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REFERENCES1. Dussault JH, Coulombe P, Laberge C, Letarte J, Guyda H, Khoury K.Preliminary report on a mass screening program for neonatal hypothyroidism.

J Pediatr 1975;86:670-4.2. Fisher DA. Congenital hypothyroidism. Thyroid Int 2002;3:3-10.3. Delange F. Neonatal screening for congenital hypothyroidism: resultsand perspective. Horm Res 1997;48:51-61.4. Derksen-Lubson G, Verkerk PH. Neuropsychological development inearly treated congenital hypothyroidism: analysis of literature data. Pediatric

Res 1996;39:561-6.5. Bongers Schokking JJ, Koot HM, Wiersma D, Verkerk PH, DeMuinck-Schrama SMPF. Influence of timing and dose of thyroid replacementon development in infants with congenital hypothyroidism. J Pediatr 2000;136:292-7.6. Salerno M, Militerni R, Bravaccio C, Micillo M, Capalbo D, DiMaio S,et al. Effect of different starting doses of levothyroxine on growth andintellectual outcome at four years of age in congenital hypothyroidism.

Thyroid 2002;12:45-52.7. Selva KA, Mandel SH, Rien L, Sesser D, Miyahira R, Skeels M, et al.Initial treatment dose of L-thyroxine in congenital hypothyroidism. J Pediatr2002;141:786-92.8. Fisher DA. Thyroid disorders. In: Rimoin DL, Connors JM, PyeritzRE, et al, eds. Principles and practice of medical genetics. 4th ed. New York:Churchill Livingstone; 2002. p. 2183-202.9. Chopra IJ. Fetal and neonatal hyperthyroidism. Thyroid 1992;2:161-3.

10. McKenzie JM, Zakarija M. Fetal and neonatal hyperthyroidism andhypothyroidism due to maternal TSH receptor antibodies. Thyroid 1992;2:155-9.11. Zimmerman D. Fetal and neonatal hyperthyroidism. Thyroid 1999;9:727-33.12. Mitsuda N, Tanaki H, Amino N, Hosono T, Miyai K, Tanizawa O.Risk factors for development disorders in infants born to women with Gravesdisease. Obstet Gynecol 1992;80:359-64.13. Kopp P. Human genome and diseases: review. The TSH receptor and itsrole in thyroid disease. Cell Molec Life Sci 2001;58:1301-22.

14. Schwab KO, Gerlich M, Broecker M, Soblemann P, Derwahl M, LobseMJ. Constitutively active germline mutation of the thyrotropin receptor geneas a cause of congenital hyperthyroidism. J Pediatr 1997;131:899-904.15. Weiss RE, Balzano S, Scherberg NH, Refetoff S. Neonatal detection ofgeneralized resistance to thyroid hormone. JAMA 1990;264:2245-50.16. Mastorakos G, Mitsiadis NS, Doufas AG, Koutras DA. Hyperthyroid-ism in McCune-Albright syndrome with a review of thyroid abnormalitiessixty years after the first report. Thyroid 1997;7:433-9.17. La Franchi SH, Snyder DB, Sesser DE, Skeels MR, Singh N, BrentGA, et al. Follow-up of newborns with elevated screening T4 concentrations.

J Pediatr 2003;143:296-301.18. Refetoff S. Inherited thyroxine-binding globulin abnormalities in man.Endocrine Rev 1989;10:275-93.19. Gharib H, Cobin RH, Dickey RA. Subclinical hypothyroidism duringpregnancy: position statement from the American Association of ClinicalEndocrinologists. Endocrine Pract 1999;5:367-8.

IMMUNE OR IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP) IN

CHILDHOOD: WHAT ARE THE RISKS AND WHO SHOULD BE TREATED?

In this issue of the Journal, Rosthj et al1 describe aprospective unselected series of 501 children with idio-pathic thrombocytopenic purpura (ITP) presenting with

a platelet count of 6months) recovered a platelet count of >20,000/mm3 by 6months; 15 patients (3%) had severe bleeding requiring

transfusions, but none had an intracranial hemorrhage (0%).From the moment that effective therapy to increase

platelet counts in childhood ITP became available, it has beencontroversial. In the 1970s corticosteroids became available,and although they increased platelet counts, their usefulness aseffective therapy became controversial.2,3 In the 1980s Imbachet al introduced therapy with intravenous immune globulin(IVIG),4 and Salama et al introduced therapy with anti-Dimmunoglobulin.5 Although these newer therapies may in-

crease the platelet count a little faster than corticosteroids, the

controversy continues.6,7 The controversy centers on whetherwe should treat the platelet count. Diametrically opposed

guidelines from Great Britain and the United States haveeither recommended observation or therapy with pharmaco-logic agents.8-10 Analysis of actual practice suggests that onboth sides of the Atlantic, children with ITP are treated withmedication.11-13

But is the platelet count the indicator for treatment andits increase the goal? Medications have side effects. In theoriginal randomized trial of corticosteroid therapy versusintravenous immunoglobulin by Imbach et al, 77% of childrentreated with steroids and 22% of those treated with IVIGhad side effects.14 Intracranial hemorrhage and/or death fromITP certainly are outcomes we

would like to avoid. For-tunately these are rare.15 Inthe 1980s these serious out-comes were thought to occurin 1% to 4% of children withITP.16When investigators an-alyzed the incidence of intra-cranial hemorrhage in subjectsreferred to tertiary care hospi-tals,theincidencewasnotmuchdifferent than that originallyreported.17,18 The current

See related article, p 302.

Reprint requests: Pedro A. de Alar-con, MD, University of Virginia HealthSystem, Pediatric Hematology/Oncol-ogy, PO Box 800386, Barringer 4thFloor RM 4383, Charlottesville, VA22908.

J Pediatr 2003;143:287-9.

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ITP Idiopathic thrombocytopenic purpuraIVIG Intravenous immunoglobulin

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study, and the International Childhood ITP Registry reportpublished recently, have placed the risk of having anintracranial hemorrhage at a lower level, 0/501 and 2/1496.1,15

The risks of ITP, however, are not limited to theseserious outcomes. Bleeding can cause anemia that requirestransfusion therapy. Even petechiae and bruising can cause

worry in parents and lead to changes in lifestyle of the patients.The risk of hemorrhage of any kind in ITP and the duration of

this risk constitute better outcome measures to determinewhether therapy of ITP is needed.

Medeiros and Buchanan retrospectively analyzed thepatients with a clinically significant hemorrhage among thepatients with ITP referred to Dallas17; 58 of 332 availablepatients for review (17%) had a clinically significant hemor-rhage defined as either intracranial hemorrhage, epistaxisrequiring cautery or nasal packing, gross hematuria, or otherbleeding severe enough to cause a drop in hemoglobin to 2 gm/dL. The majority (62%) of clinicallysignificant hemorrhages occurred within 48 hours of pre-sentation; 9% of the episodes occurred in spite of therapy with

corticosteroids, IVIG, or both. Eighty-seven percent of theepisodes occurred when the platelet count was 6 months.

In line with the assessment of actual practices in GreatBritain and the United States, the Scandinavian pediatricianstend to treat ITP with corticosteroids or IVIG (57%).However, there were regional differences. In Denmark andIceland, 73% to 80% of children were treated, whereas inFinland only 38% were treated.

So, what can we learn from the available information on

childhood ITP? Hospital series have higher incidence ofserious adverse events. The most serious complications of ITP,death, and intracranial hemorrhage are rare. To resolve thecontroversy of whether to treat a child with ITP, we need tobetter understand the true clinical course of ITP. Studies likethe one by Rosthj et al1 are critical to our defining the trueincidence of complications in this disorder. It is clear from thisstudy, also well supported by other studies,19-21 that themajority of children with ITP recover very quickly, with mostpatients increasing their platelet count to >20,000/mm3 by onemonth. Although treating the platelet count may not be theonly focus of therapy, the platelet count is predictive of

bleeding. In the studies by both Medeiros and Buchanan17 andRosthj et al,1 patients with platelet counts of

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10. George JN, Woolf SH, Raskob GE, Wasser JS, Aledort LM, Ballem PJ,et al. Idiopathic thrombocytopenic purpura: a practice guideline developed byexplicit methods for the American Society of Hematology [review]. Blood1996;88:3-40.11. Sutor AH, Harms A, Kaufmehl K. Acute immune thrombocytopenia(ITP) in childhood: retrospective and prospective survey in Germany. Semin

Thromb Hemost 2001;27:253-67.12. Bolton-Maggs PH, Moon I. Assessment of UK practice for manage-ment of acute childhood idiopathic thrombocytopenic purpura againstpublished guidelines. Lancet 1997;350:620-3.

13. Vesely SK, Buchanan GR, Adix L, George JN, Cohen AR, BlanchetteVS, et al. Self-reported initial management of childhood idiopathicthrombocytopenic purpura: results of a survey of members of the AmericanSociety of Pediatric Hematology/Oncology, 2001. J Pediatr Hematol Oncol2003;25:130-3.14. Imbach P, Wagner HP, Berchtold W, Gaedicke G, Hirt A, Joller P,et al. Intravenous immunoglobulin versus oral corticosteroids in acuteimmune thrombocytopenic purpura in childhood. Lancet 1985;2:464-8.15. Kuhne T, Imbach P, Bolton-Maggs PH, Berchtold W, Blanchette V,Buchanan GR. Newly diagnosed idiopathic thrombocytopenic purpura inchildhood: an observational study. Lancet 2001;358:2122-5.

16. Woerner SJ, Abildgaard CF, French BN. Intracranial hemorrhage inchildren with idiopathic thrombocytopenic purpura. Pediatrics 1981;67:453-460.17. Medeiros D, Buchanan GR. Major hemorrhage in children withidiopathic thrombocytopenic purpuraimmediate response to therapy andlong-term outcome. J Pediatr 1998;133:334-9.18. Blanchette VS, Turner C. Treatment of acute idiopathic thrombocy-topenic purpura. J Pediatr 1986;108:326-7.19. Blanchette VS, Luke B, Andrew M, Sommerville-Nielsen S, Barnard D,de Veber B, et al. A prospective, randomized trial of high-dose intravenous

immune globulin G therapy, oral prednisone therapy, and no therapy inchildhood acute immune thrombocytopenic purpura. J Pediatr 1993;123:989-995.20. Dickerhoff R, Von Ruecker A. The clinical course of immunethrombocytopenic purpura in children who did not receive intravenousimmunoglobulins or sustained prednisone treatment. J Pediatr 2000;137:629-32.21. Mori PG, Lanza T, Mancuso G, de Mattia D, Catera P, Miano C,et al. Treatment of acute idiopathic thrombocytopenic purpura (AITP):cooperative Italian study group results. Pediatr Hematol Oncol 1988;5:169-178.

CELIAC DISEASE A NEVER-ENDING STORY?

The past 10 to 15 years have witnessed a plethora ofscientific publications on celiac disease (CD). Ourunderstanding of its epidemiology, etiopathogenesis,

and clinical manifestations has changed dramatically duringthis time, and our ability to identify potential cases has greatlyimproved. Despite this, it seems there are still more questionsthan answers, and the story that is CD is never ending.

Occasional reflection on where we are, and where we mostneed to go, is thus necessary to best help those who have thecondition.

CD is believed to be the most common geneticallypredetermined condition to affect humankind today. It hasa worldwide distribution, with reports from Europe, Northand South America, the Middle East, India, North and SouthAfrica, and the Australasias.1 Where data exists, prevalencerates appear remarkably similar with 0.5% to 1% of the generalpopulation in the United States and many European countriesbeing affected.2-5 Although we do not fully understand thegenetics of the condition, we do know there is a strong

association with the human leukocyte antigen (HLA) DQ2and DQ8 genotypes, as almost all known cases have one orother.6We know CD is immunologically mediated with bothhumoral and cellular components involved. The precise cas-cade of inflammatory events that lead to the characteristicremodeling of the small intestinal mucosa remains to bedefined, but we are progressing in that direction. Prolamins

derived from wheat, rye and barley are known to contain thepeptides that initiate the immune events. We are in the processof identifying more precisely the specific epitopes that are thetoxic components. Recent identification of tissue trans-glutaminase (tTG) as the autoantigen in CD was a significantbreakthrough in our understanding of the disease.7 tTGdeamidates glutamine as a crucial early step initiating the

immunologic cascade. Deamidation increases the negativecharge on the peptide, which promotes binding to the HLADQ2/8 molecule with subsequent stimulation of gliadin-specific CD4+ T cells.8 tTG is also the autoantigen against

which endomysial antibodies (EMA) are generated as part ofthe humoral response that we are able to recognize, but do not

yet understand.Our understanding of the clinical manifestations of CD

has also undergone a dramatic change in this period. We nowknow that CD is extremely variable in its manifestations andage of onset. Although thedisease typically causes damage

to the small intestinal mucosa,as many as 50% of newlydiagnosed cases do not havegastrointestinal symptoms atinitial presentation. Commonpresenting features includeane-mia, dermatitis herpeti-formis, lethargy, unexplained

weight loss, and in children,short stature.1 There is a rec-ognized association betweenCD and a variety of other

See related article, p 308.

Reprint requests: Ivor D. Hill, MB,ChB, MD, Department of Pediatrics,Wake Forest University School ofMedicine, Medical Center Blvd, Win-ston-Salem, NC 27157.

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CD Celiac diseaseEMA Endomysial antibodiesGFD Gluten-f ree d ietHLA Human leukocyte antigentTG Tissue transglutaminase

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