P R A C E K A Z U I S T Y C Z N E poł ożn i ct wo

Ginekol Pol. 2013, 84, 974-978

Prenatal diagnosis of Down syndrome in dizygotic twin pregnancy Prognoza prenatalna zespołu Downa w ciąży bliźniaczej dizygotycznej

Józef Krawczyk1, Dariusz Borowski1, 3ioWr :ĊJrzyQ1, Krzysztof Drews2, 0irosáaw :ieOJoĞ 1

1 2

First Department of Obstetrics and Gynecology – Medical University of Warsaw, Poland Division of Perinatology and Women’s Diseases – Poznan University of Medical Sciences, Poznan, Poland

Abstract We present a case of a 33-year-old pregnant woman who had a transvaginal ultrasound performed at week 9 of gestation. A dichorionic diamniotic twin pregnancy, with symmetrically developing fetuses, was confirmed. Chromosomal defect markers (NT, NB, DV, TV) were analyzed in the first genetic test, performed according to the Fetal Medicine Foundation (FMF) criteria, and the double marker test was performed (PAPP-A protein and free `-hCG concentrations in patient serum were determined). In the subsequent diagnostic procedures, the patient was offered and consented to amniopuncture after week 15 of gestation. The material obtained in the course of that invasive procedure allowed to identify a normal male karyotype – 46, XY in the first fetus (Fetus I). Cytogenetic analysis of the material from the second fetus (Fetus II) resulted in the diagnosis of an abnormal female karyotype – 47, XX, +21. Based on the analyzed clinical case, we present the difficulties of performing prenatal diagnosis in a dizygotic twin pregnancy. The results prove the applicability and efficacy of prenatal diagnostics tests based on the FMF criteria also in twin pregnancies.

Key words:SUHJQDQF\/ WZLQ SUHJQDQF\ / 'RZQ V\QGURPH / 3$33$ SURWHLQ /

Corresponding author: Józef Krawczyk First Department of Obstetrics and Gynecology Medical University of Warsaw Starynkiewicza 1/3 02-015 Warszawa, Poland e-mail: [email protected]

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Otrzymano: 20.02.2012 Zaakceptowano do druku: 30.09.2013

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P R A C E

Ginekol Pol. 2013, 84, 974-978

K A Z U I S T Y C Z N E po ł o ż n i c t wo

Józef Krawczyk et al. Prenatal diagnosis of Down syndrome in dizygotic twin pregnancy.

Streszczenie Przedstawiono opis przypadku 33 letniej ciężarnej, u której w 9 tygodniu ciąży wykonano USG z wykorzystaniem sondy przezpochwowej i potwierdzono ciążę bliźniaczą dwuowodniową dwukosmówkową z symetrycznie rozwijającymi się płodami. W pierwszym badaniu genetycznym wykonanym zgodnie z kryteriami FMF dokonano analizy markerów defektów chromosomalnych tzn.: NT, NB, DV, TV oraz wykonano test podwójny (oznaczono stężenia w surowicy ciężarnej białko PAPP-A i wolną `-hCG). W kontynuacji postępowania diagnostycznego ciężarnej zaproponowano wykonanie amniopunkcji po 15 tygodniu ciąży, na co wyraziła zgodę. Uzyskany w przebiegu procedury inwazyjnej materiał i późniejsza jego analiza pozwoliła rozpoznać u płodu pierwszego (Płód I) prawidłowy kariotyp męski – 46, XY. Cytogenetyczna analiza materiału płodu II (Płód II) dała podstawy do rozpoznania nieprawidłowego kariotypu żeńskiego – 47, XX, +21. Na podstawie analizowanego przypadku klinicznego przedstawiamy trudności realizacji diagnostyki prenatalnej w ciąży bliźniaczej dizygotycznej. Przedstawione wyniki wskazują na skuteczność diagnostyki prenatalnej opartej na kryteriach FMF także w odniesieniu do ciąży bliźniaczej.

Słowa kluczowe: FLąĪD / FLąĪD EOLĨQLDF]D / ]HVSyá 'RZQD / ELDáNR 3$33$ /

Introduction DowQ syQGroPe forPerOy PoQJoOisP EeOoQJs to tKe Post coPPoQ JeQetic aEQorPaOities causeG Ey tKe SreseQce of aOO or Sart of aQ e[tra 21st cKroPosoPe DowQ syQGroPe was ¿rst GescriEeG Ey a BritisK SKysiciaQ, JoKQ /aQJGoQ DowQ, iQ 1 >1@ 0ecKaQisPs wKicK iQcOuGe cKroPosoPaO QoQGisMuQctioQ GuriQJ Peiosis or 5oEertsoQiaQ traQsOocatioQs of SareQtaO oriJiQ are at the molecular core of the syndrome. The incidence of Down syndrome is estimated at 111. liYe Eirths and it occurs in all ethnic and social JrouSs. Due to the fact that there are ShysioloJical and Jenetic restrictions in Satients with Down syndrome that cannot always Ee acceSted Ey the Sarents, in many countries they are offered the SossiEility of SreJnancy termination in case of trisomy 21. ,n the case of twin SreJnancy with only one fetus with aneuSloid karyotySe, a selectiYe termination of that fetus is SossiEle. The time of the Srocedure does not statistically and siJni¿cantly increase the risk of Sremature Eirth of the healthy twin >2@. 3roSer Srenatal screeninJ, focused on early diaJnosis of the SroElem, followed Ey sSecialist care, family inYolYement, education and traininJ since early childhood, haYe critical inÀuence on the Tuality of life and ¿nal staJe of deYeloSment of children with Down syndrome, as well as Seer acceStance and family functioning. The standard of conducting Srenatal screening for trisomy 21 during the ¿rst trimester Eetween 11±1 weeks   days comEines the eYaluation of fetal nuchal translucency and TuantitatiYe analysis of the 3$33$ Srotein, and free ȕh&*. That recommendation is Eased on studies Ey 1icolaides et al., and is characterized Ey high sensitiYity and sSeci¿city, reÀected Ey a  detection rate of Down syndrome >@. Twin Sregnancies constitute a seSarate issue of Srenatal screening. ,n healthy twin Sregnancies, the 3$33$ Srotein concentration and free ȕh&* determined in Elood serum of Sregnant mothers reach higher Yalues when comSared to a singleton Sregnancy >@, suSSosedly due to the Yolume and function of Slacenta since 3$33$ is synthesized Srimarily Ey syncytiotroShoElast >@.

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$s a result, seSarate reference Yalues for Eiochemical Sarameters need to Ee acTuired in multiSle Sregnancies. 6Sencer >@ showed that aYerage 3$33$ Srotein and free ȕh&* concentrations in twin Sregnancies are 1. and 2. times higher, resSectiYely, when comSared to a singleton Sregnancy. Taking that into account and using statistical modeling techniques, he Sredicted that, at a  false SositiYe rate, the detection rate of trisomy 21 in twins will Ee at the leYel of 2 Eased only on Eiochemical markers. ,n contrast to maternal serum Eiochemistry, the use of ultrasound markers in multiSle Sregnancies allows to determine the indiYidual risk for each of the twins. :ith selectiYe aSSlication of the 1T measurement and aSSroSriate estimation of the risk, the detection rate is . The comEination of these Sarameters indicates an  detection rate of trisomy 21 in twin Sregnancies, which is only aEout 1 lower than for a singleton Sregnancy.

Case report :e Sresent a case of a yearold Sregnant Satient with regular menstrual cycles lasting 2 days. The Sregnancy was estimated to Ee  weeks and  days, calculated from the last menstrual Seriod. $ transYaginal ultrasound reYealed the Sresence of a intrauterine Sregnancy with gestational sacs. $t  weeks of gestation, a diamniotic, dichorionic Sregnancy, with symmetrically deYeloSing fetuses, was con¿rmed. Two weeks later a diamnioticdichorionic Sregnancy was recon¿rmed Ey the ¿rst trimester ultrasound, with symmetrical &5/ Yalues Eut also with signi¿cant asymmetry of the 1T Yalues Eetween the fetuses. The Yalue of fetal 1T, whose cytogenetic analysis of the material indicated aneuSloid female karyotySe , ;;, 21, was . mm )ig. 1, 2 . The 1T of the fetus with the normal karyotySe was 1. mm. The analysis of the consecutiYe markers of fetal chromosomal defects, Serformed in accordance with the )0) criteria, including the nasal Eone 1B )ig.  assessment, Elood Àow at the leYel of the tricusSid YalYe T9 , and the ductus Yenosus D9 )ig.  , allowed to calculate the risk of trisomy 21, 1 and 1.

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P R A C E K A Z U I S T Y C Z N E poł ożn i ct wo

Ginekol Pol. 2013, 84, 974-978

Józef Krawczyk et al. Prenatal diagnosis of Down syndrome in dizygotic twin pregnancy.

Fig. 1.

Fig. 3.

Fig. 2.

Fig. 4.

*iYen that the highest achieYaEle leYel of detection of fetal trisomy 21, 1 and 1 is SroYided Ey a screening test Serformed during the ¿rst trimester, comEining the analysis of the ultrasound markers 1T, T9, D9 and determination of 3$33$ Sroteins and free ȕh&* serum concentration, the Satient was asked to haYe a Elood analysis Serformed to comSly with the test. $ written consent was oEtained from the Satient. The ¿nal risk is calculated Eased on maternal age. The new risk is the risk calculated on the Easis of fetal chromosomal aEerration markers  Eiochemical and ultrasound. 0edian Eiochemical Yalues are adMusted to maternal Eody weight, Sarity, and twin Sregnancy. 1ew risks are calculated with the )0) software Yersion 2. $s continuation of diagnostic eYaluation, the Satient was offered amniocentesis after 1 weeks of gestation. The material oEtained in the course of this inYasiYe Srocedure helSed to identify that the ¿rst fetus )etus , carried a normal male karyotySe  , ;@. 5ecent data suggests that father¶s age also Slays a role in increasing the risk of Down syndrome in the offsSring, through the mutagenic effect of Eiological and enYironmental factors in the gametes. $dditionally, older males are also assumed to Ee in relationshiSs with their age Seers, what needs to Ee taken into consideration in the studies >@. The risk of chromosomal aEnormalities in twin Sregnancies is higher comSared to a singleton Sregnancy. Determination of zygosity helSs to select the right algorithm for calculating the risk of aneuSloidy. *enerally, three clinical situations may occur one fetus with chromosomal anomaly in dizygotic Sregnancy, Eoth fetuses with chromosomal anomaly in dizygotic Sregnancy, and Eoth fetuses with equal chromosomal anomaly in monozygotic twin Sregnancy. ,n the Sast, gender differences in twin Sregnancy demonstrated in the course of diagnostic ultrasound, could constitute an argument SroYing dizygosity. +oweYer, in recent years, different studies haYe indicated ShenotySic as well as genotySic differences in identical twins. $t their Ease the intrauterine enYironmental factors Slay a maMor role, esSecially the molecular mechanisms causing such YariaEle degree of genetic mosaicism in the fetuses >@. 0ost cases of twin Sregnancies are dizygotic, and each of the fetuses, a Sriori, has its own risk of deYeloSing Eirth defects. 8nder the rules of SroEaEility, a chance of detecting the defect in at least one of the fetuses is higher than in a singleton Sregnancy. $ccording to this thesis, Satient at the age of  in twin Sregnancy will face the risk of Down syndrome in at least one of the fetuses comSaraEle or equal to that of a year old woman in a singleton Sregnancy >@. Thus, a question aEout imSlementation of aSSroSriate Srocedures for women  in a multiSle Sregnancy has Eeen raised. ,n the Sresented case, Srenatal care scheme was Eased on ultrasound diagnosis. The imSortance of ultrasound screening Serformed in the ¿rst trimester is eYen more imSortant in case of multiSle Sregnancies. )irst trimester is the oStimal time to determine chorionicity and amniocity >, 1, 11@. Different thickness of the intertwine memErane µlamEda sign¶ or µtwin Seak¶ at the Soint of connection with the chorionic Slate shows that the Sregnancy is dichorionic. ,f the memErane is thin oYer its entire length, also at the Munctional Soint with the chorionic Slate a µT¶ sign , it is SossiEle to diagnose monochorionic and diamniotic Sregnancy with high SroEaEility. The knowledge of chorionicity is imSortant for selecting SroSer Srenatal care as monochorionicdiamniotic Sregnancies

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are associated with signi¿cantly higher risk of comSlications than dichorionic diamniotic Sregnancies. 6onograShic determination of chorionicity and the measurement of fetal 1T in Eoth fetuses haYe Eecome a key element of Srenatal diagnosis in a twin Sregnancy. ,t should Ee strongly emShasized that in monochronic  diamniotic Sregnancies the risk of twin to twin transfusion syndrome TTT6 signi¿cantly increases if there are differences in the 1T Yalues and in the analysis of Elood Àow at the leYel of D9 ± the reYersal of the waYe in one of the fetuses increases the risk of TTT6  Eetween the fetuses >12, 1@. 8sing Eiochemical markers to assess the risk of aneuSloidy in multiSle Sregnancies is a YaluaEle addition to ultrasound diagnosis. 8nfortunately, these Sarameters are not conclusiYe enough to assign the risk to a Sarticular fetus. There are not many studies inYestigating the concentration leYels of 3$33$ and Bh&* in multiSle Sregnancies with fetal aneuSloidy and they often comSrised grouSs with small numEer of Satients >1@. 6Sencer, when testing and Yerifying the concentrations of 3$33$ and Bh&* in multiSle Sregnancies, demonstrated the total aYerage of 0o0 adMusted for weight, ethnicity, smoking, and in Yitro fertilization, among twin Sregnancies, to Ee 2.2 for ȕh&* and 2.121 for 3$33$ >1@. &onsidering chorionicity, among mono and dichorionic twin Sregnancies, mean 0o0 Yalues for ȕh&*, adMusted for weight, ethnicity, smoking and in Yitro fertilization, did not signi¿cantly differ from each other and were 1. and 2.1, resSectiYely. +oweYer, the aYerage Yalue of 0o0 for 3$33$, adMusted for weight, ethnicity, smoking and in Yitro fertilization, was signi¿cantly lower in monochorionic than in dichorionic twins, and amounted to 1. and 2.2, resSectiYely >1@. 0aternal serum markers in higher order multiSle Sregnancies triSle or higher are not useful due to a greater numEer of SossiEle chorionicity tySes. There are many Eene¿ts to ¿rst trimester ultrasound screening. )irstly, the comEined ultrasound and analysis of Eiochemical markers 3$33$, free ȕh&* giYe the highest, currently achieYaEle leYel of detection of aneuSloid fetuses >, 1@. 6econdly, measurement of 1T is helSful in determining the risk of a numEer of anomalies other than aneuSloidy >1, 1, 1@. Thirdly, almost comSlete assessment of the fetal anatomy can Ee Serformed as early as the ¿rst trimester >2, 21@, thus SroYiding the Sregnant woman with a large amount of YaluaEle information at a Yery early stage of Sregnancy. ,f a fetal defect is indeed recognized, such diagnostic system offers the Sarents ma[imum SriYacy and indeSendence regarding their decisions aEout the Sregnancy. )inally, the ¿rst trimester ultrasound screening includes a measurement of &5/, which is the most reliaEle Eiometric Sarameter determining the duration of Sregnancy.

Oświadczenie autorów: 1. Józef Krawczyk – autor koncepcji i założeń pracy, przygotowanie manuskryptu i piśmiennictwa– autor zgłaszający i odpowiedzialny za manuskrypt. 2. Dariusz Borowski – współautor tekstu pracy, zebranie materiału, przygotowanie manuskryptu. 3. Piotr Węgrzyn – współautor tekstu pracy, korekta i aktualizacja piśmiennictwa. 4. Krzysztof Drews – współautor tekstu pracy, korekta i aktualizacja literatury. 5. Mirosław Wielgoś – ostateczna weryfikacja i akceptacja manuskryptu.

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Ginekol Pol. 2013, 84, 974-978

Józef Krawczyk et al. Prenatal diagnosis of Down syndrome in dizygotic twin pregnancy. KO M U NIKAT

Źródło finansowania: Praca nie była finansowana przez żadną instytucję naukowo-badawczą, stowarzyszenie ani inny podmiot, autorzy nie otrzymali żadnego wynagrodzenia. Konflikt interesów: Autorzy nie zgłaszają konfliktu interesów oraz nie otrzymali żadnego wynagrodzenia związanego z powstawaniem pracy.

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5. Kirkegaard I, Uldbjerg N, Oxvig C. Biology of PAPP-A in relation to prenatal diagnostics: an overview. Acta Obstet Gynecol Scand. 2010, 89, 1118-1125. 6. Zhu JL, Madsen KM, Vestergaard M, [et al]. Paternalage and congenital malformations. Hum Reprod. 2005, 20, 3173-3177. 7. Gringras P, Chen W. Mechanisms for differences in monozygous twins. Early Hum Dev. 2001, 64, 105-117. 8. Rodis JF, Egan JX, Craffey A, [et al.]. Calculated risk of chromosomal abnormalities in twin gestations. Obstet Gynecol. 1990, 76, 1037-1041. 9. Monteagudo A, Timor-Tritsch IE, Sharma S. Early and simple determination of chorionic and amniotic type in multifetal gestations in the first 14 weeks by high frequency transvaginal ultrasound. Am J Obstet Gynecol. 1994, 170, 824-829. 10. Sepulveda W, Sebire NJ, Hughes K, [et al.]. The lambda sign at 10-14 weeks of gestation as a predictor of chorionicity in twin pregnancies. Ultrasound Obstet Gynecol. 1996, 7, 421-423. 11. Sepulveda W, Sebire NJ, Hughes K, [et al.]. Evolution of the lambda or twin-chorionic peak sign in dichorionic twin pregnancies. Obstet Gynecol. 1997, 89, 439-41. 12. Kagan KO, Gazzoni A, Sepulveda-Gonzalez G, [et al.]. Discordance in nuchal translucency thickness in the prediction of severe twin-to-twin transfusion syndrome. Ultrasound Obstet Gynecol. 2007, 29, 527-532. 13. Maiz N, Staboulidou I, Leal AM, [et al.]. Ductus venosus Doppler at 11 to 13 weeks of gestation in the prediction of outcome in twin pregnancies. Obstet Gynecol. 2009, 113, 860-865.

Szkolenia z zakresu chirurgii w ginekologii i ginekologii onkologicznej W programie szkoleń znajdą się zabiegi: – laparoskopowe wycięcie macicy, – laparoskopowe rozszerzone wycięcie macicy oraz – operacje cytoredukcyjne u chorych na nowotwory kobiecego narządu rodnego.

16. Słowakiewicz K, Perenc M, Sieroszewski P. Biochemical prenatal tests and uterine artery Doppler examination in prediction of PIH and IUGR in the third trimester of pregnancy. Ginekol Pol. 2010, 81 (5), 352-357.

Cena za uczestnictwo w szkoleniu wynosi 900 PLN. Opłata będzie pobierana na miejscu. Cena obejmuje: – punkty edukacyjne, – udział w zabiegach, – materiały szkoleniowe, – koszty posiłków.

17. Hyett J, Moscoso G, Papapanagiotou G, [et al.]. Abnormalities of the heart and great arteries in chromosomally normal fetuses with increased nuchal translucency thickness at 11-13 weeks of gestation. Ultrasound Obstet Gynecol. 1996, 7, 245-250.

Zgłoszenia prosimy przesyłać na adres e-mail:

14. Blickstein I, Keith LG. Multiple pregnancy: epidemiology, gestation & perinatal outcome. New York: London: Parthenon, 1995. 15. Spencer K, Kagan KO, Nicolaides KH. Screening for trisomy 21 in twin pregnancies in the first trimester; an update of the impact of chorionicity on maternal serum markers. Prent Diagn. 2008, 28, 49-52.

18. Schemm S, Gembruch U, Germer U, [et al.]. Omphaloceleaxstrophy-imperforate anus-spinal defects (OEIS) complex associated with increased nuchal translucency. Ultrasound Obstet Gynecol. 2003, 22, 95-97. 19. Smrcek JM, Germer U, Krokowski M, [et al.]. Prenatal ultrasound diagnosis and management of body stalk anomalny: Analysis of nine singleton and two multiple pregnancies. Ultrasound Obstet Gynecol. 2003, 21, 322-328. 20. Gembruch U, Knopfle G, Bald R, [et al.]. Early diagnosis of fetal congenital heart disease by transvaginal echocardiography. Ultrasound Obstet Gynecol. 1993, 3, 310-317. 21. Achiron R, Rotstein Z, Lipitz S, [et al.]. First-trimester diagnosis of fetal congenital heart disease by transvaginal ultrasonography. Obstet Gynecol. 1994, 84, 69-72.

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