Pr,cs�2Review and

Education Proqram

A�Il;RIc�N ��(;AI)I�’IY OF PFI)IVfRICS

Vol. 12 No. 12June 1991

355 #{149}Use of Growth Hormone to TreatShort Stature - Saenger

364 #{149}Bone Marrow Transplantation -

Yeager

372#{149}Recording Telephone Contacts -

Nazarian

374 #{149}Record Documentation -

Nazarian

375 #{149}Alcohol Risk during Pregnancy -

Alpert and Zuckerman; Jones

CONTE NTSARTICLES

355 Use of Growth Hormone in the Treatment of Short

Stature: Boon or Abuse?Paul Saenger

364 Pediatric Bone Marrow Transplantation

Andrew M. Yeager

COMMENTARIES

372 The Value of Recording Telephone Contacts

Lawrence F. Nazanan

374 Medical Record Documentation of Acute

Gastroenteritis

Lawrence F. Nazarian

ARTICLE

375 Alcohol Use during Pregnancy: What Is the Risk?

Joel J. Alpert and Barry ZuCkerman

POINT-COUNTERPOINT

380 Fetal Alcohol Syndrome

Kenneth L. Jones; Joel J. Alpert and Barry Zuckerman

ABSTRACTS

363 Thyroid Carcinoma

371 Gastroesophageal Refiux (GER) and Cystic Fibrosis

during Infancy: Don’t Blame GER for Everything

373 Sleep Apnea and Upper Airway Obstruction

379 Surgical Treatment of Pediatric Cardiac Arrhythmia

382 Simultaneous Administration of MMR, DTP, and OPV

383 Cervical Cancer and Sexually Transmitted Diseases

383 Monitoring of pH in Gastroesophageal Reflux

384 Hypoalbuminemia at Time of Diagnosis of Cystic Fibrosis

as a Marker for Seventy of Respiratory Course

385 Cumulative Index

Cover: Two Young Girls at the Piano, by Pierre August RENOIR (© 1989The Metropolitan Museum of Art; Robert Lehman Collection, 1975.(1975.1 .201)). Two Young Girls at the Piano is one of at least five Versionsof the same scene by Renoir, including a lovely pastel recently sold atauction. Renoir was 51 years of age at the time he did this work in 1892,and at the height of his popularity. This lovely presentation evokes a formerera when adolescents, at least those in favored economic status, spent theirleisure learning skills such as playing the piano and singing. One of themajor tasks of adolescence is to develop one’s identity and sense ofcompetence.Whether it is the charming skills so beautifully depicted in thispainting or others, the task of pediatricians is to assist young people indeveloping skills of which they can be proud.

The printing and production of

Pediatrics in Review is made possible,cre� � in part, by an educational grant from

� RD S S � Ross Laboratories.

Answer Key: 1 .C; 2.A; 3.C; 4.C; 5.� - ‘ 7 B; 8.C; 9.C; lOG; 11 .B.

Vol 12, No. 12, June 1991

Pediatricsin ReviewEDITORRobert J. HaggertyNew York Hospital-CornellMedical CenterNew York, NY

Editoriai Office:The William T. Grant Foundation515 Madison Aye, 6th Floor,New York, NY 10022-5403

ASSOCIATE EDITORLawrence F. NazananPanorama Pediatric GroupRochester, NY

ABSTRACTS EDITORSteven B. Shelov, Bronx, NY

MANAGING EDITORJo A. Largent, Elk Grove Wllage, ILEDITORIAL CONSULTANTVictor C. Vaughan III, Stanford, CA

EDITORIAL BOARDMorvis A. Angulo, Mineola, NYRalph Cash, betroit, MIDaniel D. Chapman, Mn Arbor, MlEven Chamey, Worcester, MARussell W. Chesney, Memphis, TNCatherine DeAngelis, Baltimore, MDPeggy Ferry, Tucson, AZAlan L. Goldbloom, Toronto, ONRichard B. Goldbloom, Halifax, Nova ScotiaJohn L. Green, Rochester, NYRobert L. Johnson, Newark, NJAlan M. Lake, Glen Arm, MDFrederick H. Lovejoy, Jr., Boston, MAJohn T. McBride, Rochester, NYMarie C. McCormick, Boston, MAVincent J. Menna, Doylestown, PAKurt Metzel, Kansas City, MOLawrence C. Pakula, Timonium, MDPhillip A. Pizzo, Bethesda, MDRonald L. Poland, Hershey, PAJames E. Rasmussen, Mn Arbor, MlRobert Rennebohm, Columbus, OHWilliam 0. Robertson, Seattle, WAJames S. Seidel, Torrance, CARichard Sills, Newark, NJLaurie Smith, Washington, DCWilliam B. Strong, Augusta, GAVernon T. Tolo, Los Angeles, CARobert J. Touloukian, New Haven, CTW. Allan Walker, Boston, MATerry Yamauchi, Little Rock, ARMoritz M. Ziegler, Cincinnati, OH

EDITORIAL ASSISTANTElizabeth A. Nelson

PUBLISHERAmerican Academy of PediatricsErrol A. Alden, Director, Department of EducationNancy Wachter, Copy Editor

PEDIATRICS IN REVIEW (ISSN 0191-9601) is owned andcontrolled by the American Academy of PedIatrics. ft is publishedsix times a year (January through June, 1991) by the AmericanAcademy of Pediatrics. 141 Northwest Point Blvd. P0 Box

927. Elk Grove Village, IL 60009-0927.

Subscription price per year Candidate Fellow of the AAP $50;AAP Fellow $75; Allied Health or Residents $50; Nonmember or

Institution $100. Current single Issues $8.Second-class postage paid at ARUNGTON HEIGHTS, 1W-

NOIS 60009 and at additional mailing offices.o American Academy of PedIatrics, 1991.

All Rights Reserved. Printed in U.S.A. No part may be duplicated

or reproduced without permission of the American Academy ofPediatrics.POSTMASTER: Send address changes to PEDIATRICS IN RE-ViEW, American Academy of PedIatrics, 141 Northwest Point

Blvd. P0 Box 927. Elk Grove Village. IL 60009-0927.

EDUCATIONAL OBJECTIVE

158. The pediatrician shouldhave the appropriate ability to di-agnose and manage carcinoma ofthe thyroid. (Recent Advances,90/91)

ENDOCRINOLOGY

pediatrics in review #{149}vol.12 no.12 june 1991 PIR 363

51 . Lancet. 1989;1 :51 1-51 2. Editorial.52. Stabler B, Siegel PT, Clopper AR,

Holmes CS, Stoppani CE, Compton PG.Risk for academic underachievementand behavior problems in short children.Pediatr Res. 1990;27:87A

53. Siegel P,Bedway M, Koepke T,Hobart C,Postellon D. Assessment of attentionaldeficits among underachieving growthhormone deficient children. Pediatr Res.1990;27:18A

54. Cuttler L, Michon A, Aeinecke M, Stock-ing C. Attitudinal and behavioral con-comitants of short stature. Pediatr Res.1990;27:4A

55. Aotnem D, Cohen D, Hintz AL, et al. Psy-chological sequelae of relative treatmentfailure for children receiving humangrowth hormone replacement. J AmAcad Child Adolesc Psychiatry.1979;1 8:505-520

56. Aobin AA. Reshaping the psyche: theconcurrent improvement in appearanceand mental state after rhinoplasty. Br JPsychiatry. 1988;1 52:539-543

Self-Evaluation Quiz1. Of the following children who haveshort stature, which one presents the leastconvincing evidence that he or she will re-spond to growth hormone (GH) therapy?

A. Alice is 7 years old and has Turner syn-drome; she responds normally to a GHstimulation test.

B. Paul is 9 years old and has chronic renalfailure; he responds normally to a GH

stimulation test.C. Edward is 8 years old and apparently

healthy except for short stature; he hasa GH levelof 14 ng/mL in a fasting speci-men. Bone age is 8 years.

D. Barbara is 15 years old and has recently

had a craniopharyngioma successfully

removed; her bone age is 11 years.

2. Which of the following is the least ap-

propriate contribution to a decision to un-

dertake a 12-month trial of GH therapy in achild who has short stature?

A. Assurance of some psychologic benefit.

B. A growth velocity less than 25% of nor-mal during the past year.

C. Predicted height under 157 cm (62 in) ina boy.

D. Predicted height under 152 cm (60 in) in

a girl.

3. Interpretation of GH stimulation testsrequires that attention be given to each ofthe following except that:A. Standards vary among laboratories.

B. Prior thyroid tests should be done.

C. Prior liver function tests should be done.D. Variability with age, sex, or pubertal sta-

tus has not been determined.

4. Which of the following sets of findings

in a child who has short stature gives

strongest evidence of simple constitution-

al short stature?A. Advanced bone age; parental heights

average.

B. Normal bone age; parental heights be-low average.

C. Delayed bone age; parental heights av-erage.

D. Delayed bone age; parental heights be-low average.

5. Which of the following sets of findingsin a child who has short stature givesstrongest evidence of untreated congeni-tal adrenal hyperplasia?

A. Advanced bone age; parental heightsaverage.

B. Normal bone age; parental heights be-low average.

C. Delayed bone age; parental heights av-

erage.D. Delayed bone age; parental heights be-

low average.

Thyroid Carcinoma

Solitary Thyroid Nodules in Children and Adolescents. Hung W, August GP,Randolph JG, et al. J Pediatr Surg. 1 982;1 7:225-229.

Management of Thyroid Nodules in Children: A 20-Year Experience. DesjardinsJG, Khan AH, Montupet P, et al. J Pediatr Surg. 1 987;22:736-739.

A Twenty-Year Experience With Thyroid Carcinoma in Children. Desjardins JG,Bass J, Leboeuf G, et al. J Pediatr Surg. 1988;23:709-71 3.Nodular Thyroid Disease in Children and Adolescents: A High Incidence ofCarcinoma. McHenry C, Smith M, Lawrence AM, et al. Am Surg. 1988;54:444-447.Differentiated Thyroid Carcinoma in Childhood: Long-Term Follow-up of 72 Pa-dents. Schlumberger M, De Vathaire F, Travagli JP, et al. J Clin Endocrinol Metab.1987; 65:1088-1094.

Although thyroid nodules are relatively uncommon findings in the pediatric popula-tion, their detection requires careful and thorough evaluation. Several studies indicatethat as many as one third of all nodules found may represent malignancies. While thisincidence compares favorably with studies from the era of head and neck irradiationfor tonsilar or thymic enlargement, when as many as 70% of thyroid nodules provedto be malignant, early detection of thyroid tumors remains an important responsibilityof the pediatrician.

The thyroid should be carefully palpated to determine its size and consistency andto discover any evidence of additional nodules. In addition, cervical and axillary lymphnodes should be examined for evidence of enlargement or inflammation. The thyroidmay be evaluated further using ultrasonography (to determine if the nodule is cysticor solid), by computed tomography or magnetic resonance imaging procedures, or by1311 scans. A “cold” nodule (one which fails to take up radioactive iodine) carries anincreased risk of malignancy.

Although the majority of nodules are benign (most are follicular adenomas), commonthyroid malignancies include papillary, follicular, and medullary carcinoma. Surgerytypically includes partial thyroidectomy(except for medullary carcinoma, which requirestotal thyroidectomy) and dissection of involved nodes. Patients must be observeddiligently postsurgery because both neck recurrence and distant metastases may benoted many years after the initial occurrence. Long-term follow-up is essential,therefore, and should include radiographic studies of the chest, tests of the serumthyroglobulin level (typically elevated in metastatic disease), and 1311 total body scans.

(Ron G. Rosenfeld, MD, Editorial Board)

Bone Marrow Transplantation

PIR 370 pediatrics in review ‘ vol.12 no.12 june 1991

in these series. In contrast, the re-suits of autologous transplantationwith chemopurged (treated with thecompound 4-hydroperoxycyclophos-phamide) bone marrow are encour-aging for children who have acutemyeloid leukemia. Patients whohave second- or third-remission my-eloid leukemia have a disease-freesurvival rate of 30% following busu-Ifan-cyclophosphamide conditioningand the infusion of drug-incubatedautografts. The relapse rate for thisgroup is 50%, as might be expectedfor recipients of syngeneic trans-plants.

Neuroblastoma. Children olderthan 12 months of age who haveStage IV neuroblastoma have a veryunfavorable prognosis, with dis-ease-free survival of less than 10%with combination chemotherapyalone. When carried out during thefirst complete remission, allogeneicor autologous bone marrow trans-plantation in children who have dis-seminated neuroblastoma is associ-ated with cure rates of 25% to 40%,but children who undergo transplan-tation during partial or second com-plete remissions have much poorerdisease-free survival. The possiblecontamination of the autograft withoccult tumor cells has led to the useof ex vivo bone marrow autograftpurging, especially with monoclonalantibodies directed at neuro-blastoma-specific antigens or withimmunomagnetic beads.

Other Malignancies. Patients whohave relapsed Hodgkin and non-Hodgkin lymphoma may be curedwith allogeneic or autologous bonemarrow transplantation; the best re-sults (35% to 50% cure rate) are ob-served with minimal residual dis-ease or second complete remission.Patients who have bulky residuallymphoma or progressive drug-resi-stant disease at the time of trans-plant are at very high risk for tumorrecurrence. More intensive pre-transplant preparative regimensneed to be developed that effec-tively eradicate a resistant or bulkyresidual tumor with acceptable tox-icity. For example, combination pre-transplant chemotherapy with com-binations of busulfan, cyclophos-phamide, etoposide (VP-16), or cyto-sine arabinoside may be useful for

these kinds of patients. Autologoustransplantation as part of the treat-ment of other solid tumors of child-hood (eg, rhabdomyosarcoma,Ewing sarcoma, neuroectodermaltumors, Wilms tumor, and possiblycentral nervous system tumors) maylead to partial or complete response,but durable remission and pro-longed disease-free surviv�I areseen rarely. Again, the observationthat patients with refractory diseaseor large tumor burdens at the time oftransplant are at especially high riskfor relapse underscores the sugges-tion that intensive cytoreductivetherapy with bone marrow stem cellrescue should be applied duringstates of minimal residual disease(eg, first or second complete remis-sion) in children at high risk for re-currence of solid tumors.

SUMMARY

Bone marrow transplantation is ahigh-visibility, high-technology disci-pline with a growing list of poten-tially curative applications in neo-plastic, hematologic, immunologic,and genetic diseases of children.The clinical problems experiencedby children who have received bonemarrow grafts involve pediatriciansin both general and subspecialtypractice and require a workingknowledge of the applied immu-nobiology of bone marrow trans-plantation. As the transplantationprocedure has evolved from a re-search tool to an established thera-peutic modality, collaboration be-tween basic scientists and clinicianshas led to a greater understandingof the pathophysiology of the immu-nobiologic events that occur after al-logeneic bone marrow transplanta-tion and, thus, to improvements inthe clinical care of transplant recip-ients. As its applications in pediatricmedicine grow, bone marrow trans-plantation presents additional chal-lenges for the future: expansion ofthe allogeneic donor pool, use ofmore effective or aggressive pre-parative regimens and autologousbone marrow-purging strategies,more effective prevention and treat-ment of graft-versus-host disease,and development of gene-replace-ment therapy by infusion of modifiedautologous bone marrow cells.

ACKNOWLEDGMENTS

This work was supported in part by GrantsP01 CA15396, AOl NS24097, and AOlCA40282 from the National Institutes ofHealth, Bethesda, Maryland, by a grant fromThe Children’s Cancer Foundation, Balti-more, Maryland, and a contribution from theMichael V. Ruckle Memorial Fund.

SUGGESTED READING

1. Deeg HJ, Storb A, Thomas ED. Bone mar-row transplantation: a review of delayedcomplications. Br J Haematol. 1984;57:185-208

2. Johnson FL, Pochedly C, eds. Bone Mar-row Transplantation in Children. New York:Raven Press; 1990

3. Parkman A. The application of bone mar-row transplantation to the treatment of ge-netic diseases. Science. 1986;232:l373-1378

4. Santos GW, Hess AD, Vogelsang GB.Graft-versus-host reactions and disease.Immunol Rev. 1985;88:169-192

5. Santos GW, Veager AM, Jones RJ. Auto-logous bone marrow transplantation. AnnuRev Med. 1989;40:99-112

6. Winston DJ, Gale AP, Meyer DV, et al. In-fectious complications of human bonemarrow transplantation. Medicine.1989;58:l-31

7. Yeager AM, Kaizer H, Santos GW, et al.Autologous bone marrow transplantationin patients with acute nonlymphocytic leu-kemia, using ox vivo marrow treatmentwith 4-hydroperoxycyclophosphamide. NEnglJ Med. 1986;315:141-147

8. Yeager AM. Bone marrow transplantationin children. PediatrAnn. 1988;17:694-714

Self-Evaluation Quiz

6. Bone marrow transplantation has beensuccessful in the management of each ofthe following conditions except:A. �3-ThaIassemia major.

B. Neuroblastoma.

C. Leukemia.

D. Lysosomal storage disease.E. Acquired immunodeficiency syndrome

during infancy.

7. A bone marrow transplantation between unrelated persons who have identi-cal HLA types (class I and class II) is:

A. Syngeneic.B. Allogeneic.C. Heterogeneic.

0. Autologous.

8. After successful bone marrow trans-plantation, each of the following cells ofthe recipient will be of donor origin ex-cept:A.

B.

C.

0.E.

Platelets.Macrophages.Osteoblasts.Glial cells.Kupifer cells.

EDUCATIONAL OBJECTIVE

E. The pediatrician should beaware that gastroesophageal re-

flux has been reported in severalchildren with cystic fibrosis. In ad-

dition, pulmonary disease due togastroesophageal reflux during in-fancy may mask a diagnosis ofcystic fibrosis. (Recent Advances,90/91)

HEMATOLOGY

pediatrics in review #{149} vol.12 no.12 june 1991 PIR 371

9. In successful bone marrow transplanta- 10. The incidence of clinical graft-versus- 11. A pretransplantatlon regimen de-

tion, the cell of the donor marrow most host disease following bone marrow trans -signed to ablate the recipient’s bone mar-critical to repopulation of the recipient is plantation between apparently entirely his -row and bone marrow-generated cells isthe: tocompatible non-twin (sibling) persons is required prior to bone marrow transplanta-

A. T cell. closest to: tion in each of the following patients ex-B. B cell. A. 5%. cept the patient who has:C. Stem cell. B. 15%. A. Wiskott-Aldrich syndrome.D. Monocyte. C. 35%. B. Severe combined immunodeficiency.E. Erythrocyte. 0. 65%. C. Leukemia.

E. 85%. 0. Neuroblastoma.

E. Chronic granulomatous disease.

Gastroesophageal Reflux (GER) and Cystic Fibrosis during Infancy: Don’tBlame GER for Everything

Cystic Fibrosis and Gastroesophageal Reflux in Infancy. Thomas D, Rothberg AM,Lester LA. Am J Dis Child. 1 985;1 39:66Cystic Fibrosis Mistaken for Gastroesophageal Reflux with Aspiration. Frates RC,Cox KL. Am J Dis Child. 1981 ;135:719Complications of Gastroesophageal Reflux in Patients with Cystic Fibrosis. BendigDW, Seilheimer OK, Wagner ML, etal. JPediatr. 1981;100:536

Gastroesophageal refiux (GER) frequently is found in association with recurrentepisodes of pulmonary disease, although the precise causal relationships are notclear. Some children (and adults) with recurrent pneumonia or asthma together withGER improve with therapy directed at the GER. These three studies present dataconcerning cystic fibrosis and GER.

Bendig et al review seven patients, aged 8 to 31 years, with previously diagnosedcystic fibrosis who complained of pain in the upper abdomen. All had GER documentedby esophagram, endoscopy, and pH probe. Therapy included medical managementor surgery, depending on the severity of involvement and the degree of respiratoryreserve. No improvement in lung function was shown, although there were varyingdegrees of relief of the abdominal symptoms.

Frates and Cox discuss two infants who had recurrent vomiting and failure to thrive.One had documented GER, the other had presumed GER. The failure to thrive wasascribed initially to the GER, but subsequent sweat tests revealed cystic fibrosis.

Thomas et al present two infants with respiratory distress and documented GER.Both infants developed respiratory failure and required mechanical ventilation. Afterthe respiratory failure and growth of Staphylococcus aureus from the airways, cysticfibrosis was suspected and confirmed. Both babies had received bethanecho! as partof the management of their GER before the development of the respiratory failure.

Comment: These studies provide an analysis of the relationship of GER and cystic

fibrosis from two perspectives. The study of Bendig et al suggests that there may bean increased incidence of GER in patients who have cystic fibrosis. They point outthe importance of considering GER in the differential diagnosis of upper abdominalpain in such patients. Specific therapy may reduce symptoms and gastrointestinalcomplications, although there may be no effect on the respiratory complications ofcystic fibrosis.

The other two studies serve to remind pediatricians to continue including cysticfibrosis in the differential diagnoses of failure to thrive and recurrent pulmonary disease.Such patients have an increased incidence of asthma and possibly of GER. Wheneither of these diseases is diagnosed in an infant or toddler, cystic fibrosis must alsobe considered. Sweat tests should be performed by a reliable laboratory, one withhigh volume and good quality control. Liberal use of the sweat test laboratory ismandatory, particularly given the improved outlook for patients with cystic fibrosis ifthey receive early diagnosis and institution of appropriate therapy. As Dr Robert Woodof the Unive.sity of North Carolina says, “There is no reason for not doing a sweattest.” (Michael R. Bye, MD, Albert Einstein College of Medicine/Montefiore MedicalCenter, Bronx, NV)