Ernő Tóth-Pál

Prenatal detection of trisomy 21 and 18 from amniotic fluid by quantitative fluorescent polymerase chain reaction.

Prenatal diagnosis of fetal trisomies is usually performed by cytogenetic analysis on amniotic fluid. This requires lengthy laboratory procedures and high costs, and is unsuitable for large scale screening of pregnant women. An alternative method, which is both rapid and inexpensive and suitable for diagnosing trisomies even from single fetal cells, is the fluorescent polymerase chain reaction using polymorphic small tandem repeats (STRs). In this paper we present the preliminary results of a larger study comparing parallel prenatal diagnoses of trisomies 21 and 18 using cytogenetics with quantitative fluorescent polymerase chain reaction using STR markers. The results obtained by the two techniques were concordant in all cases. This is the first study reporting significant numbers of prenatal diagnoses using the quantitative fluorescent polymerase chain reaction. We believe that further studies on greater numbers of samples will determine the absolute reliability of this technique. These results also provide a model for diagnosis of trisomy from single fetal cells isolated from maternal blood.

Genetic Amniocentesis in Multiple Pregnancy

Objectives: Second-trimester genetic amniocentesis is the most frequently used invasive prenatal diagnostic technique. Several reports have been published about the effect of genetic amniocentesis on fetal loss in multiple pregnancies over the past two decades. Here we analyze our experience with genetic amniocentesis in multiple pregnancies over the past 10 years. Methods: Details of 184 multiple pregnancies were processed in all cases in whom genetic amniocentesis was performed in women who presented at our department since 1990. The outcomes of 175 cases (95.1%) out of 184 genetic amniocenteses were available to us. As a control group, we followed up the outcome of 300 twin pregnancies in which no genetic amniocenteses were performed. Results: We found that the proportion of spontaneous losses in multiple pregnancies between the 18th and the 24th gestational weeks was 2.39%, whereas if genetic amniocentesis was performed the loss rate before the 24th week was 3.87%. The perinatal mortality rate was 10.03/1,000 in the group who underwent amniocentesis, while it was 10.52/1,000 in the group without amniocentesis. Conclusions: Our results suggest that the genetic amniocentesis performed in multiple pregnancies slightly increased (1.48%) the fetal loss rate until the 24th week. Beyond 5 weeks after the procedure, no consequent fetal loss should be expected. In our study the intervention did not have any undesired effect on perinatal mortality rates.

Ultrasonographic Findings of Fetal Aneuploidies in the Second Trimester – Our Experiences

Objectives: The aim of this study was to determine the incidence of ultrasound findings in common fetal chromosomal defects on a relatively large series coming out from one institution. We also tried to evaluate possible clusters of ultrasound signs of major chromosomal defects. Methods: Of the 22,150 fetal karyotypings, 514 abnormal karyotypes (2.3%) were diagnosed prenatally between 1990 and 2004. Of them, 374 were further evaluated for abnormal ultrasound signs in this study. These represented the major chromosomal defects of Down syndrome (n = 207), trisomy 18 (n = 70), trisomy 13 (n = 28) and Turner syndrome (n = 69). Results: The incidences of major structural defects and minor anomalies were evaluated then sonographic signs with the highest incidences were established in each of the major chromosomal defects. In fetuses with trisomy 13, besides cardiac defects, the most frequently seen structural abnormalities were central nervous system anomalies and facial anomalies. In fetuses with trisomy 18 and trisomy 21, cardiac anomalies were the most common structural sonographic features, whereas the most common findings were hygroma colli and fetal hydrops in fetuses with Turner syndrome. As far as minor anomalies are concerned, increased nuchal fold was the most predictive marker of each major aneuploidy. Choroid plexus cysts were more common in trisomy 18, whereas echogenic intracardiac foci were more frequently detected in fetuses with trisomy 13 and trisomy 21. Conclusion: This study may help to select the most predictive components of the genetic sonogram which may assist the counseling of women for the actual risk of the major chromosomal abnormalities.

Incidence of chromosomal abnormalities in the presence of fetal subcutaneous oedema, such as nuchal oedema, cystic hygroma and non-immune hydrops

Introduction: The authors investigated the incidence of chromosomal abnormalities in subcutaneous oedema detected in the fetus by intrauterine ultrasonography. Material and Method: In the 10-year period, intrauterine karyotyping was performed in pregnancies with positive ultrasound findings for subcutaneous oedema, such as nuchal oedema, cystic hygroma and non-immune hydrops. Results: Intrauterine karyotyping in fetal subcutaneous oedema was carried out in 434 cases. The chromosomal investigation was made in nuchal oedema in 374 cases, in 120 patients the chromosomal examination was made in the first trimester because of nuchal translucency, and in 254 cases in the second trimester because of nuchal thickening. Cystic hygroma cases (27 patients), non-immune hydrops cases (20 patients), and combined cases of non-immune hydrops and cystic hygroma (13 patients) were investigated separately. In nuchal oedema, pathological karyotypes were detected in 8.33% in the first trimester and in 5.51% in the second trimester. Chromosomal abnormality was found in 48.15, 20, and 53.8% in cystic hygroma, non-immune hydrops, and combined occurrence of non-immune hydrops and cystic hygroma, respectively. Considering all of the changes accompanied by subcutaneous oedema, 50, 25 and 18.75% of the pathological karyotypes was X-monosomy, trisomy 18 and trisomy 21, respectively. Discussion: It was important to distinguish nuchal oedema and cystic hygroma, and in the case of non-immune hydrops, it was also important to discuss cases with or without cystic hygroma separately. During the investigations, cases of non-immune hydrops with or without cystic hygroma were evaluated as separate categories. Conclusions: The authors emphasize the differentiation of the various types of subcutaneous oedema and the importance of precise information about the risks, provided during genetic counselling.

Risk of chromosome abnormalities in the presence of bilateral or unilateral choroid plexus cysts

Objectives: To evaluate the rate of chromosome abnormalities in cases of uni- and bilateral choroid plexus cysts (CPCs). Methods: A total of 10,875 ultrasound (US) examinations were performed in the second trimester, and 435 cases with CPC (4%) were found. After genetic counseling, 45 patients decided not to undergo karyotyping. The authors performed a chromosome analysis in 390 cases of CPCs. Results: The total risk of chromosome abnormalities was 3.59% (n = 14) and risk of trisomies was 2.05% (n = 8). Trisomy 18 was found in 6 cases (1.54%), trisomy 21 in 1 case (0.26%), and trisomy 9 in 1 case (0.26%). The risk of 45,X karyotype was 0.77% (n = 3). One case of 47,XXY karyotype and 2 cases with other chromosome abnormalities were found. In 212 unilateral cases there were 7 with chromosome abnormalities (3.3%). In 178 bilateral cases there were 7 with abnormal karyotypes (3.93%). The CPC was associated with additional fetal US anomalies (with or without polyhydramnios/oligohydramnios) in 112 cases; chromosome abnormalities were detected in 4 cases (3.57%). 66 cases were associated with polyhydramnios/oligohydramnios but not with other fetal US anomalies; 3 cases of abnormal karyotypes were found (4.55%). The CPC was isolated in 212 cases and 7 cases were associated with chromosome disorders (3.3%). Conclusions: US plays an important role in prenatal diagnostics. Further genetic counseling is recommended in cases with CPCs.

Prenatal Diagnosis, Phenotypic and Obstetric Characteristics of Holoprosencephaly

The diagnosis of fetal malformations, especially those of the central nervous system, is strikingly important in the practice of genetic counseling. Early diagnosis is very significant, not only because of the prognosis, but also because of the emotional effects caused by the accompanying craniofacial malformations. The summary of the obstetrical and diagnostical characteristics should be useful in the management of holoprosencephaly. The analysis of the 50 cases we encountered between 1981 and 2000, including the anatomical, diagnostic and clinical aspects, as well as the associated craniofacial malformations, forms the essence of our publication. In one of the examined cases a familiar recurrence was verified.

Recurrent trisomy 21 and uniparental disomy 21 in a family

Objective: A 32-year-old pregnant woman was referred to our genetic counselling because of recurrent trisomy 21 in the family. Analysis of amniotic fluid cell culture revealed karyotype 47,XY+21 of the fetus. Methods: Karyotyping and molecular analysis were undertaken in the fetal and parental samples to determine the origin of the extra chromosome 21. Results: Both parents had a normal blood karyotype. Microsatellite marker analysis showed maternal origin of the fetal extra chromosome 21. As the mother showed homozygosity for all investigated markers on chromosome 21, we also tested her family. We detected the same homozygosity in some family members which was consistent with isodisomy of the chromosome 21 caused by uniparental disomy (UPD). Conclusions: Here we report on a family in which multiple aneuploid conceptions occurred with trisomy 21, and molecular analysis showed that the euploidy of the investigated healthy family members is due to UPD21. This observation stresses the importance of prenatal cytogenetic and molecular analysis in case of parental UPD.

Familial Association of Congenital Left Heart Abnormalities and Sustained Fetal Arrhythmia

Abstract. Hypoplastic left heart syndrome (HLHS) is the most common cause of death from heart disease in the first week of life. There are reports about familial concordance by presumed morphogenetic mechanisms of abnormal embryonic blood flow with phenotypes of varying severity. The risk of having a child with a left heart lesion after a previously affected child may be as high as 5% to 12%. We present case reports from four families in which sustained fetal arrhythmia (three ectopic atrial tachycardias and one severe bradycardia due to excessive ectopic atrial beats) was demonstrated. Within these four families a close relative of the mother (a previous child, a brother, or a nephew) had severe left heart abnormality (three with HLHS and one with severe aortic valve stenosis). The association of sustained fetal arrhythmia of ectopic atrial origin and severe left heart abnormalities could be expected to occur by chance in a very low percentage of cases. We conclude that sustained fetal atrial ectopic arrhythmia is a congenital abnormality and should be considered as a risk factor for inherited congenital heart abnormalities.

[Craniospinal malformations in a twelve-year fetopathological study; the efficiency of ultrasonography in view of fetopathological investigations].

Background: Craniospinal malformations represent a heterogeneous group of congenital malformations by their morphology and etiology alike. Certain craniospinal malformations could be diagnosed as early as the dawn of ultrasonography and this group of malformations has been the focus of attention ever since. Aims: The aim of theauthors was to review the main characteristics ofcraniospinal malformations, as well as to evaluate the efficiency of ultrasonography based on autopsy examinations during twelve years. Study design: The current study comprises the details of 339 pregnancies terminated by induced abortion for craniospinal malformation between 1995 and 2006. Results: Maternal median age was 27±5.8 years, ranging from 15 to 47 years. In 24.5% of the cases, there was a positive obsterical–gynecological or genetic history. In 68.1% of the cases, ultrasonographic and autopsy findings were completely identical; in 24.2% a partial coincidence was found, but autopsy allowed for further diagnoses, while in 26 cases (7.7%) different findings wereobtained byprenatal ultrasonographyand fetopathologicalinvestigations.Inhalfof thelatter 26 cases, induced abortion was suggested due to hydrocephalus confirmed by ultrasonography but notjustifiedbyautopsyortheautopsyrevealedthepresenceofothercraniospinalmalformation(s).

Pre- and perinatal relations of hemophilia A and B

Objective: The authors conducted a retrospective study of obstetric and genetic data, obstetric problems, and pregnancy outcome by investigating 149 pregnancies of patients who received genetic counselling because of hemophilia A or B over a 20-year period. Methods: In cases with a heterozygous mother, fetal sex was determined. In 23 of 35 cases with male fetuses, a DNA examination was performed. In cases with hemophilic male fetuses, the couple made a decision on whether or not to continue the pregnancy after thorough counselling regarding genetic risk. Hemophilia A occurred 135 pregnancies (98 pregnancies from 55 heterozygous mothers and 37 pregnancies from 20 hemophilic fathers). Hemophilia B occurred in 14 pregnancies (9 pregnancies from 3 heterozygous mothers and 5 pregnancies from 4 hemophilic fathers). Results: In pregnant women who were carriers of hemophilia A, 32 of the fetuses were male, and DNA examinations were performed in 22 cases. In 16 cases abortions were induced (in 10 cases hemophilia was confirmed by DNA examination), and in 4 of 16 deliveries affected males were born (the disease was confirmed by DNA examination during pregnancy). Of 3 confirmed male fetuses of heterozygous women with hemophilia B, 1 healthy male was born. In 2 cases abortions were induced (in 1 case on the basis of DNA diagnosis). Conclusions: In cases of heterozygous mothers (hemophilia A and B together) the rate of spontaneous abortions was 13.1%. The rates of premature deliveries (8.2%) and cesarean sections (8.2%) were no higher than national average. The rate of bleeding complications during pregnancy was 18.7%, in 2.7% of cases transfusions were necessary. In case of hemophilic fathers (in heterozygous female fetuses the hemostasis may change from the fetal side) the rate of bleeding complications during pregnancy was 18.2%. In terms of deliveries, obstetrical bleeding complications occurred in 12.2%, atonia in 2%, curettage after delivery in 4.1%, and transfusion in 10.2% of the heterozygous mothers with hemophilia A and B combined. Neonatal complications were cerebral hemorrhage in 1 case and bleeding from the umbilical stump in another case (both newborns were hemophilic males). In connection with delivery, there was no sign of hematoma development on the skull of the newborns, nor were transfusions necessary. In cases of paternal disease the rate of curettage was 6.7% and there were no neonatal or other obstetrical complications.