Phenotype to genotype characterization by array-comparative genomic hydridization (a-CGH) in case of fetal malformations: A systematic review.

The aim of the current review is to report a-CGH abnormalities identified in fetuses with prenatally diagnosed fetal malformations in whom a normal karyotype was diagnosed with conventional cytogenetic analysis. A systematic electronic search of databases (PubMed/Medline, EMBASE/SCOPUS) has been conducted from inception to May, 2017. Bibliographic analysis has been performed according to PRISMA statement for review. The following keywords were used: 'array-CGH' and 'fetal malformations" and "prenatal diagnosis"; alternatively, "microarray", "oligonucleotide array", "molecular biology", "antenatal diagnostics", "fetal diagnostics", "congenital malformations" and "ultrasound" were used to capture both "a-CGH" and "prenatal". One-hundred and twelve fetuses with prenatally diagnosed fetal malformations with normal karyotyping and a-CGH abnormalities detected are described. Single or multiple microarray abnormalities diagnosed have been classified in relation to different organ/system affected. The most frequent a-CGH abnormalities were detected in cases of congenital heart diseases (CDHs), multiple malformations and central nervous system (CNS) malformations. Maternal or paternal carrier-state was seen in 19.64% (22/112), of cases while the number of reported de novo mutations accounted for 46.42% (52/112) of all CNVs microarray abnormalities. Array-comparative genomic hydridization (a-CGH) may become an integral and complemantary genetic testing when fetal malformations are detected prenatally in fetuses with normal cytogenetic karyotype. In addition, a-CGH enables the identification of CNVs and VOUS and improves the calculation of recurrent risk and the genetic counseling.

Neurological Outcome in Fetuses with Mild and Moderate Ventriculomegaly.

Introduction Ventriculomegaly (VM) is one the most frequent anomalies detected on prenatal ultrasound. Magnetic resonance imaging (MRI) may enhance diagnostic accuracy and prediction of developmental outcome in newborns. Purpose The aim of this study was to assess the correlation between ultrasound and MRI in fetuses with isolated mild and moderate VM. The secondary aim was to report the neurodevelopmental outcome at 4 years of age. Methods Fetuses with a prenatal ultrasound (brain scan) diagnosis of VM were identified over a 4-year period. Ventriculomegaly was defined as an atrial width of 10-15 mm that was further divided as mild (10.1-12.0 mm) and moderate (12.1-15.0 mm). Fetuses with VM underwent antenatal as well as postnatal follow-ups by brain scan and MRI. Neurodevelopmental outcome was performed using the Griffiths Mental Development Scales and conducted, where indicated, until 4 years into the postnatal period. Results Sixty-two fetuses were identified. Ventriculomegaly was bilateral in 58% of cases. A stable dilatation was seen in 45% of cases, progression was seen in 13%, and regression of VM was seen in 4.5% respectively. Fetal MRI was performed in 54 fetuses and was concordant with brain scan findings in 85% of cases. Abnormal neurodevelopmental outcomes were seen in 9.6% of cases. Conclusion Fetuses in whom a progression of VM is seen are at a higher risk of developing an abnormal neurodevelopmental outcome. Although brain scan and MRI are substantially in agreement in defining the grade of ventricular dilatation, a low correlation was seen in the evaluation of VM associated with central nervous system (CNS) or non-CNS abnormalities.

Neurological Outcome in Fetuses with Mild and Moderate Ventriculomegaly / Resultado neurológico em fetos com ventriculomegalia leve e moderada

Abstract Introduction Ventriculomegaly (VM) is one the most frequent anomalies detected on prenatal ultrasound. Magnetic resonance imaging (MRI) may enhance diagnostic accuracy and prediction of developmental outcome in newborns. Purpose The aim of this study was to assess the correlation between ultrasound and MRI in fetuses with isolated mild and moderate VM. The secondary aim was to report the neurodevelopmental outcome at 4 years of age. Methods Fetuses with a prenatal ultrasound (brain scan) diagnosis of VM were identified over a 4-year period. Ventriculomegaly was defined as an atrial width of 10- 15 mm that was further divided as mild (10.1-12.0 mm) and moderate (12.1-15.0 mm). Fetuses with VM underwent antenatal as well as postnatal follow-ups by brain scan and MRI. Neurodevelopmental outcome was performed using the Griffiths Mental Development Scales and conducted, where indicated, until 4 years into the postnatal period. Results Sixty-two fetuses were identified. Ventriculomegaly was bilateral in 58% of cases. A stable dilatation was seen in 45% of cases, progression was seen in 13%, and regression of VM was seen in 4.5% respectively. Fetal MRI was performed in 54 fetuses and was concordant with brain scan findings in 85% of cases. Abnormal neurodevelopmental outcomes were seen in 9.6% of cases. Conclusion Fetuses in whom a progression of VM is seen are at a higher risk of developing an abnormal neurodevelopmental outcome. Although brain scan and MRI are substantially in agreement in defining the grade of ventricular dilatation, a low correlation was seen in the evaluation of VM associated with central nervous system (CNS) or non-CNS abnormalities.

Resumo Introdução Ventriculomegalia (VM) é uma das anomalias mais frequente no ultrassom pre-natal. Ressonâncias magnéticas (RM) melhoram a precisão do diagnóstico e previsão do desenvolvimento em recém-nascidos. Objetivo A proposta deste estudo foi avaliar a correlação entre ultrassom e RM em fetos com leve e moderada VM isolada. O objetivo secundário foi reportar o resultado neurológico na idade de 4 anos. Métodos Fetos com diagnóstico pré-natal pelo ultrassom de VM foram identificados na idade de 4 anos. Ventriculomegalia foi definida como medida do átrio do ventrículo lateral entre 10-15 mm, a qual foi subdividida em leve (10,1-12,0 mm) e moderada (12,1-15,0 mm). Fetos com VM foram seguidos nos períodos pré-natal e pós-natal por ultrassom e RM. O resultado neurológico foi realizado usando a escala de desenvolvimento mental de Griffiths, quando indicada, até a idade de 4 anos. Resultados Sessenta e dois fetos foram identificados. Ventriculomegalia bilateral ocorreu sem 58% dos casos. Uma dilatação estável foi observada em 45%, progressiva em 13% e regressiva em 4,5% dos casos, respectivamente. Ressonância magnética fetal foi realizada em 54 fetos, e foi concordante com os achados do ultrassom em 85% dos casos. Desenvolvimento neurológico anormal foi observado em 9,6% dos casos. Conclusão Fetos nos quais ocorreu progressão da VM são de alto risco para desenvolvimento neurológico anormal. Apesar do ultrassom e da RM mostrarem substancial concordância na definição do grau de dilatação ventricular, uma baixa correlação foi vista na avaliação da VM associada ou não com anomalias do sistema nervoso central.

Skeletal dysplasia with bowing long bones: Proposed flowchart for prenatal diagnosis with case demonstration.

OBJECTIVE: Skeletal dysplasia with bowing long bones is a rare group of multiple characterized congenital anomalies. MATERIALS AND METHODS: We introduce a simple, practical diagnostic flowchart that may be helpful in identifying the appropriate pathway of obstetrical management. RESULTS: Herein, we describe four fetal cases of bent bony dysplasia that focus on ultrasound findings, phenotype, molecular tests, distinctive X-ray features, and chondral growth plate histology. The first case was a typical campomelic dysplasia resulting from a de novo mutation in the SOX9 gene. The second fetus was affected by osteogenesis imperfecta Type II carrying a mutation in the COLA1 gene. The third case was a rare presentation of campomelic dysplasia, Cumming type, in which SOX9 examination was normal. Subsequently, a femoral hypoplasia unusual facies syndrome is also discussed. CONCLUSION: Targeted molecular tests and genetic counseling are required for supplementing ultrasound imaging in order to diagnose the correct skeletal disorders.

Early Detection of Cleft Lip by Three-Dimensional Transvaginal Ultrasound in Niche Mode in a Fetus With Trisomy 18 Diagnosed by Celocentesis.

Transabdominal ultrasound examination carried out at 11.3 weeks' gestation suggested the diagnosis of holoprosencephaly (HPE). Transvaginal three-dimensional (3D) scan performed using the niche-mode technique enabled diagnosis of HPE, hypotelorism, and cleft lip (CL). The fetus was diagnosed with trisomy 18 by means of transvaginal celocentesis at the time of pregnancy termination. Although prenatal diagnosis of orofacial cleft can be enhanced by 3D ultrasound, only a few cases have been detected early in pregnancy. Here, we report a first-trimester case in which 3D ultrasound in niche mode improved the antenatal diagnosis of CL. Early fetal karyotyping can be accomplished by celocentesis in these cases.

408 kb 15q11.2 microduplication by array comparative genomic hybridization in a fetus presenting with exomphalos, micrognathia, tetralogy of Fallot and normal karyotype: a genetic counseling dilemma in paternal carrier status.

Exomphalos may be associated with chromosomal abnormalities and syndromes. Severe exomphalos (herniation of liver, midgut and spleen) associated with increased nuchal translucency was seen at first trimester screening test. Karyotype by chorionic villus sampling showed normal male fetus. Follow up scan at 16 and 18 weeks of gestation confirmed the severe exomphalos and detected micrognathia and tetralogy of Fallot. Array comparative genomic hybridization (a-CGH) further demonstrated a 408 kb 15q11.2 microduplication, with the father-to-be as healthy carrier. This is the first case of an association between 15q11.2 micorduplication and fetal sonographic anomalies. Genetic counseling for estimation of recurrent risk of congenital anomalies is discussed.

Majewski syndrome (short-rib polydactyly syndrome type II): Prenatal diagnosis and histological features of chondral growth plate, liver and kidneys.

The Majewski syndrome or short rib-polydactyly syndrome (SRPS) type II is a lethal skeletal dysplasia characterized by severe IUGR (intrauterine growth restriction) and dysmorphic face, polydactyly, relatively proportionate head size at birth with later progression to microcephaly. A case of second trimester ultrasound diagnosis of SRPS type II is reported with review of the medical record of previous observed cases. Postmortem examination and radiogram confirmed the clinical diagnosis. Histological examination of the femoral epypheseal chondral plate showed an expanded and irregular hypertrophic zone. Moreover, characteristic cortico-medullary cysts of both kidneys and portal fibrosis were also demonstrated; findings consistent with the broad phenotypic spectrum of this rare skeletal disease.

Dysmorphic choroid plexuses and hydrocephalus associated with increased nuchal translucency: early ultrasound markers of de novo thanatophoric dysplasia type II with cloverleaf skull (Kleeblattschaedel).

Prenatal diagnosis of thanatophoric dysplasia (TD) type II presenting in the first trimester with increased nuchal translucency (NT) and cloverleaf skull (Kleeblattschaedel) have been scantly reported in the medical record. Abnormal choroid plexus has been seen in association with fetal anomalies. Here we described a case of increased NT associated with indented choroid plexuses, early onset hydrocephalus and cloverleaf skull in a fetus subsequently diagnosed at early second trimester to carry a de novo mutation encoding for TD type II. The findings of dysmorphic choroid plexus, early onset hydrocephalus and cloverleaf skull at first trimester scan may be early, useful ultrasound markers of TD type II. Molecular analysis to control for possible overlapping syndromes were performed and resulted negative. Postmortem X-ray and 3D-CT scan confirmed the cloverleaf skull, narrow thorax, straight femur with rhizomelic shortening of the limbs and the presence of a communicating hydrocephalus.

Follicular growth and oocyte maturation in GnRH agonist and antagonist protocols for in vitro fertilisation and embryo transfer.

BACKGROUND: The aim of this study was to evaluate the response to treatment in a group of patients undergoing IVF and randomised to receive GnRH-antagonist or the GnRH-agonist. The endpoints were the pattern of follicular growth, the maturity of the oocytes collected, the embryo quality and the pregnancy outcome. METHODS: A total of 136 patients undergoing IVF were included. Sixty-seven patients were allocated to the GnRH antagonist and 69 patients to the GnRH agonist. GnRH antagonist was administered when the leading follicle reached a diameter of 12-14 mm. GnRH agonist was administered in a long luteal protocol. RESULTS: The mean numbers of oocytes retrieved and mature oocytes were significantly higher in the agonist than in the antagonist group (p < 0.02 and p < 0.01, respectively). Embryo quality, implantation rate, clinical pregnancy rates, ongoing pregnancy rate and miscarriage rate were similar in both groups. CONCLUSIONS: Better follicular growth and oocyte maturation are achieved with GnRH agonist treatment. However, both regimens seem to have similar efficacy in terms of implantation and pregnancy rates. Further studies clarifying the effect of the GnRH antagonist on ovarian function are needed, as well as a clear definition of the best period of the follicular phase for the GnRH antagonist administration.

Intrauterine insemination with recombinant or urinary human chorionic gonadotropin: A prospective randomized trial.

AIM: Our aim was to compare the efficacy and safety of recombinant and urinary human chorionic gonadotropin (rhCG and uhCG, respectively) for the induction of follicle maturation in women undergoing intrauterine insemination (IUI). METHODS: Patients were randomized to receive rhCG or uhCG. IUI was carried out 24 h (day 1) and 48 h (day 2) after hCG administration, except for all cases in which ovulation occurred after 24 h. RESULTS: The two treatments were comparable in terms of progesterone levels on day 7 and day 12. Pregnancy rates were comparable between the treatment groups. Of the 64 women who received rhCG, 29.7% became pregnant; there were 16.7% clinical pregnancies and 3.1% biochemical pregnancies per started cycle, and an ongoing pregnancy rate of 93.7% was reported. Of the 61 patients who received uhCG, 24.6% became pregnant; there were 15.9% clinical pregnancies and 1.1% biochemical pregnancies per started cycle, and ongoing pregnancy rate was 92.9%. No adverse effects were noted in either group. CONCLUSION: The recombinant products can be effectively used instead of urinary products; moreover, apart from the equivalent efficacy in ovulation induction and safety described in this study, it is necessary to consider the advantages provided by the recombinant form.