11. Eddleston M, Roberts D, Buckley N. Management of severe

organophosphorus pesticide poisoning. Crit Care 2002;6:259.

12. Lifshitz M, Rotenberg M, Sofer S, Tamiri T, Shahak E, Almog S.

Carbamate poisoning and oxime treatment in children: a clinical and

laboratory study. Pediatrics 1994;93:652-5.

13. Lifshitz M, Shahak E, Sofer S. Carbamate and organophosphate

poisoning in young children. Pediatr Emerg Care 1999;15:102-3.

14. Feldmann RJ, Szajewski J. Cholinergic syndrome, in IPIC INTOX

Databank; 1998.

15. Golsousidis H, Kokkas V. Use of 19 590 mg of atropine during 24 days

of treatment, after a case of unusually severe parathion poisoning. Hum

Toxicol 1985;4:339-40.

16. McDononough JH Jr, Jaax NK, Crowley RA, Mays MZ, Modrow HE.

Atropine and/or diazepam therapy protects against soman-induced neural

and cardiac pathology. Fundam Appl Toxicol 1989;13:256-76.

17. Thiermann H, Szinicz L, Eyer F, Worek F, Eyer P, Felgenhauer N,

et al. Modern strategies in therapy of organophosphate poisoning. Toxicol

Lett 1999;107:233-9.

A TALE OF TWO CENTIMETERS

It has been said, without too great a stretch of theimagination, that a rock will grow if one gives it enoughgrowth hormone (GH).1 Indeed, experiments of nature

(eg, pituitary gigantism and acromegaly) demonstrate con-vincingly that most individuals with open epiphyses, in thepresence of high serum concentrations of GH and itshormonal mediator insulin-like growth factor (IGF)-I, arecapable of growing well beyond their genetic endowments. Ina variety of clinical conditions characterized by growth failure,such as Turner syndrome2 and intrauterine growth retarda-tion,3 for example, increasing pharmacologic dosages of GHhave resulted in accelerated growth and adult heights wellbeyond those anticipated in untreated individuals.

Not surprisingly, investigations using higher dosages ofGH have demonstrated that a dose-response effect on growthexists, although, generally, the slope is relatively shallow. Inchildren identified as GH deficient, for example, an increase inGH dosage from 0.025 to 0.05 mg/kg per day resulted ina sustained increase in growth velocity, although no additionalbenefit was observed with a further increase to 0.1 mg/kg perday.4 In recent studies in Turner syndrome, a clear dose-response was demonstrated, although, once again, with onlylimited additional benefit at the highest GH dosage.2

The current paper byWit et al5 follows on the heels of anearlier report by Leschek et al6 on the use of GH in childrenwith idiopathic short stature (ISS), a heterogeneous entity thatincludes children with familial short stature, constitutionaldelay, and normal GH production in the face of normal ordecreased serum concentrations of IGF-I. The latter study,which constituted part of the basis for FDA approval of GH inISS, demonstrated a statistically significant, albeit modest,effect of GH on adult heights of children with ISS, with anincrease in adult height of 3.7 cm in GH-treated versusplacebo-treated subjects.6 It was recognized, however, thata potentially greater benefit of GH therapy may well have beenmasked by the relatively advanced age of the subjects and themodest GH dosage of 0.074 mg/kg three times per week(0.22 mg/kg per week).

Given this background, it is not particularly surprisingthat the current study by Wit et al5 demonstrates a dose-response effect of GH in patients with ISS. The investigations,although carefully conducted and analyzed, are characterized by

GH Growth hormoneIGF Insulin-like growth factorISS Idiopathic short stature

10 Editorials

a number of the short-comings inevitable to GH studiesdesigned over a decade ago: (1) selection of a rather limited doserange for GH (0.24 vs 0.37 mg/kg per week); (2) use ofa stepwise increase inGHdosage for one arm rather than simplystarting subjects at the highest dosage; (3) a high dropout rate;(4) absence of either an observational control or placebo controlgroup; and (5) inadequate surveillance of serum concentrationsof IGF-I, as a marker of both GH responsiveness and safety.Despite these caveats, the study did demonstrate a statisticallysignificant difference in the growth response of the two‘‘extremes’’ of GH dosage tested (ie, 0.24 vs 0.37 mg/kg perweek), with mean overall height gains over the baselinepredicted adult heights of 5.4 and 7.2 cm, respectively.Although this difference in adult height is less than 2 cm, it isof note that 94% of subjects receiving the high dose of GHachieved adult heights within the normal range. Even in theabsence of a control group, this is an impressive accomplishmentand may be compared favorably with the report by Lescheket al,6 using the low GH dosage of 0.22 mg/kg per week.

Indeed, the investigations of Leschek et al6 and Witet al5 should be viewed in the same context, even though thestudies were independent in both their design and execution.Taken together, they provide strong (if not conclusive)evidence that GH is capable of accelerating growth andimproving adult height in most if not all children with ISS. Itwould appear that if initiated at a sufficiently early age and atan appropriate dosage, GH can lead to an adult height withinthe normal range in the majority of children with ISS. Asresearch continues into the molecular basis for the heteroge-neous conditions that constitute ISS,7 it is likely that ourtherapeutic acumen will be sharpened, permitting furtheroptimization of cost-benefit ratios for GH use in thispopulation as well as an assessment of the potential use ofIGF-I therapy in children who demonstrate some degree ofGH insensitivity as an etiologic factor in their growth failure.

The fact that we cantreat a condition does not inand of itself imply that weshould, and it is this issue thatremains most germane to themanagement of idiopathicshort stature. Critics of phar-macologic intervention havepointed out, with some legit-imacy, that there are few

Reprint requests: Ron G. Rosenfeld,MD, 770 Welch Road, Suite 350, PaloAlto, CA 94304.

J Pediatr 2005;146:10-1.0022-3476/$ - see front matter

Copyrightª 2005 Elsevier Inc. All rightsreserved.

10.1016/j.jpeds.2004.09.021

See related article, p 45.

The Journal of Pediatrics � January 2005

studies that have demonstrated significant psychosocialmorbidity in otherwise normal short children and that nodata exist supporting a psychologic benefit to growth-pro-moting therapy in such patients.8 Although such investigationshave tended to focus on cross-sectional evaluations of schoolchildren rather than on the more appropriate population ofchildren who are actually referred for pediatric endocrineevaluation, the issues raised do require our attention. On theother hand, if GH can be shown to shown to be effective ina significant number of children now labeled as having ISS, asin the current study byWit et al,5 it becomes difficult to justifytreatment of children carrying a diagnosis of GHD whileexcluding those with ISS.9 This matter is complicated furtherby the acknowledged difficulty in making a firm diagnosis ofGHD inmany cases and by the recognition that at least 50% ofcases diagnosed and treated as GHD probably do not havegenuine pituitary pathology. Furthermore, in many othersituations such as Turner syndrome, chronic renal failure, andintrauterine growth retardation, FDA approval of GHtreatment was predicated on the management of the growthfailure per se rather than an underlying endocrine deficiency.

A summary of this underlying conundrum would dictatethat we are limited to only two logically defensible positions:(1) restrict GH therapy to replacement for children withunequivocal GHD (and acknowledge that only a minority ofchildren diagnosed and treated as having GHD are trulydeficient in GH), or (2) recognize that the effectiveness ofgrowth-promoting therapy should dictate access and thata significantly short child who might benefit from treatmentdeserves consideration of treatment, no matter what theunderlying diagnosis might be.9 The latter option is appealingbut mandates that the following aspects are demonstrable:(1) that short stature represents a disability to the child andthat it is not amenable to more conservative approaches such ascounseling and reassurance; (2) that therapy be demonstratedto be effective (and safe) at promoting both short-term growthand adult height; (3) that growth augmentation providepsychosocial benefit to the child; and (4) that a meaningfulcost-benefit assessment be made in the light of the issues listed

CONFIRMATION OF AN OLD ADA

T he article by Dr Mitchell Cohen and his colleaguespublished in this issue of The Journal1 is bestconsidered in the context of the global problem of

diarrhea in children, which continues to plague humanity.Infants and young children are particularly prone to diarrheaand are especially vulnerable to the consequences of volumedepletion. However, extra-intestinal and delayed consequen-ces of enteric infections, such as Campylobacter jejuni–relatedand C coli–related Guillain-Barre syndrome,2 postinfectiousirritable bowel syndrome,3 and hemolytic uremic syndromecaused by Shiga toxin–producing Escherichia coli and Shigella

DAEC Diffusely adherent Escherichia coliEAEC Enteroaggregative Escherichia coli

Editorials

above. The studies by Leschek et al and Wit et al providestrong support for the efficacy of GH therapy. It is to be hopedthat future investigations will address the perhaps morecomplex issues of genuine benefit to the patient.

Ron G. Rosenfeld, MDSenior Vice-President for Medical Affairs

Lucile Packard Foundation for Children’s HealthPalo Alto, CA

Professor of PediatricsStanford University

Stanford, CAProfessor of Pediatrics

Oregon Health and Science UniversityPortland, OR

REFERENCES1. Rosenfeld RG. Ten axioms in the evaluation of short stature.

Endocrinologist 1997;7:148-52.

2. Sas TC, deMuinck Keizer-Schrama SMPE, Stijnen T, JansenM,Otten

BJ, Hoorweg-Nijman JJG, et al. Drop SLS: normalization of height in girls

with Turner syndrome after long-term growth hormone treatment: results of

a randomized dose-response trial. J Clin Endocrinol Metab 1999;84:4607-12.

3. Sas T, de Waal W, Mulder P, Houdijk M, Jansen M, Reeser M, et al.

Growth hormone treatment in children with short stature born small for

gestational age: 5-year results of a randomized, double-blind, dose-response

trial. J Clin Endocrinol Metab 1999;84:3063-70.

4. Cohen P, Bright GM, Rogol AD, Kappelgaard A-M, Rosenfeld RG.

Effects of dose and gender on the growth and growth factor response to GH

in GH-deficient children: implications for efficacy and safety. J Clin

Endocrinol Metab 2002;87:90-8.

5. Wit JM, Rekers-Mombarg LTM, Cutler GB Jr, Crowe B, Beck TJ,

Roberts K, et al. Growth hormone (GH) treatment to final height in children

with idiopathic short stature: evidence for a dose effect. J Pediatr 2004;146:

45-53.

6. Leschek EW, Rose SR, Yanovski JA, Troendle JF, Quigley CA,

Chipman JJ, et al. Effect of growth hormone treatment on adult height in

peripubertal children with idiopathic short stature: a randomized, double-

blind, placebo-controlled trial. J Clin Endocrinol Metab 2004;89:3140-8.

7. Rosenfeld RG, Hwa V. Toward a molecular diagnosis for idiopathic

short stature. J Clin Endocrinol Metab 2004;89:1066-7.

8. Sandberg DE, Bukowski WM, Fung CM, Noll RB. Height and social

adjustment: are extremes a cause for concern and action? Pediatrics 2004;114:

744-50.

9. Allen DB, Fost N. hGH for short stature: ethical issues raised by

expanded access. J Pediatr 2004;144:648-52.

GE: YOU FIND WHAT YOU SEEK

dysenteriae, type 1,4 are nowemerging as complications ofdiarrheal infections. Indeed,in a recent study undertakenin California of bacterial in-fections of the gut, sequelaesuch as protracted diarrhea,irritable bowel syndrome, andarthritis were self-reported in27% of 571 respondents.5

The majority of cases ofacute diarrhea in children arecaused by viruses. Rotavirus isthe most common cause,6 but

Dr Sherman is the recipient of aCanada Research Chair in Gastro-intestinal Disease.Reprint requests: Dr Philip M.Sherman, Gastroenterology andNutrition, Room 8409, Hospital forSick Children, 555 University Ave,Toronto, Ontario, M5G 1X8,Canada.

J Pediatr 2005;146:11-3.0022-3476/$ - see front matter

Copyrightª 2005 Elsevier Inc. All rightsreserved.

10.1016/j.jpeds.2004.10.056

See related article, p 54.

11