The expanded spectrum of human disease associated with GREB1L likely includes complex congenital heart disease.

OBJECTIVE: GREB1L has been linked prenatally to Potter's sequence, as well as less severe anomalies of the kidney, uterus, inner ear, and heart. The full phenotypic spectrum is unknown. The purpose of this study was to characterize known and novel pre- and postnatal phenotypes associated with GREB1L. METHODS: We solicited cases from the Fetal Sequencing Consortium, screened a population-based genomic database, and conducted a comprehensive literature search to identify disease cases associated with GREB1L. We present a detailed phenotypic spectrum and molecular changes. RESULTS: One hundred twenty-seven individuals with 51 unique pathogenic or likely pathogenic GREB1L variants were identified. 24 (47%) variants were associated with isolated kidney anomalies, 19 (37%) with anomalies of multiple systems, including one case of hypoplastic left heart syndrome, five (10%) with isolated sensorineural hearing loss, two (4%) with isolated uterine agenesis; and one (2%) with isolated tetralogy of Fallot. CONCLUSION: GREB1L may cause complex congenital heart disease (CHD) in humans. Clinicians should consider GREB1L testing in the setting of CHD, and cardiac screening in the setting of GREB1L variants.

De novo variants identified by trio whole exome sequencing of bladder exstrophy epispadias complex.

Bladder exstrophy epispadias complex (BEEC) encompasses a spectrum of conditions ranging from mild epispadias to the most severe form: omphalocele-bladder exstrophy-imperforate anus-spinal defects (OEIS). BEEC involves abnormalities related to anatomical structures that are proposed to have a similar underlying etiology and pathogenesis. In general, BEEC, is considered to arise from a sequence of events in embryonic development and is believed to be a multi-etiological disease with contributions from genetic and environmental factors. Several genes have been implicated and mouse models have been generated, including a knockout model of p63, which is involved in the synthesis of stratified epithelium. Mice lacking p63 have undifferentiated ventral urothelium. MNX1 has also been implicated. In addition, cigarette smoking, diazepam and clomid have been implied as environmental factors due to their relative association. By in large, the etiology and pathogenesis of human BEEC is unknown. We performed de novo analysis of whole exome sequencing (WES) of germline samples from 31 unrelated trios where the probands have a diagnosis of BEEC syndrome. We also evaluated the DECIPHER database to identify copy number variants (CNVs) in genes in individuals with the search terms "bladder exstrophy" in an attempt to identify additional candidate genes within these regions. Several de novo variants were identified; however, a candidate gene is still unclear. This data further supports the multi-etiological nature of BEEC.

A Single-Institutional Experience With Prenatal Diagnosis of Cloacal Exstrophy: Room for Improvement.

INTRODUCTION: A single institutional study characterizes the rate of prenatal diagnosis of cloacal exstrophy (CE) and examines its role on successful primary closures. MATERIALS AND METHODS: An institutional database of 1485 exstrophy-epispadias patients was reviewed retrospectively for CE patients with confirmed presence/absence of prenatal diagnostics, primary exstrophy closure since 2000, institution of closure, and at least 1 year of follow up following closure. RESULTS: The cohort included 56 domestic patients and 9 international patients. Overall, 78.6% (n = 44) of domestic patients were prenatally diagnosed while 21.4% (n = 12) were diagnosed postnatally. A positive trend was observed in the rate of prenatal diagnosis across the study period, 56.3%, 84.2%, 88.9% respectively (p = 0.025). Confirmatory fMRI was obtained in 40.9% (n = 18) of prenatally diagnosed cases. Patients diagnosed prenatally were found to be more likely to undergo treatment at exstrophy centers of excellence (72.1% v 33.3%, p = 0.020). Prenatal diagnosis was not predictive of increased rate of successful primary closure (75.6% vs 75.0%; p = 1.00; OR: 1.03, 95% CI: 0.23-4.58). Primary closures undertaken at exstrophy centers of excellence were significantly more likely to be successful compared to outside hospitals (90.9% v 50.0%, p = 0.002). CONCLUSIONS: The rate of prenatal diagnosis of CE in patients referred for management to a high-volume exstrophy center is improving. Despite this improvement, patients continue to be missed in the prenatal period. While prenatal diagnosis offers the ideal opportunity to educate, counsel, and prepare expectant families, patients diagnosed at birth are not disadvantaged in their ability to receive a successful primary closure. Further research should investigate the benefit of patient referral to high-volume exstrophy centers of care to ensure optimal care and outcomes.

Prenatal Sonography in Suspected Proximal Gastrointestinal Obstructions: Diagnostic Accuracy and Neonatal Outcomes.

BACKGROUND: The purpose of this study was to assess diagnostic accuracy and neonatal outcomes in fetuses with a suspected proximal gastrointestinal obstruction (GIO). METHODS: After IRB approval, a retrospective chart review was conducted on prenatally suspected and/or postnatally confirmed cases of proximal GIO at a tertiary care facility (2012-2022). Maternal-fetal records were queried for presence of a double bubble ± polyhydramnios, and neonatal outcomes were assessed to calculate the diagnostic accuracy of fetal sonography. RESULTS: Among 56 confirmed cases, the median birthweight and gestational age at birth were 2550 g [interquartile range (IQR) 2028-3012] and 37 weeks (IQR 34-38), respectively. There was one (2%) false-positive and three (6%) false-negatives by ultrasound. Double bubble had a sensitivity, specificity, positive predictive value, and negative predictive value for proximal GIO of 85%, 98%, 98%, and 83%, respectively. Pathologies included 49 (88%) with duodenal obstruction/annular pancreas, three (5%) with malrotation, and three (5%) with jejunal atresia. The median postoperative length of stay was 27 days (IQR 19-42). Cardiac anomalies were associated with significantly higher complications (45% vs 17%, p = 0.030). CONCLUSIONS: In this contemporary series, fetal sonography has high diagnostic accuracy for detecting proximal gastrointestinal obstruction. These data are informative for pediatric surgeons in prenatal counseling and preoperative discussions with families. LEVEL OF EVIDENCE: Diagnostic Study, Level III.

Assisted reproductive technology: Short- and long-term outcomes.

Assisted reproductive technology (ART) includes fertility treatment in which either eggs or embryos are handled outside a female's body to promote successful pregnancies and healthy offspring. Current ART procedures encompass in vitro fertilization with or without intracytoplasmic sperm injection. The most common complication of ART is related to the consequences of multiple pregnancy, which can be prevented or minimized by reducing the number of embryos transferred to the uterus, commonly single embryo transfer. ART has been shown to be variably associated with adverse short- and long-term perinatal outcomes, including cerebral palsy, autism, neurodevelopmental imprinting disorders, and cancer. However, there is uncertainty as to whether reported problems are related to the ART procedure itself, to factors related to infertility, to other medical and environmental factors, or a combination thereof. From a pathophysiological perspective, whether ART alters epigenetic mechanisms of gene expression, leading to later developmental, medical, and behavioral disorders, is an area of active investigation. With the meticulously conducted short- and long-term outcome studies completed so far, overall, and after controlling for multiple gestations and preterm delivery, the results suggest that ART is a safe procedure, offering hope to many parent(s) wishing for a healthy child. This paper highlights ART methods and the risk factors and confounders in the interpretation of short- and long-term outcome data, providing the reader with a means to evaluate findings and conclusions of outcome studies. WHAT THIS PAPER ADDS: Assisted reproductive technology (ART) is a relatively safe procedure. Single embryo implantation optimizes outcome. Informed consent, including the risks and benefits of ART, should be required. Ongoing longitudinal studies are necessary to fully understand ART outcomes.

Obstetrical and neonatal outcomes of cardio-facio-cutaneous syndrome: Prenatal consequences of Ras/MAPK dysregulation.

We systematically delineated the prenatal phenotype, and obstetrical and neonatal outcomes of the RASopathy cardio-facio-cutaneous (CFC) syndrome. A comprehensive, retrospective medical history survey was distributed to parents of children with confirmed CFC in collaboration with CFC International, Inc. Data were collected on CFC gene variant, maternal characteristics, pregnancy course, delivery, and neonatal outcomes with the support of medical records. We identified 43 individuals with pathogenic variants in BRAF (81%), MEK1 (14%), or MEK2 (5%) genes. The median age was 8.5 years. Hyperemesis gravidarum, gestational diabetes, gestational hypertension, and preeclampsia occurred in 5/43 (12%), 4/43 (9%), 3/43 (7%), and 3/43 (7%) of pregnancies, respectively. Second and third trimester ultrasound abnormalities included polyhydramnios, macrocephaly, macrosomia, and renal and cardiac abnormalities. Delivery occurred via spontaneous vaginal, operative vaginal, or cesarean delivery in 15/42 (36%), 7/42 (16%), and 20/42 (48%), respectively. Median gestational age at delivery was 37 weeks and median birth weight was 3501 grams. Germline pathogenic vaiants had mutiple congenital consequences including polyhydramnios, renal and cardiac abnormalities, macrosomia, and macrocephaly on second and third trimester ultrasound. Elevated rates of operative delivery and neonatal complications were also noted. Understanding and defining a prenatal phenotype may improve prenatal prognostic counseling and outcomes.

Molecular testing strategies in the evaluation of fetal skeletal dysplasia.

OBJECTIVE: The aim of this study was to characterize the fetal sonographic findings and the approach utilized to obtain a definitive diagnosis through molecular testing strategies. METHODS: This is a retrospective case series of fetuses referred for consultation for prenatal findings suggestive of a skeletal dysplasia between March 1, 2014 and March 1, 2016. Ultrasound images, their timing in gestation and reported findings were reviewed and skeletal abnormalities were documented. Unique features were ascertained. The approach for molecular evaluation, and molecular results were extracted. RESULTS: Nine cases were referred for evaluation secondary to prenatal sonographic features suggestive of a skeletal dysplasia. In 4 cases a skeletal dysplasia was suspected prior to 16 weeks gestation. Three of these, with mutations in CANT1, NEK1, and COL2A1 were considered lethal, while the fourth case had a non-lethal ALPL mutation. Similarly 2 of 3 cases diagnosed at 16-22 weeks gestation had lethal mutations in COL1A and DYNC2H1 while the fetus with Russell Silver survived. The final 2 cases diagnosed in the third trimester, both hypochondroplasia, were non-lethal dysplasias. A molecular diagnosis was obtained in 8/9 (88.9%) cases which encompassed eight different skeletal dysplasias. The final case declined molecular testing. CONCLUSION: Features of specific skeletal dysplasias can be visualized in utero and guide appropriate molecular testing. Sonographic details in addition to molecular genetic results aid in prognostic counseling.

Obstetrician patterns of steroid administration for the prenatal management of congenital pulmonary airway malformations.

BACKGROUND: Congenital pulmonary airway malformation (CPAM) is the most common prenatally-diagnosed lung malformation. This lesion, classified as macrocystic or microcystic, can lead to significant fetal compromise. Management options include observation, maternal antenatal steroid administration, and fetal surgical intervention. Current evidence suggests that microcystic (but not macrocystic) lesions and those with a cyst volume ratio (CVR) >1.6 are responsive to steroid therapy. The objective of this study was to identify patterns of prenatal steroid administration for the management of CPAMs and to identify characteristics of CPAMs prompting steroid administration. METHODS: An 18-question survey was distributed to obstetricians from the Pregnancy-Related Care Research Network (PRCRN) and the North American Fetal Therapy Network (NAFTNet), from January to April 2019, to capture antenatal steroid prescribing patterns. RESULTS: Response rates were 28.3% (138/487) for PRCRN and 63.3% (19/30) for NAFTNet. Among PRCRN members, 16.8% administered prenatal steroids, with most (77.2%) doing so for both microcystic and macrocystic CPAMs; corresponding percentages for NAFTNet members were 90.9% and 52.6%. Two thirds (65.6%) of obstetricians who administer steroids do so for a CVR > 1.6, without evidence of mediastinal shift or hydrops fetalis. CONCLUSIONS: There is a lack of consensus among obstetricians as to the CPAM characteristics that should prompt administration of prenatal steroids. Many surveyed obstetricians do not use cyst type or CVR to guide decision-making regarding steroid therapy.

Sacral protuberance with cleft lip and palate: Prenatal presentation of 3MC syndrome.

3MC syndromes are rare heterogeneous autosomal recessive conditions previously designated as Mingarelli, Malpuech, Michels, and Carnevale syndromes, characterized by dysmorphic facial features, facial clefts, growth restriction, and intellectual disability. 3MC is secondary to mutations in the MASP1, MASP3, COLEC11, and COLEC10 genes. The number of patients with 3MC syndrome with known mutations in the COLEC11 or MASP1 is, to date, less than 50. At the time this case presented (2015), the only gene identified in Online Mendelian Inheritance in Man to be associated with 3MC syndrome was MASP1. We present, to the best of our knowledge, the first prenatal report of 3MC syndrome, secondary to a homozygous variant in MASP1. Fetal findings included bilateral cleft lip and palate, abnormality of the sacral spine, a right echogenic pelvic kidney, and brachycephaly. 3MC syndrome should be considered as part of the differential diagnosis when fetal ultrasound detects facial clefts and spinal defects, as the risk of recurrence is significant and a molecularly confirmed diagnosis allows for alternate reproductive options.

Etiology and management of early pregnancy renal anhydramnios: Is there a place for serial amnioinfusions?

Early pregnancy renal anhydramios (EPRA) comprises congenital renal disease that results in fetal anhydramnios by 22 weeks of gestation. It occurs in over 1 in 2000 pregnancies and affects 1500 families in the US annually. EPRA was historically considered universally fatal due to associated pulmonary hypoplasia and neonatal respiratory failure. There are several etiologies of fetal renal failure that result in EPRA including bilateral renal agenesis, cystic kidney disease, and lower urinary tract obstruction. Appropriate sonographic evaluation is required to arrive at the appropriate urogenital diagnosis and to identify additional anomalies that allude to a specific genetic diagnosis. Genetic evaluation variably includes karyotype, microarray, targeted gene testing, panels, or whole exome sequencing depending on presentation. Patients receiving a fetal diagnosis of EPRA should be offered management options of pregnancy termination or perinatal palliative care, with the option of serial amnioinfusion therapy offered on a research basis. Preliminary data from case reports demonstrate an association between serial amnioinfusion therapy and short-term postnatal survival of EPRA, with excellent respiratory function in the neonatal period. A multicenter trial, the renal anhydramnios fetal therapy (RAFT) trial, is underway. We sought to review the initial diagnosis ultrasound findings, genetic etiologies, and current management options for EPRA.

The utility of exome sequencing for fetal pleural effusions.

OBJECTIVE: We sought to evaluate the performance of exome sequencing (ES) in determining an underlying genetic etiology for cases of fetal pleural effusions. STUDY DESIGN: We examined a prospective cohort series of fetal pleural effusions visualized sonographically between 1 April 2016 and 31 August 2017. Fetal pleural effusions attributed to twin sharing, anemia, or structural anomalies were excluded, as were all cases with a genetic diagnosis established by karyotype or chromosomal microarray analysis. The remaining cases with pleural effusions of unclear etiology were offered ES. ES was performed by clinical sequencing and/or sequencing under the Baylor-Hopkins Center for Mendelian Genomics' (BHCMG) research platform. All cases were evaluated for novel genes or phenotypic expansion of disease-causing genes. RESULTS: ES was performed on six probands affected by pleural effusions. A pathogenic variant was identified in one case (16.7%). Four additional cases had variants of uncertain significance (VUS) in candidate genes of pathological interest. Neither clinical nor candidate genes were evident in the final case. CONCLUSION: ES should be considered in the evaluation of prenatally detected idiopathic pleural effusions when other diagnostic workup for a genetic etiology has failed.

The sixth international RASopathies symposium: Precision medicine-From promise to practice.

The RASopathies are a group of genetic disorders that result from germline pathogenic variants affecting RAS-mitogen activated protein kinase (MAPK) pathway genes. RASopathies share RAS/MAPK pathway dysregulation and share phenotypic manifestations affecting numerous organ systems, causing lifelong and at times life-limiting medical complications. RASopathies may benefit from precision medicine approaches. For this reason, the Sixth International RASopathies Symposium focused on exploring precision medicine. This meeting brought together basic science researchers, clinicians, clinician scientists, patient advocates, and representatives from pharmaceutical companies and the National Institutes of Health. Novel RASopathy genes, variants, and animal models were discussed in the context of medication trials and drug development. Attempts to define and measure meaningful endpoints for treatment trials were discussed, as was drug availability to patients after trial completion.

Prenatal ABO/RHD Genotyping: A New Paradigm to Allow for Fresh Whole Blood for Cardiopulmonary Bypass in the Immediate Newborn Period.

Compared to standard component therapy, fresh whole blood (FWB) offers potential benefits to neonates undergoing cardiopulmonary bypass (CPB) in the context of open cardiac surgery: decreased blood loss and subsequent risk of volume overload, improved coagulation status, higher platelet counts during and following CPB, circumvention of limited vascular access, and significantly reduced donor exposures. Obtaining FWB, however, entails 2-5 days of preparation, which often precludes its availability for neonates requiring CPB in the immediate newborn period. Using a multidisciplinary approach and molecular ABO/RHD genotyping on amniotic fluid, we developed a protocol to allow procurement of FWB for timed delivery followed by open cardiac surgery. Eligible subjects include patients undergoing genetic amniocentesis following the diagnosis of a fetal cardiac anomaly likely to require open surgical repair in the initial days after birth. This protocol has been successfully implemented following prenatal diagnosis of severe fetal cardiac anomalies. Taking advantage of the prenatal time period and the ability to perform fetal blood typing prenatally using molecular genotyping makes possible a new paradigm for the availability of FWB for CPB to improve perioperative, short-term, and long-term outcomes in a population comprised of some of the smallest and sickest patients who will undergo CPB.

Maternal co-morbidities and neonatal outcomes associated with cystic fibrosis.

OBJECTIVE: To evaluate maternal co-morbidities and adverse perinatal outcomes associated with cystic fibrosis (CF). METHODS: This is a retrospective cohort study of 2 178 954 singleton pregnancies at ≥20 weeks' gestation with and without CF in the state of California during the years 2005-2008. ICD-9 codes and linked hospital discharge and vital statistics data were utilized. Rates of maternal co-morbidities, fetal congenital anomalies and adverse perinatal outcomes were compared in those with CF and those without. Maternal co-morbidities included gestational hypertension, preeclampsia, gestational diabetes and primary cesarean delivery. Perinatal outcomes included neonatal demise, preterm birth, intrauterine growth restriction, macrosomia, anomaly, fetal demise, asphyxia, respiratory distress syndrome, jaundice, intraventricular hemorrhage, hypoglycemia and necrotizing enterocolitis. RESULTS: The cohort included 2 178 954 pregnancies of which 77 mothers had CF. Mothers with CF were more likely to have pre-gestational diabetes and had higher rates of primary cesarean delivery. Neonates delivered to mothers with CF were more likely to be born preterm and have congenital anomalies but otherwise were not at increased risk for significant neonatal morbidity or mortality when adjusted for gestational age. CONCLUSION: Mothers with CF are more likely to have pre-gestational diabetes, deliver preterm (<37 weeks gestation) and have a primary cesarean delivery. Infants are more likely to have congenital anomalies. In addition to early diabetic screening and genetic counseling, a detailed fetal anatomy ultrasound should be performed in women with CF.

Fatal Congenital Retroperitoneal Neuroblastoma Diagnosed by Fetal Magnetic Resonance Imaging.

Congenital extra-adrenal neuroblastoma is a rare condition, which typically has a favorable prognosis. We present a unique case of extra-adrenal retroperitoneal neuroblastoma diagnosed by fetal magnetic resonance imaging, which ultimately leads to fetal hydrops and neonatal death.

Obstetrician and gynecologists' population-based screening practices.

BACKGROUND: The ability to obtain genetic information can now be accomplished in far greater detail, and more quickly than in the past. It is important to understand obstetrician-gynecologists' (ob-gyns) screening practices as these changes occur. METHODS: Cross-sectional survey was performed by mailing paper surveys to Fellows of the American College of Obstetricians and Gynecologists and a subset of Fellows who belong to the Collaborative Ambulatory Research Network (CARN). RESULTS: Response rates were 57% for the CARN network. Almost all responders (92%) offer population-based genetic screening in the prenatal period and almost all (93%) conduct counseling prior to the provision of genetic testing. Almost all (92%) counsel patients when the result is positive, with 46% being the primary counselor and 55% calling the patient themselves. When results are negative, 73% counsel with 58% indicating they are the primary counselor and 17% call patients themselves. A total of 72% have received continuing medical education (CME) on genetics within 5 years, with 79% receiving CME at conferences and 21% receiving CME online. CONCLUSION: Ob-gyns have a large role in providing patients new genetic screening technologies. This role requires a significant knowledge base, some of which can be obtained by online modules; however, our study suggests online education is underutilized as a means for CME on genetic screening among ob-gyns.

Clefting in trisomy 9p patients: genotype-phenotype correlation using microarray comparative genomic hybridization.

Duplication 9p syndrome (partial trisomy 9p) is characterized by craniofacial anomalies, mental retardation, and distal phalangeal hypoplasia. Here, we present a female patient with microcephaly and incomplete bilateral cleft lip and palate, whose initial cytogenetic analysis revealed a de novo trisomy 9p. The patient, now 21 years old, has persistent microcephaly, craniofacial and hand anomalies, history of a seizure disorder, and global mental retardation. Oligonucleotide-based array comparative genomic hybridization was performed and revealed partial trisomy 9p21.1->9pter and a deletion of 9p12.1 to 9p11.2. Our case supports the utility of array comparative genomic hybridization for the precise characterization of chromosomal anomalies and for the ascertainment of genotype-phenotype correlation in patients with partial trisomy 9p.