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6OXåED]DNDUGLRORJLMR3HGLDWULþQDNOLQLND8QLYHU]LWHWQLNOLQLþQLFHQWHU/MXEOMDQD/MXEOMDQD Slovenija
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6LQGURP GRNRQþQR SRWUGLPR ] JHQHWVNLPL SUHLVNDYDPL =D VLQGURP /(23$5' VR ]QDþLOQH PXWDFLMH Y genih PTPN 11RAF 1 in BRAF NL NRGLUDMR EHOMDNRYLQH L] VLJQDOQH SRWL 5$60$3. )HQRWLSVNR VR EROQLNL QDMEROM SRGREQL EROQLNRP V VLQGURPRP 1RRQDQ 3RGREQL VR WXGL SDWR¿]LRORãNL Y]URNL EROH]QL 5D]OLNRYDQMH PHG VLQGURPRPD MH SRPHPEQR ]DUDGL QDSRYHGL SRWHND EROH]QL LQ GROJRURþQH REUDYQDYH bolnikov.
.OMXþQHEHVHGHQL]NDUDVWNDUGLRPLRSDWLMDOHQWLJLQHVVLQGURP/(23$5'VLQGURP1RRQDQ
ABSTRACT
7KHFDVHRIDER\ZLWKDYHU\UDUHV\QGURPLFGLVHDVHEHORQJLQJWRWKHJURXSRIQHXURFDUGLRIDFLRFXWDQHRXV V\QGURPHV±V\QGURPH/(23$5'LVSUHVHQWHG7\SLFDOFOLQLFDOIHDWXUHVRIWKHV\QGURPHDUHPXOWLSOHVNLQ OHQWLJLQHV(&*FRQGXFWLRQDEQRUPDOLWLHVRFXODUK\SHUWHORULVPK\SHUWURSKLFFDUGLRP\RSDWK\SXOPRQDU\
VWHQRVLVDEQRUPDOJHQLWDOLDJURZWKUHWDUGDWLRQDQGVHQVRULQHXUDOGHDIQHVV
7KHGLDJQRVLVRIWKHV\QGURPHLVFRQ¿UPHGE\JHQHWLFDQDO\VLV0XWDWLRQVLQWKHPTPN 11RAF 1 and BRAF JHQHVHQFRGLQJSURWHLQVLQWKH5$60$3.VLJQDOOLQJSDWKZD\DUHDVVRFLDWHGZLWK/(23$5'V\QGURPH 6ORY3HGLDWU
7KHUHLVDVLJQL¿FDQWRYHUODSLQFOLQLFDOSUHVHQWDWLRQDQGSDWKRSK\VLRORJLFDOPHFKDQLVPVZLWK1RRQDQV\Q- GURPH7KHGLVWLQFWLRQEHWZHHQWKHWZRV\QGURPHVLVLPSRUWDQWEHFDXVHRIWKHGLVHDVHSURJQRVLVDQGORQJ term patient management.
.H\ZRUGVVKRUWVWDWXUHFDUGLRP\RSDWK\OHQWLJLQHV/(23$5'V\QGURPH1RRQDQV\QGURPH
6OLND=QDþLOQDGLVSODVWLþQD]QDPHQMDREUD]DSRXGDUMHQLIURQWDOQLWXEHULKLSHUWHORUL]HPSWR]DãLURNQRVQLNRUHQQLåMHSRORåHQD XãHVDOHQWLJLQR]QHVSUHPHPEHNRåHLQYVWDYOMHQVOXãQLDSDUDWRERERMHVWUDQVNLVHQ]RULQHYUDOQLQDJOXãQRVWL
)LJXUH7\SLFDOG\VPRUSKLFIDFLDOIHDWXUHVKLJKIRUHKHDGK\SHUWHORULVPSWRVLVZLGHQDVDOEULGJHORZVHWHDUVOHQWLJLQHVRIWKH VNLQKHDULQJDLGVGXHWRELODWHUDOVHQVRU\QHXUDOGHDIQHVV
UVOD
6LQGURP /(23$5' XYUãþDPR Y VNXSLQR QHYUR- NDUGLRIDFLRNXWDQLKVLQGURPRY=DYVHVLQGURPH L] WH VNXSLQH VR ]QDþLOQL GLVSODVWLþQD ]QDPHQMD REUD]DWLSLþQHNRåQHVSUHPHPEHDQRPDOLMHVUFDLQ QDYDGQRWXGLXPVNDPDQMUD]YLWRVWR]XþQHWHåDYH í 0HGQMH XYUãþDPR WXGL VLQGURP 1RRQDQ VLQGURP QHYUR¿EURPDWR]D1RRQDQ NDUGLRIDFLRNX-
WDQLVLQGURP&RVWHOORYVLQGURP/HJLXVRYVLQGURP YþDVLKSR]QDQNRWQHYUR¿ERPDWR]LWLSDSRGREHQ VLQGURPLQGUXJHí
,QFLGHQFDFHORWQHVNXSLQHEROH]QLMHí åLYRURMHQLKRWURN=QDþLOQDMHKHWHURJHQRVWNOLQLþQH VOLNH]QRWUDMSRVDPH]QHJDVLQGURPD)HQRWLSVNRVR si najbolj podobni bolniki s sindromom LEOPARD WHUEROQLNLVVLQGURPRP1RRQDQ2EDVLQGURPDVH
GHGXMHWDDYWRVRPQRGRPLQDQWQRLQSULREHK MH QDMSRJRVWHMãD PXWDFLMD JHQDPTPN11 UHGNHMH RAF 1 in BRAF 3ROHJQDãWHWLKVRPRåQHWXGL PXWDFLMHYGUXJLKJHQLKVLJQDOQHSRWL5$60$3.
kar velja tudi za ostale nevrokardiofaciokutane sin- GURPH]DWRMLKLPHQXMHPRWXGLª5$6RSDWLMH©
ýHSUDYMHSULREHKVLQGURPLKY]URNEROH]QLPXWD- FLMD Y LVWHP JHQX MH QMXQD NOLQLþQD VOLND UD]OLþQD 5D]ORJVHVNULYDYGHMVWYXGDVRSULVLQGURPX1RR- QDQPXWDFLMHDNWLYLUDMRþHNDUSRPHQLGDPXWDFLMD SRY]URþLSRYHþDQRHQFLPVNRDNWLYQRVWEHOMDNRYLQH NL MR NRGLUD PXWLUDQL JHQ PXWDFLMH SUL VLQGURPX /(23$5'SD]PDQMãDMRDNWLYQRVWNRGLUDQHEHOMD- NRYLQHí
Diferencialno diagnosticiranje je pomembno zaradi QDSRYHGLSRWHNDEROH]QLWHUGROJRURþQHREUDYQDYH bolnikov.
PRIKAZ PRIMERA
'HþHNMHELOURMHQNRWWUHWMLRWURNPDWHUHLQRþHWD NL QLVWD Y VRURGX 2þH VH ]GUDYL ]DUDGL VODGNRUQH EROH]QL WLSD 0DWL MH ELOD RE SRURGX VWDUD OHW 1RVHþQRVW MH SRWHNDOD EUH] ]DSOHWRY Y SHWHP PHVHFXQRVHþQRVWLSDMH]DUDGLDNXWQHRNXåEHGLKDO SUHMHPDODDQWLELRWLNDPRNVLFLOLQ'HþHNMHELOURMHQ RE L]UDþXQDQHP URNX SRURGD Y JODYLþQL YVWDYL V SRURGQRGROåLQRFPLQWHåRJ2ESRURGX MHSUHMHORFHQRSR$SJDUMHYLNDVQHMHVRXJR- WDYOMDOLEODJRKLSRWRQLMR]DUDGLNDWHUHJDMHRGþHWU- WHJDPHVHFDREUDYQDYDOQHYUR¿]LRWHUDSHYW
7DNRM SR URMVWYX VR QDG VUFHP VOLãDOL ãXP ]DUDGL katerega sta ga obravnavala neonatolog in kardio- ORJ 8JRWRYLOL VR KLSHWUR¿þQR NDUGLRPLRSDWLMR LQ uvedli zdravljenje z blokatorjem beta.
'HþHNMHVODERSULGRELYDOQDWHOHVQLWHåL]DWRVHMH NRW GRMHQþHN ]GUDYLO SUL JDVWURHQWHURORJX 7DNUDW opravljene preiskave so bile v mejah normalnih YUHGQRVWLYREGREMXQRYRURMHQþNDXJRWRYOMHQDSUH- REþXWOMLYRVWQDNUDYMHPOHNRSDMHL]]YHQHOD 3UL VWDURVWL PHVHFHY VR ]DUDGL KLSHUWUR¿þQH NDU- GLRPLRSDWLMH RSUDYLOL SUHJOHG SUL JHQHWLNX NL MH XJRWRYLOGLVNUHWQDGLVSODVWLþQD]QDPHQMDNRWVRWUL- kotno oblikovana glavica s poudarjenim kranialnim GHORPL]ERþHQLPþHORPVSRXGDUMHQLPLIURQWDOQLPL WXEHUL YHþMLPL QL]NR SRORåHQLPL LQ QD]DM ]DVXND- QLPLXKOMLYLVRNRRERNDQLPWUGLPQHERPWHUãLUãH distalne falange prstov rok in izrazito hiperlaksne VNOHSH8JRWRYLOLVRWXGLQL]NRUDVWNLVLFHUQLGUX- åLQVNRSRJRMHQD6SUHPHPESRNRåLQLVRRSLVDOL 2EUHGQLQHYUR¿]LRWHUDSLMLMHGHþHNVKRGLOSULVWD- URVWL PHVHFHY LQ VH WXGL PRWRULþQR SULPHUQR UD]YLMDO8SRþDVQMHQMHELOJRYRUQLUD]YRM2WRULQR- laringolog je potrdil obojestransko senzorinevralno QDJOXãQRVW]DUDGLNDWHUHVRPXSULGYHKOHWLKYVWD- YLOLSROåHYYVDGHN3RYVWDYLWYLSROåHYHJDYVDGNDMH GHþHNWXGLJRYRUQRQDSUHGRYDO
Pri dveh letih so ob rednem pregledu v kardiolo- ãNLDPEXODQWLQDNRåLRSD]LOLãWHYLOQHOHQWLJLQR]QH
6OLND=JUDGEDEHOMDNRYLQH3731=DVLQGURP/(23$5']QDþLOQLPXWDFLMLVWDORFLUDQLQDHNVRQXLQGRPHQH373QD
&WHUPLQDOQHPGHOXEHOMDNRYLQH
)LJXUH3731SURWHLQVWUXFWXUH)RU/(23$5'V\QGURPHUHSRUWHGPXWDWLRQVDUHORFDOL]HGRQH[RQHDQGLQWKH373 GRPDLQRQWKH&WHUPLQDOHQGRIWKHSURWHLQ
VSUHPHPEH]DUDGLNDWHULKVRSRVXPLOLQDVLQGURP /(23$5'.DUGLRORJMHGHþNDQDSRWLONGHUPDWR- ORJXNLVHMHVWULQMDOVSRGDQRGLDJQR]R2SUDYLOLVR PROHNXODUQRJHQHWVNHSUHLVNDYHNLVRSRWUGLOHKHWH- rozigotno mutacijo v sedmem eksonu gena PTPN11.
3RWUMHQDPXWDFLMDF$!*S7KU&\VMH]QD- þLOQD]DVLQGURP/(23$5'
=DUDGL QL]NH UDVWL KLSHUWUR¿þQH NDUGLRPLRSDWLMH ãWHYLOQLK OHQWLJLQR]QLK VSUHPHPE NRåH LQ VHQ]RUL- QHYUDOQHQDJOXãQRVWLGHþNDãHQDSUHMUHGQRREUDYQD- YDMRXVWUH]QLVSHFLDOLVWL±HQGRNULQRORJNDUGLRORJ GHUPDWRORJ RWRULQRODULQJRORJ LQ VXUGRSHGDJRJ Redno prejema blokatorje beta. Ob stabilnem stanju kardiomiopatije in zaradi nizke rasti ob dokazanem ]PDQMãDQHPL]ORþDQMXUDVWQHJDKRUPRQDVRSUHGOD- JDOL]GUDYOMHQMH]UDVWQLPKRUPRQRP]DNDWHUHJDSD VHVWDUãL]DHQNUDWQLVRRGORþLOL
OPIS SINDROMOV IN
DIFERENCIALNO DIAGNOSTICIRANJE 6LQGURP/(23$5'
/HWDMH5-*|UOLQVVRGHODYFLSUYLþRSLVDOVLQ- drom LEOPARD in ga je poimenoval z akronimom QDMSRJRVWHMHXJRWRYOMHQLKNOLQLþQLK]QDNRY /±OHQWLJLQR]QHVSUHPHPEHNRåH
(±PRWQMHSUHYDMDQMDYLGQHQDHOHNWURNDUGLRJUDPX VUFD
2±RþHVQLKLSHUWHORUL]HP 3±SXOPRQDOQDVWHQR]D
$±DEQRUPDOQDVSRORYLOD 5±UHWDUGDFLMDYUDVWL
'±VHQ]RULQHYUDOQDJOXKRVWDQJO. deafness /HWD MH 'LJLOLR V VRGHODYFL SRWUGLO GLDJQR]R VLQGURPD/(23$5']PROHNXODUQRDQDOL]R1D bolezen navadno posumimo na podlagi fenotipskih ]QDþLOQRVWL SRWUGLPR SD MR ] PROHNXODUQRJHQHW- VNLPL SUHLVNDYDPL í 3UL EROQLNRY EROH]HQSRY]URþDPXWDFLMDJHQDPTPN11 na dolgem NUDNXNURPRVRPDT
6+3MHVHVWDYOMHQDL]GYHK6+GRPHQDQJOSRC homology 2LQGRPHQH]DEHOMDNRYLQRWLUR]LQIRV- fatazo - PTP (angl. protein thyrosine phosphatase .DGDU MH 373 YH]DQD QD 6+ MH 373 NDWDOLWLþQR QHDNWLYQD9H]DYDIRVIRSHSWLGDQD6+SDSRY]URþL VIHULþQR NRQIRUPDFLMR NDWDOLWLþQHJD PHVWD 373 LQ 6+3 SRVWDQH NDWDOLWLþQR DNWLYHQ 1HVPLVHOQH PXWDFLMHQD373GRPHQLNLVR]QDþLOQH]DVLQGURP /(23$5'YSOLYDMRQDLQWHUDNFLMRPHG6+LQ373 WDNRGDMH373YHVþDVDNWLYQD
'R VHGDM MH ]QDQLK QHVPLVHOQLK PXWDFLM JHQD PTPN11 1HNDWHUH VR YH]DQH QD GRPHQR 6+
GUXJH SD QD GRPHQR 373 0HQLMR GD VWD PXWDFLML 7\U&\V QD HNVRQX LQ 7KU0HW QD HNVRQX NL VWD YH]DQL QD GRPHQR 373 QDMEROM ]QDþLOQL ]D VLQGURP /(23$5' LQ SRY]URþDMR ]D VLQGURP ]QDþLOQHOHQWLJH
0XWDFLMH Y HNVRQLK LQ SRYH]XMHMR V SRMDYRP KLSHUWUR¿þQHNDUGLRPLRSDWLMHPXWDFLMHYHNVRQX SD]KLWURQDSUHGXMRþRKXGRRERMHVWUDQVNRREVWUXN- WLYQRKLSHUWUR¿þQRNDUGLRPLRSDWLMRNLVHSRJRVWR SULþQH åH SUHQDWDOQR WHU KXGLPL NDUGLRORãNLPL ]DSOHWL NRW MH VUþQR SRSXãþDQMH PRWQMH VUþQHJD ULWPDLQQHQDGQDVPUW
Gen PTPN11,NRGLUDEHOMDNRYLQR6+3DQJOSRC homology 2NLMHFLWRSOD]HPVNDVLJQDOQDPROHNXOD Y UHFHSWRUMLK ]D UDVWQH GHMDYQLNH FLWRNLQH LQ KRU- PRQHSUHGYVHPYVLJQDOQLSRWL5$60$3.DQJO 5$6PLWRJHQDFWLYDWHGSURWHLQNLQDVHSDWKZD\
9VLQGURPSRY]URþDPXWDFLMDJHQDRAF1 na NUDWNHPNUDNXNURPRVRPDSDOLJHQDBRAF QDGROJHPNUDNXNURPRVRPDT3ULERO- nikih brez mutacije gena PTPN11 RSLVXMHMR YHþMR SRJRVWRVW QHQDGQH VPUWL Y GUXåLQL EUDGLDULWPLM LQ GUXJLKPRWHQMVUþQHJDULWPDWHUSRJRVWHMãHSRYHþD- QMHOHYHJDDWULMDí
Bolezen se deduje avtosomno dominantno s preno- VRP]REROHOLKPDWHUHRþHWDSRJRVWHSDVRWXGLQD QRYRQDVWDOHPXWDFLMH%ROH]HQMHUHGNDVDMQDMEL QDVYHWXGRVHGDMSUHSR]QDOLSULEOLåQREROQLNRY
6LQGURPXJRWRYLPRSRVWQDWDOQR1RYRURMHQFLLPDMR navadno za gestacijsko starost normalni porodno WHOHVQRWHåRLQGROåLQR3ULSRORYLFLEROQLNRYVHUDVW NDVQHMHXSRþDVQL]DWRXJRWDYOMDPRQLåMRDOLQL]NR rast. Pri nekaterih bolnikih ugotavljamo pomanjka- QMHL]ORþDQMDUDVWQHJDKRUPRQDí
=D VLQGURP VR SDWRJQRPRQLþQH OHQWLJLQR]QH VSUH- PHPEHNRåH6OLND*UH]DUD]SUãHQHWHPQRUMDYH PDNXOH Y UDYQL NRåH 1DYDGQR MLK RE URMVWYX QH QDMGHPR 3RMDYOMDWL VH ]DþQHMR SR þHWUWHP DOL SHWHP OHWX VWDURVWL LQ VLFHU SUHGYVHP SR REUD]X vratu in trupu. Pojavljanje ni povezano z izposta- YOMDQMHP VRQFX âWHYLOR OHQWLJLQR]QLK VSUHPHPE ODKNRGRRGUDVORVWLSRUDVWHWXGLQDWLVRþLQYHþ 3RPHPEQRMHVOHGHQMHSULGHUPDWRORJXVDMVHYþD-
7DEHOD)HQRWLSVNH]QDþLOQRVWLEROQLNRYVVLQGURPRP/(23$5'LQVLQGURPRP1RRQDQ Table 1. Phenotypic characteristics of subjects with LEOPARD and Noonan syndrome.
6LQGURP/(23$5' 6LQGURP1RRQDQ
.RåD
• lentiginozne spremembe
• PDGHåLEDUYHEHOHNDYH
/
6UFH
• KLSHUWURILþQDNDUGLRPLRSDWLMD
• pulmonalna stenoza
• pulmonalna stenoza
• KLSHUWURILþQDNDUGLRPLRSDWLMD
• SULURMHQHVUþQHQDSDNHGHIHNWDWULMVNHJDVHSWXPDWLSD VHNXQGXPGHIHNWLDWULRYHQWULNXODUQHJDVHSWXPD
2þL
• hipertelorizem • hipertelorizem
• DQWLPRQJRORLGQRSRORåHQHRþL
• epikantus
8ãHVD • QL]NRSRORåHQDXãHVD • QL]NRSRORåHQDXãHVD
6OXK • senzorinevralna gluhost • gluhost
5DVW • QLåMDQL]NDUDVW • nizka rast
9UDW
• kratek vrat • kratek vrat
• pterigij 6SROQHåOH]H
• NULSWRUKLGL]HPKLSRVSDGLMD
• DWURILMDMDMþQLNRY
• redko kriptorhidizem
8PVND UD]YLWRVW
• UHGNRXSRþDVQMHQUD]YRM • XSRþDVQMHQUD]YRM
• XþQHWHåDYH
• KXMãDPDQMUD]YLWRVW
.UL
/ • von Willebrandova bolezen
• SRPDQMNDQMHIDNWRUMHY;,LQ;,,
• trombocitopenija
/LPIQRWNLYR / • limfangiektazija
2NRVWMH
• UHGNRGHIRUPDFLMHKUEWHQLFHVNROLR]D
• pectus excavatum
• pectus carinatum
• GHIRUPDFLMHKUEWHQLFHVNROLR]Dpectus excavatum
• pectus carinatum
• cubitus valgus
• anomalije vretenc
6OLND/HQWLJLQR]QHVSUHPHPEHNRåH Figure 3. Lentigines of the skin.
VLKPDOLJQRSUHREUD]LMR
3UL EROQLNRY XJRWDYOMDPR VHQ]RULQHYUDOQR L]JXERVOXKDNLMRODKNRSUHSR]QDPRVSUHVHMDOQLPL testi ob rojstvu ali kasneje. Bolniki z izgubo sluha potrebujejo redno vodenje pri otorinolaringologu z UHGQLPVSUHPOMDQMHPDYGLRPHWULMDWHUREUDYQDYR pri surdopedagogih.
%ROQLNL LPDMR ODKNR QRUPDOQH XPVNH VSRVREQRVWL WHåDYHSULXþHQMXDOLFHORWHåMRXPVNRPDQMUD]YLWRVW
3RJRVWR VR SULVRWQD GLVSODVWLþQD ]QDPHQMD NL SD VR ODKNR EODJD =QDþLOQD GLVSODVWLþQD ]QDPHQMD VR KLSHUWHORUL]HPSWR]DLQQL]NRSRORåHQDXãHVD 3ULEROQLNRYXJRWDYOMDPRVSUHPHPEHYHOHN- WURNDUGLRJUDPXVUFD(.*LQKLSHUWUR¿þQRNDUGL- RPLRSDWLMRSULSDSXOPRQDOQRVWHQR]R 9 (.* MH QDMSRJRVWHMH SULVRWHQ OHYRVWUDQVNL DOL GHVQRVWUDQVNLRGNORQRVL456YIURQWDOQLKRGYR- dih kljub odsotnosti strukturnih anomalij srca.
1DMGHPRãH]QDNHOHYRVWUDQVNHDOLRERMHVWUDQVNH KLSHUWUR¿MHYHQWULNORYYDORYHTSRGDOMãDQRGRER 47FLQPRWQMHUHSRODUL]DFLMH=DUDGLQHYDU- QRVWL QHQDGQH VUþQH VPUWL PRUD EROQLNH UHGQR VSUHPOMDWLNDUGLRORJ9þDVLKPRUDPR]GUDYLWLNDU- GLRPLRSDWLMR DOL SRPHPEQR ]RåLWHY SXOPRQDOQH ]DNORSNH2EPRUHELWQHPXYDMDQMXUDVWQHJD hormona za zdravljenje nizke rasti je pomembno sodelovanje kardiologa in endokrinologa.
3ULGHþNLKODKNR]DVOHGLPRWXGLNULSWRUKLGL]HPDOL KLSRVSDGLMR RELþDMQR MH ]PDQMãDQD WXGL SORGQRVW 3UL GHNOLFDK VR VODEãH UD]YLWL MDMþQLNL SXEHUWHWD MH QDYDGQR]DNDVQMHQD
6LQGURP1RRQDQ
=DUDGLYHOLNHSRGREQRVWLVVLQGURPRP/(23$5' Y SULVSHYNX VLQGURP 1RRQDQ SUHGVWDYOMDPR QD NUDWNR 6LQGURP MH SUYD RSLVDOD NDUGLRORJLQMD -DFTXHOLQH1RRQDQOHWD-HSRJRVWHMãLRG VLQGURPD/(23$5'VDMSUHYDOHQFRRFHQMXMHMRQD íåLYRURMHQLKRWURN'HGXMHVHDYWRVR-
PQRGRPLQDWQRQRYHPXWDFLMHSDVRUHGNHMãH
*UH]DJHQHWVNRKHWHURJHQVLQGURPSRYH]DQ]YHþ RSLVDQLPLPXWDFLMDPL9VLQGURPSRY]URþDMR mutacije genov PTPN11, SOS1, KRAS, RAF1, BRAF in MEK1
=D VLQGURP VR ]QDþLOQD GLVSODVWLþQD ]QDPHQMD YLVRNR þHOR KLSHUWHORUL]HP DQWLPRQJRORLGQR SRORåHQH RþL HSLNDQWXV SWR]D QL]NR SRORåHQD LQ SRVWHULRUQR]DVXNDQDXãHVDNUDWHNYUDWVSWHULJLMHP LQQL]NRQDUDVWLãþHODVQDWHPHQX
1DYDGQR VR SULVRWQH WXGL UD]OLþQH DQRPDOLMH VUFD NRW VR GHIHNWL DWULMVNHJD VHSWXPD GHIHNWL DWULR- YHQWULNXODUQHJD VHSWXPD UHGNR WXGL NRDUNWDFLMD DRUWH 3RJRVWL VWD KLSHUWUR¿þQD NDUGLRPLRSDWLMD LQ SXOPRQDOQD VWHQR]D 3UL YVHK QRYRURMHQþNLK SUL NDWHULK VXPLPR QD VLQGURP 1RRQDQ SULSRURþDPR XOWUD]YRþQR SUHLVNDYR VUFD ]D RSUHGHOLWHY PRUHEL- WQHSDWRORJLMHVUFDNLVHODKNRSRMDYLWXGLNDVQHMHY åLYOMHQMXí
1RYRURMHQþNL V VLQGURPRP 1RRQDQ VR RELþDMQR QRUPDOQRGROJLLQWHåNL]DJHVWDFLMVNRVWDURVWQHND- WHUL VR FHOR YHþML LQ WHåML 9 SUYHP OHWX LQ SRO VH SRMDYLMRWHåDYHSULKUDQMHQMX]DUDGLNDWHULKQHNDWHUL SRWUHEXMHMR JDVWURVWRPR =DVWRM Y UDVWL VH SULþQH SRVWQDWDOQRLQVHRGUD]LYQL]NLUDVWL]DUDGLNDWHUH VH YHþNUDW RGORþLPR WXGL ]D ]GUDYOMHQMH ] UDVWQLP KRUPRQRP
3RJRVWRVHRWURFLXPVNRSRþDVQHMHUD]YLMDMRLQYVDM WUHWMLQD RWURN LPD NDVQHMH SUHFHMãQMH XþQH WHåDYH 2SLVXMHMR WXGL YHþMR SRJRVWRVW PRWHQM SR]RUQRVWL
'LIHUHQFLDOQRGLDJQRVWLFLUDQMHVLQGURPD /(23$5'LQVLQGURPD1RRQDQ
Diferencialno diagnosticiranje sindromov LEO- 3$5'LQ1RRQDQQDSRGODJLIHQRWLSVNLK]QDþLOQRVWL bolnika je v prvih letih zelo zahtevno. Lentiginozne VSUHPHPEHNRåHWHUPDGHåLEDUYHEHOHNDYHNLVR
SDWRJQRPRQLþQL ]D VLQGURP /(23$5' VH YHþL- QRPD SRMDYLMR NDVQHMH ãHOH SR þHWUWHP OHWX 3UHQDWDOQR QD VLQGURP /(23$5' SRPLVOLPR þH pri plodu z normalnim kariotipom ugotovimo hiper- WUR¿þQRNDUGLRPLRSDWLMR9WHPSULPHUXMHQD PHVWX NOLQLþQL SUHJOHG VWDUãHY ] LVNDQMHP ]QDNRY sindroma LEOPARD ter molekularno diagnostici- UDQMH]LVNDQMHPPXWDFLMQDSRGURþMXJHQRYPTPN 11RAF 1 in BRAF
7DEHOD *HQRWLSVNH ]QDþLOQRVWL EROQLNRY V VLQGURPRP LEOPARD in sindromom Noonan. Prizadeti geni so razporejeni YSDGDMRþHPYUVWQHPUHGXJOHGHQDSRJRVWRVW
Table 2. Genotypic characteristics of subjects with LEOPARD and Noonan syndrome. Possible causal genes are listed in decreasing order according to the frequency of their involvement.
6LQGURP/(23$5' 6LQGURP1RRQDQ
PTPN11 PTPN11
RAF1 SOS1
BRAF RAF1
SHOC2 BRAF KRAS MEK1
5$=35$9/-$1-(,1=$./-8ý., 6LQGURP /(23$5' WHU VLQGURP 1RRQDQ VRGLWD Y VNXSLQR QHYURNDUGLRIDFLRNXWDQLK VLQGURPRY LPHQRYDQLKWXGLª5$6RSDWLMH©6LQGURPLYWHM VNXSLQLVHJHQRWLSVNRLQIHQRWLSVNRYGRORþHQLPHUL prekrivajo. Diferencialna diagnostika med sindromi je pomembna zaradi napovedi poteka bolezni ter GROJRURþQHREUDYQDYHEROQLNRY
9QDMYHþMLPHULVHJHQRWLSVNRLQIHQRWLSVNRSUHNUL- YDWD VLQGURPD /(23$5' LQ 1RRQDQ = PROHNX- ODUQR JHQHWVNLPL ãWXGLMDPL VR XJRWRYLOL GD ODKNR VLQGURPD ORþLPR JOHGH QD RSUHGHOMHQH PXWDFLMH PTPN11 gena. Mutacija domene PTP beljakovine 6+37KU0HWQDHNVRQXMH]QDþLOQD]D EROQLNRYVVLQGURPRP/(23$5'UHGNHMãDSDMH PXWDFLMD7\U&\VQDHNVRQX3UDYWRPXWDFLMR VPRQDãOLWXGLSULQDãHPEROQLNX=DEROQLNH]1RR- QDQRYLPVLQGURPRPVRSUDYWDNR]QDþLOQHPXWDFLMH PTPN11 JHQD YHQGDU Y GYHK WUHWMLQDK SULPHURY
QDGRPHQL6+WRUHMQDGUXJLGRPHQLEHOMDNRYLQH 6+3
/RþHYDQMHEROQLNRYJOHGHQDIHQRWLSVNHODVWQRVWLMH WHåNR SUHGYVHP Y ]JRGQMHP REGREMX NR NOLQLþQD VOLND SUHGYVHP OHQWLJLQR]QH VSUHPHPEH NRåH LQ PDGHåLEHOHNDYHãHQLSRYVHPL]REOLNRYDQD 3RPHPEQR MH GD EROQLNH VSUHPOMDPR LQ YRGLPR JOHGHQDQMLKRYHWHåDYHYRNYLUXãLUãHVNXSLQHVSH- FLDOLVWRY±JHQHWLNHQGRNULQRORJNDUGLRORJRWRUL- QRODULQJRORJ GHUPDWRORJ RUWRSHG 6RGHORYDQMH MH SRPHPEQRWXGLREXYDMDQMX]GUDYLOVDMODKNR]GUD- YLODODMãDMRWHåDYHHQHJDRUJDQVNHJDVLVWHPDREWHP SDVODEãDMRGHORYDQMHGUXJHJD
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