Exploring pregnant individuals' counseling needs regarding urgent imaging to rule out pulmonary embolism.

Background: Computed tomography pulmonary angiogram and lung scintigraphy with ventilation/perfusion scan are needed to diagnose pulmonary embolism (PE) in pregnancy. Their associated ionizing radiation doses are considered safe in pregnancy. A standardized patient information tool may improve patient counseling and reduce testing hesitancy. Objectives: In this context, we sought to address 1) what patients want to know before undergoing these tests and 2) how they want the information to be provided to them. Methods: We used a qualitative descriptive methodology. We recruited pregnant participants at the McGill University Health Center in Montreal, Canada. Structured interviews explored information needs about PE and diagnostic imaging for PE. The interview transcripts' themes were analyzed with a hybrid deductive and inductive approach. Results: Of 21 individuals approached, 20 consented to participate. Four had been previously investigated for PE. Participants requested information about the risks associated with PE and radiation and their effects on maternal and fetal health. They preferred for radiation doses to be presented in comparison with known radiation thresholds for fetal harm. They suggested that a written tool should be developed using an accessible language. Participants also indicated that the tool would be integrated into their decision-making process, emphasizing a lower risk tolerance for their fetus than for themselves. Conclusion: This single-center group of pregnant patients wished to be informed about the risks of PE and radiation associated with imaging. A written tool could help put information into context and facilitate decision making. These new insights may be used to inform counseling.

Identifying Targets to Improve the Management of Severe Hypertension in Pregnancy and Postpartum.

OBJECTIVES: To (1) define quality indicators, (2) describe care gaps, and (3) identify process issues in severe hypertension (sustained systolic blood pressure [BP] ≥160 mm Hg or diastolic BP ≥110 mm Hg) management at our tertiary care centre. METHODS: Pregnant and postpartum persons diagnosed with a hypertensive disorder of pregnancy from 2018 to 2019 were identified. A retrospective cohort of patients with severe hypertension was constructed, and data were collected through chart review. Severe hypertension management was assessed according to defined quality indicators. Clinical characteristics were compared between participants with and without time-to-target BP within 60 minutes. Process issues were examined for each severe hypertension occurrence. RESULTS: Of 608 participants with a hypertensive disorder of pregnancy, 90 (15%) experienced severe hypertension. Median time-to-target BP was 76 minutes (interquartile range 47-123 minutes), and target BP (<155/105 mm Hg) was achieved within 60 minutes in 31/90 (34%) participants. Appropriate antihypertensives for severe hypertension were used in 55/90 (61%), and time-to-treatment initiation was within 30 minutes in 42/54 (78%). Chronic hypertension and oral labetalol use were associated with delays in achieving target BP. Process issues related to severe hypertension management included inappropriate treatment (n = 35/90; 39%), failure to recognize severe hypertension as an emergency (n = 21/90; 23%), and delayed treatment initiation (n = 12/54; 22%). CONCLUSION: We defined quality indicators for severe hypertension management. Time-to-target BP within 60 minutes was achieved in a minority of patients, and chronic hypertension was associated with delayed severe hypertension resolution. Process issues in severe hypertension management were described.

The multidisciplinary management of a mechanical mitral valve thrombosis in pregnancy: a case report and review of the literature.

Background: The management of anticoagulation for mechanical heart valves during pregnancy poses a unique challenge. Mechanical valve thrombosis is a devastating complication for which surgery is often the treatment of choice. However, cardiac surgery for prosthetic valve dysfunction in pregnant patients confers a high risk of maternofetal morbidity and mortality. Case summary: A 39-year-old woman in her first pregnancy at 30 weeks gestation presented to hospital with a mechanical mitral valve thrombosis despite therapeutic anticoagulation with low-molecular-weight heparin. She underwent an emergent caesarean section followed immediately by a bioprosthetic mitral valve replacement. This occurred after careful planning and organization on the part of a large multidisciplinary team. Discussion: A proactive, rather than reactive, approach to the surgical management of a mechanical valve thrombosis in pregnancy will maximize the chances of successful maternal and fetal outcomes.

A novel biallelic loss-of-function variant in DAND5 causes heterotaxy syndrome.

The majority of heterotaxy cases do not obtain a molecular diagnosis, although pathogenic variants in more than 50 genes are known to cause heterotaxy. A heterozygous missense variant in DAND5, a nodal inhibitor, which functions in early development for establishment of right-left patterning, has been implicated in heterotaxy. Recently, the first case was reported of a DAND5 biallelic loss-of-function (LoF) variant in an individual with heterotaxy. Here, we describe a second unrelated individual with heterotaxy syndrome and a homozygous frameshift variant in DAND5 (NM_152654.2:c.197del [p.Leu66ArgfsTer22]). Using an in vitro assay, we demonstrate that the DAND5 c.197del variant is unable to inhibit nodal signaling when compared with the wild-type expression construct. This work strengthens the genetic and functional evidence for biallelic LoF variants in DAND5 causing an autosomal recessive heterotaxy syndrome.

Variants in STXBP3 are Associated with Very Early Onset Inflammatory Bowel Disease, Bilateral Sensorineural Hearing Loss and Immune Dysregulation.

BACKGROUND AND AIMS: Very early onset inflammatory bowel disease [VEOIBD] is characterized by intestinal inflammation affecting infants and children less than 6 years of age. To date, over 60 monogenic aetiologies of VEOIBD have been identified, many characterized by highly penetrant recessive or dominant variants in underlying immune and/or epithelial pathways. We sought to identify the genetic cause of VEOIBD in a subset of patients with a unique clinical presentation. METHODS: Whole exome sequencing was performed on five families with ten patients who presented with a similar constellation of symptoms including medically refractory infantile-onset IBD, bilateral sensorineural hearing loss and, in the majority, recurrent infections. Genetic aetiologies of VEOIBD were assessed and Sanger sequencing was performed to confirm novel genetic findings. Western analysis on peripheral blood mononuclear cells and functional studies with epithelial cell lines were employed. RESULTS: In each of the ten patients, we identified damaging heterozygous or biallelic variants in the Syntaxin-Binding Protein 3 gene [STXBP3], a protein known to regulate intracellular vesicular trafficking in the syntaxin-binding protein family of molecules, but not associated to date with either VEOIBD or sensorineural hearing loss. These mutations interfere with either intron splicing or protein stability and lead to reduced STXBP3 protein expression. Knock-down of STXBP3 in CaCo2 cells resulted in defects in cell polarity. CONCLUSION: Overall, we describe a novel genetic syndrome and identify a critical role for STXBP3 in VEOIBD, sensorineural hearing loss and immune dysregulation.

Thrombotic Microangiopathy in a Pregnant Woman With Kidney Transplantation: A Case Report.

BACKGROUND: The differential diagnosis of thrombotic microangiopathy (TMA) in pregnancy includes common conditions, such as preeclampsia. In women with kidney transplantation, additional causes of TMA must be considered. CASE: A 22-year-old primigravid woman with a transplanted kidney presented with fetal growth restriction, hypertension, acute kidney injury, and hemolysis at 28 weeks gestation. While her clinical presentation was initially consistent with preeclampsia, hemolysis persisted beyond 1 week postpartum. Diagnoses of TMA associated with tacrolimus and antibody-mediated rejection were considered. An elevated tacrolimus level likely contributed to her TMA and a decrease in dosage improved her clinical picture and laboratory markers. CONCLUSION: We report the case of a pregnant kidney transplant recipient with TMA. A multidisciplinary approach is required to optimize the maternal health outcomes in this complex population.

Ludwig's Angina in Pregnancy: A Case Report.

BACKGROUND: Physiologic changes in pregnancy may predispose pregnant women to oral health problems. However, most women are not counselled on oral health during pregnancy. Lack of proper oral health care predisposes pregnant women to odontogenic infections, which can lead to severe complications. CASE: A 34-year-old multiparous woman presented at 400 weeks gestation with a 3-day history of severe, progressive neck swelling, jaw pain, and trismus. She was diagnosed with Ludwig's angina secondary to an untreated dental cavity. She required emergency fiberoptic intubation to secure her airway, urgent delivery via cesarean section, and subsequent surgical drainage performed by otolaryngology. CONCLUSION: Ludwig's angina during pregnancy is associated with severe morbidity. Dental care should not be denied or postponed due to pregnancy, and dental infections should be treated promptly. Health care providers should counsel women on the importance of maintaining good oral health during pregnancy.

Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study.

BACKGROUND: Identification of chromosomal aneuploidies and copy number variants that are associated with fetal structural anomalies has substantial value. Although whole-exome sequencing (WES) has been applied to case series of a few selected prenatal cases, its value in routine clinical settings has not been prospectively assessed in a large unselected cohort of fetuses with structural anomalies. We therefore aimed to determine the incremental diagnostic yield (ie, the added value) of WES following uninformative results of standard investigations with karyotype testing and chromosomal microarray in an unselected cohort of sequential pregnancies showing fetal structural anomalies. METHODS: In this prospective cohort study, the parents of fetuses who were found to have a structural anomaly in a prenatal ultrasound were screened for possible participation in the study. These participants were predominantly identified in or were referred to the Columbia University Carmen and John Thain Center for Prenatal Pediatrics (New York, NY, USA). Fetuses with confirmed aneuploidy or a causal pathogenic copy number variant were excluded from WES analyses. By use of WES of the fetuses and parents (parent-fetus trios), we identified genetic variants that indicated an underlying cause (diagnostic genetic variants) and genetic variants that met the criteria of bioinformatic signatures that had previously been described to be significantly enriched among diagnostic genetic variants. FINDINGS: Between April 24, 2015, and April 19, 2017, 517 sequentially identified pregnant women found to have fetuses with a structural anomaly were screened for their eligibility for inclusion in our study. 71 (14%) couples declined testing, 87 (17%) trios were missing at least one DNA sample (from either parent or the fetus), 69 (13%) trios had a clinically relevant abnormal karyotype or chromosomal microarray finding, 51 (10%) couples did not consent to WES or withdrew consent, and five (1%) samples were not of good enough quality for analysis. DNA samples from 234 (45%) eligible trios were therefore used for analysis of the primary outcome. By use of trio sequence data, we identified diagnostic genetic variants in 24 (10%) families. Mutations with bioinformatic signatures that were indicative of pathogenicity but with insufficient evidence to be considered diagnostic were also evaluated; 46 (20%) of the 234 fetuses assessed were found to have such signatures. INTERPRETATION: Our analysis of WES data in a prospective cohort of unselected fetuses with structural anomalies shows the value added by WES following the use of routine genetic tests. Our findings suggest that, in cases of fetal anomalies in which assessment with karyotype testing and chromosomal microarray fail to determine the underlying cause of a structural anomaly, WES can add clinically relevant information that could assist current management of a pregnancy. The unique challenges of WES-based prenatal diagnostics require analysis by a multidisciplinary team of perinatal practitioners and laboratory specialists. FUNDING: Institute for Genomic Medicine (Columbia University Irving Medical Center).

Fetal Exome Sequencing on the Horizon.

Prenatal whole exome sequencing has recently been introduced. It is evolving and although not currently ready for everyday clinical practice, it will likely become part of the diagnostic arsenal available to clinicians caring for couples carrying a pregnancy for which fetal anomalies have been identified. This commentary discusses what it is, its indications, its benefits, and its limitations.

Laboratory considerations for prenatal genetic testing.

New genetic tests have rapidly entered clinical care with little consistency in laboratory testing and reporting. Non-invasive prenatal screening using cell free DNA (cfDNA) may either screen for common aneuploidies alone or include chromosomal microdeletions. All cfDNA screening tests have false positives and false negatives, and accordingly laboratories should report positive and negative predictive values. In addition, since fetal fraction plays a significant role in the reliability of results, this should also be reported with all test results. Chromosomal microarray addresses significant clinically relevant information beyond that detected with standard karyotype testing but may, in less than one percent of cases, result in a variant of uncertain significance (VUS). Laboratories should indicate their policies for reporting these VUS findings. In addition, physicians using this testing should be aware of the advantages and disadvantages of the laboratory platforms. Whole-exome and whole-genome sequencing are just entering clinical care and issues of VUS, incidental findings, and phenotype/genotype correlations need to be investigated before these techniques enter routine clinical care.

Refining the phenotype associated with GNB1 mutations: Clinical data on 18 newly identified patients and review of the literature.

De novo germline mutations in GNB1 have been associated with a neurodevelopmental phenotype. To date, 28 patients with variants classified as pathogenic have been reported. We add 18 patients with de novo mutations to this cohort, including a patient with mosaicism for a GNB1 mutation who presented with a milder phenotype. Consistent with previous reports, developmental delay in these patients was moderate to severe, and more than half of the patients were non-ambulatory and nonverbal. The most observed substitution affects the p.Ile80 residue encoded in exon 6, with 28% of patients carrying a variant at this residue. Dystonia and growth delay were observed more frequently in patients carrying variants in this residue, suggesting a potential genotype-phenotype correlation. In the new cohort of 18 patients, 50% of males had genitourinary anomalies and 61% of patients had gastrointestinal anomalies, suggesting a possible association of these findings with variants in GNB1. In addition, cutaneous mastocytosis, reported once before in a patient with a GNB1 variant, was observed in three additional patients, providing further evidence for an association to GNB1. We will review clinical and molecular data of these new cases and all previously reported cases to further define the phenotype and establish possible genotype-phenotype correlations.

Parental perceptions of prenatal whole exome sequencing (PPPWES) study.

OBJECTIVE: The objective of the study is to investigate the experiences of couples who underwent prenatal whole-exome sequencing (WES) for fetal anomalies and the amount/type of information couples want from prenatal WES. METHOD: Participants in the Fetal Sequencing Study who had genetic testing for fetal anomalies were invited for a semistructured interview about their experience with prenatal WES. A constructivist grounded theory approach with an inductive coding style was used for coding and analysis. RESULTS: We interviewed 29 participants from 17 pregnancies. Two pregnancies had positive prenatal WES results, and 4 were terminated prior to receipt of WES results. The main themes were anxiety and stress around the time of diagnosis, education and consent for WES, coping and support while waiting for results, and receiving genetic testing results. In response to hypothetical scenarios probing the desire for uncertain results, 86% would like to be told about results for which the provider had some degree of uncertainty, and the percent desiring results decreased as the certainty of the results decreased. CONCLUSION: Participants' experience with exome sequence was similar to other prenatal genetic diagnostic tests, except for the longer wait time for results. When probed with hypothetical scenarios, participants desired more results than were provided in the study, including uncertain results that might diagnose the fetal condition. This highlights the need for specialized prenatal genetic counseling to have nuanced discussions of multiple dimensions of uncertainty with implementation of prenatal WES.

Promises, pitfalls and practicalities of prenatal whole exome sequencing.

Prenatal genetic diagnosis provides information for pregnancy and perinatal decision-making and management. In several small series, prenatal whole exome sequencing (WES) approaches have identified genetic diagnoses when conventional tests (karyotype and microarray) were not diagnostic. Here, we review published prenatal WES studies and recent conference abstracts. Thirty-one studies were identified, with diagnostic rates in series of five or more fetuses varying between 6.2% and 80%. Differences in inclusion criteria and trio versus singleton approaches to sequencing largely account for the wide range of diagnostic rates. The data suggest that diagnostic yields will be greater in fetuses with multiple anomalies or in cases preselected following genetic review. Beyond its ability to improve diagnostic rates, we explore the potential of WES to improve understanding of prenatal presentations of genetic disorders and lethal fetal syndromes. We discuss prenatal phenotyping limitations, counselling challenges regarding variants of uncertain significance, incidental and secondary findings, and technical problems in WES. We review the practical, ethical, social and economic issues that must be considered before prenatal WES could become part of routine testing. Finally, we reflect upon the potential future of prenatal genetic diagnosis, including a move towards whole genome sequencing and non-invasive whole exome and whole genome testing. © 2017 John Wiley & Sons, Ltd.

Whole exome sequencing identifies a homozygous POLG2 missense variant in an infant with fulminant hepatic failure and mitochondrial DNA depletion.

Mitochondrial DNA (mtDNA) depletion syndrome manifests as diverse early-onset diseases that affect skeletal muscle, brain and liver function. Mutations in several nuclear DNA-encoded genes cause mtDNA depletion. We report on a patient, a 3-month-old boy who presented with hepatic failure, and was found to have severe mtDNA depletion in liver and muscle. Whole-exome sequencing identified a homozygous missense variant (c.544C > T, p.R182W) in the accessory subunit of mitochondrial DNA polymerase gamma (POLG2), which is required for mitochondrial DNA replication. This variant is predicted to disrupt a critical region needed for homodimerization of the POLG2 protein and cause loss of processive DNA synthesis. Both parents were phenotypically normal and heterozygous for this variant. Heterozygous mutations in POLG2 were previously associated with progressive external ophthalmoplegia and mtDNA deletions. This is the first report of a patient with a homozygous mutation in POLG2 and with a clinical presentation of severe hepatic failure and mitochondrial depletion.

Chromosomal Microarrays for the Prenatal Detection of Microdeletions and Microduplications.

Chromosomal microarray analysis has replaced conventional G-banded karyotype in prenatal diagnosis as the first-tier test for the cytogenetic detection of copy number imbalances in fetuses with/without major structural abnormalities. This article reviews the basic technology of microarray; the value and clinical significance of the detection of microdeletions, microduplications, and other copy number variants; as well as the importance of genetic counseling for prenatal diagnosis. It also discusses the current status of noninvasive screening for some of these microdeletion and microduplication syndromes.

Cell-free DNA versus intact fetal cells for prenatal genetic diagnostics: what does the future hold?

Prenatal screening and diagnosis is currently focused on the development of a noninvasive prenatal diagnostic test capable of detecting abnormalities similar to those attainable with an invasive test. One contender is cell-free fetal DNA circulating in maternal plasma and the other is intact fetal cells either from the maternal blood or the cervix. Once adequate fetal DNA is available, laboratory analytic techniques, such as sequencing and microarray, can be applied allowing detection of most cytogenetic and Mendelian fetal disorders. The question is: how close are we to achieving this feat, and what does the future hold?

Comparison of the aetiology of stillbirth over five decades in a single centre: a retrospective study.

OBJECTIVE: To compare the rates and aetiologies of stillbirth over the past 50 years. STUDY DESIGN: We reviewed all autopsy reports for stillbirths occurring between 1989 and 2009 at the McGill University Health Centre to determine the pathological aetiology of stillbirths. We also reviewed maternal characteristics. We compared our results with a previous study published in 1992 on aetiologies of stillbirth from 1961 to 1988 at the same institution. RESULTS: From among the 79 410 births between 1989 and 2009, 217 stillbirths were included in our study. The mean maternal age was 31.05 (±5.8) years. In 28.1% of cases, there was a history of subfertility. The mean gestational age at diagnosis was 32.69 (±5.58) weeks, with a birthweight of 1888 (±1084) g. The main causes of stillbirth were unknown (26.7%), placental factors (19.8%) and abruptio placentae (12.9%). Other causes included haematogenous or ascending infection (10.6%), fetal malformations (8.3%), maternal hypertension (3.2%), intrauterine growth restriction (2.8%), diabetes (1.8%) and intrapartum asphyxia (1.4%). Other fetal causes were found in 12.4% of cases. CONCLUSIONS: Owing to detailed pathological examination of most stillbirth cases over the past five decades at our tertiary obstetrical centre, we could study the trends in the aetiology of stillbirths in a cohort of more than 150 000 births. In 50 years, the rate of stillbirth has decreased from 115 to 32 cases/10 000 births from the 1960s to 2000s, which represents a reduction of 72%. Stillbirth from unknown cause remains the most common contributor, with 40% of these cases occurring in late pregnancy.

Vulvar carcinosarcoma secondary to radiotherapy: a case report and review of the literature.

BACKGROUND: Carcinosarcomas, a malignancy consisting of squamous cell carcinoma with sarcomatous features, are extremely rare and aggressive tumor of the vulva. Including this case, there are 17 cases reported in the literature. Risk factors for this entity are poorly understood. CASE REPORT: We describe the case of a rapidly growing primary vulvar carcinosarcoma developing in an 84-year-old woman. The patient had previously received pelvic radiation for a squamous carcinoma of the anal canal. The excised vulvar tumor showed a superficial squamous carcinomatous element, associated vulvar intraepithelial neoplasia, and a transition into deeper sarcomatous component. By immunohistochemistry, the carcinomatous component was positive for keratins and negative for vimentin and smooth muscle actin, whereas the sarcomatous component was negative for keratins and positive for vimentin and smooth muscle actin. The patient was treated with hemivulvectomy with sentinel lymph node dissection followed by limited postoperative chemotherapy. The FIGO stage of the vulvar cancer was stage IB (T1 N0 M0), but even with this low stage, the patient had recurrence 17 months after treatment and died of her disease 8 months later. We compared age and stage at presentation, treatment, disease-free survival, and overall survival of our case to other reported vulvar carcinosarcomas. CONCLUSIONS: Vulvar carcinosarcomas are poorly characterized aggressive tumors with poor outcome. This is the first case reported that points to previous radiation exposure as a possible etiologic agent for this lesion.