Prenatal diagnosis of Down syndrome in dizygotic twin pregnancy

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1 Prenatal diagnosis of Down syndrome in dizygotic twin pregnancy Prognoza prenatalna zespołu Downa w ciąży bliźniaczej dizygotycznej Józef Krawczyk 1, Dariusz Borowski 1, io r rzy 1, Krzysztof Drews 2, iros aw ie o 1 1 First Department of Obstetrics and Gynecology Medical University of Warsaw, Poland 2 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: / / / / Corresponding author: Józef Krawczyk First Department of Obstetrics and Gynecology Medical University of Warsaw Starynkiewicza 1/ Warszawa, Poland jozef.krawczyk@wum.edu.pl Otrzymano: Zaakceptowano do druku:

2 Ginekol Pol. 2013, 84, P R A C E K A Z U I S T Y C Z N E 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: / / / / Introduction Dow sy ro e for er y o o is e o s to t e ost co o e etic a or a ities cause y t e rese ce of a or art of a e tra 21 st c ro oso e Dow sy ro e was rst escri e y a Britis ysicia, Jo a o Dow, i 1 1 ec a is s w ic i c u e c ro oso a o is u ctio uri eiosis or o ertso ia tra s ocatio s of are ta ori i are at the molecular core of the syndrome. The incidence of Down syndrome is estimated at li e irths and it occurs in all ethnic and social rou s. Due to the fact that there are hysiolo ical and enetic restrictions in atients with Down syndrome that cannot always e acce ted y the arents, in many countries they are offered the ossi ility of re nancy termination in case of trisomy 21. n the case of twin re nancy with only one fetus with aneu loid karyoty e, a selecti e termination of that fetus is ossi le. The time of the rocedure does not statistically and si ni cantly increase the risk of remature irth of the healthy twin 2. ro er renatal screenin, focused on early dia nosis of the ro lem, followed y s ecialist care, family in ol ement, education and trainin since early childhood, ha e critical in uence on the uality of life and nal sta e of de elo ment of children with Down syndrome, as well as eer acce tance and family functioning. The standard of conducting renatal screening for trisomy 21 during the rst trimester etween 11 1 weeks days com ines the e aluation of fetal nuchal translucency and uantitati e analysis of the rotein, and free h. That recommendation is ased on studies y icolaides et al., and is characterized y high sensiti ity and s eci city, re ected y a detection rate of Down syndrome. Twin regnancies constitute a se arate issue of renatal screening. n healthy twin regnancies, the rotein concentration and free h determined in lood serum of regnant mothers reach higher alues when com ared to a singleton regnancy, su osedly due to the olume and function of lacenta since is synthesized rimarily y syncytiotro ho last. s a result, se arate reference alues for iochemical arameters need to e ac uired in multi le regnancies. encer showed that a erage rotein and free h concentrations in twin regnancies are 1. and 2. times higher, res ecti ely, when com ared to a singleton regnancy. Taking that into account and using statistical modeling techniques, he redicted that, at a false ositi e rate, the detection rate of trisomy 21 in twins will e at the le el of 2 ased only on iochemical markers. n contrast to maternal serum iochemistry, the use of ultrasound markers in multi le regnancies allows to determine the indi idual risk for each of the twins. ith selecti e a lication of the T measurement and a ro riate estimation of the risk, the detection rate is. The com ination of these arameters indicates an detection rate of trisomy 21 in twin regnancies, which is only a out 1 lower than for a singleton regnancy. Case report e resent a case of a year old regnant atient with regular menstrual cycles lasting 2 days. The regnancy was estimated to e weeks and days, calculated from the last menstrual eriod. trans aginal ultrasound re ealed the resence of a intrauterine regnancy with gestational sacs. t weeks of gestation, a diamniotic, dichorionic regnancy, with symmetrically de elo ing fetuses, was con rmed. Two weeks later a diamniotic dichorionic regnancy was recon rmed y the rst trimester ultrasound, with symmetrical alues ut also with signi cant asymmetry of the T alues etween the fetuses. The alue of fetal T, whose cytogenetic analysis of the material indicated aneu loid female karyoty e,, 21, was. mm ig. 1, 2. The T of the fetus with the normal karyoty e was 1. mm. The analysis of the consecuti e markers of fetal chromosomal defects, erformed in accordance with the criteria, including the nasal one B ig. assessment, lood ow at the le el of the tricus id al e T, and the ductus enosus D ig., allowed to calculate the risk of trisomy 21, 1 and 1. Nr 11/2013 Polskie Towarzystwo Ginekologiczne 975

3 Fig. 1. Fig. 3. Fig. 2. Fig. 4. i en that the highest achie a le le el of detection of fetal trisomy 21, 1 and 1 is ro ided y a screening test erformed during the rst trimester, com ining the analysis of the ultrasound markers T, T, D and determination of roteins and free h serum concentration, the atient was asked to ha e a lood analysis erformed to com ly with the test. written consent was o tained from the atient. The nal risk is calculated ased on maternal age. The new risk is the risk calculated on the asis of fetal chromosomal a erration markers iochemical and ultrasound. edian iochemical alues are ad usted to maternal ody weight, arity, and twin regnancy. ew risks are calculated with the software ersion 2. s continuation of diagnostic e aluation, the atient was offered amniocentesis after 1 weeks of gestation. The material o tained in the course of this in asi e rocedure hel ed to identify that the rst fetus etus carried a normal male karyoty e,, whereas the cytogenetic analysis of the material from the second fetus etus re ealed an a normal female karyoty e, 21 ig.. The atient decided to continue with the regnancy and its course was une entful until the end of weeks of gestation. t weeks of gestation a cesarean section was erformed due to Fig. 5. s ontaneous onset of la or and trans erse osition of one of the twins. Two new orns were deli ered male weigh g, g 1 and female weight 2, g. The new orn diagnosed with an aneu loidal female karyoty e,, 21 manifested reduced muscle tension and dysmor hic features characteristic for Down syndrome, such as at ro le, rotruding tongue 976

4 Ginekol Pol. 2013, 84, P R A C E K A Z U I S T Y C Z N E glosso tosis, single crease across the alms and small and low set ears. The mother and oth infants were discharged on day 1 of hos italization in good o erall condition. Discussion The risk of ha ing a child with Down syndrome is 1 1 for mothers aged 2 2 at the age of the risk is 1, and years of age it increases to 1 11 li e orn infants. The risk increases with maternal age, howe er of children with Down syndrome are deli ered y mothers years, which is associated with the highest ercentages of deli eries in that age grou. ecent data suggests that father s age also lays a role in increasing the risk of Down syndrome in the offs ring, through the mutagenic effect of iological and en ironmental factors in the gametes. dditionally, older males are also assumed to e in relationshi s with their age eers, what needs to e taken into consideration in the studies. The risk of chromosomal a normalities in twin regnancies is higher com ared to a singleton regnancy. Determination of zygosity hel s to select the right algorithm for calculating the risk of aneu loidy. enerally, three clinical situations may occur one fetus with chromosomal anomaly in dizygotic regnancy, oth fetuses with chromosomal anomaly in dizygotic regnancy, and oth fetuses with equal chromosomal anomaly in monozygotic twin regnancy. n the ast, gender differences in twin regnancy demonstrated in the course of diagnostic ultrasound, could constitute an argument ro ing dizygosity. owe er, in recent years, different studies ha e indicated henoty ic as well as genoty ic differences in identical twins. t their ase the intrauterine en ironmental factors lay a ma or role, es ecially the molecular mechanisms causing such aria le degree of genetic mosaicism in the fetuses. ost cases of twin regnancies are dizygotic, and each of the fetuses, a riori, has its own risk of de elo ing irth defects. nder the rules of ro a ility, a chance of detecting the defect in at least one of the fetuses is higher than in a singleton regnancy. ccording to this thesis, atient at the age of in twin regnancy will face the risk of Down syndrome in at least one of the fetuses com ara le or equal to that of a year old woman in a singleton regnancy. Thus, a question a out im lementation of a ro riate rocedures for women in a multi le regnancy has een raised. n the resented case, renatal care scheme was ased on ultrasound diagnosis. The im ortance of ultrasound screening erformed in the rst trimester is e en more im ortant in case of multi le regnancies. irst trimester is the o timal time to determine chorionicity and amniocity, 1, 11. Different thickness of the intertwine mem rane lam da sign or twin eak at the oint of connection with the chorionic late shows that the regnancy is dichorionic. f the mem rane is thin o er its entire length, also at the unctional oint with the chorionic late a T sign, it is ossi le to diagnose monochorionic and diamniotic regnancy with high ro a ility. The knowledge of chorionicity is im ortant for selecting ro er renatal care as monochorionic diamniotic regnancies are associated with signi cantly higher risk of com lications than dichorionic diamniotic regnancies. onogra hic determination of chorionicity and the measurement of fetal T in oth fetuses ha e ecome a key element of renatal diagnosis in a twin regnancy. t should e strongly em hasized that in monochronic diamniotic regnancies the risk of twin to twin transfusion syndrome TTT signi cantly increases if there are differences in the T alues and in the analysis of lood ow at the le el of D the re ersal of the wa e in one of the fetuses increases the risk of TTT etween the fetuses 12, 1. sing iochemical markers to assess the risk of aneu loidy in multi le regnancies is a alua le addition to ultrasound diagnosis. nfortunately, these arameters are not conclusi e enough to assign the risk to a articular fetus. There are not many studies in estigating the concentration le els of and B h in multi le regnancies with fetal aneu loidy and they often com rised grou s with small num er of atients 1. encer, when testing and erifying the concentrations of and B h in multi le regnancies, demonstrated the total a erage of o ad usted for weight, ethnicity, smoking, and in itro fertilization, among twin regnancies, to e 2. 2 for h and for 1. onsidering chorionicity, among mono and dichorionic twin regnancies, mean o alues for h, ad usted for weight, ethnicity, smoking and in itro fertilization, did not signi cantly differ from each other and were 1. and 2. 1, res ecti ely. owe er, the a erage alue of o for, ad usted for weight, ethnicity, smoking and in itro fertilization, was signi cantly lower in monochorionic than in dichorionic twins, and amounted to 1. and 2.2, res ecti ely 1. aternal serum markers in higher order multi le regnancies tri le or higher are not useful due to a greater num er of ossi le chorionicity ty es. There are many ene ts to rst trimester ultrasound screening. irstly, the com ined ultrasound and analysis of iochemical markers, free h gi e the highest, currently achie a le le el of detection of aneu loid fetuses, 1. econdly, measurement of T is hel ful in determining the risk of a num er of anomalies other than aneu loidy 1, 1, 1. Thirdly, almost com lete assessment of the fetal anatomy can e erformed as early as the rst trimester 2, 21, thus ro iding the regnant woman with a large amount of alua le information at a ery early stage of regnancy. f a fetal defect is indeed recognized, such diagnostic system offers the arents ma imum ri acy and inde endence regarding their decisions a out the regnancy. inally, the rst trimester ultrasound screening includes a measurement of, which is the most relia le iometric arameter determining the duration of regnancy. 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. Nr 11/2013 Polskie Towarzystwo Ginekologiczne 977

5 Źródło finansowania: Praca nie była finansowana przez żadną instytucję naukowo-badawczą, stowarzyszenie ani inny podmiot, autorzy nie otrzymali żadnego wynagrodzenia. KOMUNIKAT Konflikt interesów: Autorzy nie zgłaszają konfliktu interesów oraz nie otrzymali żadnego wynagrodzenia związanego z powstawaniem pracy. References 1. Down JLH. Observations on an Ethnic Classification of Idiots. London Hospital Reports. 1866, 3, Sebire NJ, Snijders RJ, Santiago C, [et al.]. Management of twin pregnancies with fetal trisomies. Br J Obstet Gynaecol. 1997, 104, Sonek JD, Glover M, Zhou M, [et al.]. First Trimester Ultrasound Screening: An Update. Donald School J Ultrasound Obstet Gynecol. 2010, 4, Spencer K. Screening for trisomy 21 in twin pregnancies in the first trimester using free betahcg and PAPP-A, combined with fetal nuchal translucency thickness. Prenat Diagn. 2000, 20, Kirkegaard I, Uldbjerg N, Oxvig C. Biology of PAPP-A in relation to prenatal diagnostics: an overview. Acta Obstet Gynecol Scand. 2010, 89, Zhu JL, Madsen KM, Vestergaard M, [et al]. Paternalage and congenital malformations. Hum Reprod. 2005, 20, Gringras P, Chen W. Mechanisms for differences in monozygous twins. Early Hum Dev. 2001, 64, Rodis JF, Egan JX, Craffey A, [et al.]. Calculated risk of chromosomal abnormalities in twin gestations. Obstet Gynecol. 1990, 76, 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, Sepulveda W, Sebire NJ, Hughes K, [et al.]. The lambda sign at weeks of gestation as a predictor of chorionicity in twin pregnancies. Ultrasound Obstet Gynecol. 1996, 7, 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, 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, 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, Blickstein I, Keith LG. Multiple pregnancy: epidemiology, gestation & perinatal outcome. New York: London: Parthenon, 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, 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), 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 weeks of gestation. Ultrasound Obstet Gynecol. 1996, 7, 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, 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, Gembruch U, Knopfle G, Bald R, [et al.]. Early diagnosis of fetal congenital heart disease by transvaginal echocardiography. Ultrasound Obstet Gynecol. 1993, 3, Achiron R, Rotstein Z, Lipitz S, [et al.]. First-trimester diagnosis of fetal congenital heart disease by transvaginal ultrasonography. Obstet Gynecol. 1994, 84, Świętokrzyskie Centrum Onkologii w Kielcach Szkoła Elektrochirurgii i Chirurgii Małoinwazyjnej oraz 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. Cena za uczestnictwo w szkoleniu wynosi 900 PLN. Opłata będzie pobierana na miejscu. Cena obejmuje: punkty edukacyjne, udział w zabiegach, materiały szkoleniowe, koszty posiłków. Zgłoszenia prosimy przesyłać na adres mmisiek@me.com lub Adres do korespondencji: Świętokrzyskie Centrum Onkologii Dział Kliniczny Ginekologii Onkologicznej Kielce ul. Artwińskiego 3 tel./fax: (41) Serdecznie zapraszamy Prof. dr hab. n.med. Mariusz Bidziński 978