Overestimation of final height prediction in patients with classical congenital adrenal hyperplasia using the Bayley and Pinneau method

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1 DOI /jpem J Peditr Endocr Met 2012; 25(7-8): Wlter Bonfig * nd Hns Peter Schwrz Overestimtion of finl height prediction in ptients with clssicl congenitl drenl hyperplsi using the Byley nd Pinneu method Abstrct Bckground: A typicl growth pttern with decresed pubertl growth spurt hs been identified in ptients with clssicl congenitl drenl hyperplsi (CAH). Objective: To evlute the ccurcy of finl height predictions in ptients with CAH using the Byley nd Pinneu (B&P) method. Ptients nd Methods: Using growth nd finl height dt of 92 ptients (57 F/35 M) with CAH due to 21-hydroxylse deficiency (38 SV/54 SW), finl height predictions with the B&P method were compred to ctul finl heights. Results: In femles, men finl height ws ± 5.3 cm ( 1.0 ± 0.7 SDS) compred to predicted men finl height of ± 10.7 cm ( +0.5 ± 1.7 SDS), p < 0.001, overestimtion 7.3 ± 9.5 cm. In mles, men finl height ws ± 6 cm ( 1.2 ± 0.8 SDS) compred to predicted men finl height of ± 13.4 cm ( +1.2 ± 1.9 SDS), p < 0.001, overestimtion 13.9 ± 10.8 cm. Conclusion: In clssicl CAH, finl height prediction using the B&P method results in significnt overestimtion of finl height. Keywords: bone ge; congenitl drenl hyperplsi; growth; growth prediction. *Corresponding uthor: Dr. Wlter Bonfig, Division of Peditric Endocrinology, Deprtment of Peditrics, Technische Universit ä t M ü nchen, Przivlstr. 16, D Munich, Germny, Phone: , Fx: , E-mil: wlter.bonfig@lrz.tum.de Hns Peter Schwrz: Division of Peditric Endocrinology nd Dibetology, Dr. von Hunersches Kinderspitl, Ludwig Mximilins Universität München, Munich, Germny Introduction Congenitl drenl hyperplsi (CAH) comprises group of utosoml recessive disorders cused by deficiency of one of five enzymes required for the synthesis of cortisol (1, 2). The most common form is 21-hydroxylse deficiency (21OHD), which ccounts for more thn 90 % of the cses (3). The clssicl form of 21OHD results in genitl msculiniztion in girls, erly viriliztion with ccelertion of growth nd pubertl development or in slt-wsting crises. Worldwide incidence of CAH clculted from neontl screening progrms hs been estimted t 1:14,000. Overproduction of ndrogens cuses viriliztion, ccelerted growth, dvnced skeletl mturtion nd erly epiphysel fusion. Wheres the vrious forms of CAH differ in their degree of enzymtic deficiency, they ll represent therpeutic chllenge to peditric endocrinologists ttempting to optimize growth. Trditionl tretment consists of the suppression of drenocorticotropic hormone (ACTH) through glucocorticoid replcement in n ttempt to reduce excessive ndrogen production nd its consequences. Prsimonious tretment with glucocorticoids my result in ndrogen excess with dvncement of bone ge nd reduced finl height. In over tretment, growth is suppressed by growth inhibiting effects of glucocorticoids. Alternte pproches to the tretment of CAH hve been investigted recently, including the use of ntindrogens, romtse inhibitors nd drenlectomy (4). However, the minsty of therpy remins judicious glucocorticoid tretment long with creful monitoring of growth velocity nd skeletl mturtion, s well s urine, serum nd slivry steroid hormone levels (5). Reports on long-term follow-up nd finl height outcomes in ptients with CAH re heterogeneous. Previously, we nd other uthors hve shown tht totl pubertl growth is significntly reduced in CAH ptients who hve received trditionl steroid tretment with hydrocortisone (6 8). According to n Endocrine Society consensus sttement, growth promoting therpy cn be offered to CAH ptients with predicted finl height below 2.25 SD in the context of clinicl studies (9). Therefore, finl height predictions should be s ccurte s possible. Recently, finl height dt of CAH ptients treted with growth hormone were published (10). In tht study, finl height ws compred to both control group nd to predicted finl height using the B&P method (10).

2 646 Bonfig nd Schwrz: Overestimtion of finl height prediction in CAH ptients As ptients with CAH hve decresed pubertl growth spurt, it is questionble whether finl height prediction is pproprite when the B&P tbles for helthy children re used. Bsiclly, finl height prediction is reserved for helthy children when the B&P tbles re used (11). In the present study, we evluted the ccurcy of finl height prediction using the B&P method in ptients with clssicl CAH nd estblished new tbles for finl height prediction in these ptients considering the chrcteristics of their growth pttern. Ptients nd methods We followed 92 ptients (57 femles, 35 mles) with 21-hydroxylse deficiency continuously from infncy until finl height in our clinic. All ptients were exclusively treted with hydrocortisone. We extrcted the dt retrospectively from ll ptients born between 1969 nd The dignosis of CAH ws bsed on both clinicl symptoms nd signs nd hormonl nlysis nd ws confirmed by subsequent comprehensive genotyping (12). At the time of dignosis, newbornscreening for CAH ws not yet vilble. Fifty-four ptients (32 femles) hd slt-wsting CAH (elevted plsmrenin ctivity nd sodium < 130 mmol/l t dignosis), wheres 38 ptients hd the simple virilizing form (25 femles, 13 mles). Ptients with non-clssicl forms of CAH were not included in this study. All ptients were continuously cred for in our clinic, with follow-up ppointments every 3 months during the first 2 yers of life, nd t lest every 6 months in childhood nd dolescence. All 92 ptients hd received hydrocortisone (three times dily) for glucocorticoid replcement, nd ptients with slt-wsting CAH lso received fludrocortisone (tretment gol: plsm renin ctivity < 18 ng/ml/h until 6 months of ge, < 5.5 ng/ml/h bove the ge of 6 months). Adjustment of the glucocorticoid dose ws mde using uxologicl dt (liner growth), skeletl mturity (tretment gol: bone ge within 1 yer of chronologicl ge) nd hormonl dt (tretment gol: morning serum 17-hydroxyprogesterone < 18 nmol/l). None of the ptients received GnRH nlog or romtse inhibitor tretment to dely onset of puberty. None of the ptients were treted with growth hormone. As ptients were followed t single center, these dt represent homogeneously treted cohort of ptients with CAH. Ptients older thn 18 yers of ge were considered to hve reched finl height. In ddition, fused epiphyses on X-ry were documented t finl height. Totl pubertl growth ws defined s growth from onset of puberty (B2 in girls nd testes volume of > 3 ml in boys) until finl height. Trget height ws clculted using the formul: [mternl height + pternl height 13 cm for girls nd + 13 cm for boys]/2. Dt on height nd weight, nd glucocorticoid dosge were nlyzed t 2 yers of ge, t the onset of puberty (defined s brest Tnner stge two in girls, nd testiculr volume of 3 ml in boys) nd t finl height. Height stndrd devition scores (H-SDS) were clculted with growth clcultor using reference dt from Prder et l. (13), which is used in the Alpine region (Switzerlnd, Austri, Southern Germny). Bone ge ws ssessed yerly by X-ry of the left hnd using the Greulich nd Pyle method (11). Bone ge ws red by both n experienced peditric endocrinologist nd rdiologist. Finl height prediction ws ssessed t onset of puberty (s defined bove) by the B&P method using the tbles for verge girls nd boys, when bone ge ws within 1 yer of chronologicl ge. When bone ge ws delyed more thn 1 yer, the tbles for retrded boys nd girls were used, nd in ptients with ccelertion of bone ge of more thn 1 yer, tbles for ccelerted boys nd girls were used. The finl height prediction ws then compred to the rel finl height. Corrected FH ws defined s the difference between chieved dult height nd trget height (FH-SDS TH-SDS) nd ws clculted individully for ech ptient. Prentl heights were sked nd vilble on ll ptients. Sttisticl nlyses were performed with the non-prmetric Mnn-Whitney U-test for comprison of rel nd predicted finl heights nd for between-group comprisons. Sttisticl nlyses were done with the SPSS 10.0 softwre (SPSS Inc., Chicgo, Illinois, 2002). A p < 0.05 ws considered sttisticlly significnt. Results Dt from 92 ptients (57 femles nd 35 mles) with clssicl CAH re presented in this nlysis. All ptients were exclusively treted with hydrocortisone s glucocorticoid. Ptients with slt-wsting CAH (n = 54, 32 femles, 22 mles) were dignosed erly t men ge of 0.2 yers [rnge yers, medin 0 yers], wheres ptients with the simple virilizing form (n = 38, 25 femles, 13 mles) were dignosed t men ge of 2.2 yers [rnge yers, medin 2.0 yers]. During puberty, the men dily hydrocortisone dose in the whole group ws 16.7 ± 4.1 mg/ m 2 body surfce re. In femles, the men dily hydrocortisone dose ws 16.4 ± 4.1 mg/m 2 (simple virilizing CAH femles 17.5 ± 4.1 mg/m2 nd slt-wsting CAH femles 15.6 ± 4.1 mg/m2 ), nd in mles the men dily hydrocortisone dose ws 17.5 ± 4.3 mg/m 2 (simple virilizing CAH mles 17.7 ± 5.2 mg/m2 nd slt-wsting CAH mles 16.6 ± 3.5 mg/m 2 ). None of the ptients hd suffered from drenl crisis once SW-CAH ws dignosed. Auxologicl dt Men finl height ws ± 5.3 cm ( 0.8 ± 0.6 SDS) in femles (n = 57): femles with slt-wsting CAH were s tll (160.4 ± 4.9 cm, 0.7 ± 0.8 SDS) s femle ptients with the simple virilizing form (159.3 ± 5.8 cm, 0.9 ± 1.0 SDS), p > In mles (n = 35), men finl height ws ± 6.1 cm ( 1.1 ± 0.9 SDS): mle ptients with slt-wsting CAH reched men finl height of ± 5.5 cm ( 0.9 ± 0.8 SDS), nd mles with simple virilizing CAH reched finl height of ± 6.8 cm ( 1.3 ± 1.0 SDS). There ws no significnt height difference between slt-wsting nd

3 Bonfig nd Schwrz: Overestimtion of finl height prediction in CAH ptients 647 simple virilizing CAH mles (p > 0.05), lthough metbolic control ws worst in SV CAH mles, indicted by the most dvnced bone ge t onset of puberty (Tble 1 ). Trget height ws 0.4 ± 0.8 SDS in femles, nd 0.2 ± 0.7 in mles. This mens tht prents of the ptients with CAH were slightly shorter on verge thn dults in the norml popultion. Therefore, corrected FH (FH- SDS TH-SDS) ws 0.6 ± 0.9 in femles with SW CAH, nd 0.3 ± 0.9 in femles with SV CAH, p > In mles with SW CAH, corrected FH ws 0.8 ± 0.8 nd 1.0 ± 1.0 SDS in SV CAH mle ptients, p > Men height SDS t the strt of puberty ws 0.4 ± 1.4 SDS (in femles 0.3 ± 1.3 SDS nd in mles 0.5 ± 1.5 SDS) nd decresed significntly to 0.4 ± 1.1 SDS t the end of puberty (in femles 0.5 ± 1.1 SDS nd in mles 0.3 ± 1.1 SDS), p < 0.01, which indictes n insufficient pubertl growth spurt. Totl pubertl growth in femles ws 13.5 ± 6.9 cm nd 17.2 ± 6.3 cm in mles, which is significntly less thn in the reference popultion of Prder et l. (13 15), with men pubertl growth in femles 20.3 ± 6.8 cm nd 28.2 ± 8.2 cm in mles, p < 0.01 (Tble 1). Finl height prediction In femles, men finl height ws ± 5.3 cm ( 1.0 ± 0.7 SDS) compred to men predicted finl height of ± 10.7 cm ( +0.5 ± 1.7 SDS), p < 0.001, overestimtion 7.3 ± 9.5 cm. Bone ge ws ccelerted in 14 femles, pproprite for chronologicl ge in 38 femles nd retrded in 5 femles (Tble 2). In mles, men finl height ws ± 6 cm ( 1.2 ± 0.8 SDS) compred to men predicted finl height of ± 13.4 cm ( +1.2 ± 1.9 SDS), p < 0.001, overestimtion 13.9 ± 10.8 cm. Bone ge ws ccelerted in 15 mles, pproprite for chronologicl ge in 18 mles nd retrded in 2 mles. Tbles 3 nd 4 show the CAH finl height prediction model derived by our dt. Discussion To our knowledge, this is the first study to ssess the ccurcy of finl height prediction using the B&P method in ptients with clssicl CAH. Of course, the G&P nd B&P methods re intended to be used for helthy children, but in mny studies these methods re used to evlute the effect of growth-promoting therpies in ptients with CAH (10, 4, 16 18). We found tht using the B&P tbles results in significnt overestimtion of finl height prediction, which cn be explined by significnt decrese of totl pubertl growth in our cohort of CAH ptients. Metbolic control ws very good in our cohort, s bone ge t the strt of puberty ws within 1 yer of chronologic ge in more thn two-thirds of the ptients. Decresed totl pubertl growth hs lso been observed in other growth studies of CAH ptients: In multintionl study of growth ptterns in ptients with CAH, Frisch et l. found reduced mximum growth velocity during puberty (19). In their nlysis of 41 CAH ptients, Mnoli et l. confirmed tht the height gin during puberty is one of the most potent predictors of finl height, in ddition to the type of Type of CAH Sex n FH, cm FH-SDS Corr FH-SDS ΔFH-TH SDS TPG, cm Norml TPG, cm (Ref. 13) ΔBA-CA t strt of puberty SV F ± ± ± ± ± 6.8 cm 0.9 ± 1.9 M ± ± ± ± ± 8.2 cm 2.7 ± 2.4 SW F ± ± ± ± ± 6.8 cm 0.0 ± 1.2 M ± ± ± ± ± 8.2 cm 0.4 ± 1.3 Tble 1 Auxologic dt on 92 ptients with CAH (men ± SD). p < 0.05 (sme sex comprison between SV nd SW forms of CAH SV, FH, finl height; corr FH, corrected finl height (FH-SDS-TH-SDS); TPG, totl pubertl growth; SV, simple virilizing; SW, slt-wsting; TH, trget height; BA, bone ge; CA, chronologicl ge. Men rel finl height, scm Predicted finl height B&P, cm Overestimtion of finl height with the B&P method Femles n = ± 5.3 cm ± 10.7 cm 7.3 ± 9.5 cm Mles n = ± 6.0 cm ± 13.4 cm 13.9 ± 10.8 cm Tble 2 Finl height prediction t onset of puberty with the Greulich nd Pyle & Byley & Pinneu methods compred to rel finl height in n = 92 ptients with CAH.

4 648 Bonfig nd Schwrz: Overestimtion of finl height prediction in CAH ptients Femles (n = 52) Mles (n = 33) Bone ge Bone ge, yers Percentge of mture height Percentge of mture height B&P Bone ge Bone ge, yers Percentge of mture height Percentge of mture height B&P Accelerted (n = 14) Norml (n = 38) Accelerted (n = 15) Norml (n = 18) Tble 3 New tble for finl height prediction for femle ptients with clssicl drenl hyperpsi compred to B&P tbles. Tble 4 New tble for finl height prediction for mle ptients with clssicl drenl hyperpsi compred to B&P tbles. CAH, men hydrocortisone dose in the first 2 yers nd the men BMI-SDS in erly childhood nd fter puberty (20). Attenuted growth during puberty ws lso reported in multicenter study of 54 ptients with CAH in by Muirhed et l. in 2002 (21), s well s in two subsequent studies (22, 23). These dt suggest tht pubertl growth is significntly ttenuted in both forms of clssicl CAH, irrespective of gender. This decrese in pubertl growth could be explined by excess glucocorticoid dministrtion t the onset of puberty, s suprphysiologic doses of glucocorticoids hve been shown to increse hypothlmic somtosttin tone (24) nd result in decresed growth hormone secretion, which normlly peks during puberty. Alterntively decresed pubertl height gin my be explined by inpproprite ccelertion of bone mturtion in ptients with poor metbolic control. According to the ltest Endocrine Society clinicl prctice guideline, growth-promoting therpy could be offered to CAH ptients with predicted finl height below 2.25 SD in the context of clinicl studies (9). Therefore, finl height prediction should be s ccurte s possible. We hve developed new tbles for finl height prediction in CAH ptients considering the chrcteristics of the growth pttern in these ptients. These new tbles now should be evluted in ptients with erly CAH dignosis by newborn-screening nd treted with reltively low doses of hydrocortisone from erly infncy (25). As glucocorticoid doses hve been slightly lowered to mg hydrocortisone/m 2 /dy in the pst decde, it will be interesting to see, if these ptients exhibit the sme growth pttern with decresed pubertl growth spurt. In summry, ptients with CAH exhibit typicl growth pttern with decresed pubertl growth spurt under dequte conventionl glucocorticoid therpy. Therefore, finl height prediction results in significnt overestimtion of finl height when the B&P tbles re used. This is n importnt finding becuse in studies using growth-promoting therpies, the chieved finl height is frequently compred to the predicted finl height. New finl height prediction tbles were derived from lrge group of homogeneously treted ptients receiving trditionl glucocorticoid nd minerlocorticoid tretment, which now need to be evluted in the future. Conflict of interest sttement The uthors hve no conflict of interest to disclose. Funding: No grnt support ws received. Received My 25, 2012; ccepted My 27, 2012; previously published online July 27, 2012 References 1. Merke DP, Bornstein SR. Congenitl drenl hyperplsi. Lncet 2005;365: Speiser PW, White PF. Congenitl drenl hyperplsi. N Engl J Med 2003;349:

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