheet was developed in partnership with the National Birth Defects Prevention Network (NBDPN).

9. Did you know there is no known safe amount of alcohol or safe time to drink during pregnancy?

Fact: Fetal alcohol spectrum disorders (FASDs) are a group of conditions that can occur in a person whose mother drank alcohol during pregnancy. These ef-fects can include physical problems and problems with behavior and learning which can last a lifetime. There is no known safe amount, no safe time, and no safe type of alcohol to drink during pregnancy. FASDs are 100% preventable if a woman does not drink alcohol while pregnant.

10. Did you know that an unborn child is not always protected from the outside world?

Fact: The placenta, which attaches a baby to the mother, is not a strong

barrier. When a mother uses cigarettes, alcohol, or other drugs, or is exposed to infectious diseases, her baby is exposed also. Healthy habits like

taking folic acid daily and eating nutritious foods can help ensure

that a child is born healthy.




Group A Streptococcal InfectionsDebra M. Langlois, MD*,

Margie Andreae, MD*

Author Disclosure

Drs Langlois and

Andreae have

disclosed no financial



commentary does not


of an unapproved/


commercial

product/device.


1. Discuss the symptoms and signs that help differentiate group A streptococcal pharyn-gitis from viral pharyngitis.

2. Review the recommended diagnostic evaluation and antibiotic treatment regimens forgroup A streptococcal pharyngitis.

3. Recognize the clinical manifestations of group A streptococcal skin infections.4. Describe the nonsuppurative and suppurative complications of group A streptococcal

infections.5. Know the Jones criteria for the diagnosis of acute rheumatic fever and the diagnostic

criteria for streptococcal toxic shock syndrome.

IntroductionGroup A Streptococcus (GAS) is a gram-positive bacterium that grows in pairs or chains andcauses complete, or �-hemolysis when cultured on sheep blood agar. GAS cause a broadspectrum of disease, from primary upper respiratory tract and skin infections to secondarycomplications such as acute rheumatic fever (ARF) and glomerulonephritis, as well assevere invasive illness, including toxic shock syndrome (TSS) and necrotizing fasciitis,which may involve almost every organ system. Despite the beneficial effects of antibiotics,clinicians continue to encounter GAS disease frequently in practice.

PharyngitisGAS pharyngitis, the most common GAS infection, occurs most often in school-age childrenand accounts for 15% to 30% of all cases of pharyngitis in this age group, with the peakincidence seen during winter and early spring. Transmission results from contact with infectedrespiratory tract secretions and is facilitated by close contact in schools and child care centers.The rate of GAS transmission from an infectious case to close contacts is approximately 35%.The incubation period for GAS pharyngitis is 2 to 4 days. Although one specific symptom or

sign cannot distinguish GAS infection from other causes ofpharyngitis, comparison of composite features may help differ-entiate GAS pharyngitis from viral pharyngitis (Table 1). Typi-cal findings in GAS pharyngitis include sore throat, fever, head-ache, abdominal pain, nausea, vomiting, pharyngeal erythema,palatal petechiae, inflammation of the uvula, and anterior cer-vical lymphadenopathy. Scarlet fever, characterized by a diffuse,erythematous, blanching, fine papular rash that resembles sand-paper on palpation, is another manifestation of GAS infection.Scarlet fever is caused by erythrogenic toxin-producing strainsof GAS and may manifest desquamation after the rash starts tofade. Exudative pharyngitis may occur, but this finding also iscommon with viral pharyngitis. In children younger than 3years, an atypical symptom complex known as streptococcosismay occur, consisting of persistent nasal congestion, rhinor-rhea, low-grade fever, and anterior cervical lymphadenopathy.In infants, the only symptoms may be low-grade fever, fussiness,and decreased feeding.

*Division of General Pediatrics, Department of Pediatrics and Communicable Diseases, University of Michigan Medical School,Ann Arbor, MI.

Abbreviations

ARF: acute rheumatic feverGAS: group A StreptococcusIGIV: immune globulin intravenousIV: intravenousNSAID: nonsteroidal anti-inflammatory drugOCD: obsessive compulsive disorderPANDAS: pediatric autoimmune neuropsychiatric

disorder associated with group A streptococciPSGN: poststreptococcal glomerulonephritisPSRA: poststreptococcal reactive arthritisRADT: rapid antigen detection testSSRI: selective serotonin reuptake inhibitorTSS: toxic shock syndrome

Article infectious diseases



Diagnosis of acute GAS pharyngitis requires microbio-logic testing. The decision to test should take into consid-eration patient age, clinical symptoms and signs, time ofyear, and exposure to sick contacts who have confirmedGAS infection. Testing for GAS pharyngitis, therefore, isrecommended for the following patients who have symp-toms suggestive of GAS: those who do not have symptomsor signs of viral infection, those exposed to diagnosed GASinfection, and those who are ill when there is a high preva-lence of GAS infection in the community. Of note, testingof asymptomatic contacts in homes, child care centers, orschools is not indicated unless the contact is at increased riskof developing complications from GAS infection.

Microbiologic testing includes the rapid antigen detec-tion test (RADT) and throat culture. Throat culture is thegold standard, with 90% to 95% sensitivity. RADT is sug-gested for initial use in patients who are likely to have GASpharyngitis and in those whose throat culture results willnot be available for more than 48 hours. RADT has aspecificity of 95% and greater and a sensitivity of 65% to90%. If RADT is negative, a back-up throat culture shouldbe performed. Anecdotal evidence indicates that the RADTmay remain positive for “a week or so” after a 10-daytreatment course, despite a bacteriologic cure.

Serologic testing may be used to confirm GAS pharyn-gitis. However, because this antibody response occurs 2 to3 weeks after the onset of infection, it is not useful for thediagnosis of acute GAS pharyngitis. Serologic testing con-sists of measurements of antistreptococcal antibody titers,such as antistreptolysin O and antideoxyribonuclease B, and

may be useful in identifying the cause of conditions thatmay occur as complications of GAS infection.

Treatment of GAS pharyngitis has several goals: reduc-ing the incidence of suppurative and nonsuppurative com-plications, reducing the duration and relieving symptomsand signs of infection, and reducing transmission to others.Oral penicillin V K (250 mg to 500 mg twice to three timesa day for 10 d) is the antibiotic treatment of choice for GASpharyngitis because of its efficacy, safety, and narrow spec-trum. No GAS isolate to date has shown penicillin resis-tance. For patients who cannot swallow pills, amoxicillin(50 mg/kg, maximum 1 g, once daily for 10 d) often isused instead of oral penicillin because of its more palatableliquid formulation. Cephalosporins or macrolides may beused as first-line therapy in patients allergic to �-lactamantibiotics but otherwise are not recommended as first-linetherapy. A 5-day course of the cephalosporins cefpodoximeor cefdinir or the macrolide azithromycin at a higher dose(12 mg/kg per day) is comparable in terms of clinical andbacteriologic cures to a typical 10-day course of penicillin(Table 2).

For patients who experience recurrent acute pharyngitisand positive repeat diagnostic test results shortly after treat-ment, the same oral drug can be administered or an intra-muscular injection of penicillin G benzathine can be pro-vided if poor adherence is suspected. Alternative choicesinclude a narrow-spectrum cephalosporin, amoxicillin-clavulanate, clindamycin, erythromycin, clarithromycin, oran azalide such as azithromycin. There is no expert consen-sus on this issue.

Patients who have multiple recurrent episodes may rep-resent a carrier state. Pharyngitis in carriers is likely due tointercurrent viral infection, but if a GAS carrier develops anacute illness consistent with GAS pharyngitis, treatment isindicated. It is estimated that up to 20% of asymptomaticschool-age children may be GAS carriers.

Chronic carriers are unlikely to transmit infection tocontacts and are at low risk for developing complications ofGAS. Diagnosis of GAS carriage should take into consider-ation whether signs and symptoms of recurrent illness aremore suggestive of a viral cause, the prevalence of GAScurrently in the community, the patient’s response to anti-biotic therapy, and throat culture results when the patient isasymptomatic. Treatment to eradicate GAS carriage may beconsidered for patients who have a history of acute rheu-matic fever or a close contact who has a history of rheumaticfever, for families experiencing repeated episodes of GASpharyngitis, and for patients who are carriers when there isan outbreak of serious GAS infections in their community.

Eradication regimens include clindamycin, cephalospo-rins, amoxicillin-clavulanate (45 mg/kg per dose of the

Table 1. Differential Features ofGroup A Streptococcus (GAS)and Viral Pharyngitis

Findings Suggestive ofGAS Infection

Findings Suggestive ofViral Infection

SymptomsSore throat CoughDysphagia Runny noseFever Hoarse voiceHeadache DiarrheaAbdominal painNauseaVomitingSignsSoft palate petechiae StomatitisAnterior cervical

lymphadenopathyConjunctivitis

Scarlet fever rash

infectious diseases group A Streptococcus




amoxicillin component twice a day), azithromycin, or pen-icillin plus rifampin (10 to 20 mg/kg per day, maximum600 mg/d, administered once daily or divided twice a dayfor the last 4 d of the penicillin treatment course). The mosteffective treatment regimen for eradicating streptococcalcarriage is reported to be a 10-day course of clindamycin at20 mg/kg per day in 3 doses (maximum 1.8 g/d).

Indications for tonsillectomy include more than sevendocumented GAS infections in 1 year or more than fiveepisodes in each of the preceding 2 consecutive years.Because the incidence of streptococcal pharyngitis declineswith age, the potential benefits of tonsillectomy must bebalanced against the risks and cost of surgery.

Skin InfectionsSkin is the second most common site of GAS infection. Thelocation of the infection and the inflammatory responsedetermine the clinical picture, which ranges from superficialimpetigo to the more severe suppurative complication ofnecrotizing fasciitis. In general, the characteristic features ofGAS skin infection are profuse edema, rapid spread throughtissue planes, and dissemination through lymphatic or he-matogenous routes.

ImpetigoGAS impetigo is a superficial skin infection that begins withacquisition of GAS on healthy skin (usually from closecontacts whose skin was colonized or infected with GAS)and leads to development of skin infection at sites of minortrauma, such as abrasions, lacerations, insect bites, andburns. The incubation period for GAS impetigo is 7 to10 days. GAS impetigo initially appears as a discrete papu-lovesicular lesion surrounded by localized erythema. As theinfection evolves, the lesion becomes purulent and coveredwith an amber-colored crust. Diagnosis is clinical and usu-

ally straightforward at the stage of crusting. Cultures oflesions are not indicated routinely because they often yieldboth streptococci and staphylococci. Treatment for local-ized disease consists of topical mupirocin or retapamulin.Multiple localized lesions may require systemic treatmentthat covers both GAS and staphylococcal infections, such ascephalexin or clindamycin.

ErysipelasErysipelas is a superficial cellulitis caused by GAS that isconfined to the lymphatics and subcutaneous tissues. Ery-sipelas occurs most commonly in infants and young chil-dren. The source of GAS commonly is the upper respiratorytract of the patient or a close contact. The head and face areinvolved most often, although the neonate may developperiumbilical infection (omphalitis). Lesions are character-ized by erythema and edema, with a sharply defined andelevated border tender to palpation. Systemic signs such asfever often are present. Lymphangitis may occur. Diagnosisis primarily clinical. Treatment consists of systemic antibi-otic therapy; parenteral antibiotics may be needed, espe-cially in immunocompromised patients.

CellulitisGAS cellulitis involves the deeper subcutaneous tissues andmay appear anywhere on the body, including the perianalarea. History of a preceding skin lesion or skin trauma iscommon. Cellulitis is characterized by erythematous andedematous skin with poorly defined margins that is tenderto palpation. Systemic signs such as fever often are present.Lymphangitis may occur. Diagnosis is clinical, althoughGAS can be isolated readily from the perianal skin in peri-anal infection. Treatment consists of systemic antibiotictherapy; parenteral antibiotics may be needed if there is aninadequate response to oral antibiotics.

Table 2. Treatment of Group A Streptococcal PharyngitisAntibiotic Dose Duration

Penicillin V K 250 mg bid or tid if <27 kg (60 lb); 500 mg bid or tid if >27 kg (60 lb) 10 dAmoxicillin 50 mg/kg, maximum 1 g, once daily 10 dBenzathine penicillin G 600,000 U if <27 kg (60 lb); 1,200,000 U if >27 kg (60 lb) Single doseFor penicillin-allergic patients:Cephalexin 25 to 50 mg/kg per day divided bid; maximum 1 g/d 10 dCefpodoxime 5 mg/kg, maximum 100 mg, bid 5 dCefdinir 7 mg/kg bid, maximum 600 mg/d 5 dClindamycin 20 mg/kg per day divided tid; maximum 1.8 g/d 10 dAzithromycin 12 mg/kg, maximum 500 mg, once daily 5 dClarithromycin 15 mg/kg per day divided bid; maximum 250 mg/dose 10 d

bid�twice a day, tid�three times a dayAll doses are for oral administration, except for benzathine penicillin G, which is administered intramuscularly.




Streptococcal Nonsuppurative ComplicationsRheumatic Fever

ARF is caused by previous GAS pharyngeal infection, with alatent period of 2 to 4 weeks. The disorder is most commonamong children ages 5 to 15 years. Currently, most cases ofARF occur in developing countries, a distribution that isbelieved to be due to improved hygiene and routine use ofantibiotics for GAS pharyngitis in developed countries.

ARF presents as an acute febrile illness, with clinicalmanifestations that include arthritis, carditis or valvulitis,skin lesions, and neurologic disturbances. The arthritis,occurring in 75% of patients who have ARF, is a migratorypolyarthritis, affecting several joints in rapid succession,most commonly larger joints. Synovial fluid analysis ofinvolved joints displays sterile inflammation. Treatmentwith nonsteroidal anti-inflammatory drugs (NSAIDs) orsalicylates may lead to resolution, potentially blunting themigratory feature; thus, monoarticular arthritis may occur.The relationship between poststreptococcal reactive arthri-tis (PSRA), a migratory arthritis that occurs after a strepto-coccal infection, and ARF is debated. Some speculate this isa separate disorder; others think PSRA is part of the clinicalspectrum of ARF.

The carditis of ARF is a pancarditis that occurs in 50%of patients. Symptoms and signs include chest pain,pericardial friction rub or murmur on auscultation, andheart failure. Varying degrees of heart block may be seenon electrocardiography, and cardiomegaly may be notedon chest radiographs. Echocardiography may show avariety of findings, including valvular regurgitation orstenosis, chamber enlargement or dysfunction, and peri-cardial effusion. Rheumatic heart disease is the mostserious complication of ARF, consisting of inflammationof the valves and endocardium, which leads to valvularinsufficiency or stenosis. The mitral valve is involvedmost commonly, followed by the aortic valve; right-sidedvalvular lesions are rare. Rheumatic heart disease mayoccur up to 20 years after the onset of ARF, making thediagnosis difficult in the absence of other acute features.

Skin findings, which tend to occur only in patientswho have carditis, consist of subcutaneous nodules anderythema marginatum. The firm, painless, noninflamma-tory subcutaneous nodules, typically located over bonyprominences or near tendons, may be present for up to 1month. Erythema marginatum, also known as erythemaannulare, is an evanescent, nonpruritic, rapidly advanc-ing, pink-to-slightly red rash that typically is found onthe trunk or proximal limbs and spares the face.

Central nervous system involvement in ARF manifestsas Sydenham chorea, which consists of abrupt, purpose-less, nonrhythmic involuntary movements that ceaseduring sleep; muscular weakness; and emotional distur-bances that range from outbursts of inappropriate behav-iors to transient psychosis. Sydenham chorea can occur aslate as 8 months after GAS infection and usually resolvescompletely but occasionally lasts 2 to 3 years.

The diagnosis of ARF is based on the Jones criteria(Table 3), which were published initially in 1944 andlater revised by Jones and subsequently the AmericanHeart Association, with the most recent revision pub-lished in 2002. Diagnosis requires evidence of a preced-ing GAS infection along with the presence of two majormanifestations or one major and two minor manifesta-tions. The rate of isolation of GAS from the oropharyn-ges of patients who have ARF is only between 10% and20%. Therefore, serologic testing, which demonstrateseither elevated antibody titers or rising titers with serialtesting, is used more often for confirmation of infection.The streptozyme test measures five streptococcal anti-bodies: antistreptolysin O (ASO), antihyaluronidase(AHase), antistreptokinase (ASKase), antinicotinamide-adenine dinucleotidase (anti-NAD), and antideoxyribo-nuclease B (anti-DNase B) antibodies.

Treatment of ARF focuses on eradication of GAS,relief of acute disease manifestations, and prophylaxisagainst future GAS infection to prevent recurrent ARF.Eradication of GAS requires the same antibiotic regi-mens that are used to treat GAS pharyngitis. In addition,

Table 3. Jones Criteria for the Diagnosis of Acute Rheumatic FeverDiagnosis: Requires 2 major criteria or 1 major and 2 minor criteria plus evidence of recent group A streptococcal infection

Major Criteria Minor Criteria Evidence of Recent GAS Infection

Carditis Fever Positive throat culture or RADTPolyarthritis Arthralgia ORChorea Elevated acute-phase reactants Elevated or rising antistreptococcal antibody titersErythema marginatum Prolonged PR intervalSubcutaneous nodules

RADT�rapid antigen detection test





household contacts should have throat cultures per-formed and be treated if the cultures are positive forGAS. Aspirin, administered at 80 to 100 mg/kg per dayand continued until all symptoms have resolved, is themajor anti-inflammatory agent used for symptom relief.Carditis is managed with therapies used for heart failure.Valve repair or replacement is indicated when heart fail-ure due to valvular lesions cannot be managed withmedical therapy alone. Because patients who have ahistory of ARF are at high risk for recurrent ARF withsubsequent GAS pharyngitis infections, antimicrobialprophylaxis is indicated. Prophylactic antibiotics shouldbe started immediately after the therapeutic antibioticcourse is complete. Options for prophylaxis include pen-icillin V K, sulfadiazine, or macrolides for patients atlower risk of ARF recurrence and benzathine penicillin Gintramuscularly every 4 weeks for patients at higher riskof ARF recurrence. Prophylaxis should continue for sev-eral years, typically until a patient is an adult andrecurrence-free for 10 years; longer prophylaxis is indi-cated if the patient has residual heart disease.

Poststreptococcal GlomerulonephritisPoststreptococcal glomerulonephritis (PSGN) is themost common cause of acute nephritis worldwide.PSGN is caused by previous throat or skin infection withnephritogenic strains of GAS. Although the exact mech-anism is unclear, antigens of nephritogenic streptococciare believed to induce immune complex formation in thekidneys. The latent period is 1 to 3 weeks following GASpharyngitis and 3 to 6 weeks following GAS skin infec-tion. Deposition of GAS nephritogenic antigens withinthe glomerular subendothelium leads to glomerular im-mune complex formation, which triggers complementactivation and subsequent inflammation; depositionwithin the glomerular subepithelium leads to epithelialcell damage and subsequent proteinuria.

The clinical presentation of PSGN ranges fromasymptomatic microscopic hematuria to a nephritic syn-drome consisting of hematuria, proteinuria, edema, hy-pertension, and elevated serum creatinine values. Grosshematuria is present in up to 50% of patients. Edemaoccurs because of sodium and fluid retention, which maylead to secondary hypertension. Decreased glomerularfiltration rate results in increased serum creatinine con-centration; acute renal failure requiring dialysis is possi-ble. Urinalysis shows hematuria with or without redblood cell casts, proteinuria, and often pyuria. Serum C3complement values are low due to activation of the alterna-tive complement pathway, and C4 and C2 values are nor-mal to mildly decreased. Throat or skin cultures often are

negative at the time of diagnosis, given the latent periodfrom onset of infection to onset of nephritis.

Diagnosis requires clinical findings of acute nephritis inthe setting of a recent GAS infection. If throat or skincultures are negative, confirmation of a recent GAS infec-tion may be obtained through serologic testing. Low C3 ischaracteristic of, but not specific to, PSGN. Renal biopsytypically is not performed to confirm the diagnosis ofPSGN.

Treatment for PSGN focuses on supportive manage-ment of the clinical manifestations. Loop diuretics suchas furosemide may be prescribed for the hypertensionand edema in addition to sodium and water restriction.Hypertensive urgencies and emergencies, although un-common, require immediate attention. Some patientsrequire dialysis during their acute illness because of thereduction in renal function. Evidence of persistent GASinfection requires antibiotic treatment.

The clinical manifestations of PSGN typically resolvequickly. Diuresis usually begins within 1 week, withserum creatinine concentrations returning to baseline by3 to 4 weeks and hematuria resolving within 3 to 6months. Proteinuria starts to resolve as the patient recov-ers, but at a slower rate, and may persist for up to 3 years.Failure to treat the primary infection, if persistent, maydelay recovery. The prognosis for most children whohave PSGN is excellent. Although rare, recurrent pro-teinuria, hypertension, and renal insufficiency may de-velop up to several years after the initial illness.

Streptococcal Toxic Shock SyndromeGAS TSS is a form of invasive GAS disease associatedwith the acute onset of shock and organ failure. InvasiveGAS disease is defined as isolation of GAS from a nor-mally sterile body site. Another form of invasive GASdisease is necrotizing fasciitis. Risk factors for the devel-opment of invasive GAS infections include injuries result-ing in bruising or muscle strain, surgical procedures, viralinfections including varicella, and use of NSAIDs.

The pathogenesis of GAS TSS is believed to be mediatedby streptococcal exotoxins that act as superantigens, whichactivate the immune system. The resultant release of cyto-kines causes capillary leak, leading to hypotension and or-gan damage.

GAS TSS typically presents with fever and the abruptonset of severe pain, often associated with a precedingsoft-tissue infection such as cellulitis. GAS TSS also maypresent in association with other invasive GAS diseasessuch as necrotizing fasciitis, bacteremia, pneumonia, os-teomyelitis, myositis, or endocarditis. However, casesmay present with no identified focus of infection. Pa-




tients may be normotensive initially, but hypotensiondevelops quickly. Erythroderma, a generalized erythem-atous macular rash, may occur. Laboratory findings in-clude leukocytosis with immature neutrophils, elevatedserum creatinine values, hypoalbuminemia, hypocalce-mia, increased creatine kinase concentration, myoglobin-uria, hemoglobinuria, and positive blood cultures.

Diagnosis of GAS TSS requires isolation of GAS froma normally sterile body site such as blood, cerebrospinalfluid, pleural fluid, peritoneal fluid, or a surgical woundin the presence of hypotension plus two or more addi-tional signs (Table 4). Probable GAS TSS may be diag-nosed when GAS is isolated from a nonsterile site such asthroat, skin, or vagina and the other criteria are fulfilled.

Treatment for GAS TSS includes hemodynamic sup-port, surgical therapy, antibiotic therapy, and manage-ment of multiorgan system failure, including respiratoryfailure and cardiac failure. Aggressive fluid replacement isessential to maintain adequate perfusion to prevent end-organ damage; vasopressors also may be required. Imme-diate surgical exploration and debridement is necessary,and repeated resections may be required. Empiric ther-apy with broad-spectrum intravenous (IV) antibiotics tocover both streptococcal and staphylococcal infections isrecommended pending identification of GAS. Once GAShas been identified, antibiotic therapy with clindamycinIV (13 mg/kg, maximum 600 mg, every 8 h) pluspenicillin G IV (300,000 U/kg per day divided every4 to 6 h) may be continued. The duration of antibiotictherapy depends on the clinical course. In general, anti-biotics should be continued for a minimum of 14 days inpatients who have bacteremia and for 14 days after the

last positive culture obtained during surgical debride-ment for patients who have deep soft-tissue infections.Of note, immune globulin intravenous (IGIV) also maybe used as adjunctive therapy.

Pediatric Autoimmune NeuropsychiatricDisorder Associated With GroupA Streptococci

Pediatric autoimmune neuropsychiatric disorder associatedwith group A streptococci (PANDAS) describes a group ofneuropsychiatric disorders, in particular obsessive compul-sive disorder (OCD), tic disorders, and Tourette syndrome,that are exacerbated by GAS infection. GAS infection in asusceptible host is believed to lead to an abnormal immuneresponse, with production of autoimmune antibodies thatcrossreact with brain tissue, which leads to central nervoussystem manifestations. This proposed association is contro-versial, with uncertainty focused on whether the associationis causal or incidental, given the rates of GAS infection andGAS carriage and the frequency of OCD and tic disorders inchildren.

The clinical course is characterized by abrupt onset ofexacerbations that are associated with GAS infection, withgradual resolution over weeks to months. Diagnostic crite-ria for PANDAS include OCD and tic disorders, includingTourette syndrome; abrupt onset in childhood; an episodiccourse of symptoms; and a temporal relationship betweenGAS infection confirmed by RADT, throat culture, or skinculture or serologic testing. Evaluation for GAS infectionshould be considered in children who present with theabrupt onset of OCD or tic disorder.

Management of PANDAS includes treatment of theGAS infection and neuropsychiatric therapy. Behavioraltherapy and pharmacological therapies, including selec-tive serotonin reuptake inhibitors (SSRIs) for OCD andclonidine for tics, are used in treatment. Of note, becauseof the proposed autoimmune pathogenesis, immuno-modulatory therapies such as plasma exchange and IGIVmay be beneficial and are under study. The prognosis isnot known. The use of prophylactic antibiotics to pre-vent PANDAS recurrence also is under review.

Streptococcal Suppurative ComplicationsTonsillopharyngeal Cellulitis and Abscess

Cellulitis or abscess can arise in the peritonsillar or retro-pharyngeal spaces. Retropharyngeal infection is morecommon in younger children; peritonsillar disease occursmore commonly in older children and adolescents. Al-though these infections are often polymicrobial, GAS isthe predominant bacterial species due to the spread ofGAS pharyngitis to adjacent structures. Clinical manifes-

Table 4. Diagnostic Criteria forGroup A Streptococcal ToxicShock Syndrome● Isolation of group A Streptococcus from a normally

sterile site such as blood, cerebrospinal fluid, pleuralfluid, peritoneal fluid, or surgical wound

● Hypotension AND two or more of the following:–Renal impairment–Coagulopathy: thrombocytopenia or disseminatedintravascular coagulation

–Hepatic involvement: elevated bilirubin ortransaminases values

–Acute respiratory distress syndrome–Erythematous macular rash that may desquamate

● Soft-tissue necrosis, such as necrotizing fasciitis ormyositis





tations include an ill-appearing child who has fever,severe sore throat, dysphagia or odynophagia, muffled or“hot potato” voice, trismus, neck swelling and pain, ortorticollis. Physical findings may include pharyngeal ery-thema and enlarged exudative tonsils in peritonsillarcellulitis; a swollen and fluctuant tonsil with deviation ofthe uvula to the opposite side in peritonsillar abscess; andswelling of the posterior pharyngeal wall in retropharyn-geal cellulitis or abscess. In all cases, cervical and subman-dibular lymphadenopathy is present. Laboratory findingsinclude leukocytosis with a predominance of neutrophilsand immature neutrophils and a positive RADT result orthroat culture for GAS. Imaging studies such as com-puted tomography scan with IV contrast and lateral neckradiographs that show thickening of the retropharyngealspace in retropharyngeal infections may be necessary todifferentiate peritonsillar from retropharyngeal infec-tions and abscess from cellulitis.

Treatment starts with rapid assessment of the degree ofupper airway obstruction. Supportive care, including hydra-tion, pain control, and monitoring for progression of infec-tion, is essential. Empiric therapy with broad-spectrum IVantibiotics to cover streptococcal, staphylococcal, and respi-ratory anaerobic infections is recommended. If drainage isperformed, culture results may be used to guide antibiotictherapy. Patients may be transitioned to oral antibiotictherapy with amoxicillin-clavulanate or clindamycin whenthey are afebrile and improving clinically. The duration ofantibiotic therapy is 14 days. For peritonsillar and retropha-ryngeal cellulitis, medical management alone is sufficient.Peritonsillar abscess and retropharyngeal abscess, however,require medical and surgical management. Surgical drain-age options include needle aspiration, incision and drain-age, and tonsillectomy.

Necrotizing FasciitisGAS necrotizing fasciitis is a form of invasive GAS diseasethat may be found in association with other invasive GASdiseases, such as GAS TSS. This infection is characterizedby extensive local necrosis of subcutaneous soft tissuesand skin. The pathogenesis of GAS necrotizing fasciitis isbelieved to be mediated by GAS pyrogenic exotoxinsthat act as superantigens, which activate the immunesystem. The resultant release of cytokines leads to tissuedestruction. Clinical manifestations of GAS necrotizingfasciitis include systemic findings such as fever, hypoten-sion, malaise, and myalgias; rapidly increasing pain; anderythematous skin that progresses to blisters, bullae, andcrepitus with subcutaneous gas. Laboratory findings in-clude leukocytosis with a predominance of neutrophils;elevated creatine kinase, lactate, and creatinine values;

and positive blood cultures. Diagnosis is clinical andrequires a high degree of suspicion because of the rapidprogression of infection.

Treatment of GAS necrotizing fasciitis includes earlyand aggressive surgical exploration and debridement,antibiotic therapy, and hemodynamic support if GASTSS is present as well. Surgical exploration facilitatesdebridement of necrotic tissue and obtaining of culturesto guide antibiotic therapy. Repeat surgery is necessaryuntil all necrotic tissue has been removed. Antibiotictherapy with penicillin G IV (300,000 U/kg per daydivided every 4 to 6 h) plus clindamycin IV (13 mg/kg,maximum 600 mg, every 8 h) is recommended. Antibi-otic therapy should continue for several days after com-pletion of surgical debridement.

References1. American Academy of Pediatrics. Group A streptococcal infections.In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, eds. Red Book:2009 Report of the Committee on Infectious Diseases. 28th ed. Elk GroveVillage, IL: American Academy of Pediatrics; 2009:616–6282. Gerber MA, Baltimore RS, Eaton CB, et al. Prevention ofrheumatic fever and diagnosis and treatment of acute streptococcalpharyngitis: a scientific statement from the American Heart Associ-ation Rheumatic Fever, Endocarditis, and Kawasaki Disease Com-mittee of the Council on Cardiovascular Disease in the Young, theInterdisciplinary Council on Functional Genomics and Transla-tional Biology, and the Interdisciplinary Council on Quality of Careand Outcomes Research: endorsed by the American Academy ofPediatrics. Circulation. 2009;119:1541–1551

Suggested ReadingWald ER, Green MD, Schwartz B, Barbadora K. A streptococcal

score card revisited. Pediatr Emerg Care. 1998;14:109–111

Summary• GAS is a common cause of upper respiratory tract

and skin infections.• Based on strong research evidence, (1) throat culture

is the gold standard for diagnosing GAS pharyngitis.• Based on strong research evidence, (1) oral penicillin

V K is the antibiotic treatment of choice for GASpharyngitis because of its efficacy, safety, andnarrow spectrum.

• Based on strong research evidence, (2) primaryprevention of complications of GAS such as ARFinvolves prompt diagnosis and antibiotic treatmentof GAS pharyngitis.

• GAS nonsuppurative and suppurative complicationsmay occur and are mediated by interactions betweenGAS antigens or exotoxins and the patient’s immunesystem.




PIR QuizQuiz also available online at: http://pedsinreview.aappubliations.org.NOTE: Beginning in January 2012, learners will only be able to take Pediatrics in Review quizzes and claim creditonline. No paper answer form will be printed in the journal.

6. Among the following symptoms, the one that is seen most commonly in both toddlers and infants whohave streptococcosis is:

A. Anterior cervical adenopathy.B. Diffuse rash.C. Joint inflammation.D. Low-grade fever.E. Mucopurulent rhinorrhea.

7. Testing of asymptomatic contacts for GAS is typically recommended only when the contact is:

A. At risk of developing complications.B. Living in the same household.C. Not a known carrier.D. Suffering from exudative pharyngitis.E. Younger than age 12 months.

8. The antibiotic treatment of choice for GAS pharyngitis is:

A. Amoxicillin.B. Azithromycin.C. Cefdinir.D. Cefpodoxime.E. Penicillin.

For each of the following conditions, which finding is most characteristic?9. Cellulitis.

10. Erysipelas.11. Impetigo.

A. Amber-colored crust.B. Fever.C. Lymphangitis.D. Omphalitis.E. Perianal lesions.

12. The cause of PANDAS has been suggested to be a GAS infection in a susceptible host that leads to theproduction of:

A. Autoimmune antibodies.B. Cytokines.C. Nephritogenic antigens.D. Pyrogenic exotoxins.E. Superantigens.

Parent Resources From the AAP at HealthyChildren.orgThe reader is likely to find material to share with parents that is relevant to this article byvisiting this link: http://www.healthychildren.org/English/health-issues/conditions/infections/pages/Group-A-Streptococcal-Infections.aspx





Unintentional Injuries in PediatricsKaren Judy, MD*

Author Disclosure

Dr Judy has disclosed

no financial



commentary does not


of an unapproved/


commercial

product/device.


1. Describe the role that unintentional injuries play in the morbidity and mortality ofchildren.

2. List the risk factors that predispose children and adolescents to the risk of death froma motor vehicle crash.

3. Detail strategies to counsel parents effectively about bicycle safety.4. Describe the safety measures that need to be taken to reduce the risk of drowning in

children.5. Discuss preventive measures with parents that can reduce the likelihood of scald burns

occurring in the home.6. Recite the national poison control number.7. Detail strategies to avoid accidental firearm injuries in the home.

IntroductionUnintentional injuries are the leading cause of morbidity and mortality among children inthe United States. The definition of an injury is “tissue damage secondary to acuteexposure (inadvertent or deliberate) to physical agents (eg, thermal, kinetic, chemical, orelectrical energy, or water) or chemicals (eg, poisoning).” Unintentional injuries are notaccidents because they are understandable, predictable, and preventable occurrences.

In the United States, injuries kill more children between the ages of 1 and 19 years thanall other causes combined (Table 1). Data from the Centers for Disease Control andPrevention (CDC) Childhood Injury Report indicate that 20 children die every day frompreventable injuries. (1) The problem is even more profound in developing countries,where more than 95% of deaths occur from injury, accounting for nearly 1 million deathsannually. Injuries also result in significant childhood morbidity. It is estimated that 1 in 4children sustains an unintentional injury that requires medical care each year. Injuriesproduce acute morbidity, short- and long-term disability, and high medical costs; UnitedStates medical costs for these injuries approach $17 billion per year.

The CDC, World Health Organization, and United Nations Children’s EmergencyFund (UNICEF) have completed “A World Report on Childhood Injury Prevention” andinitiated a new campaign, “Protect the Ones You Love,” to raise parents’ awareness aboutthe leading causes of child injury and detail methods of prevention. As part of the initiative,the CDC’s Injury Center offers resources to help parents keep their children safe frominjuries, including fact sheets, podcasts, media outreach, and event planning guides. Allmaterials are available free of charge at www.cdc.gov/safechild.

Risk FactorsYoung children and teenagers are at greatest risk from suffering acute unintentionalinjuries. Males have twice the risk of injury as females, primarily due to greater exposure toactivities that result in injury and patterns of risk-taking and rougher play. NativeAmericans and Alaskan natives have the highest rate of unintentional injury in the UnitedStates. Further, more than 40% of Native American children are from low-income familiesand are more likely to have difficulty obtaining medical care. They are less likely to practicesafe behaviors and to receive lifesaving preventive services. Substance abuse, especially

*Pediatric Program Director, Vice Chair of Education, Loyola University Medical Center, Maywood, IL.

Article preventive pediatrics



alcohol abuse, is a risk factor in motor vehicle crashes andis associated with injury mortality.

Prevention ActivitiesAttempts to decrease injury rates in children includeactive and passive measures. Active measures require thehost (child or parent) to be involved every time protec-tion is needed. For example, seat belt use requires com-pliance during each and every car trip. These measuresare least likely to be adopted by the persons most at risk.Such efforts often require a change in cultural norms andare the only option in some areas of protection (eg,bicycle helmets). Passive measures have been more suc-cessful because the host does not have to change humanbehavior for the measure to be effective. For example, airbags automatically protect automobile passengers.

Health-care professionals can make an impact on in-jury prevention by providing counseling at health carevisits (Table 2). The American Academy of Pediatrics(AAP) web site www.healthychildren.org is an excellentresource for parents. The Injury Prevention Program(TIPP) of the AAP offers helpful material for pediatri-cians to use for office-based injury prevention anticipa-tory guidance. Parents need to be reminded that closesupervision is the best way to prevent unintentionalinjuries in children.

Counseling is most effective at the time of an encoun-ter for assessment of an injury and in the context ofcommunity action. The most effective prevention pro-grams are woven into the fabric of communities as theydevelop and grow. Sweden followed this pattern as theyindustrialized after World War II, making injury preven-tion a part of urban planning, road construction, trans-portation, health systems, and education. The result isthat Sweden has the lowest rates of child injury deaths in

the world. Community action was well demonstrated bythe community effort of pediatricians to pass bicyclehelmet regulation in Seattle in the 1990s. Partnershipswith community or school-based organizations such asStudents Against Destructive Decisions (SADD) canmaximize the impact of physicians’ participation in injuryprevention. Pediatricians must advocate for legislationand regulation to keep children safe.

Motor Vehicle InjuriesMotor vehicle crashes are the leading cause of injurydeath and disability in all age groups (Figure). In 2005,20 children younger than 19 years of age were killed eachday from motor vehicle crashes, and more than 200,000were injured in that year, based on information from theCDC web-based Injury Statistics (WISQARS™) data athttp://www.cdc.gov/injury/wisqars/. More than onethird of children who were fatally injured were passengersin cars driven by drunk drivers. Fortunately, the mortalityrate has been falling over the past several years, mostlikely due to more stringent child restraint laws. Cur-rently, all 50 states have child restraint laws that vary byage, weight, and restraint system. Child safety seats re-duce the risk of death by 50% to 70%, and positioning thechild in the back seat is associated with a 40% reduction inrisk of serious injury. Of note, child restraint use dependson the adult’s restraint use; 40% of children who travelwith an unbelted driver are themselves unrestrained.

Children younger than 2 years of age are safest ridingrear-facing in a car seat. Recent evidence indicates thatchildren generally are safer when riding backwards andmay benefit from riding backwards for longer than 1year. At 40 lb, children can be moved to a booster seatuntil they are at least 80 lb and 57 in tall. After that,children should remain restrained by a seatbelt in the

Table 1. Leading Causes of Unintentional Injury Death Among ChildrenAge 0–10 Years, 2000–2005

Rank

Age Group in Years

Younger than 1(n�5,883)

1 to 4(n�10.203)

5 to 9(n�7,144)

10 to 14(n�9,088)

15 to 10(n�40,734)

1 Suffocation 66% Drowning 27% MVT occupant 22% MVT occupant 26% MVT occupant 41%2 MVT occupant 8% Pedestrian 15% MVT unspecified 15% MVT unspecified 15% MVT unspecified 28%3 Drowning 7% Fires/Burns 14% Pedestrian 13% Pedestrian 12% Poisoning 7%4 MVT unspecified 5% MVT occupant 13% Fires/Burns 13% Drowning 10% MVT other 6%5 Other injuries 5% MVT unspecified 9% Drowning 13% MVT other 9% Pedestrian 5%

MVT�motor vehicle trafficFrom Borse, NN, Gilchrist J, Dellinger AM, Rudd RA, Ballesteros MF, Sleet DA. CDC Child Injury Report Patterns of Unintentional Injuries Among 0–19 YearOlds in the United States, 2000–2006. Atlanta, GA: Centers for Disease Control and Prevention, National Center for Injury Prevention and Control; 2008

preventive pediatrics unintentional injury




backseat away from the airbag untilthey are at least 13 years of age.Correct installation of car seats can-not be overemphasized. Studiesshow that most car seats are notinstalled correctly and allow for toomuch movement (�1 in side to sideand forward), thereby not provid-ing appropriate protection. A valu-able resource is www.seatcheck.org, a site where parents can entertheir zip code and find out the lo-cation of the nearest certified carseat technician, who will help theminstall their car seat correctly forfree.

Motor vehicle collisions are theleading cause of death for teenag-ers. In 2005, 12 teens died everyday from such collisions. Teens aremost at risk because they are newlylicensed and distracted by otherpassengers. In addition, they un-derestimate dangerous situations,often speed, use alcohol, and havelower seat belt use. The intent ofthe graduated driver’s license pro-gram is to allow new drivers to prac-tice driving under low-risk condi-tions, with the goal of improvingteen driving skills and safety. In-creasing the legal age of drinkingalcohol has lowered the rate of mo-tor vehicle deaths in adolescents.Parents must reinforce the dangersof drinking and driving and addressinfractions seriously. A safe rideagreement encourages the teen tocall the parent for a ride rather thandrive while impaired or ride withanother impaired driver. In thisagreement, the parent must con-tract to provide a ride home andrefrain from judgment. Pediatri-cians should encourage families todevelop a parent-teen driving con-tract that specifies restrictions forthe teen drivers, determines whenrestrictions will be lifted, and out-lines the consequences for violatingrestrictions. An example of such a

Table 2. Injury Prevention TipsMotor Vehicle Crash

● Back seat (middle) placement of child● Rear-facing car seat until age 2 y● Forward-facing car seat until at least 40 lb● Booster seat until at least 80 lb and 57 in● Always check manufacturer’s specifications on car seat● Proper use of seat belts

Drowning

● Enclose pools completely with at least 4-ft fence and self-closing gate● Wear life jackets on boats and when playing near water● Do not leave children unattended in baths● Supervise closely (adult within one arm’s reach of a child in or near water)● Teach swimming and water safety

Fire and Burns

● Install smoke detectors on every level of the home and near sleeping areas● Test smoke detectors monthly, replace batteries yearly● Establish a family fire escape plan● Keep lighters, matches out of reach● No smoking in bed!● Reduce water heater temperature to 120°F● Do not drink hot fluids near children● Never leave the stove unattended● Keep appliance cords, pot handles, grills, and fireplaces out of reach● Cover outlets with protective devices

Poisoning

● Keep all potential poisons in original containers and out of reach● Keep all medication out of reach● Place child-resistant caps on medications● Dispose of medications immediately and safely● Install carbon monoxide detectors on every level of home● Keep poison control number near the phone: 1–800-222–1222

Threats to Breathing

● Back to Sleep● Remove comforters, pillows, bumpers, and stuffed animals from crib● Avoid nuts, carrots, popcorn, and hotdog pieces● Keep coins, batteries, small toys, magnets, and toy parts away from children

<4 y old● Cut blind cords short and tie them out of reach● Ensure cribs and mattresses meet safety precautions

Falls

● No baby walkers with wheels● Supervise children closely● Use safety straps in high chairs, shopping carts, and for diaper changes● Keep car seats and “bouncy chairs” on the floor

Recreation

● Ensure helmets are fitted and worn properly● Keep children <10 y off the road● Remove drawstrings, scarves, and ropes from clothing when children are on

playground● Supervise children closely● Ensure playground equipment has deep soft surface underneath




driving contract can be found at http://www.teendriving.com/drivingcontract2.htm.

Young children are at risk for pedestrian injuries be-cause they are not aware of traffic threats. Childrenshould not be allowed to cross streets independentlyuntil they are at least 10 years of age. Bicycles are anothersource of injury in young children. Bicycle helmets re-duce pediatric head injuries by 85%, and it is estimatedthat 75% of all bicycle-related fatalities among childrencould be prevented with a bicycle helmet. All statesshould mandate bicycle helmets for children becausesuch laws have proven to be effective in increasing helmetuse and decreasing head injury rates. The annual cost ofbicycle-related injuries and death (for all ages) in theUnited States is $8 billion. Every dollar spent on bikehelmets saves Americans $30 in indirect medical costsand other costs. Helmets should be Snell or AmericanNational Standards Institute (ANSI)-approved to be ap-propriately protective during an impact. Helmets alsomust be fitted properly to provide optimum safety. Forinformation on how to fit a bicycle helmet correctly, visithttp://bhsi.org/fit.htm. Separate bicycle lanes are an-other protective measure.

DrowningThe formal definition of drowning is a process resultingin primary respiratory impairment from submersion in aliquid medium. In 2005, drowning killed more than1,100 children in the United States. Four times as manychildren receive emergency department care for nonfataldrowning injuries for every child that dies. Nonfataldrowning has the highest average lifetime health andeconomic impact, with affected children often neurolog-

ically devastated and requiring prolonged medical andrehabilitative care. Factors that determine the clinicaloutcome of the victims include age, submersion time,water temperature, water tonicity, degree of water con-tamination, symptoms after a near-drowning event, asso-ciated injuries (especially cervical spine and head), pres-ence of coingestants, underlying medical conditions,type and timing of rescue and resuscitation efforts, andresponse to initial resuscitation.

Drowning is the #1 cause of childhood death in Asia.The overall rate of drowning for African American chil-dren is 1.7 times higher than that for white children inthe United States. A bimodal distribution of deaths isobserved, with an initial peak in the toddler age groupand a second peak in male adolescents. Children youngerthan 1 year of age often drown in bathtubs, buckets, andtoilets. Children 1 to 4 years of age are more likely todrown in swimming pools where they have been unsu-pervised temporarily (usually for �5 min). Typical inci-dents involve a toddler left unattended temporarily orunder the supervision of an older sibling. In the adoles-cent and young adult age groups (ages 15 to 24 y), mostincidents occur in natural bodies of water. Approximately90% of drownings occur within 10 yards of safety. Pedi-atricians should be educated about “touch supervision”in which a parent should be within an arm’s length of aswimming child.

Preventive measures for drowning at home includedraining water from bathtubs and buckets and securingtoilet seats. Swimming pools must be enclosed on all foursides by a fence (minimum 4 ft high) with a self-closinglatch gate. Such fencing can reduce the incidence ofdrowning by 50% to 80%. Use of life vests seems to be anobvious preventive intervention for all age groups whenthey are around water, including toddlers playing aroundpools or open water, boaters, and even poor swimmers.Improving swimming ability with swim lessons makessense but has not been proven effective; other conditions(eg, cold water, water currents, loss of consciousness,hypothermia) may preclude the effectiveness of swim-ming skills. Although swimming “buys time” to rescue, alife vest buys more time. It is clear that increasing life vestuse among adolescents and adults is critical. Legislationrequiring children to wear life vests when in small boatsexists. Raising the age requirement for life vests to olderthan 6 to 14 years of age would be appropriate, given theage groups at risk.

Adolescents, a particularly high-risk group for drown-ing, must be informed about water safety and the dangersof intoxication while in and around the water. Changingculture to advertise the dangers of, instead of promoting,

Figure. Unintentional injury death rates among children 0 to19 years, by cause, United States. 2000–2005. Data source:Centers for Disease Control and Prevention, National VitalStatistics System. www.cdc.gov/nchs





the mixing of alcohol and water-related activities shouldbe a goal, similar to that undertaken for drinking anddriving. Driving under the influence (DUI) laws exist forboaters in all 50 states, but they have been poorly en-forced. Recently, several states have linked boating vio-lations with motor vehicle DUI violations.

BurnsAbout 120,000 children are treated in United Statesemergency departments each year for burn-related inju-ries. Most pediatric burns occur at home and are largelypreventable. Most children 4 years of age and youngerwho are hospitalized for burn-related injuries suffer fromscald burns (65%) or contact burns (20%). Most scaldburns in children, especially children ages 6 months to 2years, are caused by hot foods or liquids spilled in thekitchen where food is prepared and served. A key preven-tive measure is to set water heater temperatures no higherthan 120°F. Within 3 seconds, a child’s skin can beburned severely enough to require surgery when scaldedwith water at a temperature greater than 120°F.

After 6 years of age, the incidence of burn injuriestapers off, but it increases again as adolescents enter thework force and sustain activity- and work-related injuries,such as from motor vehicle crashes and repairs. In all agegroups, accidental injuries most often are the result ofcarelessness and inattention to basic safety measures. Thenumber of deaths due to fires and burns has declinedsince the “The Flammable Fabrics Act of 1971,” whichregulates the sale of flammable children’s clothing, espe-cially sleepwear. Overall, the most important factors inthe reduction of burn-related deaths have been the use ofsmoke detectors and regulations on hot water heatertemperature. In the United States, most people killed inhouse fires die from smoke inhalation rather than fromburns.

PoisoningAnnually, more than 1 million children younger than 6years of age experience toxic exposures, making poison-ing a major and persistent cause of injury-related mor-bidity among children in the United States. Almost 90%of poisonings occur at home, and although more than50% of poison exposures involve children younger thanthe age of 6 years, most fatal poisonings occur amongadults. On average, United States poison control centers(PCCs) receive one call concerning a suspected or actualhuman poison exposure every 12.7 sec. Fortunately, thenumber of pediatric poisoning deaths has declined sub-stantially over the past 30 years. This decline can beattributed to numerous factors, including child-resistant

packaging, heightened parental awareness of producttoxic effects, intervention by poison information centers,and specially trained health professionals.

The compounds most likely to be involved in pediat-ric poisonings are cosmetics and personal care products,cleaning substances, analgesics, cough and cold prepara-tions, and plants. Fortunately, most of these exposuresdo not result in toxic symptoms or cause only minor toxicsymptoms in young children. Most ingestions can bemanaged at home after careful consultation with theregional PCC. However, physicians and parents shouldbe aware of compounds that pose high risk to children.Syrup of ipecac is no longer recommended for the homemanagement of pediatric poisonings because there is noevidence that it improves outcomes and it may delay theadministration or reduce the effectiveness of other treat-ments, such as activated charcoal or other oral antidotes.Parents should be instructed to call the PCC immediatelyif they suspect a child has ingested a toxic substance. Theregional PCC telephone number is 1–800–222–1222anywhere in the United States.

Pharmaceutical products responsible for significantmorbidity and mortality in young children have includediron supplements, tricyclic antidepressants, cardiovascu-lar medications (calcium channel blockers, �-blockers),oral hypoglycemic agents, narcotic analgesics, and anti-malarials (chloroquine). During the past 10 years, pedi-atric poisoning fatalities have remained at 2% to 3% of allpoisoning fatalities. This plateau in the number of pedi-atric poisoning fatalities may be due to inefficient use ofresources. Many parents do not call the PCC for infor-mation when their child has experienced a potentiallytoxic ingestion. Primary care clinicians and emergencydepartments must continue to emphasize the importanceof contacting the PCC immediately upon suspicion oftoxic ingestion by a child.

Gun ViolenceIn the United States, more than 33% of householdsadmit to having firearms, and almost 70% of parentsadmit that their guns are unlocked. Most accidentalshootings result from having a gun in the home. Forevery instance in which a gun in the home is used inself-defense, there are four accidental shootings. Notonly are children strong enough to fire most guns on themarket, but they are also very curious and likely to wantto play with novelty items, including the guns they findhidden at home. One study found that 75% of childrenwho found a handgun played with it, and 50% of thesechildren pulled the trigger. (2) All of these children hadbeen educated previously about gun safety, including




instructions never to touch a gun and to find an adult if agun is discovered. However, in one telephone survey ofhouseholds, nearly 90% (regardless of gun ownership orage of child) responded that they believed that if theirchild found a gun, he or she would “know better” thanto touch it. (3)

Removing guns from homes is the only action thatcan ensure decreased rates of accidental firearm deaths inthe home. Parents need to be counseled, beginning atthe newborn visit, about the hazards of having a gun intheir home. Parents of older children should ask otherparents about guns in the home before setting up play-time. If parents choose to keep a firearm in the home, theunloaded gun and ammunition must be kept in separatelocked cabinets. Project Child Safe (www.projectchildsafe.org) is a program that provides gun safety kits at nocost to gun owners.

SuffocationThe #1 cause of mortality for children younger than 1year of age is suffocation. Food, coins, and toys are theprimary causes of choking-related injury and death. Cer-tain characteristics, including shape, size, and consistencyof certain toys and foods, increase the potential to causechoking among children. All babies and toddlers shouldavoid small objects and foods because of the threat ofchoking. Batteries, buttons, jewelry, coins, and small toysshould be eliminated from the child’s environment. Themost dangerous foods include peanuts, popcorn, hotdogs, whole grapes, raisins, bites of meat and apple,carrots, and candy. Young children are at increased risk ofchoking because their molars have not erupted, so theyare unable to grind food adequately in preparation forswallowing.

Behavioral factors also may affect a child’s risk forchoking. High activity levels while eating, such as walk-ing or running, talking, laughing, and eating quickly,may increase a child’s risk of choking. Other agents thatcan cause suffocation are dangling cords, which maystrangle a child (eg, cords on blinds, electrical cords), anddry cleaning bags. Parents, teachers, child care workers,and other child caregivers must be educated to superviseand create a safer environment for children. The UnitedStates Consumer Product Safety Commission (CPSC)has well-established surveillance systems and an array oflegislation and regulations to protect children againstchoking and injury on toys and other consumer prod-ucts. The CPSC works to ensure that toys have appropri-ate choking-hazard warnings and provides recall infor-mation for products that pose choking risks to children.

FallsThe leading cause of nonfatal injuries in children is fallsfrom heights off the ground (Table 3). Most of theseinjuries occur at home during the warmer months of theyear. Infants most often fall from furniture, toddlers fromwindows, and older children from playground equip-ment. The greater the height of the fall, the more severethe injury. Mortality rates increase at falls greater than 15ft. Children younger than 3 years of age are less likely tohave serious injuries from falls because they are smallerand have more fat and cartilage to dissipate energy. Mostchildren suffer head, musculoskeletal, or thoracic injuriesfrom falls.

Falls from windows, roofs, and balconies occur moreoften in urban areas in low-income housing. These fallscan be prevented with window guards that keep childrenin, yet allow for egress during a fire. Openings in win-dows or railings should be less than 4 in to impede ayoung child from falling. In 1976 in New York City,window guards decreased mortality from falls by 35% anddecreased hospital admissions for falls by 96%. Double-hung windows should be opened from the top. Childrenshould be restricted from playing on fire escapes, roofs,or balconies. Furniture should not be placed near win-dows or balconies, and grass or shrubbery should beplanted at bases of buildings to soften a fall.

Many parents purchase walkers with the belief thatthey encourage mobility, promote walking, and keeptheir infants safe. In contrast, evidence shows that walk-ers can delay normal motor and mental development andare dangerous. Reported injuries from the use of thewalkers are overwhelmingly caused by falls; falls downstairs are implicated in 75% to 96% of cases. The AAPrecommends that walkers be banned. Parents shouldbe discouraged from using walkers with wheels; sta-tionary activity centers are a safer alternative to mobilewalkers.

Parents must be educated to restrain their children inhighchairs and on changing tables. Infant seats should beplaced only on the floor. Falls from beds can be pre-vented by lowering the mattress in the crib when thetoddler learns to stand in the crib. Bunk beds requireguardrails that open less than 3.5 in to prevent egress,and children younger than 6 years of age should not sleepin a top bunk. Supervision cannot be overemphasized.Bathtubs are a common site of injuries from falls, espe-cially in children younger than age 4. Such children mostoften suffer head and facial lacerations, even while adultsare supervising. Safety measures include slip-resistantdevices, shatterproof enclosures, and elimination ofsharp edges.





Playgrounds are a frequent site of falls in school-agechildren. Emergency departments treat more than200,000 children per year who sustain playground inju-ries. Upper extremity fractures are the most commoninjury. Injuries are related to the height of the fall, usuallygreater than 5 to 6 ft, as well as to the type of playgroundundersurface (sand is safer than grass). Measures to im-prove the safety of playgrounds include creating energy-absorbing surfaces below the structures, lowering theheight of playground equipment, inspecting the units,securing ropes at open ends, maintaining guardrails, andsupervising at all times.

In 2005, 20,700 children younger than 5 years of agewere seen in emergency departments for falls from shop-ping carts, most of whom had head injuries. Measures toprotect children in shopping carts include using seatbelts, prohibiting riding in the cart basket, restrictingstanding or climbing on carts, ensuring that adults push

carts, and designing carts to keep children closer to thefloor.

Recreational activities, including bicycling, inlineskating, skateboarding, and riding scooters, are a com-mon cause of injuries in children. In 1998, the AAPrecommended full protective gear for inline skating(eg, helmet, wrist guards, knee pads, and elbow pads).This recommendation led to a decrease in skatinginjuries in 1999. Parents must be counseled to set anexample by wearing protective gear themselves whenparticipating in sports. They must lead by example.Children are not likely to wear protective gear unlesstheir parents do.

Pediatricians must continue to work diligently to pre-vent childhood injuries by educating parents, workingwith legislators, and advocating within communities.Such efforts should be rewarded with lives saved andinjuries prevented.

Table 3. Leading Causes of Nonfatal Unintentional Injuries AmongChildren 0 to 19 Years, by Age Group, United States, 2001–2006

Rank

Age Group in Years

Younger Than 1(n�1,430,364)

1 to 4(n�12,243,896)

5 to 9(n�11,070,041)

10 to 14(n�14,124,306)

15 to 19(n�16,206,250)

1 Falls52%

Falls43%

Falls37%

Falls28%

Struck by/Ag21%

2 Struck by/Ag14%

Struck by/Ag19%

Struck by/Ag23%

Struck by/Ag25%

Falls17%

3 Bites/Stings6%

Bites/Stings9%

Bites/Stings8%

Overexertion12%

MV occupant17%

4 Fires/Burns5%

Foreign Body6%

Cut/Pierce7%

Cut/Pierce7%

Overexertion14%

5 Foreign Body4%

Cut/Pierce4%

Pedal cyclist6%

Pedal cyclist6%

Cut/Pierce8%

6 MV occupant3%

Overexertion4%

Overexertion4%

Unknown/Unspecified

5%

Other injuries4%

7 Cut/Pierce3%

Fires/Burns3%

MV occupant4%

Bites/Stings4%

Unknown/Unspecified

4%8 Poisoning

3%Poisoning

3%Foreign Body

3%MV occupant

4%MV other

4%9 Overexertion

3%Unknown/Unspecified

2%

MV other3%

MV other4%

Bites/Stings4%

10 Suffocation3%

MV occupant2%

Unknown/Unspecified

2%

Other injuries1%

Pedal cyclist2%

Struck by /Ag�struck by or against an object, MV�motor vehicleData from Centers for Disease Control and Prevention National Vital Statistics System. www.cdc.gov/nchs




References1. Borse NN, Gilchrist J, Dellinger AM, Rudd RA, Ballesteros MF,Sleet DA. CDC Child Injury Report Patterns of UnintentionalInjuries Among 0–19 Year Olds in the United States, 2000–2006.Atlanta, GA: Centers for Disease Control and Prevention, NationalCenter for Injury Prevention and Control; 20082. Jackman GA, Farah MM, Kellerman SLTK. Seeing is believing:what do boys do when they find a real gun? Pediatrics. 2001;107:12473. Connor SM, Wesolowski KL. “They’re too smart for that”:predicting what children would do in the presence of guns. Pediat-rics. 2003;111:e109–e114

Suggested ReadingAmerican Academy of Pediatrics, Committee on Injury, Violence,

and Poison Prevention. Falls from heights: windows, roofs, andbalconies. Pediatrics. 2001;107:1188–1191

American Academy of Pediatrics, Committee on Injury, Violence,and Poison Prevention Policy Statement. Prevention of chokingamong children. Pediatrics. 2010;125:601–608

American Academy of Pediatrics, Committee on Injury, Violence,and Poison Prevention. Shopping cart-related injuries to chil-dren. Pediatrics. 2006;118:825–827

American Academy of Pediatrics, Committee on Injury, Violence, andPoison Prevention. The teen driver. Pediatrics. 2006;118:2570–2581

American Academy of Pediatrics, Gardner HG and Committee onInjury, Violence, and Poison Prevention. Office based counselingfor unintentional injury prevention. Pediatrics. 2007;119:202–206

American Academy of Pediatrics, Section on Orthopaedics, Com-mittee on Pediatric Emergency Medicine, Section on CriticalCare, Section on Surgery, Section on Transport Medicine,Committee on Pediatric Emergency Medicine, and PediatricOrthopaedic Society of North America. Management of pedi-atric trauma. Pediatrics. 2008;121:849–854

D’Souza AL, Nelson NG, McKenzie LB. Pediatric burn injuriestreated in United States emergency departments between1990 and 2006. Pediatrics. 2009;124:1424–1430

National Highway Traffic Safety Administration at: www.nhtsa.dot.gov

Rivara F. The global problem of injuries to children and adoles-cents. Pediatrics. 2009;123:168–169

Tinsworth D, McDonald J. Special Study: Injuries and DeathsAssociated with Children’s Playground Equipment. Washington,DC: United States Consumer Product Safety Commission;2001

Summary• Injuries are the leading killer of children.• A variety of host factors contribute to different

types of injury.• Motor vehicles remain the biggest threat.• Both active and passive preventive strategies are

necessary to prevent injuries.• For maximal safety effectiveness, physicians must be

active in their communities.

Parent Resources From the AAP at HealthyChildren.orgThe reader is likely to find material to share with parents that is relevant to this article byvisiting this link: http://www.healthychildren.org/English/Safety-prevention/pages/default.aspx.





PIR QuizQuiz also available online at: http://pedsinreview.aappublications.org.NOTE: Beginning in January 2012, learners will only be able to take Pediatrics in Review quizzes and claim creditonline. No paper answer form will be printed in the journal.

13. In the United States, the number of children who die every day due to preventable injuries is closest to:

A. 5.B. 10.C. 20.D. 35.E. 50.

14. Among the major population groups in the United States, which has the highest rate of unintentionalinjury?

A. African Americans.B. Asian Americans.C. European Americans.D. Hispanic Americans.E. Native Americans.

15. Children should ride in the back seat of a motor vehicle until they are at least:

A. 10 years old.B. 11 years old.C. 12 years old.D. 13 years old.E. 14 years old.

16. What percentage of fatal bicycle injuries could have been prevented by wearing a helmet?

A. 25%.B. 50%.C. 66%.D. 75%.E. 90%.

17. The leading cause of accidental death in children younger than 1 year of age is:

A. Falling.B. Motor vehicle crash.C. Poisoning.D. Scalding.E. Suffocation.




Anxiety and Separation DisordersAlexa L. Bagnell, MD,

FRCPC*

Author Disclosure

Dr Bagnell has

disclosed no financial



commentary does


of an unapproved/


commercial

product/device.


1. Describe the basic neurobiology of anxiety and fear.2. Know the epidemiology of anxiety disorders in children and adolescents.3. Differentiate separation anxiety disorder from other forms of school refusal and know

how to approach it therapeutically.4. Know the signs and symptoms of anxiety disorders in children and adolescents.5. Understand the pharmacologic and nonpharmacologic management of anxiety

disorders.

DefinitionAnxiety is a physiologic response necessary for all human beings to survive. It helps protectindividuals in dangerous situations and prepares them for challenges. Fears are theemotional response to a given stimuli or situation that is identified as threatening or scary.Fears are a normal part of development throughout childhood and adolescence, and theychange throughout the life course (Table 1). Worries are the cognitive or thinkingmanifestations of fear and anxiety.

Anxiety disorders are diagnosed when fears, worries, or anxiety occur outside the rangeof normal developmental responses or are extreme and cause significant distress orimpairment in functioning (school, home, social settings). In anxiety disorders, the fearresponse is no longer adaptive and is either out of proportion to a stressor or occurs whenthere is no threat. Due to the physiologic mechanisms activated with the anxiety and stressresponse in the body, individuals who have chronic anxiety and stress have a greater risk ofboth physical and mental health problems. Individuals who have anxiety often present totheir primary clinicians with frequent physical complaints, not necessarily reportinganxiety. Parents also may report significant changes in behavior, with increased oppositionand tantrums in certain situations that are triggered by anxiety.

EpidemiologyAnxiety disorders are the most common psychiatric illnesses in children and adolescents,affecting 8% to 10% of this population. (1) The age of onset of anxiety disorders can be asearly as the preschool years, but the condition generally does not cause substantialimpairment until school age. Anxiety disorders can occur throughout the lifespan, butmost adult anxiety disorders begin by early adolescent years. (2) Girls have twice thelikelihood of developing anxiety disorders as boys. (1) Anxiety disorders can cause familydistress and dysfunction, school refusal and avoidance, and social isolation. Untreatedanxiety disorders increase the risk of developing further anxiety disorders, depression, andsubstance abuse. The long-term social impact of untreated anxiety disorder includesdecreased academic and occupational achievement and poorer social and relationshipoutcomes. Anxiety disorders can be accompanied by comorbid conditions, such as medicalillnesses, secondary anxiety disorders, attention-deficit/hyperactivity disorder, disruptivebehavior disorders, learning disorders, and mood disorders.

Anxiety disorders tend to run in families, and this finding is believed to be related to acombination of genetic predisposition and environmental factors. The reasons childrendevelop an anxiety disorder are complex, but genetics, temperament, modeling, physio-logic factors, and exposure to psychosocial and environmental stressors all can contribute.Some young children have temperament styles that cause them to be more anxious and

*IWK Health Centre and Dalhousie University, Halifax, Nova Scotia, Canada.

Article mental health




avoidant in new or unfamiliar situations, also known asbehavioral inhibition. This temperament style increasesthe risk of developing an anxiety disorder in childhood,(3) but many children have no identifiable predisposingfactors and still develop anxiety disorders. Some individ-uals have a heightened physiologic arousal to stressful oranxiety-provoking situations, which also can increase therisk of developing an anxiety disorder. Maternal depres-sion and anxiety have a significant influence on attach-ment, affecting the early environment and brain devel-opment of children. Maternal depression and anxiety caninfluence appropriate emotion regulation and stress re-sponses, the effects of which can manifest as psychiatricillnesses, such as disruptive behavior disorders, anxietydisorders, and mood disorders. Environmental and psy-chosocial stressors, including school issues, social diffi-culties, family dysfunction, trauma, and loss, can contrib-ute to anxiety disorders.

PathogenesisAnxiety is a physiologic response that is essential to thesurvival of human beings, involving fright/flight neuro-biology and the stress response system. (4) The fright/flight response in the brain is regulated through sensoryinput (thalamus), context and memory (hippocampus),and emotion regulation (amygdala) systems, often re-ferred to as components of the limbic system. This sys-tem is activated under stress and danger and prepares thebody physiologically by activating the sympathetic adre-nal medullary system and the hypothalamic-pituitary-adrenal axis. The prefrontal cortex helps to modulate thisresponse in the brain and to modify fear responses.

In anxiety disorders, the fright/flight mechanism isactivated in situations that are not a threat or overre-sponds in reaction to the stressor without appropriateresponse modulation. The release of stress hormones andadrenaline in the body inappropriately or in excess (giventhe situation) without appropriate regulation causes thefeelings of fear and physical symptoms of anxiety (eg,

stomachaches, nausea, headaches, increased heart rate,dizziness, sweating, shortness of breath, paresthesias,chest pain). Avoidance, tantrums, aggression, crying,trembling, somatic complaints, and seeking of reassur-ance all are common manifestations of anxiety. Theavoidance and reliance on others to help manage fearsmay help to decrease anxiety temporarily but can becomeextreme and interfere with functioning at home, school,and socially and cause anxiety to worsen over time.

Clinical AspectsAnxiety for some children may occur only in very specificsituations or environments and for others can be moregeneralized. It is important to distinguish between ap-propriate and adaptive anxiety and stress and an anxietydisorder. An anxiety disorder is of long duration (usuallylasting for many months), interferes substantially withfunctioning, and is out of synch with the magnitude ofthe stressor and developmental stage of the child. Adap-tive anxiety and stress occur after a substantial change ortransition (eg, starting school) and are expected re-sponses to change or adversity. Anxiety disorders usuallyrequire intervention by a clinician; stress usually is ofshort duration (fewer than 2 weeks) and is likely toresolve spontaneously or be substantially ameliorated bysocial support or environmental modification alone.

Diagnosis of the many types of anxiety disorders isbased on criteria outlined according to the Diagnosticand Statistical Manual of Mental Disorders, Fourth Edi-tion (DSM-IV TR). (5) Separation anxiety disorder andspecific phobia are the most common childhood anxietydisorders, and social phobia (or social anxiety disorder) isthe most common anxiety disorder in adolescence. Sev-eral anxiety disorder screening tools have been wellvalidated for use in children and adolescents. The Multi-dimensional Anxiety Scale for Children (MASC) is aself-report screen for identifying anxiety disorders inchildren and adolescents. The Screen for Child AnxietyRelated Emotional Disorders (SCARED) and the SpenceChildren’s Anxiety Scale (SCAS) both have parent andself-report versions to screen for anxiety disorders inyouth. These three scales are helpful for identifyingyouth at risk for anxiety disorders and for monitoringresponse to treatment. (6)

Separation Anxiety DisorderSeparation anxiety disorder is one of the most commonanxiety disorders in school-age children. Separation anx-iety is a normal stage of early development in preschool-ers and during the initial few months of first attendingschool. It is considered a disorder if it continues past

Table 1. Common Childhood FearsInfant/Toddler: Loud noises, dark, strangers, large

objects, separationPreschool: Separation, dark, monsters and ghosts,

animals, stormsSchool age: Bodily injury and death, school

performance, natural disasters and stormsAdolescent: Public speaking, social situations, school

performance, health

mental health anxiety and separation disorders



these stages or causes substantial distress for the child andfamily and interferes with normal functional develop-mental tasks. Children who have separation anxiety dis-order fear something bad will happen to them or some-one they love (usually parent or caregiver) when they areapart. This fear causes children to avoid being out of sightfrom the parent or caregiver or to have substantial dis-tress and anxiety when they are separated or in anticipa-tion of separation. By definition, the duration of theanxiety must be at least 4 weeks. Anxiety symptoms canmanifest as physical complaints on school mornings thatusually do not occur on weekend mornings or as behav-ior outbursts. The symptoms generally improve if thefeared situation (eg, school) is avoided.

Children who have separation anxiety disorder oftenare unable to be left with a babysitter, are not able to fallasleep on their own (parent falls asleep with them or theysleep in parents’ room), and avoid school. The affectedchild demands substantial attention and time, which canlead to less parental time for other children in the family.Mothers usually are the caregivers demanded, which canresult in a parent-child dyad that can exclude othermembers of the family to manage the child’s anxiety. Thechild becomes dependent on the mother for reassuranceand management of the anxiety and fear, thereby losingconfidence in his or her ability to manage situationsindependently.

Parents of children who have separation anxiety de-scribe loss of their adult relationships and occupationalconsequences because at least one parent is home withthe child who has not gone to school. Children who haveseparation anxiety disorder miss out on social opportu-nities with friends because they do not want to be awayfrom their home and parents. This disorder can causesubstantial distress and dysfunction for the child andfamily and interfere with the development of age-appropriate independence and academic success. One ofthe important functional impairments commonly associ-ated with this disorder is school phobia or school refusal.(7)

School refusal is described as a persistent pattern ofnot wanting to go to school, avoidance of school, or highdistress associated with going to school. Although it isnot a specific psychiatric diagnosis, school refusal can bea symptom of underlying psychiatric illness, most com-monly an anxiety disorder. School refusal often is acomplex problem that requires genuine understandingof individual and family factors to develop a successfultreatment approach. One of the key treatment goals inschool refusal derived from separation anxiety disorder is

getting the child back into the school environment assoon as possible.

It is important to differentiate school refusal related toanxiety from conduct problems and subsequent truancy.Youth who exhibit truancy generally do not report othersymptoms of anxiety or issues of separation from parents.They are not at school, but the reason is not that theyneed to be with a parent or caregiver due to fear andanxiety. Truancy is characterized by a pattern of skippingschool, lack of concern or embarrassment about notattending school, refusal to do any school work, andfrequently hiding school absences from parents.

Specific PhobiaSpecific phobia is the most common type of anxietydisorder, but it often is managed by avoidance of thespecific feared situation and less often presents for treat-ment. Many people have fears, with common ones in-cluding heights, spiders, snakes, blood, and needles.A specific phobia is fear of an object or situation that isnot developmentally expected and is out of proportion tothe actual danger and manifests as an anxiety responsethat is extreme and unreasonable (eg, avoidance or in-tense anxiety and panic). The specific fear must be pres-ent for at least 6 months and cause the child substantialdistress or impairment in functioning to be considered atrue phobia. Although many specific phobias do notcome to medical attention, fear of needles in a childrequiring vaccination and fear of choking with restrictionof oral intake are two examples of situations requiringtreatment due to associated health risks. Specific phobiassometimes are preceded by a traumatic event (such asbecoming afraid of dogs after being bitten by a dog).Onset also can be associated with genetic predisposition,increased stress in the environment, and modeling be-haviors in the environment (such as a parent’s fear re-sponse to a situation).

Social PhobiaSocial phobia (social anxiety disorder) is the most com-mon anxiety disorder in teens, likely because of theincreased importance of peers and social context in ado-lescent development. Youth who suffer from social anx-iety disorder have severe anxiety in social situations that isextremely distressing and can lead to avoidance andsubstantial deterioration in overall function. Youth whohave social anxiety disorder describe an overwhelmingfear of drawing attention to themselves or saying some-thing stupid or embarrassing around others, especiallypeers. This fear can lead to not being able to ask ques-tions in class, not being able to talk in front of others,





avoidance of the phone, not ordering in restaurants, andnot using public bathrooms. Severe social anxiety disor-der can result in isolation to the point of rarely leavinghome, not having contact with friends, and not attendingschool.

Generalized Anxiety DisorderGeneralized anxiety disorder can have its onset in child-hood and adolescent years. The anxiety centers aroundeveryday events and responsibilities in the child’s life,such as school, friends, health, future, and finances, butthe distress and worry are excessive, unrealistic, or un-helpful and persist for at least 6 months. Children mayreport feeling tense and irritable; have frequent muscleaches and pains; and experience poor sleep, tiredness,and difficulty concentrating due to the intensity andchronicity of the worried thoughts and feelings. Affectedindividuals may have academic performance anxiety thatinterferes with starting and completing assignments andtaking tests due to fear of failure or that the result will notbe good enough. A pattern of avoidance can develop toprevent a feared event or the youth may seek excessivereassurance from others that nothing bad will happen,leading to increased anxiety, decreased enjoyment, andavoidance of everyday activities.

Obsessive Compulsive DisorderObsessive compulsive disorder (OCD) is an anxietydisorder involving obsessions (distressing intrusivethoughts or images) and/or compulsions (repetitive be-haviors or rituals performed to relieve distress and anxietyassociated with the obsessions) that are unwanted, causesubstantial anxiety, and interfere with functioning (con-suming more than 1 hour per day). The most commonobsession themes are illness, contamination, and danger-related, and the most common compulsions are cleaning,washing rituals, and checking behaviors. OCD does notalways involve observed compulsions, and the individualcan suffer from repetitive images or thoughts (eg, ofviolent, religious, or sexual nature) that are extremelydistressing. Children who have OCD generally have poorinsight into their illness and may not recognize theobsessions and compulsions as irrational. They may havetrouble going to school, find they are unable to concen-trate in class, have difficulty getting out of the house orgetting dressed, and have decreased food intake relatedto obsessions and compulsions. Parents commonly areinvolved in OCD routines and compulsions with chil-dren and teens, and the illness can have a substantialnegative impact on family functioning.

Panic DisorderPanic disorder usually has its onset in adolescent yearsbut can occur in children. Although not the most com-mon anxiety disorder, this illness can become debilitatingrapidly. Children who have panic attacks (Table 2) mostcommonly present initially to an emergency departmentor urgent care center because the physical symptoms areacute and escalate quickly, similar to having a heartattack, asthma attack, or even a stroke or seizure. Panicattacks can occur in any anxiety disorder or high-stresssituation when the patient is presented with a fearedstimulus. However, in panic disorder, the attacks occur“out of the blue” without clear precipitants or warning.Such unpredictability causes extreme fear and anxietyabout having another attack, particularly in a place whereothers might see them or where escape or help might notbe possible. Affected individuals avoid any situation theyassociate with having a panic attack as well as placeswhere they fear that if they did have an attack they wouldnot be able to manage it or get help. Teens who havepanic disorder may stop all extracurricular activities, re-fuse to go anywhere without their parents, and stopgoing to school (or have extreme distress with schoolattendance).

ManagementAnxiety disorder treatment in children and adolescents isone of the best-researched areas in child and adolescentmental health. Treatment of childhood anxiety includesboth specific and nonspecific treatment approaches. Spe-cific approaches are evidence-based treatments for anxi-ety disorders and include structured psychotherapies(cognitive behavioral therapy [CBT]) and pharmaco-therapy (selective serotonin reuptake inhibitors [SSRIs]).

Table 2. Panic Attack Symptoms● Chest pain and discomfort● Heart racing and palpitations● Shortness of breath● Feeling of choking● Nausea● Shaking and sweating● Terror● Numbness and tingling of extremities● Dizziness and lightheaded● Fear of dying● Derealization (patient perceives outside world as

unreal)● Depersonalization (patient perceives self as unreal)● Perceptual changes




Nonspecific treatments include activities that decreasestress, improve mood, and support well-being, includingsleep hygiene, healthy eating, regular exercise, predict-able routine, and social supports.

Standard evidence-based anxiety disorder treatmentguidelines recommend the use of CBT as first-line treat-ment for children who have anxiety disorders when thistherapy is available. (8)(9) Many CBT programs andbooks are available, and the skills often are taught to bothparents and child to support the implementation of thestrategies and decrease indirect reinforcement of anxiousbehaviors and thinking. CBT includes psychoeducationand cognitive and behavior skills training to help individ-uals understand and better manage anxiety. Anxiouschildren think catastrophically or overexaggerate thenegative outcomes of situations and generate avoidantsolutions, leading to significant distress and avoidancebehaviors.

The cognitive strategies include identifying anxietysymptoms and somatic symptoms related to anxiety,developing realistic thinking, and problem-solving. Be-havioral strategies consist of relaxation and stress man-agement techniques as well as gradual exposure to thefeared situation to modify the anxiety response throughsystematic desensitization and habituation (Table 3).Many children experience improvement in their anxietywith CBT alone and do not require medication. In some

cases, children and teens are unableto learn and use CBT strategies tomanage their anxiety without phar-macologic treatment.

Medications help decrease over-all anxiety symptoms and panic re-sponse and should be considered ifthe anxiety is moderate to severe.The best evidence, supported byboth meta-analyses (10) and a Co-chrane review, (11) for pharmaco-logic treatment of childhood anxi-ety disorders favors the SSRIs. (9)Although some SSRIs have beenapproved for treating children whohave depression (fluoxetine, escita-lopram) and OCD (fluoxetine, flu-voxamine, sertraline), SSRIs do nothave United States Food and DrugAdministration (FDA) approval forthe treatment of anxiety disorders.However, considerable evidencesupports their efficacy. CBT incombination with an SSRI is rec-

ommended for moderate-to-severe anxiety disorders.(9)(12) Randomized, controlled trials of SSRI medica-tions (sertraline, fluoxetine, fluvoxamine, and parox-etine) show effectiveness in treating children and adoles-cents who have anxiety disorders. (9)(10)(11)

Evidence is insufficient to recommend non-SSRI an-tidepressants such as venlafaxine for treatment of pediat-ric anxiety disorders. (9)(10)(11) Strong evidence sup-ports the efficacy of clomipramine in treatment of OCD,but the adverse effect profile does not support its use asfirst-line treatment. (9)(11) Benzodiazepines have beenused for acute management of anxiety, but there is noevidence of their effectiveness for treatment of anxietydisorders in children. (9)(11)

The risk/benefit ratio of initiating a medication trialshould be considered in each situation, and the adverseeffects should be disclosed fully, including the FDA blackbox warning for all antidepressants (the rare but in-creased risk for youth of experiencing suicidal ideationand behaviors while taking antidepressant medications).Initial doses should be minimal, with very gradual in-creases, as tolerated, according to symptom response andadverse effects, remembering that the medications takeseveral weeks to start working and improvement contin-ues for several months at a given dose. Although suicidalideation and suicide attempts are not as common inchildhood anxiety disorders as in depressive disorders,

Table 3. Therapeutic Plan for ManagingSeparation Anxiety Disorder With SchoolRefusalEducation: Explain anxiety symptoms and how avoidance and reassurance-seeking

related to fears and worries makes anxiety worse.Coping Strategies: Review healthy living strategies, including good sleep, regular

exercise, maintaining a routine, and healthy eating.Cognitive: Have the child identify realistic and helpful thoughts. For example, “I feel

sick to my stomach because of my anxiety. It always gets better once I am inschool. I can handle this and I have to go to school. I like seeing my friends and Ihave fun once I am there.”

Behavioral: Teach relaxation strategies (deep breathing, muscle relaxation, visual/mental imagery) to use at times of anxiety, such as when preparing to go toschool.

Exposure: Develop a plan for school attendance. Youth need to take small steps indecreasing avoidance of anxiety situations. If they have not been attending schoolfor more than a few weeks, school supports and gradual increase in school timeis recommended. The goal is to tolerate the anxiety and make it through theschool time successfully on their own. School staff can be helpful in finding aplace youth can go in the school if they feel anxious. Rewards can be put inplace for school attendance, and any indirect reinforcement occurring at homeshould be minimized (eg, no video games or computer time during school hours).





they may occur, and children should be monitored. (10)Medication should be viewed as helping the child de-crease overall anxiety symptoms to allow success in learn-ing and using anxiety management strategies. Given theadverse effects and risks of SSRI medication in childrenand the limited long-term safety data of these medica-tions in the developing brain, medication interventionshould be combined with CBT and healthy living strat-egies, with the goal of trying to taper the child off themedication within 1 year if he or she is doing well.

PrognosisAnxiety has the best chance of improving when bothyouth and family are educated about anxiety disordersand when there is support of the treatment plan. Numer-ous randomized, controlled trials support CBT andSSRIs as effective treatments for pediatric anxiety disor-

ders. (8)(9)(10)(11)(12) The goal of treatment is toameliorate symptoms and reduce anxiety, with improve-ment in overall function.

References1. Costello EJ, Mustillo S, Erkanli A, Keeler G, Angold A. Preva-lence and development of psychiatric disorders in childhood andadolescence. Arch Gen Psychiatry. 2003;60:837–8442. Kessler RC, Berglund P, Demler O, Jin R, Walters EE. Lifetimeprevalence and age-of-onset distributions of DSM-IV disorders inthe National Comorbidity Survey Replication. Arch Gen Psychiatry.2005;62:593–6023. Rosenbaum JF, Biederman J, Bolduc-Murphy EA, et al. Behav-ioral inhibition in childhood: a risk factor for anxiety disorders.Harvard Rev Psychiatry. 1993;1:2–164. Cummins TK, Pinan PT. The neurobiology of anxiety in chil-dren and adolescents. Int Rev Psychiatry. 2002;14:114–1285. American Psychiatric Association. Diagnostic and StatisticalManual for Mental Disorders, Fourth Edition, Text Revision. Wash-ington, DC: American Psychiatric Association; 20006. Muris P, Merckelbach H, Ollendick T, King N, Bogie N. Threetraditional and three new childhood anxiety questionnaires: theirreliability and validity in a normal adolescent sample. Behav ResTher. 2002;40:753–7727. Kearney CA, Albano AM. The functional profiles of schoolrefusal behavior. Behav Modific. 2004;28:147–1618. James ACJ, Soler A, Weatherall RRW. Cognitive behaviouraltherapy for anxiety disorders in children and adolescents. CochraneDatabase Syst Rev. 2005;4:CD0046909. Connolly SD, Bernstein GA. Work Group on Quality Issues.Practice parameter for the assessment and treatment of children andadolescents with anxiety disorders. J Am Acad Child Adolesc Psychi-atry. 2007;46:267–28310. Bridge JA, Iyengar S, Salary CB, et al. Clinical response and riskfor reported suicidal ideation and suicide attempts in pediatricantidepressant treatment: a meta-analysis of randomized controlledtrials. JAMA. 2007;297:1683–169611. Ipser JC, Stein DJ, Hawkridge S, Hoppe L. Pharmacotherapyfor anxiety disorders in children and adolescents. Cochrane Data-base Syst Rev. 2009;3:CD00517012. Walkup JT, Albano AM, Piacentini J, et al. Cognitive behav-ioral therapy, sertraline, or a combination in childhood anxiety.N Engl J Med. 2008;359:2753–2766

Summary• Based on strong research evidence, anxiety disorders

are the most common psychiatric illness in childrenand adolescents. (1)(2)

• Based on some research evidence, the neurobiologyof anxiety disorders is linked to dysregulation in thefear and stress response system in the brain. (4)

• Based on strong research evidence, separationanxiety disorder is one of the most common causesof school refusal, and addressing both the functionof the behavior and returning to school as soon aspossible is recommended. (7)

• Based on strong research evidence, CBT is the first-line treatment for anxiety disorders in children andadolescents. (8)(9)

• Based on strong research evidence, SSRIs areeffective for treatment of moderate-to-severeanxiety disorders in children and adolescents.(9)(10)(11)(12)

Parent Resources From the AAP at HealthyChildren.orgThe reader is likely to find material to share with parents that is relevant to this article byvisiting this link: http://www.healthychildren.org/English/health-issues/conditions/emotional-problems/pages/default.aspx.




PIR QuizQuiz also available online at: http://pedsinreview.aappublications.org.NOTE: Beginning in January 2012, learners will only be able to take Pediatrics in Review quizzes and claim creditonline. No paper answer form will be printed in the journal.

18. When evaluating anxiety in children, it is important to distinguish adaptive anxiety from an anxietydisorder. Which of the following clinical features is more likely to be indicative of an anxiety disorderthan adaptive stress and anxiety?

A. Anxiety is likely to resolve spontaneously.B. Anxiety lasts for 2 weeks or less.C. Anxiety occurs after a key transition event, such as a new sibling or new school.D. Daily functioning is substantially impaired.E. Environmental modification is often sufficient to resolve symptoms.

19. Which of the following statements regarding anxiety disorders is true?

A. Anxiety disorder is best defined as a physiologic response to a physical threat.B. Boys develop anxiety disorders more often than girls.C. Comorbid conditions such as mood disorders and learning disorders are common.D. Most anxiety disorders begin in middle adulthood.E. There is no genetic predisposition for developing an anxiety disorder.

20. You are evaluating a 4-year-old boy for anxiety. His mother reports that since beginning school 5 monthsago, he refuses to separate from her when she takes him to school. In addition, he has begun to insistthat she sleep with him and cries for hours if he is left with a babysitter. Which of the following is themost likely diagnosis?

A. Adaptive anxiety and stress.B. Generalized anxiety disorder.C. School phobia.D. Separation anxiety disorder.E. Social phobia.

21. A 16-year-old girl presents with her second episode of severe chest pain and shortness of breath in thepast 4 weeks. Both episodes occurred at school without warning and were not associated with exercise.The previous episode resolved spontaneously. She admits that she is afraid that she will have an attackthat does not resolve. She is clearly fearful, but results of her heart and lung examinations, chestradiography, and electrocardiography are normal. Which of the following is the most likely cause of hersymptoms?

A. Generalized anxiety disorder.B. Obsessive compulsive disorder.C. Panic disorder.D. School phobia.E. Social phobia.





The reader is encouraged to writepossible diagnoses for each case beforeturning to the discussion.

The editors and staff of Pediatrics in

Review find themselves in the

fortunate position of having too

many submissions for the Index of

Suspicion column. Our publication

slots for Index of Suspicion are filled

through 2013. Because we do not

think it is fair to delay publication

longer than that, we have decided

not to accept new cases for the

present. We will make an

announcement in Pediatrics in

Review when we resume accepting

new cases. We apologize for having

to take this step, but we wish to be

fair to all authors. We are grateful

for your interest in the journal.

Author Disclosure

Drs Rosevear, Lightfoot, Powell,

Weisleder, Vidaurre, and Moorthy

and Mr Lehman have disclosed no

financial relationships relevant to

these cases. This commentary does

contain a discussion of an

unapproved/investigative use of a

commercial product/device.

Case 1: Voiding Difficulty in a 10-year-oldCase 2: Seizure-like Activity Precipitated by Loud

Noise in a 2-year-oldCase 3: Purplish-brown, Shiny Upper Extremity

Lesion and Stiff Hand in a 9-year-oldCase 1 PresentationA 10-year-old boy presents with se-vere abdominal pain and urinary ur-gency. He denies any dysuria, hema-turia, frequency, meatal spotting,penile discharge, or incontinence.He has had no recent viral infectionsor fevers and he denies any history ofperineal trauma. He has no signifi-cant medical or surgical past medicalhistory. Three days earlier, he wasseen at a local hospital with a 3-dayhistory of increasing difficulty withvoiding, including straining to voidand incomplete bladder emptying.A bladder scan revealed a full bladderafter he voided. Therefore, an8-French catheter was placed and hewas told to return in 3 days for avoiding trial. He failed the voiding

trial, and personnel at the local hos-pital were unable to replace the cath-eter. He was referred to our institu-tion for further management.

Physical examination reveals nor-mal Sexual Maturity Rating stage 1genitalia and a palpable bladder. Hedoes not have any sacral dimples. Ef-forts to pass a 5-French feeding tubethrough the urethra also fail. Addi-tional history and an imaging proce-dure lead to the diagnosis.

Case 2 PresentationThe neurology consultant examinesa 2-year-old boy in the outpatientclinic for “passing-out seizures.” Hismother indicates that, in response toloud sounds, her otherwise healthychild experiences episodes of gener-alized, nonrhythmic, tonic musclecontractions characterized by “stiff-ness and back-arching,” collapse, andapnea. The episodes last 30 to 45 sec-onds, and in a typical day, the boyexperiences three to four events. Noother family members experiencesimilar bouts. Findings on ECG,echocardiography, and 23-hour car-diac monitoring are unremarkable.

Physical examination reveals analert toddler who interacts appropri-ately with his mother and has noobvious signs of sensory or motordeficit. To evaluate the events, thechild is admitted to the epilepsymonitoring unit. Examination of theelectroencephalogram (EEG) revealsnormal background rhythm. Duringthe admission, two “typical” epi-sodes are recorded. Following a loud

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



sound for the first event and follow-ing frustration for the second, thechild cries and holds his breath inexpiration. Subsequently, bradycar-dia is observed on the ECG lead ofthe EEG (Fig. 1). Bradycardia is fol-lowed rapidly by asystole lasting13 to 16 seconds (Fig. 2). Elevenseconds after the cardiac arrest, thebackground EEG becomes slow andthen flat (Fig. 2). A few seconds afterthe heart starts beating again, thebrain’s electrical activity slowly re-turns to baseline (Fig. 3). Duringasystole, the patient adopts an opis-thotonic posture: back-arching,overextension of the upper extremi-ties, and flexion of the legs at the hip(Fig. 2). The episodes are not associ-ated with EEG signs of seizures.

Case 3 PresentationA 9-year-old boy presents with thecomplaint that “my right hand istight, and my fingers won’t bend.”He has a 5-year history of slowlyprogressive spots of hyperpigmenta-tion and induration on the dorsum ofthe right hand, forearm, and axilla.Over the past few months, the spotsof hyperpigmentation have enlarged;darkened to a purplish-brown hue;and coalesced into a large area in-volving the hand, forearm, arm, andshoulder. As the lesion progressed,he started experiencing stiffness ofhis hand and wrist. There is no his-tory of recent trauma, allergic reac-tion, illness, weight loss, dyspnea,telangiectasias, calcifications, weak-ness, swallowing difficulties, Ray-naud phenomenon, oral ulcers, orabdominal pain. Past medical andfamily histories contain no findingsof note.

On physical examination, the boyis afebrile, alert, and in no acute dis-tress. His vital signs are within nor-mal range. Musculoskeletal examina-tion reveals full range of motion

Figure 1. The child was stimulated (asterisk) and soon thereafter began crying(arrowhead). The EEG’s ECG lead (read tracing) shows subsequent progressivebradycardia (arrow).

Figure 2. Twenty seconds after stimulation (Fig. 1), bradycardia evolved to a16-second period of asystole (arrowhead). This was accompanied by flattening of theEEG (arrow) and opisthotonic posture (picture insert).

index of suspicion




(both active and passive) without de-fect or deformity, except for markedflexion contractures of the rightfourth and fifth metacarpophalangealand first proximal interphalangealjoints. His right wrist shows signifi-cant limitation in flexion. He has fullrange of motion in the right elbowand shoulder. A large area of contin-uous atrophic skin with subcutane-ous fat atrophy is present. The skin

over the hand is purplish-brown andshiny (Fig. 4). All other physical signsare normal.

Results of his CBC, ESR, andC-reactive protein assessment arewithin normal limits. The slowlyevolving nature and typical appear-ance of the lesions lead to the diag-nosis.

Case 1 DiscussionThe clinical picture suggested eitherprimary bladder dysfunction or ure-thral obstruction. However, primarybladder dysfunction does not occursuddenly. Further direct questioningof the mother revealed that the boyhad taken up bull riding 2 years agoand had competed in a rodeo theprevious week. The mother did notconsider this a “traumatic event” ifperformed correctly. The patient un-

derwent retrograde urethrography,which showed complete urethral ob-struction. A suprapubic catheter wasplaced to allow the bladder to drain,and definitive treatment was delayeduntil the immediate inflammatory re-sponse had settled. Three weekslater, combined retrograde and ante-grade urethrography was completed(Fig. 5). The image showed com-plete urethral obliteration at the levelof the bulbar urethra.

The ConditionThe male urethra is divided into twosections: the anterior or distal portion(containing the bulbar, penile, andfossa navicularis segments) and poste-rior or proximal portion (containingthe prostatic and membranous seg-ments). Blunt trauma associated withinjury to the pelvic bones, as seen inmotor vehicle crashes, often causesmembranous urethra injury becausethe puboprostatic ligaments limit theprostate’s ability to move, creatingshearing force on the urethra.

Urethral injuries occur in 5% to10% of all pelvic trauma injuries.Blunt trauma directly to theperineum classically is associatedwith bulbar urethral injury becauseof the urethra’s path in the perineum.These injuries typically cause directcrushing injury to the urethra andcan present clinically either immedi-ately or many years later.

Differential DiagnsosisUrethral strictures classically are de-scribed as either congenital or ac-quired. Congenital strictures are rareand diagnosed by exclusion. The mostcommon cause of acquired strictures isinstrumentation, followed byinflammatory/infectious insults andtrauma (saddle/bicycle injury andpelvic fracture). In the adult, groin in-juries account for almost 5% of allrodeo-related injures, although thepercentage of these that are urethral is

Figure 3. Following 17 seconds of asystole, the heart rate returned spontaneously(arrowhead). Electroencephalographic activity followed 6 seconds later (arrow). Thetracing revealed generalized slowing, with gradual return to baseline backgroundactivity.

Figure 4. Purplish-brown and shiny le-sion on the dorsum of the hand.

index of suspicion



not known. Data on pediatric rodeoinjuries are not available.

The presumed mechanism of ac-tion for this injury is well described inthe literature and is termed a “saddle-horn” injury, in which the rider isthrown into the air and lands with hisperineum in direct contact with thesaddle. This contact causes a crush-ing force to the perineum, which re-sults in the damage to the urethra.

TreatmentDefinitive treatment of urethral inju-ries caused by blunt perineal traumausually is delayed to allow for thelocal inflammatory response to sub-side. After 2 to 3 months, the injurycan be repaired either with a primaryend-to-end anastomosis, if the dam-aged area is short, or by using graft

material if the damaged area is lon-ger. In the interim, it is important toensure good bladder drainage to pre-vent any damage to the bladder orkidneys. This patient underwent a re-pair using a graft and is doing well.

Lessons for the Clinician

● Although urethral injuries are un-common, this case highlights theneed for a thorough history facili-tated by good communication be-tween the physician and the patientto ensure that the patient not onlyanswers the questions asked, but alsounderstands why they were asked.

● It is also important to realize thatboys start participating in rodeoevents at a young age and that par-ents should be counseled on the po-

tential risks inherent to this activity.The National Junior Bull Riding As-sociation (http://www.njbranow.org/) sponsors events for childrenusing age-appropriate animals andincorporates required safety equip-ment, including vests and helmets.The rarity of the injury described inthis report suggests that currentsafety protocols are likely effective,although parents should be warnedof potential long-term damage tothe urethra as a result of this activity,which may not present for manyyears after the event.

(Henry M. Rosevear, MD, AndrewJ. Lightfoot, MD, Department ofUrology, University of Iowa, IowaCity, IA; Charles R. Powell, MD, De-partment of Urology, Indiana Uni-versity School of Medicine, Indianapo-lis, IN)

Case 2 DiscussionInterview with the child’s mothermade the consultant suspect the di-agnosis of hyperekplexia or “stiffbaby” syndrome. Analysis of theevents captured during the video-EEG recording confirmed that theepisodes were not consistent withseizures. Instead, the record wascharacterized by muscle artifact, bra-dycardia leading to asystole, andnear-flattening of electrical brain ac-tivity. The clinical history and thesefindings are consistent with the diag-nosis of “major” hyperekplexia.

The ConditionHyperekplexia, or “stiff baby” syn-drome, is a rare congenital conditioncharacterized by excessive responseto unexpected stimuli. The termcomes from the Greek and means “tostartle excessively.” Bakker and asso-ciates (1) consider hyperekplexia tobe the most severe of a group ofdisorders characterized by an abnor-

Figure 5. Combined retrograde and antegrade urethrography shows complete urethralobliteration at the level of the bulbar urethra.

index of suspicion




mal response to startling events.They limit use of the term hyperek-plexia to the congenital form of thecondition. Neuropsychiatric startlesyndrome and startle-induced epi-lepsy are other events that fall underthe rubric “startle syndromes.”

Two primary types of hyperekplexiahave been identified: major and minor.Major hyperekplexia, which frequentlyis identified in the neonatal period, ischaracterized by a disproportionate re-sponse to common and innocuousstimuli (sound, touch) in the form ofgeneralized muscle contractions andstartle-associated falls. Breath-holdingspells and anoxic seizures also havebeen described in this condition, mak-ing the diagnosis difficult at times. Thisform of the condition has a well-established genetic cause: mutations inthe gene for the �-1 subunit of theglycine receptor (GLRA1) on chro-mosome 5q33.1. The most commonGLRA1 defect leading to major hyper-ekplexia is an autosomal dominantmissense mutation. However, GLRA1mutations also can have recessive in-heritance. Finally, mutations of genesother than GLRA1, ones coding forglycinergic synapse proteins, also havebeen linked to sporadic cases of majorhyperekplexia.

Minor hyperekplexia is also charac-terized by exaggerated startle re-sponses but without tonic muscle con-tractions. The genetic basis of minorhyperekplexia is yet to be determined.

Genetic testing of this child failedto reveal GLRA1 mutations. Such afinding is not surprising because thedefect is identified most commonlyin patients who have the disease’shereditary form. Sporadic hyperek-plexia has been linked to abnormali-ties of other genes, such as that cod-ing for the glycine-receptor beta-subunit (GLRB); the gene coding forgephyrin (GPHN), a protein respon-sible for clustering of glycine recep-tors at inhibitory synapses; and the

gene coding for collybistin (ARH-GEF9), a protein that interacts withgephyrin. Regardless of genetic flaw,most forms of hyperekplexia have aglycine-gated chloride-channel de-fect as a common denominator.

Animal models of hyperekplexiainclude knockout and naturally oc-curring examples. The former groupcomprises mice that have mutationsin genes coding for either the �- orthe �-subunit of the glycine receptoror for gephyrin. The latter group in-cludes cattle born with a GLRA1nonsense mutation. Specifically, PollHereford cattle exhibit spontaneousand startle-evoked myoclonic jerksleading to death because the calvesare unable to stand and feed. In ad-dition, a missense mutation in theSLC6A5 gene, encoding the presyn-aptic glycine transporter 2 (GlyT2),causes hyperekplexia in the Belgianblue cattle. These animals die in theperinatal period from apnea due tomuscle rigidity. This last example isunique because the defect, unlikethose involving the glycine receptor,is presynaptic, which leads to de-creased glycine reuptake.

Differential DiagnosisIn children, the differential diagnosisof hyperekplexia includes stimulus-induced seizures, tetanus, Tourettesyndrome, and anxiety disorder.Stimulus-induced seizures are, as thename implies, convulsions that aretriggered by external stimuli. Theseevents, which have a correlating EEGpattern, are common in children whohave severe brain damage. Signs andsymptoms of tetanus include, in addi-tion to muscle contractions, fever and ahistory of an infected wound. In thecase of Tourette syndrome, tics are nottriggered by stimuli but by an internalurge. Finally, the exaggerated startleresponse seen in patients with anxietydisorder has been deemed to be relatedto a state of hyperarousal.

TreatmentClonazepam has become the treat-ment of choice for all forms of hyper-ekplexia. The medication’s use is pred-icated on two counts. First, as a�-aminobutyric agonist, clonazepam isassumed to compensate for theglycine-gated chloride channel defect.Thus, the medication increases post-synaptic hyperpolarization and synap-tic inhibition. Second, clonazepam hasanxiolytic properties. The latter effectcannot be underestimated becausechildren who have hyperekplexia havebeen reported to shy away from bicycleriding, running, and climbing for fearof falls and injury. This patient hasbeen treated with clonazepam, and hisresponse to the medication has beenencouraging.

Lessons For The Clinician

● Although hyperekplexia can be aclinical diagnosis, this case illus-trates the contribution of video-EEG monitoring in diagnosingparoxysmal events.

● Like breath-holding spells, hyperek-plexia is a disturbance of auto-nomic regulation in response toadverse stimuli.

● Breath-holding spells and hyperek-plexia are involuntary responses;they cannot be attributed to achild’s temperament.

(Pedro Weisleder, MD, PhD, JorgeVidaurre, MD, Division of ChildNeurology, Nationwide Children’sHospital, The Ohio State University,Columbus, OH)

Reference1. Bakker MJ, van Dijk JG, van denMaagdenberg AMJM, Tijseen MAJ. Startlesyndromes. Lancet Neurol. 2006;5:513–524

index of suspicion



Case 3 DiscussionThe disease process in this patientevolved steadily over a 5-year periodfrom the initial appearance of whitespots to darkening, induration, andcoalescence along the arm. This clin-ical picture established the diagnosisof linear scleroderma.

The ConditionLocalized scleroderma typically hastwo primary forms: morphea and lin-ear scleroderma. Children who havemorphea exhibit irregular patches ofthickened skin, most commonly onthe trunk but sometimes on thelimbs as well. In linear scleroderma,the pattern of involvement is more ina line over one arm or leg and usuallyinvolves only one side of the body.The lesion can start as an oval orround patch in morphea and as lin-ear, bandlike patches in linear sclero-derma. The lesions can be of differ-ent sizes, and if active, usually arewaxy, indurated, and pinkish-purple,with a surrounding reddish halo.

Some of the lesions may expandover months to years. Over severalyears, the lesion heals with a whitishscar and causes either hyper- or hypo-pigmentation, depending on thechild’s skin color. The lesion can belimited to the skin alone or can extenddeeper, even to the bone, and lead tosignificant deformity and disability(joint contractures). If the lesioncrosses joints, it can result in significantdisability and deformity, as occurred inthis patient. In a growing child, linearscleroderma of the leg can result inleg-length discrepancy.

It is critical to differentiate the local-ized condition from systemic sclerosis,which is associated with skin thicken-ing and visceral involvement. Usually,children who have the localized type ofscleroderma do not have any internalorgan involvement and do not developsystemic symptoms. Occasionally, theymay have mild arthritis.

Routine laboratory test resultsgenerally are within normal limits.Sometimes, the ESR and immuno-globulin titer may be elevated. Rheu-matoid factor and anti-nuclear-antibody testing results may bepositive. Diagnosis of linear sclero-derma is based on clinical manifesta-tions, although in some cases a bi-opsy may be helpful.

ManagementTopical emollients are sufficient forsmall lesions that have stopped en-larging and are not hampering phys-ical function. However, if the lesionsare spreading, are cosmetically unde-sirable, or are impeding function(causing contractures, especially ifthey cross over the joints), treatmentis recommended. It is important todiagnose localized scleroderma earlyto institute early treatment that canpreserve function and minimize dis-ability. Methotrexate, hydroxychlo-roquine, phototherapy, and cortico-steroids, although not approvedspecifically for this purpose, are usedseparately or in combination to treatlocalized scleroderma. Physical ther-apy often is used to improve mobil-ity. The affected skin should be keptsupple with regular moisturizing andprotected from trauma because opti-mum healing may not take place. Ifpossible, affected children should beevaluated and monitored by a pediat-ric rheumatologist.

The prognosis for children whohave localized scleroderma usually isexcellent unless there is significantinvolvement of muscle and bone or ifthe lesions are large and cross multi-ple joints, in which case surgicalcorrection may be necessary, butonly after the disease has becomeinactive.

This patient was treated withmethotrexate and regular physicaltherapy, which decreased his skintightness and softened the skin le-

sions (Fig. 6). He regained mobilityand function of his joints.

Lessons for the Clinician● Linear scleroderma is a rare condi-

tion characterized by a slow progres-sion.

● Often, mild discoloration may notraise concern for the patient orphysician. In addition, the lack ofdistinct laboratory abnormalitiesdelays the diagnosis.

● Early institution of treatment is nec-essary to ensure the best outcome.Untreated disease can result in de-formity and cosmetic problems.

(Nathan Lehman, Keck School ofMedicine/University of Southern Cal-ifornia, Los Angeles, CA; L. NandiniMoorthy, MD, MS, University of Med-icine and Dentistry of New Jersey,New Brunswick, NJ)

ACKNOWLEDGMENTS. We wouldlike to thank Thomas J. A. Lehman,MD, Chief, Division of PediatricRheumatology, Hospital for SpecialSurgery in New York City, and Profes-sor of Clinical Pediatrics, Cornell Uni-versity Medical College, for providingphotographs and case details to helpmake this case presentation possible.

To view suggested Reading lists forthese cases, visit pedsinreview.aappublications.org and click on Index ofSuspicion.

Figure 6. Significant improvement inthe skin lesion on the dorsum of thehand after the treatment.

index of suspicion




The following Suggested Readinglists are included online only for the“Index of Suspicion.”

Case 2 Suggested ReadingBakker MJ, van Dijk JG, van den Maagden-

berg AMJM, Tijseen MAJ. Startle syn-dromes. Lancet Neurol. 2006;5:513–524

Harvey RJ, Topf M, Harvey K, Rees M. Thegenetics of hyperekplexia: more thanstartle! Trends Genet. 2008;24:439–447

Meinck HM. Startle and its disorders. Neu-rophysiol Clin. 2006;36:357–364

Case 3 Suggested ReadingLehman TJA. Scleroderma. In A Clinician’s

Guide to Rheumatic Diseases in Chil-dren. New York, NY: Oxford; 2009:210–218

Li SC, Feldman BM, Higgins GC, HainesKA, Punaro MG, O’Neil KM. Treat-ment of pediatric localized scleroderma:results of a survey of North Americanpediatric rheumatologists. J Rheumatol.2010;37:175–181

Zulian F. New developments in localizedscleroderma. Curr Opin Rheumatol.2008;20:601–607

Zulian F. Systemic sclerosis and localizedscleroderma in childhood. Rheum DisClin North Am. 2008;34:239–255

Zulian F, Athreya BH, Laxer R, et al. Juve-nile localized scleroderma: clinical andepidemiological features in 750 chil-dren. An international study. Rheuma-tology (Oxford). 2006;45:614–620



In BriefMedia Role in Violence and the Dynamics of BullyingPatrick Brown, MDCheryl Tierney, MD, MPHBaystate Children’s HospitalSpringfield, MA

Author Disclosure

Drs Brown, Tierney, and Serwint have

disclosed no financial relationships

relevant to this In Brief. This

commentary does not contain a

discussion of an unapproved/

investigative use of a commercial

product/device.

The Role of Media Violence in ViolentBehavior. Huesmann LR, Taylor LD.Annu Rev Public Health. 2006;27:393–415

Bullying Behaviors Among US Youth:Prevalence and Association WithPsychosocial Adjustment. Nansel TR,Overpeck M, Pilla RS, Ruan WJ,Simons-Morton B, Scheidt P. JAMA.2001;285:2094–2100

Preventing Youth Violence and Delin-quency Through a Universal School-based Prevention Approach. BotvinGJ, Griffin KW, Nichols TD. PreventSci. 2006;7:403–408

What Health Professionals ShouldKnow: Core Competencies for Effec-tive Practice in Youth Violence Pre-vention. Knox LM, Spivak H. Am JPrev Med. 2005;29(5 suppl 2):191–199

Violence and bullying behaviors arefacts of life for many teenagers. Violentepisodes can take the form of physicalaltercations as well as emotional taunt-ing and, more recently, cyber bullyingvia online attacks through e-mail orchat rooms. Although the cause of vi-

olence among adolescents is complex,research over several decades has con-sistently established that exposure tomedia violence causes an increase inviolent behaviors. Media violence canhave short- and long-term effects thatcan influence individual behaviors. Inthe short-term, exposure to violent me-dia can lead to an increase in violentthoughts and behaviors through physi-ologic excitation as well as specificbehavior imitation. Over the long term,repeated exposure to violence can in-fluence sensitization toward violenceand reset accepted norms about theappropriateness of violent behaviors.

The social norming of violenceamong individuals can have a profoundimpact on factors that enable schoolviolence and the role that children maytake in a violent encounter. These rolesinclude that of perpetrator, victim, andbystander. Research on the individualfactors of perpetrators suggests thatbullies and victims both have relativelypoor psychosocial adjustment com-pared with bystanders. Perpetrators ofviolence tend to have a greater ten-dency to use alcohol, smoke, and havepoor academic achievement. Victimcharacteristics include social isolation,difficulty making friends, and a persis-tent sense of isolation or “not fitting in”at school.

Although relatively few children ac-tually take on the role of the bully orthe victim, a comparatively large num-ber of children and adolescents oftenplay the role of bystander. Bystandersprovide the audience for bullying be-haviors and possibly a passive accep-tance of bullying behavior. If no onespeaks up, bad behaviors are free topersist and escalate. The bystander rolemay be affected by media violence

because viewing violence on television,movies, and video games requires theviewer to take the role of a passivebystander. The desensitization to vio-lence that occurs with repeated view-ing of violent behavior can inculcate asense of normative behavior that leadschildren to view real-life violence withsimilar detached acceptance.

However, children can adopt afourth role with respect to school vio-lence: the active bystander or nonvio-lent conflict resolver. Studies of vio-lence prevention have identified a rolefor training programs that explicitlyteach students in middle and highschool how to intervene actively whenwitnessing violence or bullying to stopthe behavior. Encouraging bystandersto be aware of their role in giving thebully power to perpetrate violence canmake them more likely to become in-volved by reporting the bullying to anadult, supporting the person being bul-lied, or standing up to the bully. Suchactive intervention removes the silentassent of the audience and diminishesthe power of the bully to perpetrateacts of violence. Programs that teachadolescents strategies of negotiationand mediation are critical for successfulconflict resolution without escalationto violent behavior.

In summary, violence is present inthe lives of many children and adoles-cents. Exposure to violence in the me-dia can have a significant impact on thelikelihood that children will engage inviolence and may affect the acceptanceof violent behavior among bystanders.Pediatricians can play a role in revers-ing this trend by informing childrenabout the positive role that they canplay in violent encounters, performingin-office screening, counseling about

in brief



violence through programs such as“Connected Kids,” and encouraging lo-cal schools to implement training pro-grams that encourage adolescents tohave an active role in nonviolent con-flict resolution using negotiation andmediation.

Comment: Media in this In Briefincludes exposure of children and ado-lescents to violence through playingvideo games and viewing music videos,

movies, and even the daily news ontelevision. However, the newest, dra-matically increasing exposure is via so-cial media and increasingly prevalentcyber bullying. Sadly, the associatedmorbidity and even mortality has beensubstantial. The imbalance of powerthat results when neither the victim norbystanders is physically present or ableto intervene creates a particularly dif-ficult situation. Combatting media vio-lence has risen to the level of a public

health initiative. Parents, teachers, pe-diatricians, and communities need torally around this cause to stop theviolence. We are able and must advo-cate at multiple levels within our com-munities and schools and at the stateand federal levels. Preventive interven-tion programs have been found to beeffective.

Janet R. Serwint, MDConsulting Editor, In Brief

Parent Resources From the AAP at HealthyChildren.orgThe reader is likely to find material to share with parents that is relevant to this article byvisiting this link: http://www.healthychildren.org/English/family-life/media/pages/default.aspx.

CorrectionThe third author of Case 1 in the “Index of Suspicion” column in the February issue(Pediatr Rev. 2011;32:75–80) is Vince Yamashiroya. The journal regrets the error.

in brief




violence through programs such as“Connected Kids,” and encouraging lo-cal schools to implement training pro-grams that encourage adolescents tohave an active role in nonviolent con-flict resolution using negotiation andmediation.

Comment: Media in this In Briefincludes exposure of children and ado-lescents to violence through playingvideo games and viewing music videos,

movies, and even the daily news ontelevision. However, the newest, dra-matically increasing exposure is via so-cial media and increasingly prevalentcyber bullying. Sadly, the associatedmorbidity and even mortality has beensubstantial. The imbalance of powerthat results when neither the victim norbystanders is physically present or ableto intervene creates a particularly dif-ficult situation. Combatting media vio-lence has risen to the level of a public

health initiative. Parents, teachers, pe-diatricians, and communities need torally around this cause to stop theviolence. We are able and must advo-cate at multiple levels within our com-munities and schools and at the stateand federal levels. Preventive interven-tion programs have been found to beeffective.

Janet R. Serwint, MDConsulting Editor, In Brief

Parent Resources From the AAP at HealthyChildren.orgThe reader is likely to find material to share with parents that is relevant to this article byvisiting this link: http://www.healthychildren.org/English/family-life/media/pages/default.aspx.

CorrectionThe third author of Case 1 in the “Index of Suspicion” column in the February issue(Pediatr Rev. 2011;32:75–80) is Vince Yamashiroya. The journal regrets the error.

in brief




Respiratory Distress:A Great Masquerader

Author DisclosureDrs Kier, Balluz, Modi, and Chandran have disclosedno financial relationships relevant to this case. Thiscommentary does contain a discussion of an unapproved/investigative use of a commercial product/device

Catherine Kier, MD,* Rula Balluz, MD,* Vikash Modi, MD,†

Latha Chandran, MD, MPH§

Case 1 Presentation: Persistent PulmonaryInfiltrateA 2-year-old boy has had several hospitalizations forright upper lobe (RUL) pneumonia associated with re-active airway disease. During this episode, he presentswith a low-grade fever, cough, wheezing, and an oxygensaturation of 90% to 91% on room air. His temperature is37.9°C (axillary), respiratory rate is 38 breaths/min,heart rate is 129 beats/min, and blood pressure is 92/60 mm Hg. Posteroanterior and lateral radiographicviews of the chest obtained in the emergency department(ED) show a density in the RUL area (Fig. 1). Onadmission, he is given intravenous hydration, intrave-nous ceftriaxone, albuterol nebulizer treatments, oralcorticosteroids, and supplemental oxygen.

Within 24 hours, the patient responds with improvedwork of breathing and resolution of hypoxia and fever.A follow-up radiograph shows persistence of the rightupper lobe infiltrate. Initial and repeat blood cultures arenegative. The patient is discharged after 6 days on a10-day course of oral antibiotics, with a 2-weekfollow-up evaluation scheduled.

Two weeks later, the patient has improved further anddoes not have fever, tachypnea, or respiratory distress.Due to the recurrent nature of the RUL infiltrate, a chestradiograph is repeated to document radiologic resolu-tion of the pneumonia. Surprisingly, the chest radio-graph shows a persistent RUL density and mediastinalshift to the right (Fig. 2). Subsequent computed tomog-raphy (CT) scan of the chest reveals the underlyingdiagnosis.

Case 2 Presentation: Persistent HypoxemiaA 5-month-old female infant is admitted for an acuteepisode of reactive airway disease. She presented to theED with a low-grade fever, cough, nasal congestion, andwheezing. Her temperature is 38.0°C (axillary), respira-tory rate is 48 breaths/min, heart rate is 130 beats/min,

Figure 1. Chest radiograph taken on day 1 of admissionshowing a right upper lobe density.

Figure 2. Chest radiograph taken 2 weeks later showing persistentright upper lobe density, with right mediastinal and tracheal shift.

*Department of Pediatrics, Stony Brook University Medical Center, Stony Brook, NY.†Department of Otorhinolaryngology, Weill Cornell Medical College, New York, NY.§Office of the Dean, Stony Brook University School of Medicine, Stony Brook, NY.

visual diagnosis

Pediatrics in Review Vol.32 No.10 October 2011 e95 at Health Internetwork on October 2, 2011http://pedsinreview.aappublications.org/Downloaded from


and blood pressure is 90/58 mm Hg. In the ED, she didnot have obvious cyanosis, but she did have hypoxemia,as evidenced by pulse oximetry readings between 83%and 87% oxygen saturation in room air.

Her past medical history is significant for cardiacdextroposition without situs inversus diagnosed at birth.Echocardiography (ECHO) at birth confirmed the car-diac dextroposition but showed otherwise normal car-diac structure. She was found subsequently to have tri-somy 2 mosaicism. She has been hospitalized twice in thepast with wheezing and hypoxemia and was diagnosed ashaving reactive airway disease during both hospitaliza-tions.

During the current admission, initial therapy consistsof bronchodilator medications, chest physiotherapy, oralcorticosteroids, and supplemental oxygen. Over the first

48 to 72 hours, she improves clinically, with decreasedwork of breathing and almost complete resolution ofwheezing. Despite improvement of the cough, wheez-ing, and nasal congestion, and her oxygen saturationremaining between 92% and 93% with supplementaloxygen, the saturation drops to the high 80s whenoxygen is discontinued. She also remains mildly tachy-pneic.

The cause of the persistent hypoxemia is investigatedfurther. A chest radiograph and chest CT scan do notreveal significant pulmonary or cardiac pathology to ex-plain her symptoms. Repeat ECHO before bronchos-copy reveals her diagnosis (Fig. 3).

Case 3 Presentation: Recurrent CroupA 3-month-old male infant is admitted for his thirdepisode of croup. In his two previous episodes, he re-sponded well to intramuscular dexamethasone and race-mic epinephrine. His first episode was at 2 weeks of age.After the second episode of croup, direct laryngoscopyperformed at a community hospital revealed erythemabelow the vocal cords. For this third episode, the patientpresents to the ED with prominent stridor, significantretractions, and increased work of breathing. His tem-perature is 36.7°C (axillary), respiratory rate is 50breaths/min, heart rate is 110 beats/min, and bloodpressure is 97/50 mm Hg. Administration of intramus-cular dexamethasone and nebulized racemic epinephrine

Figure 3. Two-dimensional echocardiography (2 D ECHO)with color in the suprasternal view. As the video (online only)plays, the left superior vena cava (SVC) drains into the leftatrium. Pulmonary veins also appear. The aorta appears withthe left SVC coursing inferiorly in its usual location. Branchesof the pulmonary artery appear briefly, followed by views ofthe left SVC entering the left atrium.

Figure 4. Preoperative view of the laryngeal inlet. Just beyondthe vocal cords, a bulge is visible.

Abbreviations

CDH: congenital diaphragmatic herniaCT: computed tomographyECHO: echocardiographyED: emergency departmentRUL: right upper lobeSVC: superior vena cava2D: two-dimensional

visual diagnosis

e96 Pediatrics in Review Vol.32 No.10 October 2011



result in improvement of retractions and respiratory dis-tress. The patient appears comfortable, with a decrease inhis stridor.

The stridor, however, does not resolve fully and isbiphasic, appearing in both inspiratory and expiratoryphases of respiration, accompanied by a peculiar “honk-ing” noise. Due to concerns about the persistence ofstridor, he undergoes laryngoscopy and bronchoscopythat reveal his diagnosis (Fig. 4).

Case 1 Diagnosis: Congenital Absence of theRight LungThe chest radiograph suggested an underlying RULabnormality with a right mediastinal shift. Further inves-tigation by CT scan revealed mediastinal shift to the rightto replace the absent RUL and absent RUL bronchus(Fig. 5). A prominent large mass of thymic tissue on theanterior mediastinum was the “reason” for the rightupper chest density on the chest radiograph series(Fig. 6).

DiscussionThe thymus, a primary lymphoid organ, develops initiallyduring the first trimester and matures rapidly. This ante-rior mediastinal structure is relatively large in infancy. It islargest relative to body size during fetal life and attains itsmature weight during the first year after birth, subse-quently involuting gradually before puberty. The thymusis mistaken commonly as an RUL infiltrate when it isprominent on the frontal view of a chest radiograph, butradiographically, the thymus has a sharp edge (“sailsign”). The inferior margin of the thymus is convex inconfiguration.

The right mainstem bronchus normally divides intothe RUL bronchus and the bronchus intermedius thatdivides into the right middle and right lower lobe bron-

chi. RUL atelectasis is common in infancy because of theelliptical configuration of the opening of the RUL seg-ment as well as the acute angle of its take-off from theright mainstem bronchus. Infants who are kept in thesupine rather than upright position have a tendency toplug the RUL bronchus during aspiration or episodes ofrespiratory illnesses. RUL atelectasis presents as volumeloss of the lung parenchyma, and in contrast with thethymic shadow, the inferior margin of the RUL infiltrateis concave.

In this patient’s case, the “RUL pneumonia” was thethymic shadow occupying the place of the congenitallyabsent RUL. It is uncommon to find an isolated case ofcongenital absence of the RUL. Review of the literatureshows that lung hypoplasia usually is associated withcongenital diaphragmatic hernia (CDH). Anatomicanomalies of the tracheobronchial tree and bronchialhypoplasia on the affected side have been identified in18% and 38% of patients born with CDH, respectively.

Patient CourseThis patient had no history of CDH. Congenital absenceof the RUL eventually was diagnosed because of concernfor the persistent density in the RUL region when thepatient presented repeatedly with what seemed to beexacerbations of reactive airway disease with RUL pneu-monia.

The patient continues to receive daily inhaled cortico-steroids, which allows good control of his reactive airwaydisease. Because the identity of the RUL density has beendetermine, he has not received any further antibioticsand has not undergone repeated chest radiographs for his“recurrent RUL pneumonia.”

Figure 5. Computed tomography scan showing absence of theright upper lobe.

Figure 6. Computed tomography scan showing the thymusoccupying the place of the congenitally absent RUL in theright upper chest area.

visual diagnosis



Case 2 Diagnosis: Bilateral Superior VenaCavaLaryngoscopy and bronchoscopy revealed normal upperand lower airway anatomy. ECHO demonstrated a leftsuperior vena cava (SVC) draining directly into the leftatrium. Contrast ECHO with agitated saline injectedthrough an intravenous line placed in the left antecubitalarea showed saline arriving in the left atrium beforeappearing in the right atrium, confirming a direct shuntbetween the left SVC and the left atrium. Magneticresonance imaging and angiography confirmed the pres-ence of bilateral SVC vessels, with the left SVC drainingdirectly into the left atrium (Fig. 7).

Two-dimensional (2D) ECHO with color demon-strated an abnormal “systemic” flow pattern in the vesseldraining to the left atrium (Fig. 8), in contrast to thenormally expected flow pattern in a pulmonary veindraining to the left atrium (Fig. 9). Without meticulous2D ECHO and Doppler imaging, the shunt to the leftatrium lesion could have been missed.

DiscussionHypoxia refers to inadequate oxygen supply to the bodyas a whole (generalized hypoxia) or to a region of thebody (tissue hypoxia). Hypoxia differs from hypoxemia.

Hypoxemia refers to low oxygen content in the blood,specifically defined as a low partial pressure of oxygenwithin the arterial blood. It is possible to experiencehypoxia (eg, due to anemia) but maintain a high partialpressure of oxygen.

Hypoxia can be classified as anoxic, anemic, stagnant,and cytochemical. Anoxic hypoxia occurs at the gasexchange level. Anoxic hypoxia (“no oxygen hypoxia”)occurs when a person breathes air with low oxygencontent, as in ascending to a high altitude or divingunderwater while breathing into a closed-circuit re-breather system. Increasing inspired oxygen can improve

Figure 7. Magnetic resonance imaging and angiography (MRI/MRA) showing bilateral superior vena cava (SVC) draining toboth atria, without a communicating vessel. MRI image showsdextroposition of the heart (green arrow: the left SVC draininginto the left atrium; yellow arrow: the right SVC draining intothe right atrium).

Figure 8. Doppler image of a systemic vein and the superiorvena cava (SVC) showing an abnormal Doppler pattern (whitearrow: Doppler of the left SVC; green arrow: abnormal SVCDoppler pattern).

Figure 9. Doppler image of pulmonary vein showing the usualDoppler pattern (green arrow: pulmonary vein Doppler; whitearrow: S wave-flow during systole; yellow arrow: D wave-flowduring diastole; pink arrow: A wave-flow reversal during atrialcontraction).

visual diagnosis




the hypoxia. However, some cases of anoxic hypoxia arenot improved by increasing the inspired oxygen, as withan intracardiac or intrapulmonary shunt.

Anemic hypoxia occurs when the oxygen-carryingcapacity is affected, as with anemia (low hemoglobin) orhemoglobinopathies (eg, sickle cell disease). Stagnanthypoxia occurs when there is decreased blood flow, aswith heart failure or septic shock. Cytochemical hypoxiaoccurs at the cellular level, when oxygen dissociationfrom oxyhemoglobin is impaired, as with cyanide poi-soning, blocking oxygen use at the mitochondrial level.

Persistent hypoxemia should prompt the clinician tolook into different organ systems as potential causes (eg,cardiac, pulmonary, and central nervous systems). In thiscase, the persistence of hypoxemia despite clinical reso-lution of the respiratory distress prompted investigationfor extrapulmonary reasons for hypoxemia. The historyof chromosomal anomaly made a cardiac or major vesselanomaly a likely consideration.

Trisomy 2 mosaicism, although very rare, is associatedwith cardiac defects. Despite lacking consistent pheno-typic features, this genetic abnormality has been associ-ated with craniofacial anomalies; digital anomalies; devel-opmental delay, including language impairment;hypotonia; brain anomalies; and cardiac defects. In thiscase, ECHO demonstrated the left SVC draining intothe left atrium, resulting in shunting of venous bloodinto the systemic circulation through the left side of theheart.

Bilateral SVC is the most common systemic venousanomaly, occurring at a rate of 0.3% to 0.5% in thegeneral population, based on autopsy series. In mostcases, the left SVC connects to the coronary sinus,thereby draining into the right atrium. If the coronarysinus is unroofed or absent, the left SVC connects di-rectly into the left atrium, creating a right-to-left shunt.In this patient, this very rare cardiac anomaly was missedon the initial ECHO. More common cardiac lesions thatcause right-to-left intracardiac shunting resulting in cya-nosis include tetralogy of Fallot, Ebstein anomaly, andtotal anomalous pulmonary venous return. These cya-notic heart diseases can present later in infancy, depend-ing on the severity of the lesion.

Intervention usually is required earlier in life forsingle-ventricle lesions and is dependent on multiplefactors, including the presence of critical obstruction toeither the systemic or the pulmonary circulation, thepresence of patent ductus arteriosus-dependent circula-tion, and the balance between the perfusion of the sys-temic and the pulmonary circulations. Other cardiaclesions, such as transposition of the great vessels, involve

two parallel circulations requiring intervention at birth,without which the lesion is not compatible with life.Most of these conditions are diagnosed shortly after birthand are seen readily on initial ECHO.

Pulmonary causes of hypoxemia include right-to-leftintrapulmonary shunting, diffusion abnormalities,ventilation-perfusion mismatch, and structural airwayabnormalities. In this patient, the unremarkable radio-graph and CT scan of the chest made a variety of disor-ders less likely, such as pneumonia, pleural effusion,pulmonary lymphangiectasia, pulmonary sequestration,and pulmonary hypoplasia. However, other rare condi-tions, such as pulmonary arteriovenous malformation,are possible and require confirmation by angiography.

Other causes of hypoxemia include hemoglobinopa-thies that limit oxygen transport, such as methemoglo-binemia. Methemoglobin has an oxidized ferric ionwithin its core rather than the naturally occurring re-duced ferrous ion found in normal hemoglobin. Thischemistry results in a molecule that does not bind oxy-gen. Should the concentration of methemoglobin in-crease in the red blood cells to a specific threshold,oxygen delivery to the tissue is impaired. A methemoglo-bin concentration of greater than 15% of the circulatinghemoglobin leads to clinically apparent cyanosis.

Pulse oximetry typically overestimates oxygen satura-tion in cases of significant methemoglobinemia due tothe variable light absorbance of methemoglobin at thetwo wavelengths used to measure oxygen saturation.However, in this patient’s case, the pulse oximetry waslower than expected, despite the absence of obviousclinical cyanosis, thereby making methemoglobinemiaunlikely.

Patient CourseThe patient was evaluated for elective surgical repair at alater date.

Case 3 Diagnosis: Large SubglotticHemangiomaLaryngoscopy and bronchoscopy revealed a large sub-glottic hemangioma causing 80% obstruction of the sub-glottic airway (Fig. 10).

DiscussionA distinct barking, seal-like cough or prominent noisyupper airway breathing typically characterizes the presen-tation of viral-induced croup (laryngotracheobronchi-tis). In general, viral croup presents with a brief pro-drome of an upper respiratory tract infection, typicallywith fever, nasal congestion, and cough. The usual pre-

visual diagnosis



sentation occurs at about 6 to 12 months of age. In thispatient, the initial presentation of upper airway symp-toms at 2 weeks of age with no prodrome was highlysuggestive of external airway compression or the pres-ence of an underlying structural anomaly within theupper airway. Recurrent episodes, each of which neces-sitated medical evaluation and intervention, further in-creased the likelihood of an underlying structural anom-aly.

Neonatal stridor is abnormal and must be investi-gated. The differential diagnosis includes laryngomala-cia, unilateral vocal cord paralysis, vascular ring, and, as inthis case, subglottic hemangioma. A recent study showedthat 30% of diagnoses of stridor made by non-otolaryngology physicians were incorrect. (1) Most pa-tients diagnosed as having tracheomalacia were found tohave laryngomalacia on endoscopy. Referral to an expe-rienced pediatric airway specialist is important for specificdiagnosis and surgical intervention.

The most common cause of stridor in an otherwisehealthy infant is laryngomalacia, which occurs when mat-uration of the cartilage supporting the laryngeal inletstructures is delayed. Upper airway noise is generatedduring the inspiratory phase of the respiratory cycle,caused by a dynamic form of obstruction (collapsibility ofthe airway). Such collapsibility is generated by the pres-sure difference between the internal and external por-tions of the airway.

The presence of the biphasic type (involving both theinspiratory and expiratory phase of respiration) of upperairway noise, as in this case, warrants further investigationbecause acquired subglottic stenosis is the most commoncause of biphasic stridor. Commonly, biphasic stridoroccurs in preterm infants who have a history of pro-longed or recurrent intubation during their neonatalcourses. Viewing of the upper airway is necessary toconfirm the diagnosis. Of note, this patient was born atterm and had no history of difficult birth or any injuryduring the perinatal period. Therefore, subglottic steno-sis was an unlikely diagnosis.

Subglottic hemangiomas can be managed medicallyor surgically. Administration of corticosteroids is first-line treatment and can be used with medications such asinterferon-�. In recent years, propranolol has been effec-tive.

Patient CourseThe patient responded transiently to administration ofracemic epinephrine and systemic corticosteroids butcontinued to have recurrent episodes of stridor. Thehemangioma was excised fully, followed by grafting of athyroid alar cartilage wedge onto the superior portion ofthe subglottic area to maintain airway patency duringhealing (Fig. 11). This surgical intervention resulted infull recovery and no residual upper airway obstruction.

This child was treated in 2008, when propranolol, anonselective �-antagonist, was not yet being used as a

Figure 10. Eighty percent obstruction caused by a hemangi-oma of the subglottic airway, as seen beyond the vocal cords.

Figure 11. Postoperative view of the laryngeal inlet showing apatent subglottic airway after excision of the hemangiomaand placement of a thyroid alar cartilage graft (white, 12o’clock position).

visual diagnosis




therapeutic agent for airway hemangiomas. Conven-tional treatment at that time included corticosteroids,laser therapy, and open surgical resection. The risks andbenefits of each treatment were explained to the parentsof this child, and they chose surgery. More recently,numerous reports of the efficacy of propranolol in themanagement of such hemangiomas have appeared in theotolaryngology and pediatric literature. Proposed thera-peutic effects of propranolol include decrease in size ofhemangiomas through vasoconstriction, decreased ex-pression of vascular endothelial and basic fibroblastgrowth factor genes, and apoptosis of capillary endothe-lial cells. (2) Adverse effects of propranolol reportedduring treatment of hemangiomas of infancy includebradycardia, hypotension, high-output cardiac compro-mise (in very large hemangiomas), hypoglycemia, andhyperkalemia. (3)(4)(5) Close monitoring, following atreatment protocol, and anticipatory guidance given tocaretakers should minimize such adverse effects. (3)(4)

Despite these potential adverse effects, the benefits ofpropranolol still may greatly outweigh risks associatedwith surgery, which include airway stenosis, granulation,scarring, infection, and bleeding. The use of propranololfor hemangiomas currently is off-label use. Treatmentoptions for airway hemangiomas must be determined ona case-by-case basis for each patient. Conservative medi-cal management with propranolol may circumvent theneed for surgery.

Conclusion● Respiratory distress, cough, stridor, and wheezing are

very common presenting signs and symptoms in apediatrician’s office. Most often, they are the result ofcommon conditions such as upper respiratory tractinfection, croup, asthma, or pneumonia.

● Sometimes, these same symptoms represent rare butimportant and treatable conditions. The three childrenpresented here had initial symptoms that were consid-ered to represent routine conditions, but their subse-quent evaluation revealed otherwise.

● If a patient has an unusual history (such as three

episodes of croup in 3 months), an unusual clinicalcourse (persistent hypoxemia despite improving“asthma” episodes), or persistent abnormal radiologicfindings (mediastinal shift, mass), the practicing clini-cian should consider the rare and unusual causes ofsuch findings and investigate further to detect anyunderlying disease.

● Accurate diagnosis of unsuspected and rare but treat-able underlying disorders is likely to result in a perma-nent cure.

References1. Zoumalan R, Maddalozzo J, Holinger LD. Etiology of stridor in

infants. Ann Otol Rhinol Laryngol. 2007;116:329–3342. Leaute-Labreze C, Dumas de la Roque E, Hubiche T, Boralevi

F, Thambo JB, Taıeb A. Propranolol for severe hemangiomas ofinfancy. N Engl J Med. 2008;358:2649–2651

3. Lawley L, Siegfried E, Todd J. Propranolol treatment for hem-angioma of infancy: risks and recommendation. Pediatr Derma-tol. 2009;26:610–614

4. Siegfried E, Keenan WJ, Al-Jureidini S. More on propranolol forhemangiomas of infancy [letter]. N Engl J Med. 2008;358:2846–2847

5. Pavlakovic H, Kietz S, Laurer P, Zutt M, LaKomek M. Hyper-kalemia complicating propranolol treatment of an infantile hem-angioma. Pediatrics. 2010;126:e1589–e1593

Suggested ReadingCloutier R, Allard V, Fournier L, Major D, Pichette J, Stonge O.

Estimation of Lungs’ hypoplasia on postoperative chest X-raysin congenital diaphragmatic hernia. J Pediatr Surg. 1993;28:1086–1089

DeBaun M, Vichinsky E. Hemoglobinopathies. In: Kliegman RM,Behrman RE, Jenson HB, Stanton BF, eds. Nelson Textbook ofPediatrics. Philadelphia, PA: Saunders Elsevier; 2007:2032–2033

Geva T, Van Praagh S. Abnormal systemic venous connections. In:Allen HD, Driscoll DJ, Shaddy RE, Feltes TF, eds. Moss andAdams’ Heart Disease in Infants, Children, and Adolescents.Philadelphia, PA: Wolters Kluwer/ Lippincott Williams &Wilkins; 2008:798

Krivchenya D, Rudenko E, et al. Lung aplasia: anatomy, history,diagnosis and surgical management. Eur J Pediatr Surg. 2007;17:244–250

Yaman Y. Persistent pneumonia. Clin Pediatr. 2006;45:478–480

visual diagnosis



Documents

10 Pediatrics in Review_October2011