NPHS2 Gene Mutation, Atopy, and Gender As Risk Factors for Steroid-Resistant Nephrotic Syndrome in Indonesians

Paediatrica Indonesiana

VOLUME 51 September NUMBER 5

Original Article

NPHS2 gene mutation, atopy, and gender as risk factors for steroid-resistant nephrotic syndrome in Indonesians

Dedi Rachmadi, Dany Hilmanto, Ponpon Idjradinata, Abdurahman Sukadi

Abstract QUHFHQW\HDUVPROHFXODUJHQHWLFVWXGLHVKDYH Background 6WHURLGUHVLVWDQWQHSKURWLFV\QGURPH 6516 RIWHQ EHHQZHOOGHYHORSHGLQFOXGLQJVWXGLHVIRU GHYHORSVLQWRHQGVWDJHUHQDOGLVHDVH3UHYLRXVVWXGLHVKDYH JHQHVLQYROYHGLQWKHSDWKRJHQHVLVRIQHSKURWLF reported that NPHS2JHQHPXWDWLRQJHQGHUDQGDWRSLFKLVWRU\ V\QGURPH2ISDUWLFXODULQWHUHVWLVWKHJHQH DUHULVNIDFWRUVDVVRFLDWHGZLWK6516,QWHUHWKQLFVRFLRFXOWXUDO I DQGHQYLURQPHQWDOGLIIHUHQFHVKDYHDOVREHHQVXJJHVWHGWRDIIHFW encoding a protein that maintains the diaphragm slit WKHVHPXWDWLRQV RISRGRF\WHV*HQHPXWDWLRQDQDO\VLVLVLPSRUWDQW Objective7RDQDO\]HSRVVLEOHULVNIDFWRUVIRU6516LQFOXGLQJ with regards to phenotype and predicting the severity NPHS2JHQHPXWDWLRQV &o7DQGGHO* JHQGHUDQG RIFOLQLFDOPDQLIHVWDWLRQV The NPHS2 gene encodes DWRSLFKLVWRU\LQ,QGRQHVLDQVXEMHFWVZLWK6516 the podocin protein and is located on chromosome Methods$FDVHFRQWUROVWXG\ZLWKVXEMHFWVFRQVLVWLQJRI 6516SDWLHQWVDQGFRQWUROVXEMHFWVZDVXQGHUWDNHQLQ T0XWDWLRQRIWKLVJHQHKDVEHHQDVVRFLDWHG ,QGRQHVLDQWHDFKLQJFHQWUHKRVSLWDOVIURP6HSWHPEHUWR ZLWKSRRUVWHURLGUHVSRQVHLQWUHDWPHQWRIQHSKURWLF 'HFHPEHU$QDO\VLVRIWKHNPHS2JHQHPXWDWLRQLQ V\QGURPH 16 3UHYLRXVVWXGLHVKDYHVKRZQWKDW &o7ZDVSHUIRUPHGE\DPSOLILFDWLRQUHIUDFWRU\PXWDWLRQV\VWHP SRNS patients with an NPHS2JHQHPXWDWLRQKDG SRO\PHUDVHFKDLQUHDFWLRQ $5063&5 ZKLOHWKDWIRUWKH NPHS2JHQHPXWDWLRQLQGHO*ZDVSHUIRUPHGE\UHVWULFWLRQ PRUHVHYHUHFOLQLFDOPDQLIHVWDWLRQVFRPSDUHGWR IUDJPHQWOHQJWKSRO\PRUSKLVP 5)/3 'DWDZDVDQDO\]HGE\ 6516SDWLHQWVZLWKRXWWKHNPHS2JHQHPXWDWLRQ PXOWLSOHORJLVWLFUHJUHVVLRQ NPHS2JHQHPXWDWLRQVKDYHEHHQIRXQGLQ Results,QRXU,QGRQHVLDQVXEMHFWVWKHVLJQLILFDQWULVNIDFWRUV RI6516SDWLHQWVPRVWO\SUHVHQWLQWKHWKLUGH[RQ IRU6516ZHUHPDOHJHQGHU 25 &, 5 3 NPHS2&o7JHQHPXWDWLRQ 25 &, RIWKHJHQH 2WKHUVWXGLHVRI6516SDWLHQWVDOVR 3 DQGNPHS2GHO*JHQHPXWDWLRQ VKRZHGPXWDWLRQVORFDWHGRQWKHWKLUGH[RQQDPHO\ 25 &,3 +RZHYHUDWRSLF DQRQVHQVHPXWDWLRQDW&o7 5; and a KLVWRU\ZDVQRWDVLJQLILFDQWULVNIDFWRUIRU6516 25 GHOHWLRQDWGHO*6 &,3 Conclusion NPHS2 &o7DQGGHO*JHQHPXWDWLRQV DVZHOODVPDOHJHQGHUDUHULVNIDFWRUVIRU6516LQ,QGRQHVLDQ VXEMHFWV$WRSLFKLVWRU\ZDVQRWVLJQLILFDQWO\DVVRFLDWHGZLWK6516 LQRXUVXEMHFWV[Paediatr Indones. 2011;51:272-6]. )URP'HSDUWPHQWRI&KLOG+HDOWK)DFXOW\RI0HGLFLQH3DGMDGMDUDQ 8QLYHUVLW\+DVDQ6DGLNLQ+RVSLWDO%DQGXQJ,QGRQHVLD Keywords: Steroid-resistant nephrotic syndrome, risk factor, NPHS2 gene mutation Reprint requests to:'HGL5DFKPDGL0''HSDUWPHQWRI&KLOG+HDOWK )DFXOW\RI0HGLFLQH3DGMDGMDUDQ8QLYHUVLW\+DVDQ6DGLNLQ+RVSLWDO-O 3DVWHXU%DQGXQJ7HO(PDLOGHGLUDFKPDGL# yahoo.com

272Paediatr Indones, Vol. 51, No. 5, September 2011 'HGL5DFKPDGLHWDO13+6JHQHPXWDWLRQDWRS\DQGJHQGHUDVULVNIDFWRUVIRU6516

Diversity in the NPHS2JHQHPXWDWLRQSDWWHUQ RIWKH3DGMDGMDUDQ8QLYHUVLW\0HGLFDO6FKRRO+DVDQ LVWKRXJKWWREHGXHWRYDULDWLRQVLQHWKQLFLW\DQG 6DGLNLQ*HQHUDO+RVSLWDO%DQGXQJ environment.6LQFHWKHUHZDVQRVWXGLHVRQ NS was diagnosed according to the International NPHS2JHQHPXWDWLRQVLQWKHSHGLDWULF,QGRQHVLDQ 6WXG\RI.LGQH\'LVHDVHLQ&KLOGUHQ ,6.'& FULWHULD SRSXODWLRQZHIRFXVHGRQWKHWKLUGH[RQRINPHS2 LHHGHPDVHYHUHSURWHLQXULDK\SRDOEXPLQHPLD DVDEDVLVIRUVWXG\LQ,QGRQHVLDQFKLOGUHQZLWK6516 JG/ ZKLOH6516ZDVGHILQHGDV16SDWLHQWV 6LQFHPDQ\IDFWRUVPD\SOD\DUROHLQWKHRFFXUUHQFH QRWDFKLHYLQJUHPLVVLRQDIWHUVLQJOHGUXJSUHGQLVRQH RI6516ZHLQFOXGHGJHQGHUDQGKLVWRU\RIDWRS\DV WKHUDS\XVLQJWKHIXOOGRVHIRUWKHILUVWIRXUZHHNV SRVVLEOHULVNIDFWRUVRI6516LQWKLVVWXG\2XUDLP NS diagnoses were made by pediatric nephrologists or ZDVWRGHWHUPLQHLINPHS2JHQHPXWDWLRQVJHQGHU SHGLDWULFLDQVVXSHUYLVHGE\SHGLDWULFQHSKURORJLVWV DQGKLVWRU\RIDWRS\DUHULVNIDFWRUVIRU6516LQ 'DWDDQDO\VHVZHUHSHUIRUPHGXVLQJ6366 Indonesian children. YHUVLRQ0XOWLSOHORJLVWLFUHJUHVVLRQDQDO\VLV ZDVXVHGWRGHWHUPLQHSRVVLEOHULVNIDFWRUVIRU6516 LQFOXGLQJJHQHPXWDWLRQV NPHS2&oT and Methods GHO*JHQGHUDQGIDPLOLDODWRSLFKLVWRU\ To detect the NPHS2&o7PXWDWLRQLQ $FDVHFRQWUROVWXG\ZDVFRQGXFWHGIURP6HSWHPEHU H[RQZHXVHG$5063&53ULPHUGHVLJQLVVKRZQ WR'HFHPEHU:HLQFOXGHGFDVHVXEMHFWV in Figure 16XEMHFWV·'1$VSHFLPHQVZHUHSODFHG with primary SRNS aged between 1-14 years old. LQGXSOLFDWHWXEHVRQHWXEHFRQWDLQLQJWKHZLOGW\SH &RQWUROVXEMHFWVZHUHKHDOWK\FKLOGUHQZLWKQR DQGUHYHUVHSULPHUVDQGWKHRWKHUWXEHFRQWDLQLQJ NLGQH\GLVHDVHVRUFRQJHQLWDODEQRUPDOLWLHV&DVH WKHPXWDWHGDQGUHYHUVHSULPHUV6LQFHNPHS2 is an DQGFRQWUROVXEMHFWVYLVLWHGWKHSHGLDWULFQHSKURORJ\ DXWRVRPDOUHFHVVLYHJHQHDPSOLILFDWLRQVKRXOGRFFXU GLYLVLRQRIHGXFDWLRQDOKRVSLWDOVLQ,QGRQHVLDLQ LQRQO\RQHWXEH WKHFLWLHVRI%DQGXQJ-DNDUWD

:LOGW\SH & SULPHU··**77*7$&$$*$*7$$7**$$$*$*7$$77$7$77$& 0XWDWHG 7 SULPHU··**77*7$&$$*$*7$$7**$$$*$*7$$77$7$77$T 5HYHUVHSULPHU··7*$$*$$$77**&$$*7&$*

Figure 1. Wild type sequence, mutated sequence and reverse primers for ARMS-PCR.

T **77*7$&$$*$*7$$7**$$$*$*7$$77$7$77$&*$&7***$&$7&&*&77 &&7**$$*$*&&$$$**&&&7**7$$$$$$$&$&7&77777777&7$$$&$&&7& 7&7&&7*$&77*&&$$777&77&$

Figure 2. Predicted PCR product, 131 base pairs.

Paediatr Indones, Vol. 51, No. 5, September 2011 273 'HGL5DFKPDGLHWDO13+6JHQHPXWDWLRQDWRS\DQGJHQGHUDVULVNIDFWRUVIRU6516

%IL,FXWSRLQW

**77*7$&$$*$*7$7*$$$*$*7$$77$7$77&&*$&7***$&$7&&*&77&& 7**$$*$*&&$$$**&&&7**7$$$$$$$&$&7&77777777&7$$$&$&&7&7& 7&&7*$&77*&&$$777&77&$

Figure 3. $ſ+TGEQIPKVKQPUGSWGPEGCPFEWVRQKPVKPVJGYKNFV[RGNPHS2 gene. The 419delG mutation is noted in red.

*HOHOHFWURSKRUHVLV DJDURVH ZDVXVHGYLVXDOL]H Results WKH3&5SURGXFWV*HOVZHUHSKRWRJUDSKHGZKLOH XQGHUXOWUDYLROHWWUDQVOXPLQDWLRQ7KHSUHGLFWHG $WRWDORIVXEMHFWVFRQVLVWLQJRI6516FDVHV ES3&5SURGXFWLVVKRZQLQFigure 2. DQGFRQWUROVXEMHFWVZHUHHQUROOHGGXULQJWKH The NPHS2 GHO*DOOHOHZDVGHWHFWHGE\ VWXG\SHULRG7KHPDMRULW\ZHUHER\VLQ6516JURXS 5)/3DQDO\VLV7KHES3&5SURGXFWVIURPWKH DQGLQWKHFRQWUROJURXS +LVWRU\RI $5063&5DQDO\VLVZHUHVXEMHFWHGWR%IL,UHVWULFWLRQ DWRS\ZDVPRUHFRPPRQLQWKH6516JURXS HQGRQXFOHDVH7KHZLOGW\SHVHTXHQFH ZLWKWKH* WKDQLQWKHFRQWUROJURXS ,QDGGLWLRQWKH SUHVHQW ZDVFXWLQWRWZRIUDJPHQWVRIESDQG NPHS2JHQHPXWDWLRQVZHUHPRUHFRPPRQLQWKH ES7KHPXWDWHGVHTXHQFH *GHOHWHG UHPDLQHG 6516JURXSWKDQLQWKHFRQWUROJURXS(Table 1) XQGLJHVWHGE\%IL,5HVWULFWLRQDQDO\VLVSURGXFWVZHUH 0XOWLYDULDWHDQDO\VHVRIWKHSRVVLEOHULVNIDFWRUV observed by gel electrophoresis as described above. IRU6516DUHGHVFULEHGLQTable 22IWKHVHULVN 7KH%IL,UHFRJQLWLRQVHTXHQFHORFDWHGLQWKHZLOG IDFWRUVPDOHJHQGHUDQGWKHNPHS2&oT and type NPHS2JHQH ES3&5SURGXFW LVVKRZQ GHO*JHQHPXWDWLRQVZHUHVLJQLILFDQWO\DVVRFLDWHG in Figure 3. ZLWKWKHRFFXUUHQFHRI6516 3 +RZHYHU WKHKLVWRU\RIDWRS\ZDVQRWVLJQLILFDQWO\DVVRFLDWHG Table 1. Characteristics of subjects ZLWK6516 3! SNRS group Control group Variable N = 88 N = 65 Gender, n (%) Discussion Female 20 (22.7) 26 (40.0) Male 68 (77.3) 39 (60.0) History of atopy, n (%) 6516LVDFRPPRQFDXVHRIFKURQLFNLGQH\GLVHDVH Positive 25 (28.4) 8 (12.3) LQFKLOGUHQ$FFRUGLQJWRWKHOLWHUDWXUHPXWDWLRQ Negative 63 (71.6) 57 (87.7) in the NPHS2JHQHHQFRGLQJIRUSRGRFLQPD\OHDG 412C T mutation, n (%) o 5,6,7 Positive 58 (65.9) 9 (13.8) to SRNS. $FDVHFRQWUROVWXG\ZDVSHUIRUPHG Negative 30 (34.1) 56 (86.2) LQFKLOGUHQSUHVHQWLQJZLWK6516LQ,QGRQHVLDQ 419delG mutation, n (%) WHDFKLQJKRVSLWDOVIURP6HSWHPEHUWR'HFHPEHU Positive 69 (78.4) 41 (63.1) Negative 19 (21.6) 24 (36.9) 2XUVWXG\UHVXOWVZHUHVLPLODUWRWKRVHIURP Table 2. The variables as risk factors for SRNS both ArabicDQG&DXFDVLDQFKLOGUHQ4,11 The strong UHODWLRQVKLSEHWZHHQWKHRFFXUUHQFHRI6516DQG Variable 14 95% CI P value NPHS2JHQHPXWDWLRQHVSHFLDOO\LQH[RQ Gender 2.21 1.07-4.56 0.036 &oT, was shown by Frishberg et al. in Israeli-Arab 412CoT mutation 18.07 6.76-48.31 < 0.001 419delG mutation 4.55 1.66-12.47 0.003 children, DQGE\&DULGLet alLQ&DXFDVLDQFKLOGUHQ 11 History of atopy 1.81 0.64-5.09 0.262 in Italy. 6LPLODUO\ZHIRXQGWKDWVXEMHFWVZLWKWKH Note: Accuracy 74.51% NPHS2&o7JHQHPXWDWLRQKDGWLPHV

274Paediatr Indones, Vol. 51, No. 5, September 2011 'HGL5DFKPDGLHWDO13+6JHQHPXWDWLRQDWRS\DQGJHQGHUDVULVNIDFWRUVIRU6516

KLJKHUULVNIRU6516WKDQWKRVHZLWKRXWWKLVJHQH ZLWKVSRUDGLF6516WKHPDOHWRIHPDOHUDWLRRI PXWDWLRQ7KHNPHS2&o7JHQHPXWDWLRQ patients with an NPHS2JHQHPXWDWLRQZDV11 LVDQRQVHQVHPXWDWLRQ7KHFKDQJHRIF\WRVLQHWR ,WLVGLIILFXOWWRGLIIHUHQWLDWHEHWZHHQHDUO\)6*6 WK\PLQHDWEDVHVHTXHQFHUHVXOWVLQWKHORVVRI DQGPLQLPDOFKDQJHQHSKURWLFV\QGURPH 0&16 WKHDPLQRDFLGDUJLQLQHDWVHTXHQFH 5; DV)6*6LVFRQVLGHUHGWREHDFRQWLQXDWLRQRI 7KLVDPLQRDFLGORVVSURGXFHVDWUXQFDWHGIRUPRI 0&1617 The relationship between male gender SRGRFLQ,WLVWKRXJKWWKDWWKHWUXQFDWHGSRGLFLQJHWV DQGQHSKURWLFV\QGURPHUHPDLQVXQFOHDU,WKDV WUDSSHGLQWKHHQGRSODVPLFUHWLFXOXPVRWKDWLWORVHV EHHQHVWDEOLVKHGWKDWSDWKRJHQHVLVRIQHSKURWLF LWVFDSDELOLW\WRELQGQHSKULQLQWKHOLSLGUDIW The V\QGURPHLQYROYHV7FHOOG\VIXQFWLRQ Abnormal WUXQFDWHGSRGRFLQZLOOVWLPXODWHDQWLERG\IRUPDWLRQ T cell clones are predominantly located in the DJDLQVWWKHWHUPLQDOSDUWRIWKHSURWHLQ14,15 WK\PXVDQGWK\PXVGLVHDVHLVPRUHFRPPRQLQ :HDOVRFRQVLGHUHGWKHHIIHFWRIDNPHS2 gene boys than girls. Another theory is that SRNS with PXWDWLRQLQDQRWKHUORFDWLRQ8VLQJWKH$5063&5 JHQHPXWDWLRQLVLQIOXHQFHGE\KRUPRQHV(VWURJHQ PHWKRGWKHH[RQ&o7ZDVWKHRQO\PXWDWLRQ PD\SUHYHQWWKHJORPHUXORVFOHURVLVSURFHVVE\ DEOHWREHGHWHFWHG&DULGLet alXVHGDVHTXHQFLQJ GHFUHDVLQJXULQDU\VH[GHSHQGHQWORZPROHFXODU method to detect all possible NPHS2JHQHPXWDWLRQ weight proteins.7KH\RXQJHUDJHRIRQVHWLQ LQH[RQRI6516SDWLHQWVZLWKIRFDOVHJPHQWDO VSRUDGLF6516UHJDUGOHVVRILWVUHODWLRQVKLSWR JORPHUXORVFOHURVLV )6*6 4,117KH\VXJJHVWHGWKDW DEQRUPDO7FHOOFORQHVLQWKHWK\PXVLVVLPLODUWR DQRWKHU NPHS2 JHQHPXWDWLRQLQH[RQGHO* WKHRFFXUUHQFHLQ0&16SDWLHQWV)XUWKHUUHVHDUFK was associated with SRNS in Italian children with is needed. SRNS11DQGLQDODUJHVDPSOHVL]HRI(XURSHDQ The NPHS2&o7JHQHPXWDWLRQOHDGV children.4%\5)/3DQDO\VLVZHDOVRIRXQGWKLV WRIRUPDWLRQRIDWUXQFDWHGSURWHLQ7KH NPHS2 PXWDWLRQWREHDVVRFLDWHGZLWK6516LQRXUVXEMHFWV GHO*JHQHPXWDWLRQUHVXOWVLQIRUPDWLRQRI Those with the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his theory JHQHPXWDWLRQVDW&o7DQGGHO*RQWKH PD\H[SODLQWKHSKHQRW\SLFGLIIHUHQFHVLQRXUVWXG\ RFFXUUHQFHRI6516ZHREVHUYHGWKDWWKH&oT UHVXOWVDQGWKRVHRISUHYLRXVVWXGLHV3UHYLRXVVWXGLHV PXWDWLRQZDVDVVRFLDWHGZLWKDWLPHVJUHDWHU KDYHVKRZQGLIIHUHQFHVLQW\SHDQGIUHTXHQF\RI SRVVLELOLW\RI6516RFFXUUHQFHWKDQWKHGHO* NPHS2JHQHPXWDWLRQVEDVHGRQUDFLDOPDNHXS PXWDWLRQ+RZHYHULQWKHRU\DIUDPHVKLIWPXWDWLRQ $FFRUGLQJWRPXOWLYDULDEOHDQDO\VLVRQTable 2, DWGHO*VKRXOGKDYHVWURQJHUHIIHFWRQWKH ZHFDQVHHWKHUROHRIJHQGHU&o7PXWDWLRQ RFFXUUHQFHRI6516FRPSDUHGWRWKDWRIDQRQVHQVH DQGGHO*PXWDWLRQWR65167KHYDOXHRI PXWDWLRQDW&oT. 162QHH[SODQDWLRQIRUWKLV DFFXUDF\LQWKLVUROHZDV,WPHDQVWKHUH UHVXOWLVWKDWRXUDVVD\VGHWHFWHGPXWDWLRQVDWRQO\ ZHUHRWKHUYDULDEOHVWKDWDIIHFWWR6516EHVLGHV WKHVHVSHFLILFVLWHVDQG:HFDQQRWH[FOXGH those variables. WKHSRVVLELOLW\WKDWPXWDWLRQVLQRWKHUNPHS2 gene ,QFRQFOXVLRQWKHNPHS2&oT and ORFDWLRQVH[LVWDIIHFWLQJWKHRFFXUHQFHRI6516 GHO*JHQHPXWDWLRQVDVZHOODVPDOHJHQGHU :HIRXQGWKHPDOHJHQGHUWREHDULVNIDFWRUIRU DUHULVNIDFWRUVIRU6516+LVWRU\RIDWRS\ZDVQRW 6516ZLWKPDOHVDQGIHPDOHVLQWKH DULVNIDFWRUIRU6516)XUWKHUVWXGLHVDUHQHHGHG 6516JURXS6LPLODUO\DQ,6.'&VWXG\UHSRUWHG to determine other possible associated NPHS2 gene WKDWRISHGLDWULFSDWLHQWVZLWK)6*6ZHUH PXWDWLRQVE\VHTXHQFLQJDVZHOODVELRSV\WRHVWDEOLVK PDOHDQGZHUHIHPDOH)XUWKHUPRUH&DULGL WKHW\SHRIKLVWRSDWKRORJLFDODEQRUPDOLWLHVLQSDWLHQWV et alREVHUYHGWKDWLQ&DXFDVLDQFKLOGUHQLQ,WDO\ with SRNS.

Paediatr Indones, Vol. 51, No. 5, September 2011 275 'HGL5DFKPDGLHWDO13+6JHQHPXWDWLRQDWRS\DQGJHQGHUDVULVNIDFWRUVIRU6516

Acknowledgments :LQP:&.RQHPDQ(:$OOHQ6-DQGD:3URFRS* 6FKUHFNHQEHUJHU3HWDO.RQHPDQ·VFRORUDWODVDQGWH[WERRN 7KLVVWXG\ZDVVXSSRUWHGLQSDUWE\5,6%,1,37(.'2. RIGLDJQRVWLFPLFURELRORJ\thHG%DOWLPRUH/LSSLQFRW DFRRSHUDWLYHJUDQWEHWZHHQWKH,QGRQHVLDQ0LQLVWU\RI :LOOLDPV :LONLQVS +HDOWKDQGWKH(LMNPDQ,QVWLWXWHIRU0ROHFXODU%LRORJ\ &DULGL&%HUWHOL5&DUUHD$'L'XFD0&DWDUVL3$UWHUR 0HWDO3UHYDOHQFHJHQHWLFVDQGFOLQLFDOIHDWXUHVRISDWLHQWV FDUU\LQJSRGRFLQPXWDWLRQVLQVWHURLGUHVLVWDQWQRQIDPLOLDO References IRFDOVHJPHQWDOJORPHUXORVFOHURVLV-$P6RF1HSKURO $QWLJQDF&*HQHWLFPRGHOVFOXHVIRUXQGHUVWDQGLQJWKH &DULGL*3HUIXPR)*KLJJHUL*013+6 SRGRFLQ SDWKRJHQHVLVRILGLRSDWKLFQHSKURWLFV\QGURPH-&OLQ,QYHVW PXWDWLRQVLQQHSKURWLFV\QGURPH&OLQLFDOVSHFWUXPDQG ILQHPHFKDQLVPV3HGLDWU5HVHDUFK5 +XEHU7%6LPRQV0+DUWOHEHQ%6HUQHW]/6FKPLGWV 1LDXGHW3*HQHWLFIRUPRIQHSKURWLFV\QGURPH3HGLDWU 0*XQGODFK(0ROHFXODUEDVLVRIWKHIXQFWLRQDOSRGRFLQ 1HSKURO QHSKULQFRPSOH[PXWDWLRQVLQWKH13+6JHQHGLVUXSW :HEHU6*ULERXYDO2(VTXLYHO(/0RULQLHUH97r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

276Paediatr Indones, Vol. 51, No. 5, September 2011