Search

Arthrogryposis, also termed arthrogryposis multiplex congenita, is a descriptive term for conditions with multiple congenital contractures (MCC). The etiology is extremely heterogeneous. More than 400 specific disorders have been identified so far, which may lead to or are associated with MCC and/or fetal hypo‐ and akinesia as a clinical sign. With improved sensitivity of prenatal ultrasound and expanding prenatal diagnostic options, clinicians are tasked with providing early detection in order to counsel the prospective parents regarding further prenatal diagnostic as well as management options. We summarize the most important knowledge to raise awareness for early detection in pregnancy. We review essential points for counseling when MCC is detected in order to provide answers to common questions, which, however, cannot replace interdisciplinary expert opinion in the individual case. Key points: What's already known about this topic? Arthrogryposis, also termed multiple congenital contractures, and fetal akinesia are often missed prenatally, but can be detected by ultrasound early when looked for.The etiology is extremely heterogeneous. There are a number of challenges for achieving a definite diagnosis during pregnancy and appropriately counsel parents for prognosis and management. What does this review add? This review serves as an update for prenatal providers who are charged with detecting, diagnosing and counseling on congenital contractures and/or fetal akinesia prenatally.This article is not a substitute for interdisciplinary expert opinion, consultation and counseling in the individual patient or family. [ABSTRACT FROM AUTHOR]

New genomic laboratory technology namely microarrays and high throughput sequencing (HTS) as well as a steady progress in sonographic image capture and processing have changed the practice of prenatal diagnosis during the last decade fundamentally. Pregnancies at high risk for common trisomies are reliably identified by non-invasive prenatal testing (NIPT) and expert sonography has greatly improved the assessment of the fetal phenotype. Preconceptional comprehensive carrier screening using HTS is available for all parents, if they should wish to do so. A definite fetal diagnosis, however, will still require invasive testing for most conditions. Chromosomal microarrays (CMA) have greatly enhanced the resolution in the detection of chromosome anomalies and other causal copy number variations (CNV). Gene panel or whole exome sequencing (WES) is becoming the routine follow up of many anomalies detected by ultrasound after CNVs have been excluded. The benefits and limitations of the various screening as well as diagnostic options are perceived as complex by many who find it challenging to cope with the need for immediate choices. The communication of facts to ensure an informed decision making is obviously a growing challenge with the advent of the new genomic testing options. This contribution provides an overview of the current practice and policies in Switzerland. [ABSTRACT FROM AUTHOR]

Abstract Objective To describe the diagnostic performance of array comparative genomic hybridization (aCGH) as a potential first line diagnostic method in first trimester high risk pregnancies. Method In a retrospective study we performed aCGH using a targeted array BAC platform (Constitutional Chip® 4.0, PerkinElmer, Turku Finland, median resolution 600 kB) and the Affymetrix Cytogenetics® Whole Genome 2.7 M array (at a resolution of 400kB) on 100 anonymized prenatal samples from first trimester high risk pregnancies with normal conventional karyotype. We studied the technical feasibility and turn-around-time as well as the detection rate of pathogenic submicroscopic chromosome anomalies and CNVs of unknown significance. Results We obtained results in 98 of 100 samples in 3 to a maximum of 5 days after DNA extraction. At the given resolution we did not identify any additional pathogenic CNVs but two CNVs of unknown significance in the chromosomal regions 1q21.1q21.2 (deletion) and 5p15.33 (duplication) (2%). Conclusion In accordance with a growing number of reports this study supports the concept that aCGH at a resolution of 400-600kB may be used as a first line prenatal diagnostic test with high diagnostic safety and rapid turn-around time in high-risk first trimester pregnancies. Detection rate of CNVs of unknown significance, considered as a major hindrance for replacing conventional karyotyping by aCGH, is 2%, but the diagnosis of additional submicroscopic anomalies in this heterogeneous group of patients seems to be rare.

Abstract Preeclampsia is a leading cause of maternal and fetal/neonatal mortality and morbidity worldwide. The early identification of patients with an increased risk for preeclampsia is therefore one of the most important goals in obstetrics. The availability of highly sensitive and specific physiologic and biochemical markers would allow not only the detection of patients at risk but also permit a close surveillance, an exact diagnosis, timely intervention (e.g. lung maturation), as well as simplified recruitment for future studies looking at therapeutic medications and additional prospective markers. Today, several markers may offer the potential to be used, most likely in a combinatory analysis, as predictors or diagnostic tools. We present here the current knowledge on the biology of preeclampsia and review several biochemical markers which may be used to monitor preeclampsia in a future, that, we hope, is not to distant from today.

Background: Agnathia‐otocephaly is a rare and lethal anomaly affecting craniofacial structures derived from the first pharyngeal arch. It is characterized by agnathia, microstomia, aglossia, and abnormally positioned auricles with or without associated anomalies. Variants affecting function of OTX2 and PRRX1, which together regulate the neural crest cells and the patterning of the first pharyngeal arch as well as skeletal and limb development, were identified to be causal for the anomaly in a few patients. Methods: Family‐based exome sequencing (ES) on a fetus with severe agnathia‐otocephaly, cheilognathopalatoschisis, laryngeal hypoplasia, fused lung lobes and other organ abnormalities and mRNA expression analysis were performed. Results: Exome sequencing detected a de novo SMAD3 missense variant in exon 6 (c.860G>A) associated with decreased mRNA expression. Variants in SMAD3 cause Loeys–Dietz syndrome 3 presenting with craniofacial anomalies such as mandibular hypoplasia, micro‐ or retro‐gnathia, bifid uvula and cleft palate as well as skeletal anomalies and arterial tortuosity. The SMAD3 protein acts as a transcriptional regulator in the transforming growth factor β (TGFB) and bone morphogenetic (BMP) signaling pathways, which play a key role in the development of craniofacial structures originating from the pharyngeal arches. Conclusion: Agnathia‐otocephaly with or without associated anomalies may represent the severe end of a phenotypic spectrum related to variants in genes in the interacting SMAD/TGFB/BMP/SHH/FGF developmental pathways. [ABSTRACT FROM AUTHOR]

Objective: Preoperative assessment of adnexal masses with ultrasound has been shown to be time-, cost-effective, and specific. When used in combination with the menopausal status and the tumor marker CA125, the risk of malignancy index (RMI) can be calculated, allowing appropriate preoperative triage of patients to a gynecologist or a gynecological oncologist. Moreover, it allows for accurate planning of the required surgical procedure (laparoscopy vs laparotomy). Methods: A large general gynecologic ultrasonic database retrospectively identified 5218 patients for a 14-year period who presented to the outpatient clinic with an adnexal mass. Additional data (menopausal status, histology, CA125 values) were available in 1108 of these patients. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated. The results were then compared with previously published data from a large Australian gynecological cancer center (GCC, n = 204). Results: With the use of an RMI cutoff of 200, malignant ovarian tumors were correctly triaged to a gynecologic oncologist in 123 of 172 cases, leading to a sensitivity of 72% and specificity of 92% in our general outpatient clinic population compared with a sensitivity of 84% and a specificity of 77% in the GCC high-risk population. The negative predictive value was 95% compared with only 85%in theGCC cohort. We hypothesize that improvement of the overall detection rate of malignancy could be improved from 72%to 85% using a 2-step model, referring patients with an ultrasonic score of 3 to an experienced sonographer who uses pattern recognition. Conclusions: The RMI is an easy and reliable tool for the accurate triage of adnexal masses. Its value is higher in an unselected gynecological outpatient setting. Our proposed 2-step model including expert pattern recognition could influence particularly the detection rate in borderline and early-stage ovarian cancers and overcome the limitations of the tumor marker CA125. [ABSTRACT FROM AUTHOR]

Microarrays have replaced conventional karyotyping as a first-tier test for unbalanced chromosome anomalies in postnatal cytogenetics mainly due to their unprecedented resolution facilitating the detection of submicroscopic copy number changes at a rate of 10-20% depending on indication for testing. A number of studies have addressed the performance of microarrays for chromosome analyses in high risk pregnancies due to abnormal ultrasound findings and reported an excess detection rate between 5% and 10%. In low risk pregnancies, clear pathogenic copy number changes at the submicroscopic level were encountered in 1% or less. Variants of unclear clinical significance, unsolicited findings, and copy number changes with variable phenotypic consequences are the main issues of concern in the prenatal setting posing difficult management questions. The benefit of microarray testing may be limited in pregnancies with only moderately increased risks (advanced maternal age, positive first trimester test). It is suggested to not change the current policy of microarray application in prenatal diagnosis until more data on the clinical significance of copy number changes are available. [ABSTRACT FROM AUTHOR]

Currently no specific biomarkers exist for the screening of pregnancies at risk for down syndrome (DS). Since a quantitative proteomic approach with isobaric labelling (iTRAQ) has recently been suggested to be highly suitable for the discovery of novel plasma biomarkers, we have now used this method to examine for potential quantitative changes in the plasma proteome of the pregnancies bearing DS fetuses in comparison to normal healthy babies. In our study, we used plasma from six women with DS pregnancies and six with uncomplicated pregnancies care were taken to match cases and controls for gestational and maternal age, as these could be a confounder. In our quantitative proteomics analysis we were able to detect 178 proteins using iTRAQ labelling in conjunction with 4800 MALDI TOF/TOF. Amongst these we observed changes in βHCG, a known screening marker for DS, indicating that our assay was functional. We found a number of elevated proteins Ig lambda chain C region, serum amyloid Pcomponent, amyloid beta A4, and under expressed proteins like gamma-actin and titin in DS pregnancies. These proteins are also found in the sera of patients with Alzheimer disease, which share similar pathologies of DS. Our study therefore indicates that the iTRAQ labelling approach may be indeed useful for the detection of novel biomarkers. [ABSTRACT FROM AUTHOR]

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Combined first-trimester screening (FTS) and noninvasive prenatal testing (NIPT) have been proven to be reliable noninvasive procedures to detect the most common chromosomal abnormalities (trisomies 21, 18, 13) in the first trimester. The aim of this paper is to demonstrate the strengths and limitations of these two procedures and to give a consensus statement of the Fetal Medicine Foundation (FMF) Germany on how to use the two techniques in the first trimester after the introduction of NIPT as a service of the statutory health insurance companies in Germany., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: The authors declare that they have no conflict of interest.

First-trimester screening between 11 + 0 and 13 + 6 weeks with qualified prenatal counseling, detailed ultrasound, biochemical markers and maternal factors has become the basis for decisions about further examinations. It detects numerous structural and genetic anomalies. The inclusion of uterine artery Doppler and PlGF screens for preeclampsia and fetal growth restriction. Low-dose aspirin significantly reduces the prevalence of severe preterm eclampsia. Cut-off values define groups of high, intermediate and low probability. Prenatal counseling uses detection and false-positive rates to work out the individual need profile and the corresponding decision: no further diagnosis/screening - cell-free DNA screening - diagnostic procedure and genetic analysis. In pre-test counseling it must be recognized that the prevalence of trisomy 21, 18 or 13 is low in younger women, as in submicroscopic anomalies in every maternal age. Even with high specificities, the positive predictive values of screening tests for rare anomalies are low. In the general population trisomies and sex chromosome aneuploidies account for approximately 70 % of anomalies recognizable by conventional genetic analysis. Screen positive results of cfDNA tests have to be proven by diagnostic procedure and genetic diagnosis. In cases of inconclusive results a higher rate of genetic anomalies is detected. Procedure-related fetal loss rates after chorionic biopsy and amniocentesis performed by experts are lower than 1 to 2 in 1000. Counseling should include the possible detection of submicroscopic anomalies by comparative genomic hybridization (array-CGH). At present, existing studies about screening for microdeletions and duplications do not provide reliable data to calculate sensitivities, false-positive rates and positive predictive values., Competing Interests: U Gembruch participated 2013 – 2015 in a clinical follow-up study on PraenaTest supported by LifeCodexx.KO Kagan runs a prospective study on cfDNA supported by Ariosa.T Schramm is member of Scientic Advisory Board at GE Healthcare Viewpoint., (© Georg Thieme Verlag KG Stuttgart · New York.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work., (© Georg Thieme Verlag KG Stuttgart · New York.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work., (© Georg Thieme Verlag KG Stuttgart · New York.)

Records of 24 pregnancies with fetal polydactyly were reviewed for the type of polydactyly, family history, associated sonographic findings, genetic testing, and postnatal/postmortem examination findings. The importance of fetal polydactyly can be mainly elucidated by the family history and absent or associated anomalies on a specialized malformation scan. Fetal karyotyping diagnoses frequent chromosomal anomalies in about half of cases with additional malformations, and array comparative genomic hybridization may be a future means of detecting cryptic chromosomal aberrations. Syndromic disorders of monogenic origin demand a careful interdisciplinary clinical assessment for establishing a clinical diagnosis and prognosis for the outcome of the child.