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SUMMARY OF RECOMMENDATIONS: 1. Oxytocin for induction or augmentation of labor should not be started when there is a previous scar on the body of the uterus (such as previous classical cesarean section, uterine perforation or myomectomy when uterine cavity is reached) or in any other condition where labor or vaginal delivery are contraindicated. (Moderate quality evidence +++-; Strong recommendation). 2. Oxytocin should not be started before at least 1 h has elapsed since amniotomy, 6 h since the use of dinoprostone (30 min if vaginal insert) and 4 h since the use of misoprostol (Low quality evidence ++- -; Moderate recommendation). 3. Cardiotocography (CTG) should be performed and a normal pattern without tachysystole should be documented for at least 30 min before oxytocin is used. Continuous CTG, with adequate monitoring of both fetal heart rate and uterine contractions, should be maintained for as long as oxytocin is used, and thereafter until delivery (Low ++- - to moderate +++- quality evidence; Strong recommendation). 4. For labor induction, at least 1-h should be allowed after amniotomy before oxytocin infusion is started, to evaluate whether adequate uterine contractility has meanwhile ensued. For augmentation of labor, if the membranes are intact and there are conditions for a safe amniotomy, the latter should be considered before oxytocin is started (Very low quality evidence +- --; Weak recommendation). 5. Oxytocin should be administered intravenously using the following regimen: 5 IU oxytocin diluted in 500 mL of 0.9% normal saline (NaCl) (each mL contains 10 mIU of oxytocin), in an infusion pump at increasing rates, as shown in Table 1, until a frequency of 3-4 contractions per 10 min is reached, a non-reassuring CTG pattern ensues, or maximum rates are reached (Low quality evidence ++ - -; Strong recommendation). If the frequency of contractions exceeds 5 in 10 min, the infusion rate should be reduced, even if a normal CTG pattern is present. With a non-reassuring CTG pattern, urgent clinical assessment by an obstetrician is indicated, and strong consideration should be given to reducing or stopping the oxytocin infusion. The minimal effective dose of oxytocin should always be used. (Low ++- - to Moderate +++- - quality evidence; Strong recommendation). 6. Use of oxytocin for induction and augmentation of labor should be regularly audited (Low quality evidence ++--; Strong recommendation).

Prenatal testing has changed greatly over the past two decades, which may affect the diagnosis of congenital heart disease (CHD) in Down syndrome. The present study aimed to analyze changes in the prevalence and distribution of CHD diagnosed via ultrasonography and fetopathology in 462 fetuses with trisomy 21 between two consecutive 10-year periods (1999-2018), as well as the associations between CHDs, ultrasound markers, and extracardiac malformations. Overall, the frequency of cardiovascular malformations in trisomy 21 was 27.7 and 26.5%, and ultrasound identified 70 and 62% of CHDs during these periods. A profound increase in first-trimester ultrasound findings and associated anomalies with CHDs (ventricular septal defect, Tetralogy of Fallot) since 2009 were observed. Second-trimester nonstructural heart abnormalities were associated with ultrasound anomalies (74%) and major extracardiac malformations (42.9%). During both study periods, mothers carrying fetuses with CHD were significantly younger than those without CHD (p = 0.038, p = 0.009, respectively). Comparing the two 10-year periods, there were no changes in the prevalence and detection of CHDs. Trend analysis revealed that, although the frequency of CHD remained stable, the diagnostic spectrum had shifted between the study periods. Detection of nonstructural heart abnormalities necessitates detailed follow-up for cardiac/extracardiac malformations and chromosomal disorders.

Terminal deletion of chromosome 4 (4q deletion syndrome) is a rare genetic condition that is characterized by a broad clinical spectrum and phenotypic variability. Diagnosis of the distinct condition can be identified by conventional chromosome analysis and small deletions by novel molecular cytogenetic methods such as microarray comparative genome hybridization (aCGH). Prenatal diagnosis is challenging; to date 10 cases have been described. We report a prenatally diagnosed case of de novo 4q deletion syndrome confirmed by conventional karyotyping and FISH due to an elevated combined risk for Down syndrome and prenatal ultrasound findings. aCGH validated the diagnosis and offered exact characterization of the disorder. Cytogenetic and microarray results described a 4q32.1qter terminal deletion of the fetus. Prenatal ultrasound detected multiple nonstructural findings (micrognathia, choroid plexus cysts, echogenic fetal bowel, short femur, and cardiac axis deviation). Pregnancy was terminated at 20 weeks. In addition to the index patient, we reviewed the 10 prenatally published cases of 4q deletion syndrome in the literature and compared these with our results. We summarize the patients' characteristics and prenatal clinical findings. Alterations of maternal serum biochemical factors, an elevated combined risk for trisomies, and distinct ultrasonographic findings can often be observed in cases of prenatal 4q deletion syndrome and may facilitate the otherwise difficult prenatal diagnosis.

Abstract: Pallister–Killian syndrome (PKS) is a rare, sporadic genetic disorder that is caused by the mosaic presence of a supernumerary marker chromosome, isochromosome 12p. The syndrome is a polydysmorphic condition characterized by mental retardation, craniofacial dysmorphism, hypotonia, seizures, epilepsy and certain organic malformations (diaphragmatic hernia, congenital heart disease). Prenatal diagnosis is challenging due to the mosaic tissue-specific distribution of the chromosomal disorder and highly variable phenotype. Prenatal diagnosis is often accidental, however, appropriate laboratory techniques based on the second trimester ultrasound anomalies provide accurate prenatal diagnosis. We report a case of a 36-year-old primipara with second trimester ultrasound markers (polyhydramnion, ventriculomegaly, rhizomelic micromelia, abnormal facial profile). The patient underwent amniocentesis, the conventional karyotyping revealed a supernumerary chromosome in nearly 50 percent of amniocytes. FISH and targeted multicolour FISH probes verified mosaic tetrasomy of the short arm of chromosome 12 of the fetus. Fetopathological examinations and analysis of fetal tissues and blood confirmed the prenatal diagnosis. To our knowledge, this is the first reported case of prenatally diagnosed Pallister–Killian syndrome in Hungary. Orv Hetil. 2018; 159(21): 847–852.

Nowadays, women's family planning intentions are postponed, and it is common that only later will the conditions be created for the woman to have children. Fortunately, in most cases, pregnancy is possible in this case, taking into account the increased genetic risk. However, this later childbirth may become impossible or significantly more difficult if we can detect sterility and infertility, and its genetic cause is revealed. Any procedure that can help to reduce the "aging" of society, the reproduction rate, must be treated as an important public health issue. It would be particularly important in cases where genetic causes can be detected in the background of female sterility and infertility. Endocrine causes, infections, immunological causes, psychic factors, stress, and weight problems may be among the causes of female infertility in addition to genetic causes and genetic developmental disorders. Infertility can also be caused by iatrogenic factors, previous interventions, and surgery. In this chapter we will discuss the diseases in which genetic factors play a role.

Background Premature ovarian failure / primary ovarian insufficiency (POF/POI) associated with the mutations of the FMR1 (Fragile-X Mental Retardation 1) gene belongs to the group of the so-called trinucleotide expansion diseases. Our aim was to analyse the relationship between the paternally inherited premutation (PIP) and the maternally inherited premutation (MIP) by the examination of the family members of women with POF, carrying the premutation allele confirmed by molecular genetic testing. Methods Molecular genetic testing was performed in the patients of the 1st Department of Obstetrics and Gynecology with suspected premature ovarian failure. First we performed the southern blot analyses and for the certified premutation cases we used the Repeat Primed PCR. Results Due to POF/POI, a total of 125 patients underwent genetic testing. The FMR1 gene trinucleotide repeat number was examined in the DNA samples of the patients, and in 15 cases (12%) deviations (CGG repeat number corresponding to premutation or gray zone) were detected. In 6 cases out of the 15 cases the CGG repeat number fell within the range of the so-called gray zone (41–54 CGG repeat) (4.8%, 6/125), and the FMR1 premutation (55–200 CGG repeat) ratio was 7.2% (9/125). In 4 out of the 15 cases we found differences in both alleles, one was a premutation allele, and the other allele showed a repeat number belonging to the gray zone. Out of 15 cases, only maternal inheritance (MIP) was detected in 2 cases, in one case the premutation allele (91 CGG repeat number), while in the other case an allele belonging to the gray zone (41 CGG repeat number) were inherited from their mothers. In 10 out of 15 cases, the patient inherited the premutation allele only from the father (PIP). In 5 out of the 10 cases (50%) the premutation allele was inherited from the father, and the repeat number ranged from 55 to 133. Out of 125 cases, 9 patients had detectable cytogenetic abnormalities (7.2%). Conclusions The RP-PCR method can be used to define the smaller premutations and the exact CGG number. Due to the quantitative nature of the RP-PCR, it is possible to detect the mosaicism as well.

Background In animal studies, the inhibition of VEGF activity results in high mortality and impaired renal and glomerular development. Mechanical stimuli, like mechanical stretch in respiratory and circulatory systems, results in an elevated expression of VEGF. In animal models, the experimental urinary obstruction is associated with stretching of tubular cells and activations of the renin-angiotensin system. This results in the upregulation of vascular endothelial growth factor (VEGF) and TNF-alfa. Material/methods Tissue samples from urinary tract obstruction were collected and immunohistochemistry was performed in 14 patients (average age: 7.1±4.1 years). The control histology group consisted of ureteropelvic junction tissue from 10 fetuses after midtrimester artificial abortion. The fetuses did not have any failure at ultrasound screening and pathological examination. The mean gestational age was 20.6 weeks of gestation (±2.2SD). Expression of VEGF was detected with immunohistochemistry method. Results Expression of VEGF was found in varying intensity in the submucosa and subserosa layers, but only in the test tissue (placental tissue). The tissue of the patients with urinary obstruction and the tissue of the fetal ureteropelvic junction without urinary obstruction were negative for expression of VEGF. The repeated examination showed negative cells and no color staining. Conclusions The pressure due to congenital urogenital obstruction resulting in mechanical stress in cells did not increase the expression of VEGF in young children in our study. To find a correlation between urogenital tract obstruction and increased expression of VEGF, we need to perform more examinations because the connection may be of therapeutic significance.

Objectives To evaluate the prevalence of toxoplasma and cytomegalovirus (CMV) infections in cases of ultrasound anomalies detected in the second trimester of pregnancy. Methods Serological examinations for toxoplasma and CMV infection were carried out in 655 cases with sonographic findings suggestive of fetal infection, 612 cases with single ultrasound markers and 43 cases with two or more markers. Results In cases of single ultrasound markers, serological examination diagnosed recent toxoplasma infection in 107/612 cases (17.5%) and recent CMV infection in 75 cases (12.3%). Recent toxoplasma infection accounted for 13.8% (52/377) of the intracranial sonographic findings and 23.9% (45/188) of the abdominal findings, whereas recent CMV infections accounted for 12.2 (46/377) and 11.7% (22/188), respectively. Recent CMV infection with sonographic manifestations had higher rates of intracranial than intra-abdominal sonographic findings (46/75 or 61% vs 22/75 or 29%), whereas recent toxoplasma infection with sonographic manifestations had similar rates of intracranial (52/107 or 49%) and intra-abdominal (45/107 or 42%) findings. In cases of two or more ultrasound markers, serological examination diagnosed recent toxoplasma infection in 12/43 cases (27.9%) and recent CMV infection in 10/43 cases (23.3%). Conclusions Ultrasound findings suspicious for toxoplasma and CMV infection are not pathognomonic for either pathologic entity. Copyright © 2011 John Wiley & Sons, Ltd.

Objectives The aim of this study was to present our results of the sonographic measurement of the fetal iliac angle during the first and second trimesters of pregnancy. Methods A total of 2168 fetal iliac angle measurements were performed in a transverse section of the fetal pelvis. The iliac angle measurements were compared in fetuses with trisomy 21 (n = 52) and fetuses with normal karyotype (n = 1980). The sensitivity, specificity, positive predictive value, negative predictive value and false positive rate in trisomy 21 fetuses were compared for multiple cut-off value. Statistical significance for measurements was estimated for trisomy 21. Results A total of 2064 fetuses had adequate images for satisfactory measurement of the iliac wing angle and 1831 patients asked for a genetic invasive procedure. Of the fetuses with chromosomal aberrations, only the fetuses with trisomy 21 were included in the investigation. The risk of trisomy 21 in our population was 1 of 39. In the euploid fetuses, the mean iliac wing angle was 63.72°. The mean iliac wing angle in the fetuses with trisomy 21 was 90.32°, significantly higher than those seen in fetuses with normal karyotype. Conclusion The proven larger iliac wing angle in neonates with Down syndrome can be demonstrated sonographically during the pregnancy, especially in the first and second trimesters. This marker may be useful in prenatal screening or exclusion of trisomy 21. Copyright © 2011 John Wiley & Sons, Ltd.

Single umbilical artery (SUA) is a relatively common malformation that may call attention to the possibility of associated malformations (often chromosome aberrations). The current study aimed at surveying malformations associated with SUA on the basis of fetopathological investigations, analyzing the role of history, summarizing the clinically important factors emerging together with this malformation. In this study, we processed the details of 204 cases in which SUA was confirmed fetopathologically after miscarriage or induced abortion between 1990 and 2007. In our sample, SUA occurred in 7.38% of the cases. The history was positive in almost 30% of the cases. The majority of the cases had a positive obstetric and the minority of them a positive genetic history. The highest association of SUA with other malformations was found for craniospinal ones, but an association with cardiovascular malformations should also be mentioned. Regarding the individual types of malformation, SUA was most commonly associated with hydrocephalus, but Potter's sequence, trisomy 21, and atrioventricular septal defect also reached a higher rate in associated SUA. Previously published articles dealing with associated malformations found that urogenital malformations were most commonly associated with SUA. 'Itemizing' the different non-chromosomal malformations in association with SUA, we found that hydrocephalus, Potter's sequence, and atrioventricular septal defect were the most frequent malformations, while in earlier studies, the association with non-chromosomal malformations such as vertebral malformations, imperforated anus, cheilognathopalatoschisis, and renal agenesis occurred more frequently than usual.

A fetopatológiai vizsgálat nagy jelentőségű, hiszen egy következő terhesség vállalásának szempontjait szem előtt tartva az előfordult rendellenesség ismétlődésének kockázatait (is) hivatott megítélni.Célkitűzés:A szerzők tanulmányuk céljaként az ultrahang-diagnosztika hatékonyságának a fetopatológiai vizsgálatok eredményei alapján történő megítélését, elemzését határozták meg a nagyobb prevalenciájú fejlődési rendellenességek tekintetében.Módszer:Vizsgálataik során az 1995–2006 között a klinikán előfordult 683, központi idegrendszert, szív- és érrendszert, húgyúti rendszert, csontvázrendszert, illetve hasfalat/mellkasfalat érintő rendellenességgel járó terhesség adatait dolgozták fel.Eredmények:Szignifikáns különbség az anyai életkor, illetve a diagnózis felállításakor meghatározható gesztációs kor főbb statisztikai jellemzői kapcsán nem volt igazolható. A központi idegrendszert, a cardiovascularis rendszert, valamint a vázrendszert érintő malformációk egynegyedében, míg a húgyúti, illetve hasfalat/mellkasfalat érintő rendellenességek egyhatodában valamilyen terhelő előzményi adat fellelhető volt. A húgyúti, valamint cardiovascularis malformációk fiúmagzatokban lényegesen gyakoribbak voltak, ugyanakkor a központi idegrendszer, illetve a hasfal/mellkasfal rendellenességei esetén mérsékelt leánytúlsúly volt megfigyelhető. A vizsgált öt rendellenesség-csoportból négyben a post mortem vizsgálat eredményének teljesen megfelelő szonográfiai kórismék aránya 70% körül vagy a felett alakult, a húgyúti rendellenesség kapcsán azonban számottevően alacsonyabbnak (38%) bizonyult. A teljes minta alapján a szonográfiai és fetopatológiai diagnózisok teljes egyezésével járó esetek (A csoport) összesített aránya több mint 63%-nak, míg az ezektől való eltéréssel járó terhességek aránya (C csoport) 18%-nak bizonyult. Az ultrahangvizsgálat és a post mortem vizsgálat során nyert diagnózisok részleges egyezésével járó esetek (B csoport) aránya szintén 18%-nak bizonyult.Következtetések:A gyakran következményesen kevesebb magzatvízzel járó húgyúti fejlődési rendellenességek esetén genetikai centrumban történő (akár többszöri) szonográfiai vizsgálat indokolt. Mivel az omphalokele és a kromoszóma-rendellenességek társulási hajlama ismert, annak tükrében, hogy az omphalokelés esetek egy része gastroschisisként kerül kórismézésre, tanácsos lehet a kromoszómavizsgálat elvégzése az ultrahangvizsgálattal gastroschisisként diagnosztizált esetekben is. VSD esetei kapcsán javasolt a magasabb kockázatú terhességekben az echokardiográfiás vizsgálat minden konkrét általános ultrahang-diagnosztikai eltérés nélküli elvégzése.

Kartagener's syndrome is an inherited disease characterized by a triad of symptoms: bronchiectasis, situs inversus and sinusitis resulting from defective cilial motility. There are few reports in the literature regarding the optimum anesthetic technique in patients with Kartagener's syndrome. The main anesthetic considerations are related to the respiratory system and increased risk of infection. We report the case of a woman with Kartagener's syndrome and a twin pregnancy conceived by in-vitro fertilization-embryo transfer, who underwent cesarean section under spinal anesthesia. Despite recurrent pulmonary problems, the twin pregnancy resulted in a successful outcome. This was facilitated by a close working relationship between the obstetrician, anesthesiologist and patient.

Background Turner syndrome, a congenital condition that affects 1/2,500 births, results from absence or structural alteration of the second sex chromosome. Turner syndrome is usually associated with short stature, gonadal dysgenesis and variable dysmorphic features. The classical 45,X karyotype accounts approximately for half of all patients, the remainder exhibit mosaicism or structural abnormalities of the X chromosome. However, complex intra-X chromosomal rearrangements involving more than three breakpoints are extremely rare. Results We present a unique case of a novel complex X chromosome rearrangement in a young female patient presenting successively a wide range of autoimmune diseases including insulin dependent diabetes mellitus, Hashimoto’s thyroiditis, celiac disease, anaemia perniciosa, possible inner ear disease and severe hair loss. For the genetic evaluation, conventional cytogenetic analysis and FISH with different X specific probes were initially performed. The complexity of these results and the variety of autoimmune problems of the patient prompted us to identify the exact composition and breakpoints of the rearranged X as well as methylation status of the X chromosomes. The high resolution array-CGH (assembly GRCh37/hg19) detected single copy for the whole chromosome X short arm. Two different sized segments of Xq arm were present in three copies: one large size of 80,3 Mb from Xq11.1 to Xq27.3 region and another smaller (11,1 Mb) from Xq27.3 to Xq28 region. An 1,6 Mb Xq27.3 region of the long arm was present in two copies. Southern blot analysis identified a skewed X inactivation with ≈ 70:30 % ratios of methylated/unmethylated fragments. The G-band and FISH patterns of the rearranged X suggested the aspect of a restructured i(Xq) chromosome which was shattered and fortuitously repaired. The X-STR genotype analysis of the family detected that the patient inherited intact maternal X chromosome and a rearranged paternal X chromosome. The multiple Xq breakages and fusions as well as inverted duplication would have been expected to cause a severe Turner phenotype. However, the patient lacks many of the classic somatic features of Turner syndrome, instead she presented multiorgan autoimmune diseases. Conclusions The clinical data of the presented patient suggest that fragmentation of the i(Xq) chromosome elevates the risk of autoimmune diseases.

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.

To evaluate factors influencing parental decisions toward continuing or terminating a pregnancy with prenatal diagnosis of sex chromosome aneuploidy.We reviewed the records of patients with fetuses with sex chromosome aneuploidy between 1990 and 2001. A questionnaire survey of women who chose to terminate such pregnancies was designed to examine aspects of their decision-making process.Forty-nine of 89 pregnancies with sex chromosome aneuploidy were terminated (termination rate 0.55; 95% confidence interval 0.45-0.65). Pregnancies with abnormal ultrasound findings (14/16, 87%), with 45,X or 47,XXY karyotypes (26/36, 72%), and with nonmosaic karyotypes (30/48, 63%) were terminated significantly more often than pregnancies with normal ultrasound findings (35/73, 48%; P.01), with 47,XXX or 47,XYY karyotypes (4/12, 33%; P.05), and with mosaic karyotypes (5/25, 20%; P =.01). There was a trend (P =.136) toward a lower rate of termination from 67% to 36% across time, with a significant decrease from 67% to 7% in pregnancies with 47,XXX; 47,XYY; and mosaic karyotypes (P.01), and no change in cases with 45,X and 47,XXY karyotypes (67% compared with 69%; P = 1.0). Abnormal sexual development and infertility were the greatest parental concerns related to termination.Fear of having a child with abnormal sexual development or infertility remains the major determinant of parental decision toward terminating pregnancy, resulting in consistently high termination rates across time in pregnancies with 45,X and 47,XXY karyotypes. In cases with 47,XXX; 47,XYY; and mosaic karyotypes, the declining termination rate across time is a consequence of recent studies reporting normal sexual development and fertility.

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.

Objective Premutation of fragile X mental retardation 1 gene is known to cause fragile X associated tremor ataxia syndrome in males at 50–60 years of age, and fragile X associated primary ovarian insufficiency (FXPOI) in females at around 40. Females rarely exhibit tremor/ataxia. The exact molecular pathomechanism of FXPOI is unknown. Our aim was to perform a systematic study on tremor, eye movements and neuropsychological performance in female Fragile X (FraX) premutation carriers. Methods We have examined 13 young female premutation carriers (mean age 38 years) with/without FXPOI. Tremor (resting, postural, intentional, kinetic) was recorded with an accelerometry-based test system. Electrooculography (EOG) system was used for qualitative and quantitative analysis of eye movements. Neuropsychological assessment was performed with a complex battery including Montreal Cognitive Assessment, Rey auditory verbal learning test, Rey Complex Figure Test, and Wisconsin Card Sorting Test. Results We could detect cerebellar tremor in only 1/13 case. Saccadic smooth pursuit eye movements and decreased velocity of the horizontal reflexive saccades were recorded in 6/11 females with valid EOG. Neuropsychology tests showed impaired verbal memory and visuo-spatial memory with preserved visuo-spatial perception. Tests showed neither impairments in the executive functions, nor decrease of general intelligence. Discussion Objective neurophysiological methods are needed to reveal neurological signs of female premutation carriers. Conclusions Female FraX premutation carriers might exhibit subclinical neurological signs at young age. Significance To best of our knowledge, this is the first quantitative study on eye movements of female FraX premutation carriers. Our study provides new insight into movement disorders of female premutation carriers.

Objective The goal of the current publication is to review isolated central nervous system malformations (CSMs) using a database in excess of 75 000 cases, with special regard to the risk of recurrence of these malformations alone or in combination. Methods In the period between 1 January 1976 and 31 December 2005, among the 75 320 documented cases, consultations were requested due to earlier isolated CSMs in the patients' histories in 3030 cases (4.2%). Processing the data we only considered disorders of genetic origin, and that was why we excluded the cases due to intrauterine infection. Monogenically inherited malformations were also excluded from the analysis. The diagnosis of the malformations was based on the prenatal diagnosis of ultrasonography as well as the findings of the foetopathological examination. Results In 65% of the cases, the couples sought counselling because of malformation in a previous pregnancy. In these cases, the risk of recurrence was thought to be 5.2%, while in the case of two affected children this figure stood at 21.9%. Analysing the values for the risk of recurrence in 5-year periods, neural tube defects (NTDs) (particularly anencephaly and spina bifida) showed a detectable decrease, which could be attributed to a growing use of folic acid supplementation around the time of conception and during pregnancy. Conclusion There is a clear decrease of risk of recurrence of NTDs, while in the case of the other CSMs in this study, there is no noteworthy chronological change in their risk of recurrence. Copyright © 2007 John Wiley & Sons, Ltd.

Objective This study was conducted to evaluate the major demographic details, diagnostical and clinical features, as well as the risk of recurrence of cases with the major types of neural tube defects (NTD). We also examined the efficiency of ultrasonography based on autopsy examinations during 26 years. Methods The investigations were made into the sample of 743 NTD diagnosed between 1 January 1976 and 31 December 2002. A computerized database was used to sum up the available information about the individual cases; in addition to surveying the couples' major demographic details, we also had the opportunity to collect detailed information about the history, diagnostics (ultrasound) and outcome of the pregnancies as well as the results of the autopsies during the investigation. Results In the 743 cases of NTD, maternal and paternal median ages turned out to be 23.7 years (±5.22 years) and 28.7 years (±5.81 years), respectively. The male:female ratio was 0.78. Comparable samples of anencephaly and spina bifida allowed for the conclusion that a positive genetic history was equally often found while a positive obstetrical history was almost twice as common in anencephaly. The sensitivity of the maternal serum-alpha fetoprotein (AFP) screening test is the highest in anencephaly and lowest in encephalocele. While the majority of cases of anencephaly were diagnosed before the 24th gestational week, examples of diagnosing spina bifida and encephalocele at a later time could also be found. Among the associated malformations other than those of the central nervous system special mentioning should be made of fetal pyelectasia, cleft palate as well as diaphragmatic herniation. No pathological karyotypes were found in association with encephalocele or spina bifida, but anencephaly was accompanied with trisomy 21 and trisomy 18 in one case each. Anencephaly was found to have the highest risk of recurrence in both nervous system malformations and malformations other than those of the nervous system. Sonography proved to be the most reliable method in cases of enecephalocele. Conclusion The respective median values of maternal and paternal age show that aetas has no role in the occurrence of NTDs. NTDs are more common among girls. Positive genetic, obstetrical and medical findings are of great importance in the incidence of NTDs. Although reliable to only a limited extent, maternal serum-AFP tests are considered to be useful and necessary in screening NTDs, while sonography is the gold standard method in recognizing these frequent malformations. The knowledge of the eventual associated malformations is mainly important in certain cases of spina bifida, which may also yield a good post-natal prognosis. Our data obtained from the sample of 26 years also confirm that the periconceptional administration of folic acid reduces the incidence and risk of recurrence of NTDs. Copyright © 2007 John Wiley & Sons, Ltd.

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 the authors was to review the main characteristics of craniospinal 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 were obtained by prenatal ultrasonography and fetopathological investigations. In half of the latter 26 cases, induced abortion was suggested due to hydrocephalus confirmed by ultrasonography but not justified by autopsy or the autopsy revealed the presence of other craniospinal malformation(s). Conclusion: It can be concluded that – in view of the diagnostic efficiency of fetopathological investigations – the ultrasonographic diagnosis of hydrocephalus should be interpreted independently from other craniospinal malformations on the basis of principles of ultrasonographic methodology and at different times.

Purpose. To investigate the role of second-trimester sonographic examination in the prenatal diagnosis of trisomy 18. Methods. Out of 22,150 fetal chromosomal analyses performed between 1990 and 2004, 70 trisomy 18 fetuses were found. The sonographic findings of this aneuploidy were analyzed. Results. The average maternal age was 32.4 years; the average gestational age was 19.5 weeks. Major anomalies were seen in 61 (87.1%) of the 70 fetuses with trisomy 18; among these, cardiac anomalies were the most common (47.1%), with a 27.1% incidence of ventricular septal defects. Anomalies of the central nervous system were seen in 35.7% of cases; abnormal head shape was the most frequently detected anomaly in this group (12.9%). Fifty-six (80%) of the fetuses had at least 1 minor anomaly; of these, choroid plexus cyst was the most common (38.6%). Increased nuchal fold thickness was detected in 17.1% of cases. Conclusion. The vast majority of trisomy 18 fetuses have sonographically detectable abnormalities in the second trimester. Both the 87.1% frequency of major anomalies and the 80% frequency of minor anomalies are substantially higher than multiple biochemical marker tests could achieve. It was also demonstrated that fetal echocardiography plays a pivotal role in the diagnosis of trisomy 18. © 2006 Wiley Periodicals, Inc. J Clin Ultrasound 35:, 2007

Objective This study was conducted to evaluate the diagnostic value of different sonographic signs of fetuses with Turner syndrome in the first and second trimesters of pregnancy. Methods Between 1990 and 2004, Turner syndrome was found in 69 of 22,150 fetal karyotypings. Congenital anomalies detected by sonography were analyzed. Results Of the 514 (2.3%; 514/22,150) chromosome aberrations that were diagnosed, 69 Turner syndrome cases were found (13.4%; 69/514). Twenty-four fetuses had a 45,X karyotype (34.8%), and 45 fetuses were mosaic (65.2%). Forty-seven fetuses (68.1%; 47/69) showed symptoms on sonography. A substantial proportion of fetuses with Turner syndrome showed early-onset signs that could be detected in the first trimester (29.8%;14/69). The most common findings with sonography were hygroma colli (26.1%; 18/69), fetal hydrops (11.6%; 8/69), cardiac defects (13%; 9/69), and increased nuchal translucency (13%; 9/69). Among heart defects, coarctation of the aorta was the most common (44.4% of all cardial defects). Soft markers were also detected with relatively high frequency (23.2%; 16/69). Conclusions The diagnosis of severe Turner syndrome is possible in early pregnancy. A search for soft markers during second-trimester sonography and extensive use of echocardiography may increase the detection rate of Turner syndrome.

Objective The purpose of this study was to investigate the role of second-trimester sonographic examination in the prenatal diagnosis of trisomy 13. Methods Of 22,150 fetal chromosome analyses, 28 fetuses with trisomy 13 were found between 1990 and 2004. Sonographic findings of this aneuploidy were analyzed in this study. Results The average maternal age was 32.4 years; the average gestational age was 19.5 weeks. There was an 89.3% (n = 25) total prevalence of sonographic abnormalities in fetuses with trisomy 13 in this series. Major (structural) malformations were seen in 23 cases (82.1%), whereas minor anomalies were detected on sonography in 16 cases (57.1%). Although in 2 fetuses 1 minor anomaly was the only sonographic sign of trisomy 13, other cases with minor anomalies (87.5% [n = 14]) were multiplex malformations, in which combinations of major and minor anomalies were detected on sonography. The most frequently seen structural abnormalities were central nervous system and facial anomalies (64.3% [n = 18]). Among central nervous system anomalies, ventriculomegaly and holoprosencephaly were seen most frequently. Cardiovascular anomalies were detected in 53.6% (n = 15) of the fetuses with trisomy 13. This high frequency underlines the importance of echocardiography in diagnosing this aneuploidy. Among minor anomalies, increased nuchal translucency (21.4%) and echogenic bowel (17.9%) were the most common findings. Conclusions Second-trimester sonographic examination is capable of showing anomalies that are characteristic of trisomy 13; thus, the scan can indicate whether fetal karyotyping is advisable. Incorporation of careful assessment of the fetal cardiovascular system by sonography certainly increases the detection rate of trisomy 13.

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.

Objectives The isolation and analysis of fetal cells in maternal blood during pregnancy is under investigation as a means of noninvasive prenatal diagnosis. The aim of our study was to detect fetal gender from maternal peripherial blood samples during pregnancy with the detection and analysis of epsilon-haemoglobin-chain positive fetal nucleated red blood cells (NRBCs) collected by a micromanipulator. Here we report our first results. Design and Methods We obtained maternal blood from 14 singleton pregnancies. After a double density gradient separation, magnetic activated cell sorting was performed by positive selection for nucleated red blood cells with anti-CD71. With the help of this enrichment step, followed by immunophenotyping with an anti-haemoglobin-e monoclonal antibody, the isolation of the epsilon haemoglobin chain positive cells with micromanipulation could be done. We performed single cell fluorescent PCR analysis of these cells; we used primers for the amelogenin gene to detect fetal gender. We compared our findings with the results of amniocentesis. Results Fetal gender was successfully determined in 11 out of 14 cases; among them, in 2 cases with Klinefelter syndrome (47,XXY). Conclusion The results of our study suggest that micromanipulation and QF-PCR analysis of anti-haemoglobin-epsilon fluorescent antibody stained fetal cells from maternal blood can be useful in prenatal diagnosis to detect fetal gender and promising to be improved to detect chromosomal abnormalities. Copyright © 2005 John Wiley & Sons, Ltd.

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.

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.

Objective: To determine whether iliac wing angle measurement in second trimester fetuses is a useful sonographic marker for the detection of trisomy 21, 18 and 13. Methods: During the period between September 1998 and September 2001, 406 fetal iliac angle measurements were performed in women in the second trimester of their pregnancies. The iliac angle measurements in fetuses with trisomy 21 (n = 25), trisomy 18 (n = 10) and trisomy 13 (n = 5) were compared with iliac angle measurement in fetuses with normal karyotypes (n = 333). Results: The mean iliac wing angle in the fetuses with trisomy 21 was 92.67 and 79.35° and 74° in fetuses with trisomy 18 and 13 (the mean iliac wing angle in the healthy fetuses was 70.09°). Conclusion: The proven larger iliac wing angle in neonates with Down’s syndrome can be demonstrated sonographically during the pregnancy, especially during the second trimester, and may be useful in prenatal screening of trisomy 21. The sonographic measurement of the fetal iliac angle cannot be used as a marker for trisomy 18 and 13. We have shown that fetuses with trisomy 18 and 13, on average, have iliac angles only a few degrees larger than healthy fetuses.

The authors summarize the perinatal effects of the main genetic disorder groupings. Diseases of autosomal dominant inheritance are usually less severe and postnatal life is possible. Diseases of autosomal recessive inheritance are serious in most cases, causing severe symptoms in postnatal life. Diseases of X-linked recessive inheritance manifest themselves in male embryos and may be mild or serious; the more severe forms may influence the perinatal outcome. Diseases of X-linked dominant inheritance occur less frequently and manifest themselves in both sexes: in some cases the life expectancy is not favorable. Chromosomal anomalies, unbalanced rearrangements and autosomal trisomies may cause severe multiplex malformation syndromes and mental retardation. The diseases are serious in most cases and intrauterine mortality is high. Conversely, in cases of numerical differences of the sex chromosomes perinatal mortality does not increase remarkably, except in X-monosomy. Diseases of multifactorial origin lead to isolated malformations, but many civilization diseases originate from similar causes. In a few cases, severe diseases (i. e. congenital heart defects and neural tube defects) occur which may influence the outcome of the pregnancy. In terms of teratogenic effects, taking medication or undergoing X-ray examination or infections during early pregnancy indicates only a small risk in most cases. The authors emphasize that genetic centers significantly influence the perinatal outcome of pregnancies with their complex activity and their role in prenatal diagnostics.

Congenital malformations are more prevalent in twin than in singleton pregnancies. The rate of congenital heart malformations is higher in monozygotic than in dizygotic twin pairs, but concordance for anomalies in monozygotic twins is less than 20%. This retrospective analysis sought to confirm a connection between twin pregnancies and types of congenital heart malformations. The study group included 486 cases of prenatally diagnosed congenital heart disease: 455 in singleton pregnancies and 31 (6.4%) in 30 twin pairs. The types of cardiac defects in twins were compared with those in singletons. In monozygotic twins, 36% of cardiac malformations were pulmonary stenosis and 45% were endocardial fibroelastosis; both of these diagnoses were significantly more common in twins than in singleton fetuses (P = .0000018 and .0019, respectively). When dizygotic twins were compared with singletons, the only defect with a different incidence was Ebstein malformation, which was found in 25% of dizygotic twin pregnancies but in only 0.9% of singleton pregnancies. The overall rate of congenital heart disease was higher in monozygotic twins than in dizygotic or dichorionic twins. Twin pregnancy is, by itself, an indication for fetal echocardiography to detect congenital cardiac malformations. The investigators favor doing a fetal echocardiogram between 18 and 20 weeks gestation. The type of malformations found in monochorionic twin pregnancies differs from what is found in singleton, dizygotic, or dichorionic twin pregnancies.

Background One of the frequent reasons for unsuccessful conception is premature ovarian failure/primary ovarian insufficiency (POF/POI) that is defined as the loss of functional follicles below the age of 40 years. Among the genetic causes the most common one involves the X chromosome, as in Turner syndrome, partial X deletion and X-autosome translocations. Here we report a case of a 27-year-old female patient referred to genetic counselling because of premature ovarian failure. The aim of this case study to perform molecular genetic and cytogenetic analyses in order to identify the exact genetic background of the pathogenic phenotype. Results For premature ovarian failure disease diagnostics we performed the Fragile mental retardation 1 gene analysis using Southern blot technique and Repeat Primed PCR in order to identify the relationship between the Fragile mental retardation 1 gene premutation status and the premature ovarion failure disease. At this early onset, the premature ovarian failure affected patient we detected one normal allele of Fragile mental retardation 1 gene and we couldn’t verify the methylated allele, therefore we performed the cytogenetic analyses using G-banding and fluorescent in situ hybridization methods and a high resolution molecular cytogenetic method, the array comparative genomic hybridization technique. For this patient applying the G-banding, we identified a large deletion on the X chromosome at the critical region (ChrX q21.31-q28) which is associated with the premature ovarian failure phenotype. In order to detect the exact breakpoints, we used a special cytogenetic array ISCA plus CGH array and we verified a 67.355 Mb size loss at the critical region which include total 795 genes. Conclusions We conclude for this case study that the karyotyping is definitely helpful in the evaluation of premature ovarian failure patients, to identify the non submicroscopic chromosomal rearrangement, and using the array CGH technique we can contribute to the most efficient detection and mapping of exact deletion breakpoints of the deleted Xq region.

Background Showing a prevalence rate of 0.5-0.8%, urogenital malformations discovered in newborns is regarded relatively common. The aim of this study is to examine the efficacy of ultrasound diagnostics in detecting developmental disorders in the urogenital system. Methods We have processed the prenatal sonographic and postnatal clinical details of 175 urogenital abnormalities in 140 newborns delivered with urogenital malformation according to EUROCAT recommendations over a 5-year period between 2006 and 2010. The patients were divided into three groups; Group 1: prenatal sonography and postnatal examinations yielded fully identical results. Group 2: postnatally detected urogenital changes were partially discovered in prenatal investigations. Group 3: prenatal sonography failed to detect the urogenital malformation identified in postnatal examinations. Urogenital changes representing part of certain multiple disorders associated with chromosomal aberration were investigated separately. Results Prenatal sonographic diagnosis and postnatal results completely coincided in 45%, i.e. 63/140 of cases in newborns delivered with urogenital developmental disorders. In 34/140 cases (24%), discovery was partial, while in 43/140 patients (31%), no urogenital malformation was detected prenatally. No associated malformations were observed in 108 cases, in 57 of which (53%), the results of prenatal ultrasonography and postnatal examinations showed complete coincidence. Prenatally, urogenital changes were found in 11 patients (10%), whereas no urogenital disorders were diagnosed in 40 cases (37%) by investigations prior to birth. Urogenital disorders were found to represent part of multiple malformations in a total of 28 cases as follows: prenatal diagnosis of urogenital malformation and the findings of postnatal examinations completely coincided in three patients (11%), partial coincidence was found in 22 newborns (79%) and in another three patients (11%), the disorder was not detected prenatally. In four newborns, chromosomal aberration was associated with the urogenital disorder; 45,X karyotype was detected in two patients, trisomy 9 and trisomy 18 were found in one case each. Conclusion In approximately half of the cases, postnatally diagnosed abnormalities coincided with the prenatally discovered fetal urogenital developmental disorders. The results have confirmed that ultrasonography plays an important role in diagnosing urogenital malformations but it fails to detect all of the urogenital developmental abnormalities.