Multiple Structural Anomalies Research Articles

The role of genetic testing in adult patients with unexplained epilepsy.

Genetic causes are often overlooked in patients with epilepsy of unknown etiology, particularly in adults. We aimed to evaluate clinical features of genetic epilepsy and the utility of genetic testing. We retrospectively screened consecutive unrelated adult epilepsy patients at an epilepsy clinic from April 2022 to May 2023. Patients with unknown etiology or special brain lesions were classified as unexplained epilepsy. In them, patients with young-onset seizures or family history of seizures who were recommended for and ultimately underwent genetic testing using either panel next-generation sequencing (NGS) or whole-exome sequencing (WES) were enrolled. A definite or probable genetic diagnosis was established through genotype-phenotype correlation. We compared the demographic characteristics between genetic epilepsy and other etiologies. Of the 374 adult epilepsy patients, 258 were classified as unexplained epilepsy, 129 were suspected of having genetic epilepsy due to young-onset seizures or a positive family history, 33 underwent genetic testing; 13 harbored variants classified as pathogenic, and 6 reached a definite genetic diagnosis, resulting in a yield of 18%. Among the 27 patients without a definite genetic diagnosis, 7 had a nongenetic structural etiology. Patients with genetic etiology exhibited greater multisystem involvement particularly multiple structural anomalies and early childhood-onset seizures, but wasn't directly correlated with young-onset seizures or a positive family history. The diagnostic yield was comparable between panel NGS and WES. In adult patients with unexplained epilepsy, genetic epilepsy is more associated with multisystem involvement and multiple structural anomalies but not family history of seizures or young-onset seizures.

Structured Framework for Multidisciplinary Parent Counseling and Medical Interventions for Fetuses and Infants with Trisomy 13 or Trisomy 18.

Trisomy 13 (T13) and 18 (T18) are aneuploidies associated with multiple structural congenital anomalies and high rates of fetal demise and neonatal mortality. Historically, patients with either one of these diagnoses have been treated similarly with exclusive comfort care rather than invasive interventions or intensive care, despite a wide phenotypic variation and substantial variations in survival length. However, surgical interventions have been on the rise in this population in recent years without clearly elucidated selection criterion. Our objective was to create a standardized approach to counseling expectant persons and parents of newborns with T13/T18 in order to provide collaborative and consistent counseling and thoughtful approach to interventions such as surgery. This article describes our process and presents our resulting clinical care guideline. We formed a multi- and interdisciplinary committee. We used published literature when available and otherwise expert opinion to develop an approach to care featuring individualized assessment of the patient to estimate qualitative mortality risk and potential to benefit from intensive care and/or surgeries centered within an ethical framework. Through multidisciplinary collaboration, we successfully created a patient-centered approach for counseling families facing a diagnosis of T13/T18. Other institutions may use our approach as a model for developing their own standardized approach. · Trisomy 13 and trisomy 18 are associated with high but variable morbidity and mortality.. · Research on which patients are most likely to benefit from surgery is lacking.. · We present our institution's framework to counsel families with fetal/neonatal T13/T18..

A non-coding insertional mutation of Grhl2 causes gene over-expression and multiple structural anomalies including cleft palate, spina bifida and encephalocele.

Orofacial clefts, including cleft lip and palate (CL/P) and neural tube defects (NTDs) are among the most common congenital anomalies, but knowledge of the genetic basis of these conditions remains incomplete. The extent to which genetic risk factors are shared between CL/P, NTDs and related anomalies is also unclear. While identification of causative genes has largely focused on coding and loss of function mutations, it is hypothesized that regulatory mutations account for a portion of the unidentified heritability. We found that excess expression of Grainyhead-like 2 (Grhl2) causes not only spinal NTDs in Axial defects (Axd) mice but also multiple additional defects affecting the cranial region. These include orofacial clefts comprising midline cleft lip and palate and abnormalities of the craniofacial bones and frontal and/or basal encephalocele, in which brain tissue herniates through the cranium or into the nasal cavity. To investigate the causative mutation in the Grhl2Axd strain, whole genome sequencing identified an approximately 4kb LTR retrotransposon insertion that disrupts the non-coding regulatory region, lying approximately 300 base pairs upstream of the 5' UTR. This insertion also lies within a predicted long non-coding RNA, oriented on the reverse strand, which like Grhl2 is over-expressed in Axd (Grhl2Axd) homozygous mutant embryos. Initial analysis of the GRHL2 upstream region in individuals with NTDs or cleft palate revealed rare or novel variants in a small number of cases. We hypothesize that mutations affecting the regulation of GRHL2 may contribute to craniofacial anomalies and NTDs in humans.

Partial Molar Pregnancy Coexisting with a Normal Diploid Fetus: A Case Report

Introduction: A partial molar pregnancy is a variation of a molar pregnancy in which an embryo either develops incompletely or with multiple structural anomalies. The aim of this study was to present a rare case of partial molar pregnancy coexisting with a normal diploid fetus. Case presentation: A 32-year-old woman with gravid 3, Para 2 (2 previous cesarean sections) was referred to Ghaem hospital, an academic hospital of Mashhad University of Medical Sciences, Mashhad, Iran, in 2020 at 34 weeks of gestation due to labor pain. She had an ultrasound-based diagnosis of partial molar pregnancy with the normal female fetus at 30 weeks for the first time. Due to 2 previous cesarean sections and regular uterine contractions, she underwent a cesarean section at 34 weeks and 2 days. A normal female infant with a normal Apgar score was born. The postpartum period was complicated with preeclampsia. The pathological evaluation confirmed partial molar pregnancy. The neonatal Karyotype was 46 XX and the neonatal period was uneventful. Maternal serum β-hCG reached normal after 5 weeks of cesarean. Conclusion: Partial molar pregnancy with the coexisting normal fetus is a rare condition; however, it may complicate the pregnancy outcomes, which affect both mother and fetus. So early diagnosis and close follow-up may prevent catastrophic maternal and fetal complications.

Molecular Approaches in Fetal Malformations, Dynamic Anomalies and Soft Markers: Diagnostic Rates and Challenges-Systematic Review of the Literature and Meta-Analysis.

Fetal malformations occur in 2–3% of pregnancies. They require invasive procedures for cytogenetics and molecular testing. “Structural anomalies” include non-transient anatomic alterations. “Soft markers” are often transient minor ultrasound findings. Anomalies not fitting these definitions are categorized as “dynamic”. This meta-analysis aims to evaluate the diagnostic yield and the rates of variants of uncertain significance (VUSs) in fetuses undergoing molecular testing (chromosomal microarray (CMA), exome sequencing (ES), genome sequencing (WGS)) due to ultrasound findings. The CMA diagnostic yield was 2.15% in single soft markers (vs. 0.79% baseline risk), 3.44% in multiple soft markers, 3.66% in single structural anomalies and 8.57% in multiple structural anomalies. Rates for specific subcategories vary significantly. ES showed a diagnostic rate of 19.47%, reaching 27.47% in multiple structural anomalies. WGS data did not allow meta-analysis. In fetal structural anomalies, CMA is a first-tier test, but should be integrated with karyotype and parental segregations. In this class of fetuses, ES presents a very high incremental yield, with a significant VUSs burden, so we encourage its use in selected cases. Soft markers present heterogeneous CMA results from each other, some of them with risks comparable to structural anomalies, and would benefit from molecular analysis. The diagnostic rate of multiple soft markers poses a solid indication to CMA.

Anesthetic Challenges in an Infant with Multiple Structural Airway Anomalies

Airway anomalies such as laryngomalacia, laryngeal webs, micrognathia, and retrognathia cause respiratory distress in infants and pose a significant challenge in anesthetic management. We report the case of a 2-month-old infant with laryngomalacia on continuous positive airway pressure support since birth, posted for laryngeal surgery, who was found to have micro-retrognathia during pre anaesthesia checkup. Securing the airway and preventing hypoxia were the main challenges in this child. Adequate measures were taken for continuous oxygenation during induction of anesthesia. The child underwent supraglottoplasty with an uneventful intraoperative course. However, the airway obstruction persisted in the postoperative period requiring a surgical tracheostomy. The child subsequently underwent mandibular distraction surgery after 1 month and was discharged with a tracheostomy tube. Although various anesthetic options have been described to manage the difficult pediatric airway, the anesthetic technique should be customized to ensure airway patency and oxygenation in the perioperative period as illustrated in this case report.

Peters plus syndrome mutations affect the function and stability of human β1,3-glucosyltransferase

Peters Plus Syndrome (PTRPLS OMIM #261540) is a severe congenital disorder of glycosylation where patients have multiple structural anomalies, including Peters anomaly of the eye (anterior segment dysgenesis), disproportionate short stature, brachydactyly, dysmorphic facial features, developmental delay, and variable additional abnormalities. PTRPLS patients and some Peters Plus-like (PTRPLS-like) patients (who only have a subset of PTRPLS phenotypes, have mutations in the gene encoding β1,3-glucosyltransferase [B3GLCT]). B3GLCT catalyzes the transfer of glucose to O-linked fucose on thrombospondin type-1 repeats. Most B3GLCT substrate proteins belong to the ADAMTS superfamily and play critical roles in extracellular matrix. We sought to determine whether the PTRPLS or PTRPLS-like mutations abrogated B3GLCT activity. B3GLCT has two putative active sites, one in the N-terminal region and the other in the C-terminal glycosyltransferase domain. Using sequence analysis and in vitro activity assays, we demonstrated that the C-terminal domain catalyzes transfer of glucose to O-linked fucose. We also generated a homology model of B3GLCT and identified D421 as the catalytic base. PTRPLS and PTRPLS-like mutations were individually introduced into B3GLCT, and the mutated enzymes were evaluated using in vitro enzyme assays and cell-based functional assays. Our results demonstrated that PTRPLS mutations caused loss of B3GLCT enzymatic activity and/or significantly reduced protein stability. In contrast, B3GLCT with PTRPLS-like mutations retained enzymatic activity, although some showed a minor destabilizing effect. Overall, our data supports the hypothesis that loss of glucose from B3GLCT substrate proteins is responsible for the defects observed in PTRPLS patients, but not for those observed in PTRPLS-like patients.

1027 Diagnostic yield of exome sequencing in prenatal diagnosis

Exome sequencing (ES) is increasingly utilized for prenatal evaluation of sonographic structural anomalies. Given high costs, identifying cases most likely to yield a diagnosis is warranted. We hypothesize that the diagnostic yield of ES varies by number and type of fetal anomalies. We analyzed two cohorts of fetuses that underwent ES due to one or more structural anomalies or nonimmune hydrops. The diagnostic yield (pathogenic or likely pathogenic (P/LP) variants) was compared in fetuses with one structural anomaly, multiple structural anomalies, and effusions or nonimmune hydrops (NIHF) with or without a concurrent structural anomaly. Cases with a single structural anomaly + polyhydramnios or growth restriction (FGR) were categorized as multiple anomalies, and cases with an effusion or NIHF and a structural anomaly were categorized as hydrops. We also compared the proportion of variants of uncertain significance that were thought to potentially be associated with the phenotype across these subgroups (VUS). Chi square or Fisher’s exact test compared proportions and logistic regression generated odds ratios. The cohort included 315 pregnancies with median age 33 years (IQR 29-36), 45.1% (142/315) nulliparous, and median gestational age at diagnosis of anomaly of 22.3 weeks (IQR 20.0-25.7). In all, 19.7% (62/315) had a single structural anomaly, 25.4% (80/315) had multiple anomalies, and 54.9% (173/315) had effusions/NIHF. The overall diagnostic yield of ES was 22.9% (72/315). The yield for isolated anomalies was 16.1% (10/62), for multiple anomalies was 17.5% (14/80), and for effusions/NIHF was 27.8% (48/173) (p=0.07) (Table). The OR for diagnostic yield of ES (P/LP) for multiple anomalies vs a single anomaly was 1.31 (95% CI 0.54-3.16) and for effusions/NIHF vs a single anomaly was 1.47 (95% CI 1.03-2.11). The diagnostic yields of ES for single or multiple structural anomalies are similar, while the yield in cases of NIHF is higher. Further study is needed to identify optimal candidates for prenatal ES.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Prenatal array comparative genomic hybridization in a well-defined cohort of high-risk pregnancies. A 3-year implementation results in a public tertiary academic referral hospital.

To find out whether the diagnostic yield of prenatal array comparative genomic hybridization (aCGH) can be improved by targeting preselected high-risk pregnancies. All the in-house arrays ordered by the Fetomaternal Medical Center from February 2016 until December 2018 were retrospectively analyzed. The indications for array analysis included fetal structural abnormalities, increased nuchal translucency ≥3.5mm and a chromosomal abnormality in a parent or a sibling. Common aneuploidies were excluded. Diagnostic yield was 15.1% in the entire patient cohort and as high as 20% in fetuses with multiple structural anomalies. The diagnostic yield was lowest in the group with isolated growth retardation. A total of 76 copy number variants (CNVs) were reported from a total of 65 samples, including 16 CNVs associated with a well-described microdeletion/microduplication syndrome, six autosomal trisomies in mosaic form, and three pathogenic single-gene deletions with dominant inheritance and 12 CNVs known to be risk factors for eg developmental delay. The diagnostic yield of aCGH was higher than what has previously been reported in less defined patient cohorts. However, the number of CNVs with unclear correlation to the fetal ultrasound findings was still relatively high. The importance of adequate pre- and posttest counseling must therefore be emphasized.

Genetic analysis of children with congenital ocular anomalies in three ecological regions of Nepal: a phase II of Nepal pediatric ocular diseases study

BackgroundGenetic eye diseases constitute a large and heterogeneous group of childhood ocular morbidity. Individual diseases may cause multiple structural anomalies and developmental features. Nepal Pediatric Ocular Disease Study (NPODS) was a population-based epidemiological study conducted across three ecological regions of Nepal to determine the prevalence and etiology of childhood ocular morbidity and blindness. In Phase II of this study, genetic analysis was performed for children who were found to have congenital ocular anomalies.MethodIt was a cross sectional descriptive study. A total of 10,270 children across three different ecological regions in Nepal (Low lands, hills, and mountains) underwent ocular examinations in NPODS. Out of 374 (3.6%) of children with ocular abnormalities, 30 were thought to be congenital in nature. Targeted genetic analysis, including genotyping for genes specific to presenting phenotype, was performed for 25 children using serum samples.ResultsOut of 25 children, 18 had meaningful genetic results. Analysis revealed one missense alteration G12411T of Zinc Finger Homeobox 4 (ZFHX4) gene in one participant among 10 with congenital ptosis and another missense variation T > C P. Y374 C of Signaling Receptor and Transporter Retinol 6 (STRA6) gene in one participant among 3 with microphthalmos.ConclusionThe study is first of its kind from Nepal and mutant genes were unique to Nepalese Population. Further analysis of genetic factors is crucial to better understand genetic association with ocular diseases and conditions. This helps further in genetic counseling and probably gene therapy to prevent blindness from these conditions.

Fetal Phenotype and Prenatal Diagnosis of Kabuki Syndrome

Abstract Kabuki syndrome (MIM 147920) is an autosomal dominant rare disease featured with multiple malformations and mental retardation. The main clinical manifestations of Kabuki syndrome are characteristic facial features, skeletal abnormalities, dermatoglyphic abnormalities, postpartum growth retardation, mild to moderate mental retardation, as well as other structural and functional abnormalities that may involve multiple systems. The establishment of diagnosis needs to be combined with clinical phenotype and the discovery of pathogenic mutation. Compared with the abundant descriptions and records of genotype-phenotype of postpartum patients, few prenatal diagnosis cases of Kabuki syndrome had been reported, which partially result from lacking the knowledge of its phenotype in fetuses that might suggest the diagnosis. This report performed comprehensive prenatal examinations to identify a fetus's etiology with multiple structural anomalies characterized by ascites, thickening of local skin, and cardiac abnormalities. We ruled out intrauterine infection, thalassemia, and chromosome abnormality by corresponding tests. Finally, trio whole-exome sequencing revealed a de novo heterozygous variation c.15641g > A (p.r5214h) in exon 48 of the KMT2D gene was the fetus's genetic pathogeny causing Kabuki syndrome. This result suggests that Kabuki syndrome should be in the suspected etiology list for prenatal hydrops/ascites. Our study confirmed that prenatal whole-exome sequencing is an efficient tool for diagnosing fetal abnormalities, and a multidisciplinary team is necessary for providing pregnancy guidance to patients.

Rapid whole exome sequencing in pregnancies to identify the underlying genetic cause in fetuses with congenital anomalies detected by ultrasound imaging.

ObjectiveThe purpose of this study was to explore the diagnostic yield and clinical utility of trio‐based rapid whole exome sequencing (rWES) in pregnancies of fetuses with a wide range of congenital anomalies detected by ultrasound imaging.MethodsIn this observational study, we analyzed the first 54 cases referred to our laboratory for prenatal rWES to support clinical decision making, after the sonographic detection of fetal congenital anomalies. The most common identified congenital anomalies were skeletal dysplasia (n = 20), multiple major fetal congenital anomalies (n = 17) and intracerebral structural anomalies (n = 7).ResultsA conclusive diagnosis was identified in 18 of the 54 cases (33%). Pathogenic variants were detected most often in fetuses with skeletal dysplasia (n = 11) followed by fetuses with multiple major fetal congenital anomalies (n = 4) and intracerebral structural anomalies (n = 3). A survey, completed by the physicians for 37 of 54 cases, indicated that the rWES results impacted clinical decision making in 68% of cases.ConclusionsThese results suggest that rWES improves prenatal diagnosis of fetuses with congenital anomalies, and has an important impact on prenatal and peripartum parental and clinical decision making.

Analyzing the Effects of Peters Plus Syndrome Mutations on Human β1,3‐glucosyltransferase

Peters plus syndrome (PPS) is a severe autosomal recessive congenital disorder of glycosylation characterized by multiple structural anomalies. PPS patients have classic phenotypes, including Peters anomaly (an ocular anterior segment malformation), disproportionate short stature, brachydactyly, dysmorphic facial features, developmental delay, and variable other systemic abnormalities, including cleft lip/palate, and anomalies in heart, skeletal and genitourinary system. PPS patients have mutations in the β1,3‐glucosyltransferase (B3GLCT) gene, which encodes an enzyme that catalyzes the addition of a glucose to an O‐linked fucose on thrombospondin type‐1 repeats (TSRs), forming an unusual Glucoseβ1‐3Fucose (GlcFuc) disaccharide on TSRs. Protein O‐fucosyltransferase 2 (POFUT2) is the enzyme that adds the O‐fucose to a serine or threonine in the consensus sequence C1XX(S/T)C2 found in TSRs, where C1 and C2 are the first two of six conserved cysteines in TSRs. Currently 65 human proteins are predicted to contain TSRs, and 49 out of these proteins contain the consensus sequence for this GlcFuc disaccharide modification. Half of these proteins belong to ADAMTS/ADAMTS‐like family of extracellular matrix proteins and have critical roles in mediating angiogenesis, re‐structuring extracellular matrix, and developmental processes. Previous results demonstrate that secretion of several ADAMTS/L proteins, in particular ADAMTS20 TSR2‐8, is dependent on the presence of POFUT2 and B3GLCT. Since both POFUT2 and B3GLCT are localized in endoplasmic reticulum and only modify folded TSRs, this leads to the proposal that both POFUT2 and B3GLCT assist the folding of TSRs, modulating the secretion of TSR‐containing proteins. Many identified PPS mutations in B3GLCT are splicing mutations upstream of the catalytic domain and are predicted to result in non‐functional proteins. To analyze the missense and truncation PPS mutations downstream of the catalytic domain, we introduced these mutations separately into a plasmid encoding human B3GLCT and analyzed for their ability to rescue secretion of ADAMTS20 TSR2‐8 from B3GLCT‐null cells. Our results showed that these PPS missense and truncation mutants not only abolished their ability to rescue ADAMTS20 TSR2‐8 secretion, but also greatly reduced mutant protein levels compared to wild type B3GLCT within the cells. Mutant enzymes harboring mutations associated with Peters Plus Spectrum, which is a milder form of PPS with patients who have a subset of PPS phenotypes, all rescued ADAMTS20 TSR2‐8 secretion and had the same protein levels within the cells as wild type B3GLCT. On‐going experiments are comparing the enzymatic activity and protein stability of mutants versus wild type enzyme. Overall, by analyzing the impact of PPS and Peters Plus Spectrum mutations on B3GLCT, we are aiming to discover novel therapeutic targets and advancing the development of novel treatments to alleviate the symptoms of PPS as well as other congenital disorders of glycosylation. This project is supported by NIH grant HD096030.

Umbilical Cord Ulcer and Intrauterine Death in Fetal Intestinal Atresia

Objective: To examine the incidence of umbilical cord ulcer (UCU) that causes intrauterine fetal death (IUFD) in fetal duodenal or jejunoileal atresia and the association between UCU and bile acid concentrations in amniotic fluid. Methods: Perinatal outcomes were evaluated in cases of fetal intestinal atresia between 2003 and 2017. A pathological examination of the umbilical cord was performed, and bile acid concentrations in the amniotic fluid were measured. Results: Among the 46 cases included in this study, there were 27 with duodenal atresia and 19 with jejunoileal atresia. There were 4 cases (8.7%) of IUFD and 1 (2.2%) neonatal death with multiple structural anomalies. UCUs were found in 37.5% (15/40) of cases, and severe UCUs with exposed vessels were significantly more common in IUFD (3/4) than in livebirth (0/42) cases (p < 0.01). The incidences of chromosomal abnormality and structural anomalies were not markedly different between livebirth (9/30 and 11/42, respectively) and IUFD (1/3 and 1/4, respectively) cases. Bile acid concentrations in amniotic fluid were significantly higher in cases of UCUs than in those without (p < 0.01). Conclusion: UCUs were not rare in fetal intestinal atresia and were associated with high bile acid concentrations in amniotic fluid. UCUs with exposed vessels were associated with IUFD in intestinal atresia.

Application of single nucleotide polymorphism array in prenatal diagnosis for fetuses with abnormal ultrasound findings

Objective: To investigate the value of single nucleotide polymorphism array (SNP-array) for fetuses with abnormal ultrasound findings. Method: A total of 904 fetuses with abnormal ultrasound findings were enrolled in this study from May 2015 to November 2017, and 434 (48.0%) cases received conventional karyotyping analysis at the same time. According to different abnormal ultrasound category, 904 cases were divided into 5 groups: 280 cases (31.0%) in single system structural anomalies, 31 cases (3.4%) in multiple system structural anomalies, 331 cases (36.6%) in single ultrasound soft marker abnormalities without structural anomalies, 107 cases (11.8%) in multiple soft marker abnormalities and 155 cases (17.2%) in structural abnormalities combined with soft markers abnormalities. Abnormal detection rates by SNP-array among 5 groups of abnormal ultrasound category were calculated. Result: (1) Total SNP-array results: 171 (19.0%) cases out of 904 cases analyzed by SNP-array, presented chromosomal abnormalities. Pathogenic copy number variants were detected in 27 cases (3.0%) and variants of unknown significance were detected in 81 cases (7.8%) . In addition, 7 cases (26.0%) were found with new mutation by parental validation. (2) SNP-array of 5 groups: among the 5 groups of abnormal ultrasound category, chromosomal abnormalities were identified by SNP-array in 19.3% (54/280) with single system structural abnormalities, 25.8% (8/31) with multiple system structural abnormalities, 13.9% (46/331) with single nonstructural anomalies, 19.6% (21/107) with multiple nonstructural anomalies and 27.1% (42/155) with structural abnormalities combined with nonstructural anomalies. The differences were significant (P=0.010) . No chromosome abnormalities was identified in single soft marker abnormalities, such as choroid plexus cysts, echogenic foci in the heart, single umbilical artery and pyelectasis. (3) Chromosomal abnormalities: the abnormal detection rate of aneuploidy chromosomal abnormalities by SNP-array increased with the maternal age, decreased with the gestational weeks (all P<0.05) . However, the pathogenic copy number variants and variants of unknown significance rates did not change with maternal age and gestational weeks (all P>0.05) . (4) SNP-array and karyotyping: 434 cases were analyzed by conventional karyotyping and SNP-array respectively, 10.3% (43/419) of which presented chromosomal abnormalities by conventional karyotyping and 18.7% (81/434) of which presented chromosomal abnormalities by SNP-array. Conclusions: SNP-array could be a useful genetic analysis method in prenatal diagnosis for fetuses with abnormal ultrasound findings. For different abnormal ultrasound category, SNP-array has different detection rate. Compared with conventional karyotyping analysis, SNP-array can improve the detection rates for chromosomal abnormalities and find the chromosome abnormalities which can't be detected by conventional karyotyping analysis. In clinical prenatal genetic counseling, SNP-array should be selected rationally in combination with the various abnormal ultrasound category.

Complex malformations involving the fetal body wall – definition and classification issues

The objective of the study is to analyse the sonographic features, cytogenetic results and pregnancy outcomes in complex malformations involving the body wall in a large cohort of fetuses with regard to different definitions proposed in the literature. A retrospective study on 96 fetuses with complex malformations comprising ventral wall, craniofacial structures, limbs and umbilical cord that were evaluated between 1997 and 2015. The most common sonographic finding was an extensive ventral wall defect (95.8%; 92/96) comprising liver (94.6%; 87/92), intestine (82.6%; 76/92), heart (17.4%; 16/92) and bladder (8.7%; 8/92). Acrania and encephalocoele were observed in 24 and 9 fetuses (25.0%, 24/96; 9.4%, 9/96), respectively. Limb anomalies were present in 54 fetuses (56.3%; 54/96). Rudimentary or absent umbilical cord was observed in 62 fetuses (64.6%; 62/96). In 79 fetuses, there were additional multiple structural anomalies detected prenatally. None of the currently used definitions encompasses all possible phenotypes of body wall defects present in our cohort. Chromosomal aberrations were seen in 8 out of 60 cases with conclusive cytogenetic result (13.3%, 8/60). Chromosomal anomalies are common, and karyotyping should be offered. There is a need for a more rigorous classification of complex malformations in order to better understand the underlying pathophysiology. © 2017 John Wiley & Sons, Ltd.

P01.09: Revelation of double segmental microduplications involving 11q23.3q25 and 22q11.1q11.21 by paralleled non‐invasive prenatal testing and chromosome microarray in a fetus with growth restriction and multiple structural anomalies

P01.09: Revelation of double segmental microduplications involving 11q23.3q25 and 22q11.1q11.21 by paralleled non‐invasive prenatal testing and chromosome microarray in a fetus with growth restriction and multiple structural anomalies

The effects of implementing the International Association of Diabetes and Pregnancy Study Groups criteria for diagnosing gestational diabetes on maternal and neonatal outcomes.

BackgroundIn 2010, the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) recommended a new strategy for the screening and diagnosis of gestational diabetes mellitus (GDM). However, no study has indicated that adopting the IADPSG recommendations improves perinatal outcomes. The objective of this study was to evaluate the effects of implementing the IADPSG criteria for diagnosing GDM on maternal and neonatal outcomes.Methodology/Principal FindingsPreviously, we used a two-step approach (a 1-h, 50-g glucose challenge test followed by a 3-h, 100-g glucose tolerance test when indicated) to screen for and diagnose GDM. In July 2011, we adopted the IADPSG recommendations in our routine obstetric care. In this study, we retrospectively compared the rates of various maternal and neonatal outcomes in all women who delivered after 24 weeks of gestation during the periods before (P1, between January 1, 2009 and December 31, 2010) and after (P2, between January 1, 2012 and December 31, 2013) the IADPSG criteria were implemented. Pregnancies complicated by multiple gestations, fetal chromosomal or structural anomalies, and pre-pregnancy diabetes mellitus were excluded. Our results showed that the incidence of GDM increased from 4.6% using the two-step method to 12.4% using the IADPSG criteria. Compared to the women in P1, the women in P2 experienced less weight gain during pregnancy, lower birth weights, shorter labor courses, and lower rates of macrosomia (<4000 g) and large-for-gestational age (LGA) infants. P2 was a significant independent factor against macrosomia (adjusted odds ratio [OR] 0.63, 95% confidence interval [CI] 0.43–0.90) and LGA (adjusted OR 0.74, 95% CI 0.61–0.89) after multivariable logistic regression analysis.Conclusions/SignificanceThe adoption of the IADPSG criteria for diagnosis of GDM was associated with significant reductions in maternal weight gain during pregnancy, birth weights, and the rates of macrosomia and LGA.

P02.18: Iniencephaly: case report

Background: Iniencephaly is an uncommon, but not rare, abnormality which is characterized by defect of the squamous part of the occipital bone, and body and arch of the cervical vertebrae; by prolapse of the brain from distended occipital foramen; by severe lordosis with consequent uptilting face; and often by spina bifida. Iniencephaly may be associated with several other defects, and cromossomal aneuploydia. Case Report: 26 years old primiparae women with an uneventful pregnancy until 1st trimester scan when fetal cystic hygroma was noted. CVS was performed and 46 XX normal cariotype obtained. Early 2nd trimester scan was performed and multiple structural anomalies were detected suggesting Ininencephaly. Termination of pregnancy was proposed and accepted by the couple. Diagnosis was confirmed on embryo-fetal pathology. Discussion: Iniencephaly is a rare malformation characterized by the triad of occipital bone defect, cervical dysraphism and fixed retroflexion of the fetal head. Because of its almost invariable lethal prognosis, termination of pregnancy is commonplace when this condition is diagnosed before viability. Prenatally diagnosed cases of iniencephaly are rare because careful and early ultrasonographic evaluation is necessary. Conflict of Interests: nil

Familial complex chromosome rearrangement (CCR) involving 5 breakpoints on chromosomes 1, 3 and 13 in a severe oligozoospermic patient

Complex chromosome rearrangement (CCR) is a structural chromosomal aberration that involves three or more breakpoints located on two or more chromosomes. CCRs may be grouped into three major categories depending on different characteristics. According to chromosome numbers involved and the breakpoints per chromosome, CCR can be classified into double two-way exchanges, three-way exchanges, and more complicated or the exceptional CCRs [17, 26]. Based on the origin or means of transmission, CCR can be divided into familial and de novo [11,18]. Depending on unchanging or loss/gain of genetic materials, CCR can be classified into balanced or unbalanced. It is well-known that carriers of unbalanced CCR may lead to significant clinical consequences such as dysmorphic features, multiple congenital anomalies and mental retardation or subnormality in their offspring [2, 3] while carriers of the balanced CCR usually have normal phenotypes and remain undetected in family members through multiple generations. Recently, studies have revealed that carriers of the balanced CCR are prone to infertility and recurrent abortions, and predispose to have offspring with unbalanced rearrangements due to either malsegregation of the derivative chromosomes or formation of a recombinant chromosome [17]. In general, most familial cases have a normal phenotype with apparently balanced rearrangements [20]. In contrast, half of de novo CCRs are unbalanced, and remaining half are apparently balanced but associated with multiple structural anomalies as well as mental retardation [7]. In the present study, we describe a severe oligozoospermic patient who inherited from his mother a balanced CCR that involves five breakpoints on three chromosomes 1, 3, and 13. To the best of out knowledge, this is a new case of CCRs identified in the human population.