{"id":1870,"date":"2019-10-29T13:28:48","date_gmt":"2019-10-29T12:28:48","guid":{"rendered":"https:\/\/www.newslab.sk\/2019\/10\/29\/nalez-marker-chromozomu-u-dietata-s-cat-eye-syndromom-kazuistika\/"},"modified":"2019-11-04T14:01:34","modified_gmt":"2019-11-04T13:01:34","slug":"nalez-marker-chromozomu-u-dietata-s-cat-eye-syndromom-kazuistika","status":"publish","type":"post","link":"https:\/\/www.newslab.sk\/en\/nalez-marker-chromozomu-u-dietata-s-cat-eye-syndromom-kazuistika\/","title":{"rendered":"Finding of a marker chromosome in a child with Cat-eye syndrome (case study)"},"content":{"rendered":"

*All tables, charts, graphs and pictures that are featured in this article can be found in the .pdf attachment at the end of the paper.<\/strong><\/span><\/p>\n

 <\/p>\n

\u00davod<\/strong><\/h3>\n

Cat-eye syndr\u00f3m, naz\u00fdvan\u00fd aj Schmidov-Fraccarov syndr\u00f3m (OMIM 115470), je vz\u00e1cne genetick\u00e9 ochorenie, ktor\u00e9ho prevalencia je 1 : 50 0000 \u2013 1 : 150 000. Ochorenie bolo nazvan\u00e9 pod\u013ea typick\u00e9ho tvaru ma\u010dacieho oka(1).<\/p>\n

Zdrav\u00fd jedinec m\u00e1 dva norm\u00e1lne akrocentrick\u00e9 chromoz\u00f3my 22(2). U pacientov postihnut\u00fdch CES je pr\u00edtomn\u00fd mal\u00fd nadpo\u010detn\u00fd bisatelitov\u00fd marker chromoz\u00f3m inv dup(22pter-22q11) (sSMC \u2013 small supernumerary marker chromosome) (obr\u00e1zok 1)<\/em><\/strong>. SSMC s\u00fa mal\u00e9 chromoz\u00f3my s abnorm\u00e1lnou \u0161trukt\u00farou, ktor\u00e9 sa konven\u010dnou cytogenetickou met\u00f3dou nedaj\u00fa identifikova\u0165. Ve\u013ekos\u0165ou s\u00fa rovnak\u00e9 ale bo men\u0161ie ako 20. chromoz\u00f3m(3). U pacientov s CES vznik\u00e1 n\u00e1sledkom parci\u00e1lnej tetraz\u00f3mie regi\u00f3nu 22p-22q11.21, v zriedkav\u00fdch pr\u00edpadoch n\u00e1sledkom parci\u00e1lnej triz\u00f3mie alebo intrachromoz\u00f3movej triplik\u00e1cie tohto regi\u00f3nu(4). Existuj\u00fa 2 typy marker chromoz\u00f3mu, ktor\u00e9 sa delia na z\u00e1klade bodu zlomu. Pri 1. type (\u010dastej\u0161\u00ed) bod zlomu zah\u0155\u0148a iba regi\u00f3n CESCR (Cat-eye syndrome critical region), k\u00fdm pri 2. type okrem CESCR regi\u00f3n kritick\u00fd pre DiGeorge syndr\u00f3m(5).<\/p>\n

Pre pacientov s CES s\u00fa typick\u00e9 3 klinick\u00e9 prejavy: preaurikul\u00e1rne v\u00fdrastky, atr\u00e9zia anu a kolob\u00f3m d\u00fahovky. M\u00f4\u017eu sa tie\u017e pridru\u017ei\u0165 \u010fal\u0161ie pr\u00edznaky ako abnormality obli\u010diek, srdca, intelektu\u00e1lne postihnutie a zaost\u00e1vanie v raste(6). Ochorenie vo v\u00e4\u010d\u0161ine pr\u00edpadov vznik\u00e1 sporadicky pri dozrievan\u00ed vaj\u00ed\u010dka alebo spermie. Len v zriedkav\u00fdch pr\u00edpadoch ide o z\u00edskan\u00fd genetick\u00fd syndr\u00f3m. V takom pr\u00edpade je jedinec pren\u00e1\u0161a\u010d asymptomatick\u00fd s nadpo\u010detn\u00fdm marker chromoz\u00f3mom v mozaikovej forme, ktor\u00fd sa m\u00f4\u017ee prenies\u0165 na potomkov(7).<\/p>\n

Diagnostika CES sa za\u010d\u00edna na z\u00e1klade charakteristick\u00fdch prejavov a sympt\u00f3mov po naroden\u00ed die\u0165a\u0165a. Genetick\u00e9 testovanie sa vykon\u00e1va s cie\u013eom potvrdenia diagn\u00f3zy. Genetick\u00e1 anal\u00fdza zah\u0155\u0148a cytogenetick\u00e9 vy\u0161etrenie karyotypu, fluorescen\u010dn\u00fa in situ hybridiz\u00e1ciu (FISH) a komparat\u00edvnu gen\u00f3mov\u00fa hybridiz\u00e1ciu (arrayCGH). V niektor\u00fdch pr\u00edpadoch m\u00f4\u017ee by\u0165 CES diagnostikovan\u00fd v prenat\u00e1lnom obdob\u00ed, ak sa na ultrazvuku zachytia podozriv\u00e9 n\u00e1lezy. Vtedy sa geneticky vy\u0161etr\u00ed plodov\u00e1 voda, v skor\u0161\u00edch \u0161t\u00e1di\u00e1ch gravidity choriov\u00e9 klky. Lie\u010dbu postihnut\u00fdch jedincov mana\u017euje t\u00edm lek\u00e1rov z r\u00f4znych medic\u00ednskych odborov, preto\u017ee s\u00fa postihnut\u00e9 r\u00f4zne syst\u00e9my. Progn\u00f3za pacientov s CES var\u00edruje a z\u00e1vis\u00ed od pr\u00edtomn\u00fdch sympt\u00f3mov(8).<\/p>\n

 <\/p>\n

Kazuistika<\/strong><\/h3>\n

Prezentujeme pr\u00edpad mesa\u010dn\u00e9ho chlap\u010deka hospitalizovan\u00e9ho na Neonat\u00e1lnej klinike intenz\u00edvnej medic\u00edny LF UK a N\u00daDCH. Pacient mal nasleduj\u00face pr\u00edznaky: kolob\u00f3m d\u00fahovky aj cievovky (obr\u00e1zok 2)<\/em><\/strong>, atr\u00e9ziu anu a rekta, preaurikul\u00e1rne v\u00fdrastky (obr\u00e1zok 3)<\/em><\/strong>, bilater\u00e1lnu poruchu sluchu, foramen ovale apertum a ductus arteriosus patens. Na rtg. bol zisten\u00fd r\u00e1z\u0161tep hrudn\u00e9ho stavca a \u0161truktur\u00e1lne zmeny stavcov driekovej oblasti, na ultrazvuku obli\u010diek bilater\u00e1lna dilat\u00e1cia odvodn\u00e9ho syst\u00e9mu I. \u2013 II. stup\u0148a.<\/p>\n

Chlap\u010dek sa narodil v term\u00edne z 3. tehotenstva nepr\u00edbuzn\u00fdch rodi\u010dov s potvrdenou triz\u00f3miou 21. chromoz\u00f3mu v rodinnej anamn\u00e9ze. 1. die\u0165a je zdrav\u00e9, 2. tehotenstvo bolo ukon\u010den\u00e9 pre potvrden\u00fa vo\u013en\u00fa triz\u00f3miu 21. chromoz\u00f3mu. Tretie tehotenstvo prebiehalo fyziologicky. Vzh\u013eadom na vek matky a pozit\u00edvnu rodinn\u00fa anamn\u00e9zu, druhotrimestrov\u00fd skr\u00edning uk\u00e1zal zv\u00fd\u0161en\u00e9 riziko (1 : 55) triz\u00f3mie 21. chromoz\u00f3mu. Vek bol vy\u0161\u0161\u00ed u matky (42) aj u otca (43) die\u0165a\u0165a, \u010do sa sp\u00e1ja so zv\u00fd\u0161en\u00fdm rizikom vzniku de novo <\/em>mut\u00e1cie. Pod\u013ea metodick\u00e9ho pokynu SSLG (Slovensk\u00e1 spolo\u010dnos\u0165 lek\u00e1rskej genetiky)(9) pre prenat\u00e1lnu genetick\u00fa diagnostiku u tehotnej bola na z\u00e1klade pozit\u00edvneho druhotrimestrov\u00e9ho skr\u00edningu, veku aj pozit\u00edvnej rodinnej anamn\u00e9zy indikovan\u00e1 prenat\u00e1lna genetick\u00e1 diagnostika, ktor\u00fa v\u0161ak odmietla. Vyu\u017eila mo\u017enos\u0165 neinvaz\u00edvneho prenat\u00e1lneho testovania (NIPT) zalo\u017een\u00e9ho na anal\u00fdze cirkuluj\u00facej DNA z krvi tehotn\u00fdch \u017eien, Trisomy test PLUS. Testom neboli odhalen\u00e9 aneuploidie chromoz\u00f3mov 13, 18, 21, aneuploidie pohlavn\u00fdch chromoz\u00f3mov ani v\u00fdznamn\u00e9 mikrodel\u00e9cie zodpovedn\u00e9 za vybran\u00e9 mikrodele\u010dn\u00e9 syndr\u00f3my sledovan\u00e9 Trisomy testom PLUS. Ako n\u00e1hodn\u00fd n\u00e1lez bola pozorovan\u00e1 duplik\u00e1cia \u00faseku z 22. chromoz\u00f3mu v rozsahu 1,12 Mb (na rozhran\u00ed oblast\u00ed 22q11.1-q11.21), t\u00e1 v\u0161ak nebola reportovan\u00e1 s oh\u013eadom na validovan\u00fd detek\u010dn\u00fd limit met\u00f3dy Trisomy test PLUS na \u00farovni 3 Mb.<\/p>\n

 <\/p>\n

Met\u00f3dy<\/h3>\n

Po genetickej konzult\u00e1cii bola vzorka perif\u00e9rnej krvi pacienta odoslan\u00e1 na na\u0161e oddelenie s podozren\u00edm na diagn\u00f3zu CES. Vyu\u017eili sme viacer\u00e9 dostupn\u00e9 genetick\u00e9 vy\u0161etrovacie met\u00f3dy, ktor\u00e9 n\u00e1m dopomohli k upresneniu diagn\u00f3zy.<\/p>\n

Cytogenetick\u00fdm vy\u0161etren\u00edm karyotypu (obr\u00e1zok 4) <\/em><\/strong>zo vzorky perif\u00e9rnej krvi sme zachytili nadpo\u010detn\u00fd marker chromoz\u00f3m (47,XY,+mar). Pre podozrenie na CES sme tento v\u00fdsledok na potvrdenie diagn\u00f3zy doplnili FISH anal\u00fdzou pou\u017eit\u00edm sondy XL Acro-p (MetaSystems) hybridizuj\u00facej ku kr\u00e1tkym ramen\u00e1m akrocentrick\u00fdch chromoz\u00f3mov (obr\u00e1zok 5)<\/em><\/strong>. Zistili sme nadpo\u010detn\u00fd marker chromoz\u00f3m, ktor\u00fd pozost\u00e1va z dvoch akrocentrick\u00fdch regi\u00f3nov. Na potvrdenie, \u017ee ide o \u00fasek z 22. chromoz\u00f3mu, sme pou\u017eili sondu Vysis DiGeorge Region Probe \u2013 LSI TUPLE 1 SO\/LSI ARSA SG (Abbot), ktor\u00e1 hybridizuje k DiGeorge kritick\u00e9mu regi\u00f3nu 22q11. V\u00fdsledok bol negat\u00edvny. A\u017e met\u00f3dou arrayCGH sme zachytili tetraz\u00f3miu chromoz\u00f3movej oblasti 22q11.1-q11.21 vo ve\u013ekosti 1,5 Mb, ktor\u00e1 je typick\u00e1 pre Cat-eye syndr\u00f3m (obr\u00e1zok 6)<\/em><\/strong>. T\u00fdm sme potvrdili, \u017ee nadpo\u010detn\u00fd marker chromoz\u00f3m tvoria dve k\u00f3pie kritick\u00e9ho regi\u00f3nu pre CES. Tento regi\u00f3n zah\u0155\u0148a 22 g\u00e9nov (XKR3, IL17RA, CECR2, SLC25A18, ATP6V1E1, BID, MICAL3, PEX26, TUBA8, USP18, psiTPTE22, HSFY1P1, GAB4, CECR7, CECR6, CECR5, CECR4, CECR1, BCL2L13, MIR3198, MIR648, FLJ41941), ktor\u00fdch duplik\u00e1ciu interpretuje datab\u00e1za Decipher ako patog\u00e9nne. Diagn\u00f3za CES bola potvrden\u00e1. N\u00e1sledne sme vy\u0161etrili karyotyp obidvoch rodi\u010dov s fyziologick\u00fdm v\u00fdsledkom. U pacienta sa tento marker chromoz\u00f3m objavil de novo<\/em>.<\/p>\n

 <\/p>\n

Diskusia<\/h3>\n

Cat-eye syndr\u00f3m je zriedkav\u00e9 genetick\u00e9 ochorenie, ktor\u00e9ho incidencia je 1 : 50 000 \u2013 1 : 150 000 \u017eivonaroden\u00fdch det\u00ed. Pacienti vo v\u00e4\u010d\u0161ine pr\u00edpadov maj\u00fa dobr\u00fa progn\u00f3zu pre\u017e\u00edvania(1,2). Typick\u00fdmi sympt\u00f3mami ochorenia s\u00fa kolob\u00f3m d\u00fahovky, an\u00e1lne malform\u00e1cie a preaurikul\u00e1rne v\u00fdrastky v oblasti ucha. \u010eal\u0161\u00edmi prejavmi CES s\u00fa anom\u00e1lie postihuj\u00face o\u010di, u\u0161i, kardiovaskul\u00e1rny syst\u00e9m a urogenit\u00e1lny trakt. V\u0161etky opisovan\u00e9 sympt\u00f3my boli pr\u00edtomn\u00e9 aj u n\u00e1\u0161ho probanda. Preto\u017ee i\u0161lo o novorodenca, intelektu\u00e1lne postihnutie nebolo mo\u017en\u00e9 zatia\u013e presne ur\u010di\u0165. Nadpo\u010detn\u00fd marker chromoz\u00f3m vznik\u00e1 v\u00e4\u010d\u0161inou sporadicky(6,7), \u010do dokazuje aj v na\u0161om pr\u00edpade fyziologick\u00fd karyotyp u oboch rodi\u010dov s norm\u00e1lnym fenotypom. U obidvoch bolo vy\u0161etren\u00fdch 50 metaf\u00e1z, tak\u017ee mozaikov\u00fa formu nadpo\u010detn\u00e9ho marker chromoz\u00f3mu sme s vysokou pravdepodobnos\u0165ou vyl\u00fa\u010dili.<\/p>\n

V pr\u00e1ci opisujeme vz\u00e1cny pr\u00edpad Cat-eye syndr\u00f3mu, ktor\u00fd sme na na\u0161om oddelen\u00ed zachytili prv\u00fdkr\u00e1t. Po cytogenetickej anal\u00fdze karyotypu a n\u00e1slednej FISH sme identifikovali mal\u00fd nadpo\u010detn\u00fd bisatelitov\u00fd marker chromoz\u00f3m (sSMC) v ka\u017edej vy\u0161etrenej metaf\u00e1ze. V literat\u00fare sa opisuje, \u017ee vznik\u00e1 tetraz\u00f3miou regi\u00f3nu 22q11.1-q11.21(2), \u010do sme v na\u0161om pr\u00edpade tie\u017e potvrdili met\u00f3dou arrayCGH. Tento \u00fasek sa nach\u00e1dza tesne pod regi\u00f3nom, kde hybridizuje FISH sonda pre kritick\u00fa oblas\u0165 DiGeorge syndr\u00f3mu. Pod\u013ea dostupnej literat\u00fary(5) pr\u00e1ve tento regi\u00f3n je zodpovedn\u00fd za vznik CES. Tak sa n\u00e1m podarilo rozl\u00ed\u0161i\u0165, o ktor\u00fd typ CES ide. U mal\u00e9ho pacienta sme potvrdili 1. typ CES. Prenat\u00e1lne bola s\u00edce met\u00f3dou NIPT detegovan\u00e1 duplik\u00e1cia na 22. chromoz\u00f3me v oblasti 22q11.1-q11.21, t\u00e1 v\u0161ak pre svoju ve\u013ekos\u0165 (1,12 Mb), ktor\u00e1 bola v\u00fdrazne men\u0161ia ako validovan\u00fd detek\u010dn\u00fd limit metodiky (3 Mb), nebola reportovan\u00e1. V s\u00fa\u010dasnosti prebieha valid\u00e1cia a zavedenie novej komplexnej\u0161ej verzie Trisomy testu, ktor\u00e9ho s\u00fa\u010das\u0165ou bude n\u00e1stroj na podporu klinickej interpret\u00e1cie ne\u0161tandardn\u00fdch n\u00e1lezov detegovan\u00fdch v r\u00e1mci NIPT na \u00farovni cel\u00e9ho gen\u00f3mu. V\u010faka zavedeniu tohto podporn\u00e9ho n\u00e1stroja do rutinnej praxe by mali by\u0165 reportovate\u013en\u00e9 aj v s\u00fa\u010dasnosti nereportovan\u00e9 detegovan\u00e9 aber\u00e1cie so zrete\u013eom na ich potenci\u00e1lne patog\u00e9nny vplyv na v\u00fdvoj plodu. Tehotn\u00e1 odmietla invaz\u00edvny odber plodovej vody a vybrala si met\u00f3du NIPT, ktor\u00e1 riziko triz\u00f3mie 21. chromoz\u00f3mu vyl\u00fa\u010dila. Ak by bola vykonan\u00e1 PGD, diagn\u00f3za CES by mohla by\u0165 jednozna\u010dne zisten\u00e1 u\u017e v prenat\u00e1lnom \u0161t\u00e1diu. Na uvedenom pr\u00edpade chceme demon\u0161trova\u0165 potrebu kombin\u00e1cie r\u00f4znych genetick\u00fdch a molekul\u00e1rnych met\u00f3d umo\u017e\u0148uj\u00facich stanovenie pr\u00ed\u010diny ve\u013emi zriedkav\u00fdch genetick\u00fdch por\u00fach, v tomto pr\u00edpade reprezentovan\u00fdch mikroduplika\u010dn\u00fdm syndr\u00f3mom sp\u00f4sobuj\u00facim Cat-eye syndr\u00f3m.<\/p>\n

 <\/p>\n

Z\u00e1ver<\/h3>\n

Cat-eye syndr\u00f3m je vz\u00e1cne genetick\u00e9 ochorenie postihuj\u00face hlavne o\u010di, u\u0161i a tr\u00e1viaci trakt. Pou\u017eit\u00edm r\u00f4znych molekul\u00e1rnogenetick\u00fdch met\u00f3d bolo mo\u017en\u00e9 postnat\u00e1lne identifikova\u0165 kauz\u00e1lnu chromoz\u00f3mov\u00fa aber\u00e1ciu u probanda vykazuj\u00faceho sympt\u00f3my tohto ve\u013emi zriedkav\u00e9ho genetick\u00e9ho ochorenia, ku ktor\u00e9mu je v literat\u00fare op\u00edsan\u00fdch celosvetovo len zhruba 100 pr\u00edpadov.<\/p>\n

 <\/p>\n

LITERAT\u00daRA<\/strong><\/p>\n

    \n
  1. Berends MJ, Tan-Sindhunata G, Leegte B, van Essen Phenotypic variability of cat-eye syndrome. Genetic Counseling 2001; 12(1): 23-34.<\/li>\n
  2. https:\/\/rarediseases.org\/rare-diseases\/cat-eye-syndrome\/<\/li>\n
  3. Liehr T, Claussen U, Starke Small supernumerary marker chromosomes (sSMC) in humans. Cytogenet Genome Res 2004; 107: 55-67.<\/li>\n
  4. Knijnenburg J, van Bever Y, Hulsman LOM, et A 600 kb triplication in the cat eye syndrome critical region causes anorectal, renal and preauricular anomalies in a three-generation family. European Journal of Human Genetics 2012; 20(9): 986-989.<\/li>\n
  5. McTaggart KE, Budarf ML, Driscoll DA, et Cat-eye syndrome chromosome breakpoint clustering: identification of two intervals also associated with 22q11 deletion syndrome breakpoints. Cytogenetics and Cell Genetics 1998; 81(3-4): 222-228.<\/li>\n
  6. Jedraszak G, Receveur A, Andrieux J, et Severe psychomotor Delay in a Sever Presentation of Cat-Eye Syndrome. Hindawi Publishing Corporation, Case Reports in Genetics 2015.<\/li>\n
  7. https:\/\/w<\/a>worpha.net\/consor\/cgi-bin\/OC_Exp.php?Lng=GB <\/a>& Ex- pert=195<\/li>\n
  8. https:\/\/www.omim.org\/entry\/1<\/a>15470<\/a><\/li>\n
  9. https:\/\/www.sslg.sk\/index.php\/dokumenty\/metodicke-pokyny\/71-in<\/a>– dikovanie-prenatalnych-genetickych-testov-vvch-2<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

    *All tables, charts, graphs and pictures that are featured in this article can be found in the .pdf attachment at the end of the paper.   \u00davod Cat-eye syndr\u00f3m, naz\u00fdvan\u00fd aj Schmidov-Fraccarov syndr\u00f3m (OMIM 115470), je vz\u00e1cne genetick\u00e9 ochorenie, ktor\u00e9ho prevalencia je 1 : 50 0000 \u2013 1 : 150 000. Ochorenie bolo nazvan\u00e9 pod\u013ea<\/p>\n","protected":false},"author":7,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_mi_skip_tracking":false,"footnotes":""},"categories":[290],"tags":[1365,1364,1366,1363],"class_list":["post-1870","post","type-post","status-publish","format-standard","hentry","category-genetics","tag-bisatellited-marker-chromosome","tag-cat-eye-syndrome","tag-genetic-diagnostics","tag-geneticka-diagnostika-en","typ_clanku-casuistry"],"acf":{"abstrakt":"

    Cat-eye syndrome (CES) is a rare genetic disease. Individuals with normal karyotype have two normal acrocentric chromosomes 22, which are composed of a short arm 22p, centromere and long arm 22q. In individuals with CES, the short arm and a small region of the long arm of chromosome 22 are present in four copies. Resulting in partial tetrasomy of region 22p-22q11.21 that appears as small supernumerary bisatellited marker chromosome. In a small proportion of cases with CES, this region is present in three copies (partial trisomy). CES is divided into two types depending on the breakpoint site. The symptoms vary widely, but all individuals are characterised by the presence of three symptoms: preauricular pits, anal atresia and iris coloboma. Here we report\u00a0 a case of a newborn patient with Cat-eye syndrome type 1.<\/p>\n

    Keywords<\/strong>: Cat-eye syndrome, bisatellited marker chromosome, genetic diagnostics<\/p>\n","casopis":[{"ID":1883,"post_author":"7","post_date":"2019-10-28 13:35:57","post_date_gmt":"2019-10-28 12:35:57","post_content":"

      \r\n \t
    • Detection and validation of subchromosomal aberrations detected as additional findings in routine noninvasive prenatal testing for common trisomies<\/li>\r\n \t
    • Finding of a marker chromosome in a child with Cat-eye syndrome (case study)<\/li>\r\n \t
    • Experimental therapy with stem cells is promissing in the treatment of chronic diabetic ulcer \u2013 a case study<\/li>\r\n \t
    • Colonic mucosal Schwann cell hamartoma with tactile corpuscle-like bodies: a case report<\/li>\r\n \t
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