[Prenatally detected aortic arch anomalies and their consequences after birth]. / Praenatalisan felismert magzati aortaív-rendellenességek és megszületés utáni következményeik.

INTRODUCTION: Aortic arch anomalies are frequently associated with cardiac or extracardiac malformations, chromosomal aberrations and postpartum esophagus/trachea compression. OBJECTIVE: We aimed to establish the prevalence of associated cardiac and extracardiac malformations, the frequency of chromosomal aberrations in fetuses with the diagnosis of aortic arch anomalies and to assess the pregnancy and the postnatal outcome. METHOD: Retrospective cohort study of all fetuses with aortic arch anomalies and genetic diagnosis in a tertiary referral obstetric and fetal cardiology centre between 2016 and 2020. Postpartum data were collected within 24 months after birth. RESULTS: In a cohort of 11.380 pregnant women, the prevalence of aortic arch anomalies was 0.25%. Among 28 cases of right aortic arch anomalies, in 27 fetuses prenatal genetic diagnosis was available. We diagnosed 4 fetuses with mirror-image branching (right sided V-sign) and 23 fetuses with U-sign (4 fetuses with complete double aortic arch). 18 cases (66%) were isolated. Associated anomalies were cardiac in 3 cases and extracardiac in 7 cases (33%). The most frequent cardiac anomaly was tetralogy of Fallot (2/27), the extracardiac anomalies were thymus hypoplasia, single umbilical artery and subclavian artery malformations. In 1 case (3.7%), fluorescent in situ hybridization diagnosed 22q11.2 microdeletion. 75% of fetuses with right sided V-sign were associated with conotruncal malformations. Pregnancy and postpartum outcome were known in 24 pregnancies. Postnatal diagnosis was different from prenatal in 2 cases, the concordance rate was 93%. Isolated cases resulted in live birth in 17/18 pregnancies (93%). The frequency of postpartum trachea/esophagus compression was 42,9% (9 cases) due to vascular ring, in 6 children (28,6%) operation was necessary. CONCLUSION: Fetal aortic arch anomalies are multidisciplinary diseases to be diagnosed by proper prenatal ultrasound examination. Associated fetal anomalies necessitate extended obstetric and cardiac sonography, invasive prenatal testing should be offered, and thorough postnatal long-term follow-up is recommended. Orv Hetil. 2023; 164(28): 1111-1120.

Genotype-phenotype correlation in a newborn with de novo 3p25 deletion syndrome / De novo 3p25-deletiós szindróma genotípus-fenotípus vizsgálata.

Összefoglaló. A 3p25-deletiós szindróma nagyon ritka genetikai rendellenesség, a nemzetközi szakirodalom jelenleg kevesebb mint 60 esetet ír le. A kórképre általánosan jellemzo a növekedési és pszichomotoros visszamaradottság, a microcephalia, a hypotonia, a veleszületett szívfejlodési rendellenesség, a ptosis és micrognathia, de nagyon ritkán elofordul klinikai tünetek nélküli megjelenése is. Általában újonnan kialakult rendellenesség, bár egyes esetekben elofordulhat familiáris formája. A kromoszomális töréspont változó helyen fordul elo. Közleményünkben egy 3p25-deletiós szindrómával született gyermek esetét mutatjuk be: a deletiót kariotipizálással és fluoreszcens in situ hibridizációval igazoltuk, majd microarray-komparatív genomhibridizálással meghatároztuk a pontos töréspontot és a hiányzó géneket. Az érintett régióban 43 OMIM-gént találtunk, melyek szerepet játszanak a megkésett pszichomotoros és növekedési elmaradásban, valamint az intellektuális zavarban. A genetikai háttér pontos karakterizálása hozzásegít a várható tünetek és a prognózis meghatározásához, egyben támpontot biztosíthat a jövobeli terápia tervezéséhez és a személyre szabott fejlesztés kivitelezéséhez. Orv Hetil. 2022; 163(12): 478-483. Summary. The 3p25 deletion syndrome is a very rare genetic abnormality, characterized by growth and psychomotor retardation, microcephaly, hypotonia, congenital heart defects, ptosis and micrognathia. Less than 60 cases have been published in the literature so far. However, a few patients with normal or mild phenotype have also been described. The majority of the cases are de novo mutations, with variable chromosomal breakpoints. We present the case of a newborn infant with 3p25 deletion syndrome, whose genetic analysis was done by karyotyping, fluorescent in situ hybridization and array comparative genomic hybridization. The latter method enabled us to define the precise breakpoint and the genes involved in the deletion, thus we could provide information for further clinical management. We identified 43 OMIM genes in the deleted region, which may have a causative effect on the pscychomotor and developmental delay and also on the intellectual disability. Exact cytogenomic characterisation of a rare genetic syndrome may allow to employ personalised treatment. Orv Hetil. 2022; 163(12): 478-483.

The significance of rare chromosomal abnormalities and fetoplacental mosaicism in prenatal diagnosis in the non-invasive prenatal testing era / A ritka kromoszóma-rendellenességek és a fetoplacentaris mozaikosság jelentosége a praenatalis diagnosztikában a nem invazív szurovizsgálatok tükrében.

Összefoglaló. Bevezetés és célkituzés: A gyakori autoszomális trisomiák és a nemi kromoszómaeltérések a mikroszkóppal észlelheto kromoszóma-rendellenességek kb. 80-85%-át képviselik. A ritka kromoszóma-rendellenességek klinikai következménye jelentos, kimutatásukat a jelenlegi szurovizsgálatok ugyan nem célozzák, de a teljes kromoszómaszerelvényt vizsgáló, nem invazív praenatalis tesztelés új lehetoséget nyitott a korai felismerésükre. Módszer: Retrospektív analízis (2014-2019) a mikroszkóppal kimutatható kromoszóma-rendellenességek eloszlására, a fetoplacentaris mozaikosság elofordulására, klinikai összefüggéseire a praenatalis vizsgálatok tükrében egy hazai tercier centrumban. Eredmények: 2504 invazív beavatkozást végeztünk és 200 kromoszómaeltérést mutattunk ki (8%), melyek közül újonnan kialakult, ritka rendellenesség 27 volt (13,5%). Ritka autoszomális trisomia 14, poliploidia 6, de novo szerkezeti kromoszómaeltérés 5, marker kromoszóma 2 esetben igazolódott. A fetoplacentaris mozaikosság aránya a gyakori/ritka kromoszómaeltérésekben 12,4%/77,8% volt (p = 0,001), 17/40 esetben lepényre korlátozódott. A gyakori trisomiákkal kóros tarkóredo-vastagság 58%-ban, major ultrahangeltérés 35%-ban társult, melyek jelentosen különböztek a ritka kromoszómaeltérésekben (11%, p = 0,006; 67%, p = 0,047). A ritka kromoszómaeltérések jellemzo praenatalis major ultrahangeltérése a facialis dysmorphismus volt. A teljes kromoszómaszerelvényt vizsgáló praenatalis tesztelés a ritka kromoszómaeltérések 12 lepényi mozaikos esetében (44%) feltételezhetoen álpozitív, 1 esetben (3,7%) álnegatív eredményt generált volna, miközben a ritka autoszomális trisomiák 2 esetében ultrahangeltérés nélkül is korán detektálta volna a ritka magzati kromoszómaeltérést (7,4%). Következtetés: A normális tarkóredo-vastagság esetén észlelt major ultrahangeltérések felhívhatják a figyelmet a döntoen mozaikos ritka kromoszóma-rendellenességekre. A teljes kromoszómaszerelvényt vizsgáló, nem invazív szuroteszt a korai diagnosztika alternatívája lehet, a mozaikosságból adódó álpozitív eredményekre azonban számítani kell. A fetoplacentaris mozaikosság ismerete fontos klinikai információt biztosít, mely befolyásolhatja a terhesség kimenetelét, a terhesség követésének módját. A pontos citogenetikai karakterizálás elengedhetetlen. Orv Hetil. 2021; 162(29): 1156-1165. INTRODUCTION AND OBJECTIVE: To determine the prevalence of microscopically visible de novo atypical chromosomal aberrations and fetoplacental mosaicism in a prenatal tertial referral center, and to investigate the maternal and fetal characteristics in connection with genomewide non-invasive prenatal screening. METHOD: Retrospective cohort study from 2014 to 2019 of pregnancies with invasive genetic analysis. RESULTS: In the cohort of 2504 cases, the proportion of CVS was 53.3%. We diagnosed 200 chromosomal aberrations (8%), including 13.5% of de novo rare chromosomal aberrations (14 rare autosomal trisomies, 6 polyploidies, 5 structural aberrations and 2 small supernumerary marker chromosomes). The rate of fetoplacental mosaicism was 12.4%/77.8% in common/atypical chromosomal aberrations (p = 0.001) and confined to placenta in 17/40 cases. Associated ultrasound abnormalities were abnormal nuchal translucency and major malformations in 58% and 35% with common trisomies and 11% (p = 0.006) and 67% (p = 0.047) with true mosaic cases of rare abnormalities, respectively. Major ultrasound malformation was facial dysmorphism with rare aberrations. Potential application of genomewide non-invasive prenatal test in atypical chromosomal aberrations presumably would have been false-positive in 12 cases (44%), false-negative in 1 case (3.7%), and would have early detected 2 cases of rare autosomal trisomies (7.4%) without ultrasound anomalies. CONCLUSION: Structural ultrasound malformations with normal nuchal translucency thickness may be indicative of rare chromosomal aberrations. Application of genomewide non-invasive prenatal test is an alternative of early diagnostic methods with a potential of discordant results due to mosaicism. Knowledge about the presence of fetoplacental mosaicism influences risk estimation and genetic counseling, detailed cytogenetic characterization is of utmost importance. Orv Hetil. 2021; 162(29): 1156-1165.

Trends in the prenatal diagnosis of trisomy 21 show younger maternal age and shift in the distribution of congenital heart disease over a 20-year period.

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.

Prenatal Diagnosis of 4q Terminal Deletion and Review of the Literature.

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.

[Chromosomal microarray comparative genome hybridization (arrayCGH) in prenatal settings. Proposal for Hungarian application in clinical practice]. / A microarray-komparatív genomhibridizálás (arrayCGH) praenatalis alkalmazása. Javaslat a hazai bevezetésre.

Invasive prenatal testing and conventional G-banding chromosome analysis have been considered to be the gold standard of fetal cytogenetic diagnosis. Standard karyotyping is, however, constrained by the limits of the resolution of using a microscope. The advantage of molecular karyotyping, array based methods is the evaluation of sub-microscopic copy number changes across the whole genome in a single analysis. The application of array comparative genome hybridization has greatly increased the detection of pathogenic chromosomal abnormalities in prenatal settings. Based on available data in the international literature of the last decade, the clinical utility of arrayCGH is the recognition of some 1-2% and 5-7% additional genetical information compared to metaphase karyotype alone in fetuses without ultrasound anomaly and in fetuses with ultrasonographically detected malformations, respectively. Thus arrayCGH improves the prenatal diagnosis of genetic abnormalities mainly in fetuses with structural sonographic findings. In the present paper we review the literature of chromosomal microarray and make a proposal for the application of the method in Hungarian prenatal genetical practice. Orv Hetil. 2019; 160(13): 484-493.

[Prenatally diagnosed case of Pallister‒Killian syndrome]. / Praenatalisan diagnosztizált Pallister­Killian-szindróma esete.

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.

Efficacy of Prenatal Ultrasound in Craniospinal Malformations According to Fetopathological and Postnatal Neonatological, Pathological Results.

OBJECTIVE: Our objective is to examine the effectiveness of prenatal ultrasound diagnosis of craniospinal malformations compared to postnatal neonatological and pathological findings. METHODS: Over a 7-year period, we preformed approximately 82.500 prenatal ultrasounds of 26.827 pregnancies. We detected 290 fetuses with 351 craniospinal malformations. RESULTS: Craniospinal abnormalities were found as a part of multiplex malformations in 84/290 cases: in 47/84 cases (55.95%) there was complete concurrence between prenatal and postnatal results. In 15/290 fetuses the craniospinal malformation was associated with chromosomal abnormalities. In 9/15 (60%) of these fetuses, malformations were fully diagnosed with ultrasound. Isolated craniospinal malformations occurred in 191/290 cases, in 162/191 (84.82%) the results of prenatal ultrasonography and postnatal or post abortion examinations showed complete concurrence. In addition to the 290 fetuses with craniospinal malformations, there were an additional 17 who were thought by ultrasound to have a craniospinal malformation, which could not be documented after birth (false positives). CONCLUSIONS: Prenatal ultrasound accurately diagnosed 218/290 (75,17%) craniospinal abnormalities, and partially defined the abnormalities in 9.66%, failed to detect abnormalities in 15.17%, with an approximate 0.06% false detection rate.