Department of Pediatrics, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands

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1 Hidawi Publishig Corporatio Iteratioal Joural of Pediatric Edocriology Volume 2, Article ID , 7 pages doi:.55/2/ Cliical Study The Auxological ad Biochemical Cotiuum of Short Childre Bor Small for Gestatioal Age (SGA) or with Normal Birth Size (Idiopathic Short Stature) Jaia Caliebe, David D. Marti, Michael B. Rake, ad Ja M. Wit 2 Uiversity Childre s Hospital, Hoppe-Seyler-Strasse, 7276 Tübige, Germay 2 Departmet of Pediatrics, Leide Uiversity Medical Ceter, P.O. Box 96, 23 RC, Leide, The Netherlads Correspodece should be addressed to Jaia Caliebe, jaia.caliebe@gmx.de Received 9 Jauary 2; Accepted March 2 Academic Editor: Ferado Cassorla Copyright 2 Jaia Caliebe et al. This is a ope access article distributed uder the Creative Commos Attributio Licese, which permits urestricted use, distributio, ad reproductio i ay medium, provided the origial work is properly cited. Objective. Retrospective sigle-cetre aalysis of growth characteristics i 82 healthy short childre bor small for gestatioal age (SGA) or appropriate for gestatioal age (idiopathic short stature, ISS). Methods. Birth size refereces from the USA ad Swede were compared, ad for the classificatio as SGA or ISS the Swedish referece was chose. Height, target height (TH), boe age (BA), predicted adult height (PAH), IGF-I ad IGFBP-3 values were compared betwee SGA ad ISS. Results. I the combied group, birth weight ad legth showed a symmetric Gaussia distributio. The America referece overestimates the percetage of short birth legth ad uderestimates that of low birth weight. I childhood, SGA childre were shorter tha ISS (. versus.6 SDS, P<.), also i compariso to TH (.6 versus.9 SDS, P<.). TH, height SDS chage over time, BA delay, ad PAH were similar. IGF-I ad IGFBP-3 were lower i ISS (P =.3 ad.9). Coclusios. SGA childre represet the left tail of the Gaussia distributio of birth size i short childre. The distictio betwee SGA ad ISS depeds o birth size referece. Childhood height of SGA is lower tha of ISS, but the other auxological features are similar.. Itroductio The evaluatio of growth is a essetial part of the diagostic work-up of childre attedig the pediatricia s practice, particularly childre referred for short or tall stature. Based o a thorough medical history together with a physical examiatio ad various characteristics of the growth patter, followed by a laboratory screeig, the pediatricia estimates the probability of a pathological cause. With respect to growth characteristics, we have recetly reported a evidece-based guidelie for referrig patiets to a pediatricia icludig iformatio o birth size, height ad paretal target, as well as growth falterig (deflectio). This guidelie has a good sesitivity to detect pathology, at a low percetage of false egatives []. However, oly i approximately 5% of short childre ca a pathological cause be detected [2]. Short childre i whom o pathology ca be foud are the subdivided ito short childre bor small for gestatioal age (SGA) ad childre bor with a ormal birth size but becomig short i ifacy ad childhood (idiopathic short stature, ISS). There is cosesus amog pediatric edocriologists about the defiitios of SGA [3] ad ISS [4, 5] but it has also bee argued that the distictio betwee the two diagostic categories is arbitrary. The distictio betwee SGA ad ISS is based o birth weight ad birth legth SDS (SGA if birth weight ad/or legth <. SDS) ad the availability of these data ad the choice of the referece ifluece the diagostic label. Aother issue i the diagostic classificatio is the way ISS ca be subcategorized. I the report of a cosesus workshop [4], cofirmed at a recet ISS cosesus meetig [5], ISS was divided ito familial short stature (height SDS close to the paretal target height) ad ofamilial short stature (height below the target rage). For this distictio, there is ucertaity about the proper cut-off, as there are may formulas to calculate target height [6, 7]. Both subgroups ca be further subdivided ito childre with

2 2 Iteratioal Joural of Pediatric Edocriology Table : Auxological parameters of the total cohort at iclusio. Dimesio All ISS SGA Number Boys % Gestatioal age weeks 38.9 (2.2) 38.9 (2.2) 38.3 (2.4) Preterms (<37wks) % 4 22 Age at iclusio yrs ($) 7.88 ± ± ± 2.92 Height ($).7 ± ±.46.3 ±.82 Height ( ).5 (.8 to.).44 (.5 to.).95 (.8 to.2) $ = mea ± SD; = media ad rage Height SDS was calculated based o Prader et al. []. ormal or delayed puberty. It is assumed that boe age delay is ot a reliable diagostic criterio for costitutioal delay of growth ad puberty [4], but there are o data about boe age delay i the various subgroups of ISS. I this study, we first aimed at ivestigatig the impact of the use of differet refereces of birth weight ad legth for gestatioal age [8, 9] o differetiatig SGA ad ISS i a well-characterized cohort of short childre collected i a sigle large growth cetre. Secodly, we aimed at comparig auxological ad biochemical characteristics of SGA ad ISS. Thirdly, we ivestigated boe age delay i the two subcategories of ISS based o distace to target height. 2. Patiets ad Methods We collected a group of 82 short (height < SDS) but otherwise healthy prepubertal childre who preseted betwee mid 22 ad mid 25 at our pediatric edocriology outpatiet cliic ad who were regularly see for followup. They were older tha 3 years at recruitmet for the study. Very preterm birth (<3 weeks of gestatio) ad serious complicatios postatally (vetilatio > 72 hours) were exclusio criteria, as well as chroic diseases that might iterfere with height developmet such as asthma, chroic diarrhea, celiac disease, edocrie disorders (e.g., growth hormoe deficiecy), cogeital malformatios, kow sydromes, chromosomal aberratios, ad abormal body proportios. Iformed coset was obtaied from the parets ad the patiet. The study was approved by the Medical Ethics Committee of the Uiversity of Tübige. Birth data were obtaied from the yellow prevetive health care check-up booklet that every Germa child receives at birth. Based o the established defiitio of SGA (birth weight ad/or weight < SDS) ad usig the 98 Swedish referece data [9], 45 childre were diagosed as SGA ad the remaiig 37 childre as ISS. Birth weight ad legth were available for all 82 patiets, ad birth head circumferece i 26 of them. For the aalysis of height i childhood, the height measuremets carried out at our outpatiet cliic at iclusio i the study were used ( = 82). For childre who subsequetly received growth hormoe (GH) treatmet, the last measuremet before the start of therapy was used. For all childre, we searched either from the yellow booklet or from a visit to our outpatiet cliic for a additioally documeted height measuremet (at least.5 years, but preferably betwee ad 3 years before the measuremet at iclusio), so that there would be a sufficiet time spa betwee the first ad the secod measuremets for assessig growth rate. Suitable measuremets were foud to be documeted i 77 patiets. Out of the total cohort of 82 childre, data o target height, boe age, ad plasma IGF-I ad IGFBP-3 were available i 4 childre. For 57 childre, the predicted adult height could be calculated. Birth weight (BW), legth (BL) ad head circumferece (BHC) were expressed as SDS usig Swedish referece data reported by Niklasso et al. (NIK) [9] or Usher ad McLea (UML) [8], ad the discrepacies betwee both values were assessed. Postatal height i childhood ad adolescece was expressed as SDS for Swiss refereces [], which is represetative for this South-West Germa populatio. Target height was calculated accordig to Hermausse ad Cole [] ad expressed as SDS []. Below target rage was defied as HSDS THSDS <.6. Boe age was assessed accordig to Greulich ad Pyle [2] ad Predicted adult height mius target height was aalyzed accordig to Bayley ad Pieau [3]. IGF-I ad IGFBP-3 values were expressed as SDS for the refereces accordig to Blum [4, 5]. The studet s t-test was used toassess differeces betwee groups. Fisher s exact test was used to aalyze 2 2 cotigecy tables. Target height was aalyzed with the oe-sample-ttest. 3. Results 3.. Birth Data. Table shows data o geder distributio, gestatioal age (GA), ad age ad height at iclusio ito the study of the total cohort as well as childre classified as ISS ad SGA. The mea GA was similar betwee groups. The rate of prematurity (GA < 37 weeks) was lower i the ISS group tha i the SGA group (P =.8). The media ad rage values for the three differet birth parameters BW, BL, ad BHC are listed i Table 2 for the whole group ad the ISS ad SGA groups separately, accordig to the two refereces. I the whole cohort, birth weight SDS accordig to NIK teded to be lower tha accordig to UML (P =.), but birth legth SDS was higher (P =.2). Head circumferece SDS teded to be higher accordig to NIK tha UML (P =.4).

3 Iteratioal Joural of Pediatric Edocriology 3 Table 2: Athropometric data at birth: SDS (media ad rage) comparig the refereces of Niklasso et al. [9] ad of Usher ad McLea [8]. Whole Whole cohortnik ISSNIK ISSUML SGANIK SGAUML cohortuml.94 (.27 to +.46) (.95 to +.46) (.27 to.6).2 BW ( = 82) (.48 to +.63) ( = 37) (.74 to +.63) ( = 45) (.48 to.37).56 (.6 to +2.3).9.35 (.9 to +2.3) (.6 to.29). BL ( = 82) ( 6.2 to +.89) ( = 37) (.56 to +.89) ( = 45) ( 6.6 to.33).36 (.3 to +2.3).68.8 (. to +2.3).8.43 (.3 to +.9). BHC ( = 26) (.2 to +2.67) ( = 88) (.48 to +2.67) ( = 38) (.2 to +.48) BW = birth weight. BL=birth legth. BHC = birth head circumferece. 6 2 BW SDS (a) Birth legth SDS Niklasso 6 Birth weight SDS Niklasso 2 Figure 2: Birth legth SDS versus birth weight SDS accordig to Niklasso [9] i all patiets ( = 82). SGA childre are idicated with crosses ad ISS childre with squares. R 2 =.6. 6 BL SDS (b) Figure : Distributio of birth weight SDS (a) ad birth legth SDS (b) for the whole cohort ( = 82). Mea (SD) birth weight =.9 (.5), mea (SD) birth legth =.88 (.4). Dark areas sigify SGA cases. The distributio of birth weight ad birth legth SDS i the whole group is show i Figures (a) ad (b). Both histograms show a Gaussia distributio, suggestig that SGA of ukow origi ca be cosidered as the left tail of the ormal distributio of birth size i short childre. This is further illustrated by the plot of birth legth SDS versus birth height SDS for the whole cohort (Figure 2). Table 3 shows the classificatio of the cases ito SGA ad ISS o the basis of a BW ad/or BL of less tha SDS accordig to the two refereces. Accordig to NIK, 45 of the 82 patiets (24.7%) are classified as SGA, with a homogeeous patter of smalless for weight ad legth. I cotrast, with the UML referece, 48 (26.4%) childre are classified as SGA, with a large majority beig short for gestatioal age. Forty oe patiets are classified as SGA accordig to both refereces. 2 Head circumferece data at birth are available for 26 patiets. Accordig to NIK, 4 patiets (3 SGA, ISS) had microcephaly at birth, defied by a BHC of less tha SDS (% of the cohort). Accordig to UML, 3 patiets (23 SGA, 7 ISS) were microcephalic (24% of the cohort) Growth i Childhood. Table shows auxological data for the whole cohort, ad ISS ad SGA separately. Childre with ISS were slightly older tha childre with SGA (P =.). The youger age of SGA patiets ca be explaied by early start (<5 years)ofgrowthhormoe(gh)i9cases. The media height SDS of the SGA group aroud 8 years was sigificatly lower tha i the ISS group (P <.). The distributio of the height SDS of the whole cohort at iclusio is show i Figure 3(a). As expected, the form of this histogram resembles the left tail of the Gaussia distributio. I the childre with logitudial measuremets ( = 77), the chage i height SDS betwee the two time poits (T was take betwee.2 ad.6 years, T2 betwee years) was close to zero, ad eve teded to be positive (.8 SD/year). It was ot statistically differet betwee ISS ad SGA (P =.8).

4 4 Iteratioal Joural of Pediatric Edocriology Ht THT.5.5 (a) (b) Ht SDS-THT.5 BA-CA (c) (d) Figure 3: Histograms of the distributio of: (a) Height SDS at iclusio. N = 82 (37 ISS, 45 SGA). Media (rage) =.5 (.8 to 2.); (b) target height SDS. N = 4 (93 ISS, 2 SGA); (c) height SDS mius target height SDS with cut-off of.6 SDS idicatig target height rage. N = 4 (93 ISS, 2 SGA); (d) distributio of boe age delay (BA-CA) i years. N = 4 (93 ISS, 2 SGA). Table 3: Birth weight (BW) ad legth (BL) of short childre classified as SGA based o the refereces of Niklasso (NIK) [9] ad Usher- McLea (UML) [8]. = 45 BW (NIK) > SDS BW(NIK) < SDS = 48 BW (UML) > SDS BW(UML) < SDS BL (NIK) > SDS 8 (7.8%) BL (UML) > SDS 2(4.2%) BL (NIK) < SDS 9 (2%) 28 (62.2%) BL (UML) < SDS 2 (43.7%) 25 (52.%) For aalysis of the additioal parameters, 4 patiets were available, with a similar height SDS as i the total group, but a slightly differet compositio (82% ISS istead of 75% i the complete cohort) (Tables ad 4). Auxological ad biochemical data for all 4 patiets, ad ISS ad SGA separately, are show i Table 4. Target height(th) is preseted i Table 4 ad its distributio is show i Figure 3(b). For both groups, TH SDS was sigificatly below the populatio mea (ISS P <., SGA P =.). Height SDS was approximately 2 SD lower tha TH (Figure 3(c)). The differece betwee height SDS ad TH SDS was more i SGA patiets tha i ISS (P <.), but the umber of patiets below a cut-off of.6 SDS (the lower limit of the target rage) was similar (8% ad 73%, resp.). The distributio of the differece of boe age mius chroological age ( = 97) is show i Figure 3(d) ad mea (SD) values are show i Table 4.Boeagedelaywas similar i ISS ad SGA patiets, but there were more ISS childre with a boe age delay >.6 year (54%) tha SGA childre (24%) (P =.2). Mea (SD) values for predicted adult height (PAH) SDS ( = 57) are show i Table 4.Mea PAH SDS was.83,.2 SD lower tha TH. The percetage of childre with ISS who had a PAH SDS below the target height was lower tha that of childre with SGA (P =.2). May cliicias assume that childre with familial short stature have less boe age delay tha childre with ofamilial short stature, some of whose may later tur out to have costitutioal delay of growth ad puberty. However, whe aalyzig the distace betwee height SDS ad target height SDS agaist boe age mius chroological age, o correlatio was observed (Figure 4) Biochemical Data. Table 4 shows that IGF-I was sigificatly lower i ISS tha i SGA (P =.2). For IGFBP-3, the differece did ot reach statistical sigificace (P =.2). IGFBP-3 teded to be higher i girls (media of.7 versus.3 i boys, P =.6). 4. Discussio We have show that childre with SGA represet the left tail of the Gaussia distributio of birth size i short childre.

5 Iteratioal Joural of Pediatric Edocriology 5 Table 4: Auxological ad biochemical parameters of patiets with available target height, boe age, ad biochemical data. Dimesio All ( = 4) ISS ( = 93) SGA ( = 2) Age at T Years 6.7 ± 2.45 ( = 77) 6.2 ± 2.37 ( = 63) 5.42 ± 2.78 ( = 4) Age at T2 (years) years 7.88 ± 2.73 ( = 82) 8.6 ± 2.65 ( = 37) 7.29 ± 2.92 ( = 45) Height at T SDS.83 ± ± ±.94 Height at T2 SDS.66 ±.6.53 ± ±.9 Delta height gai SDS.8 ±.2. ±.9.2 ±.24 Target height # SDS.65 ± ± ±.72 Ht at T2 mius THT SDS. ± ± ±.6 Below target rage (, %) 85 (74.6%) 68 (73%) 7 (8.%) BA-CA ## years.54 ±.6.6 ±.6.26 ±.5 PAH SDS.83 ±.8 ( = 57).7 ±.5 ( = 47).4 ±.9 ( = ) Ht-PAH SDS.7 ±. ( = 57).76 ±.2 ( = 47).48 ±.97 ( = ) Ht SDS<PAH SDS (, %) 43 (75%) 37 (79%) 6 (6%) PAH-THT SDS.4 ±.2 ( = 57). ±.8 ( = 47).78 ±.96 ( = ) PAH SDS<target rage (,%) 3 (22.8%) 9 (9.%) 4 (4%) IGF-I SDS.2 ± ± ±.73 IGF-I < (,%) 9 (6.7%) 8 (9.4%) (4.8%) IGFBP-3 SDS.9 ±.94 ( = 9).2 ±.95 ( = 9).52 ±.8 ( = 9) IGFBP-3 SDS < (, %) 8 (7.3%) 6 (6.7%) 2 (.5%) Mea (SD) are show, except whe idicated otherwise. T: First prepubertal measuremet T2: Timepoit of iclusio ito the study Height SDS was calculated based o Prader et al. [] # Target height (TH) was calculated accordig to Hermausse ad Cole [] ## Boe age (BA) mius chroological age (CA) Predicted adult height (PAH). The choice of the birth size referece has a cosiderable impact o the distictio betwee the diagostic labels short child bor small for gestatioal age (SGA) ad idiopathic short stature (ISS). The asymmetric distributio for birth weight ad birth legth suggests that the UML refereceforbirthlegthistoohighadforbirthweighttoo low. This is ot surprisig, as the 969 America referece was oly based o 3 cases, ot eve sufficiet to prepare separate charts for boys ad girls [8], while the relatively recet Swedish referece [9] was based o 475, babies. Mea height of childre bor SGA is lower tha ISS, but the other auxological features (TH, height SDS chage over time, BA delay, PAH) are similar betwee the two groups. IGF-I SDS was lower i ISS tha i SGA, ad cosiderably lower tha IGFBP-3 i both groups. The importat cosequeces of the choice of the birth size referece for the diagosis SGA should be bor i mid if oe judges the results of studies o the atural history of SGA, or the effect of growth hormoe treatmet. I particular, the birth legth UML referece chart seems to be far too high, so that what would appear a small legth for gestatioal age is ofte ormal for preset day wester babies. Our fidig, that usig the UML charts for head circumferece doubles the icidece of microcephaly i compariso to the NIK referece charts, is a idicatio that the UML referece is also iferior o that measure. Comparig growth characteristics of childre labeled ISS or SGA, mea height SDS of childre bor SGA is approximately.5 SD lower tha that i ISS. This fidig is compatible with previous reports o the associatio of birth weight with stature i childhood [6 2]. The distace betweeheightsdsadtargetheighttededtobegreater i SGA (2.6 versus.9 SD), which ca be explaied by the otio that part of the childre with ISS fall ito the category of familial short stature (height SDS withi the target rage). Other auxological features, such as the target height itself, height SDS chage over time, boe age delay, ad predicted adult height, are remarkably similar betwee both diagostic categories. I combiatio with the symmetric Gaussia distributio of birth weight if ISS ad SGA are combied, this cofirms that the distictio betwee SGA ad ISS is arbitrary. I the workshop report o the defiitio of ISS [4], it was proposed to subcategorize ISS ito two subgroups: familial short stature (FSS) ad o-familial short stature. This was recetly cofirmed by a cosesus meetig [5] (although ot

6 6 Iteratioal Joural of Pediatric Edocriology HSDS-THSDS BA-CA Figure 4: DifferecebetweeheightSDSadtargetheightSDS plotted versus boe age delay (boe age mius chroological age) i childre with ISS. R 2 =.. N = 4 (93 ISS, 2 SGA). uaimously), ad by the ESPE Classificatio of Paediatric Edocrie Diagoses [22]. We have previously emphasized that also this subcategorizatio is a arbitrary oe, ad depedet o the choice of the target height formula [23]. I the preset study, we show that if the target height formula by Hermausse ad Cole [] is used, approximately 75% of the ISS ad SGA patiets have a height below the lower limit of the target rage (TH SDS mius.6). These arbitrary subgroups have a similar boe age delay, so either boe age delay is ot a good marker of familial versus ofamilial short stature or the routie Greulich-Pyle ratigs were too iaccurate to reflect the differeces. While oe may expect that part of the childre with o-familial short stature may eter ito puberty late, ad ca the be diagosed as costitutioal delay of growth ad puberty, the predictive value of boe age delay for delayed puberty is ucertai. I lie with earlier observatios [24 27], average plasma IGF-I is low i ISS ad SGA, ad the percetage (2%) of low values (<. SDS) is similar to percetages foud previously. Remarkably, average plasma IGFBP-3 levels are ormal. This combiatio would suggest that cases of mild GH deficiecy or resistace are rare, but that disorders at the level of GH sigal trasductio, causig a selective ihibitio of IGF-I rather tha of IGFBP-3, may be ivolved i short stature. Aother explaatio is that IGFBP-3 is less depedet o the biological actio of GH tha IGF-I [28 3]. I coclusio, birth size should be assessed with a recet ad reliable referece chart; the Usher ad McLea data should o loger be used as referece data. Childre with SGA form the left tail of the distributio of birth weight i short childre ad auxological ad biochemical characteristics of childre with SGA ad ISS are similar. I familial ad o-familial short stature, there appears to be a wide variatio i boe age delay of similar magitude. Refereces [] F. K. Grote, P. Va Dommele, W. Oostdijk, et al., Developig evidece-based guidelies for referral for short stature, Archives of Disease i Childhood, vol. 93, o. 3, pp , 28. [2] F. K. Grote, W. Oostdijk, S. M. P. F. de Muick Keizer-Schrama, et al., The diagostic work up of growth failure i secodary health care; a evaluatio of cosesus guidelies, BMC Pediatrics, vol. 8, article 2, 28. [3] P. E. Clayto, S. Ciafarai, P. Czerichow, G. Johasso, R. Rapaport, ad A. D. Rogol, Cosesus statemet: maagemet of the child bor small for gestatioal age through to adulthood: a cosesus statemet of the Iteratioal Societies of Pediatric Edocriology ad the Growth Hormoe Research Society, Joural of Cliical Edocriology ad Metabolism, vol. 92, o. 3, pp. 84 8, 27. [4] M. B. Rake, Towards a cosesus o the defiitio of idiopathic short stature, Hormoe Research, vol. 45, o. 2, pp , 996. [5] P. Cohe, A. D. Rogol, C. L. Deal, et al., Cosesus statemet o the diagosis ad treatmet of childre with idiopathic short stature: a summary of the Growth Hormoe Research Society, the Lawso Wilkis Pediatric Edocrie Society, ad the Europea Society for Paediatric Edocriology Workshop, Joural of Cliical Edocriology ad Metabolism, vol. 93, o., pp , 28. [6]J.M.Wit,P.E.Clayto,A.D.Rogol,M.O.Savage,P.H. Saeger, ad P. Cohe, Idiopathic short stature: defiitio, epidemiology, ad diagostic evaluatio, Growth Hormoe ad IGF Research, vol. 8, o. 2, pp. 89, 28. [7] S. Poyrazoglu, F. Daredeliler, F. Bas, et al., Target height estimatio i childre with idiopathic short stature who are referred to the growth cliic, Hormoe Research, vol. 72, o. 3, pp , 29. [8] R. Usher ad F. McLea, Itrauterie growth of live-bor Caucasia ifats at sea level: stadards obtaied from measuremets i 7 dimesios of ifats bor betwee 25 ad 44 weeks, The Joural of Pediatrics, vol. 74, o. 6, pp. 9 9, 969. [9] A. Niklasso, A. Ericso, J. G. Fryer, J. Karlberg, C. Lawrece, ad P. Karlberg, A update of the Swedish referece stadards for weight, legth ad head circumferece at birth for give gestatioal age (977 98), Acta Paediatrica Scadiavica, vol. 8, o. 8-9, pp , 99. []A.Prader,R.H.Largo,L.Moliari,adC.Issler, Physical growth of Swiss childre from birth to 2 years of age. First Zurich logitudial study of growth ad developmet, Helvetica Paediatrica Acta, vol. 52, pp. 25, 989. [] M. Hermausse ad J. Cole, The calculatio of target height recosidered, Hormoe Research, vol. 59, o. 4, pp. 8 83, 23. [2] W. W. Greulich ad S. I. Pyle, Radiographic Atlas of Skeletal Developmet of the Had ad Wrist, Staford Uiversity Press, Staford, Calif, USA, 959. [3] N. Bayley ad S. R. Pieau, Tables for predictig adult height from skeletal age: revised for use with the greulich-pyle had stadards, The Joural of Pediatrics, vol. 4, o. 4, pp , 952. [4]W.F.Blum,M.B.Rake,K.Kietzma,E.Gauggel,H.J. Zeisel, ad J. R. Bierich, A specific radioimmuoassay for the growth hormoe (GH)-depedet somatomedi-bidig

7 Iteratioal Joural of Pediatric Edocriology 7 protei: its use for diagosis of GH deficiecy, Joural of Cliical Edocriology ad Metabolism, vol. 7, o. 5, pp , 99. [5] W. F. Blum ad B. H. Breier, Radioimmuoassays for IGFs ad IGFBPs, Growth Regulatio, vol. 4, supplemet, pp. 9, 994. [6] J. M. Wit, Growth hormoe treatmet of idiopathic short stature i KIGS, i Growth Hormoe Therapy- Years Experiece, M. B. Rake ad P. Wilto, Eds., pp , Joha Ambrosius Barth, Heidelberg, Germay, 999. [7] V. Giacobbi, C. Trivi, E. Lawso-Body, M. Foseca, J.-C. Souberbielle, ad R. Brauer, Extremely short stature: ifluece of each paret s height o cliical-biological features, Hormoe Research, vol. 6, o. 6, pp , 23. [8] S. Zucchii, M. Wasiewska, M. Cisterio, et al., Adult height i childre with short stature ad idiopathic delayed puberty after differet maagemet, Europea Joural of Pediatrics, vol. 67, o. 6, pp , 28. [9] E. C. Crowe, S. M. Shalet, W. H. B. Wallace, D.M. Emiso, ad D. A. Price, Fial height i boys with utreated costitutioal delay i growth ad puberty, Archives of Disease i Childhood, vol. 65, o., pp. 9 2, 99. [2] E. C. Crowe, S. M. Shalet, W. H. B. Wallace, D. M. Emiso, ad D. A. Price, Fial height i girls with utreated costitutioal delay i growth ad puberty, Europea Joural of Pediatrics, vol. 5, o., pp , 99. [2]K.Albertsso-WikladadJ.Karlberg, Naturalgrowthi childre bor small for gestatioal age with ad without catch-up growth, Acta Pediatrica, vol. 399, pp. 64 7, 994. [22] ESPE Classificatio of Paediatric Edocrie Diagoses, Karger, Basel, Switzerlad, 27. [23] J. M. Wit, Idiopathic short stature: reflectios o its defiitio ad spotaeous growth, Hormoe Research, vol. 67, o., pp. 5 57, 27. [24] L. M. S. Carlsso, K. M. Attie, P. G. Compto, R. V. Vitagcol, ad T. J. Merimee, Reduced cocetratio of serum growth hormoe-bidig protei i childre with idiopathic short stature, Joural of Cliical Edocriology ad Metabolism, vol. 78, o. 6, pp , 994. [25] C. M. Hall, M. S. Gill, P. Foster, et al., Relatioship betwee serum ad uriary isuli-like growth factor-i through childhood ad adolescece: their use i the assessmet of disordered growth, Cliical Edocriology, vol. 5, o. 5, pp. 6 68, 999. [26] P. E. Clayto ad C. M. Hall, Isuli-like growth factor I levels i healthy childre, Hormoe Research, vol. 62, supplemet, pp. 2 7, 24. [27] M. B. Rake, Defiig isuli-like growth factor-i deficiecy, Hormoe Research, vol. 65, o., pp. 9 4, 26. [28] M. H. Aguiar-Oliveira, M. S. Gill, E. S. de A Barretto, et al., Effect of severe growth hormoe (GH) deficiecy due to a mutatio i the GH-releasig hormoe receptor o isuli-like growth factors (IGFs), IGF-bidig proteis, ad terary complex formatio throughout life, Joural of Cliical Edocriology ad Metabolism, vol. 84, o., pp , 999. [29] J.-G. Scharf, G. Ramadori, T. Braulke, ad H. Hartma, Sythesis of isulilike growth factor bidig proteis ad of the acid-labile subuit i primary cultures of rat hepatocytes, of kupffer cells, ad i cocultures: regulatio by isuli, isulilike growth factor, ad growth hormoe, Hepatology, vol. 23, o. 4, pp , 996. [3] Z. S. Gucev, Y. Oh, K. M. Kelley, J. I. Labarta, P. Vorwerk, ad R. G. Rosefeld, Evidece for isuli-like growth factor (IGF)-idepedet trascriptioal regulatio of IGF bidig protei-3 by growth hormoe i SKHEP- huma hepatocarcioma cells, Edocriology, vol. 38, o. 4, pp , 997.