Third case of Bardet-Biedl syndrome caused by a biallelic variant predicted to affect splicing of IFT74.

Bardet-Biedl syndrome (BBS) is a rare ciliopathy characterized by rod-cone dystrophy, postaxial polydactyly, truncal obesity and renal anomalies with autosomal recessive inheritance. We describe a 6-year-old male with early onset retinal dystrophy, postaxial polydactyly, truncal obesity and motor delays. Exome sequencing revealed a homozygous variant predicted to affect splicing of the IFT74 gene, c.1685-1G > T. This is the third patient with BBS due to variants predicting loss of function in IFT74. All three patients have had retinal dystrophy, polydactyly, obesity, developmental differences, and a notable lack of renal anomalies. We recommend that IFT74 is added to gene panels for the diagnosis of BBS.

Diagnostic testing after positive results on cell free DNA screening: CVS or Amnio?

OBJECTIVE: The positive predictive values of cell free DNA (cfDNA) and rates of confined placental mosaicism (CPM), imprinting and other factors vary by chromosome. METHODS: We sought to review the literature for each of these features for each chromosome and provide recommendations on chorionic villus sampling (CVS) versus amniocentesis after an abnormal cfDNA result. RESULTS: For chromosomes with high rates of CPM (trisomy 13, monosomy X and rare autosomal trisomies [RATs]), an amniocentesis should be considered if the first trimester ultrasound is normal. For monosomy X on cfDNA with an unaffected fetus, maternal karyotyping should be considered after normal fetal diagnostic testing. In cfDNA cases with a trisomy involving a chromosome with imprinted genes (6, 7, 11, 14, 15 and 20), CVS should be considered, followed by amniocentesis if abnormal. If the fetus is unaffected, methylation studies should be considered given the risk of uniparental disomy. A third trimester growth ultrasound should be considered for patients with a positive cfDNA screen for a RAT and an unaffected fetus, especially in the case of trisomy 16. For patients with multiple aneuploidy results on cfDNA, a work-up for maternal malignancy should be considered. CONCLUSIONS: Clinicians should consider rates of CPM, imprinting, ultrasound findings and maternal factors when considering whether to recommend amniocentesis or CVS after an abnormal cfDNA result.

In Utero Gene Therapy for Primary Immunodeficiencies.

Primary immunodeficiencies (PIDs) have become a prime target for gene therapy given the morbidity, mortality, and the single gene etiology. Given that outcomes are better the earlier gene therapy is implemented, it is possible that fetal gene therapy may be an important future direction for the treatment of PIDs. In this chapter, the current treatments available for several PIDs will be reviewed, as well as the history and current status of gene therapy for PIDs. The possibility of in utero gene therapy as a possibility will then be discussed.

Maternal genetic disorders and fetal development.

With improvements in early diagnosis and management of genetic diseases, more women with genetic disorders are reaching reproductive age and becoming pregnant. While pregnancy can have a significant impact on a woman's health when there is an underlying genetic disorder, there can also be fetal effects, including embryopathy, fetal growth restriction, and brain injury. Some maternal genetic disorders are associated with adverse perinatal outcomes, including a high risk of perinatal loss and preterm birth. In this article, we review several maternal genetic disorders associated with fetal risk that are important for clinicians and patients to understand and manage appropriately. These include phenylalanine hydroxylase (PAH) deficiency and other inborn errors of metabolism, tuberous sclerosis complex, myotonic dystrophy, cystic fibrosis, Turner syndrome, sickle cell disease, and connective tissue disorders.

Utility of chromosomal microarray for diagnosis in cases of nonimmune hydrops fetalis.

PURPOSE: Chromosomal microarray (CMA) is recommended in the diagnostic evaluation of cases with fetal structural anomalies when invasive testing is pursued. However, the utility of CMA for nonimmune hydrops fetalis (NIHF) specifically is not well known. Our objective was to describe the overall yield of CMA in the diagnostic evaluation of NIHF, comparing isolated cases to those with concurrent structural anomalies. METHODS: This was a retrospective cohort study of all prenatally diagnosed NIHF cases evaluated at the University of California, San Francisco from 2008 to 2018. NIHF due to twin-twin transfusion syndrome was excluded. RESULTS: There were 131 cases of prenatally diagnosed NIHF. In 43/44 cases with a CMA performed, results were categorized as normal or likely benign. One case was found on CMA to have a large pathogenic duplication of 21p11.2q22.3, which could have been detected by karyotype and was consistent with a diagnosis of Down syndrome. There was no incremental yield demonstrated for CMA over karyotype. CONCLUSIONS: Among a cohort of prenatally diagnosed NIHF cases, CMA did not identify any copy number variants beyond those detectable by karyotype, and the vast majority of CMAs were normal. These results suggest that CMA has low diagnostic utility for NIHF.

X-linked duplication copy number variation in a familial overgrowth condition.

We describe an overgrowth condition associated with X-linked copy number variation. Three brothers displayed an overgrowth pattern at birth that continued postnatally. Clinical findings included macrocephaly, distinctive facial features, developmental delay and variable clubfoot. Normal fetal growth was noted until the third trimester by Hadlock standards, revealing a late gestational overgrowth pattern. Microarray analysis in the family showed a maternally inherited 680 kb copy number duplication at Xq26.1-q26.2 in all three brothers. Molecular sequencing for known overgrowth conditions including GPC3, Sotos 1 (NSD1), Malan (NFIX), Perlman (DIS3L2), Weaver (EZH2), Opitz-Kaveggia (MED12) loci were negative. BWS IC1 and IC2 methylation and CDKN1C testing was also negative. Normal IGF1 levels excluded X-linked acrogiantism. The duplicated region Xq26.1-q26.2 contained IGSF1 and at least part of the lncRNA FIRRE. IGSF1, a highly expressed pituitary immunoglobulin superfamily gene, was recently implicated in a genome-wide association study of canine size. IGSF1 variants were associated with large canine breeds compared to smaller breeds. Our findings support the hypothesis that an X-linked variant encompassing the IGSF1 region may be associated with body size. Although IGSF1 loss has been noted in human hypothyroidism, this is the first reported phenotype in a family with copy number duplication in the region. Our findings suggest that prenatal evaluation, cross-species evaluation, Mendelian, and GWAS studies may describe a distinctive familial condition and its corresponding phenotypic features.

Nonimmune hydrops fetalis: identifying the underlying genetic etiology.

PURPOSE: Numerous etiologies may lead to nonimmune hydrops fetalis (NIHF), and the underlying cause often remains unclear. We aimed to determine the proportion of NIHF cases in which the etiology was clearly determined in a large, contemporary, and diverse cohort, as well as to describe the etiologies with a focus on genetic causes. METHODS: Retrospective review of NIHF cases between 2015 and 2017 from the five University of California Fetal-Maternal Consortium sites. Singleton pregnancies with prenatally diagnosed NIHF were included, and cases with maternal alloimmunization were excluded. Cases were categorized as being of confirmed, suspected, or unknown etiology. RESULTS: Sixty-five NIHF cases were identified. Forty-six percent (30/65) remained of unknown etiology, while 9.2% (6/65) had a suspected etiology and 44.6% (29/65) were of confirmed etiology. Among confirmed cases, 11 resulted from aneuploidy; 7 from fetal structural anomalies; 2 each from fetal arrhythmia, Noonan syndrome, and generalized lymphatic dysplasia; and 1 each from arthrogryposis, parvovirus, neonatal alloimmune thrombocytopenia, fetal goiter, and Kasabach-Merritt syndrome. CONCLUSION: In this contemporary, multicenter study, the cause of prenatally diagnosed NIHF was confirmed in only 44% of cases, and a genetic etiology was found in only 25% of those that received standard of care genetic testing.

A system-based approach to the genetic etiologies of non-immune hydrops fetalis.

A wide spectrum of genetic causes may lead to nonimmune hydrops fetalis (NIHF), and a thorough phenotypic and genetic evaluation are essential to determine the underlying etiology, optimally manage these pregnancies, and inform discussions about anticipated prognosis. In this review, we outline the known genetic etiologies of NIHF by fetal organ system affected, and provide a systematic approach to the evaluation of NIHF. Some of the underlying genetic disorders are associated with characteristic phenotypic features that may be seen on prenatal ultrasound, such as hepatomegaly with lysosomal storage disorders, hyperechoic kidneys with congenital nephrosis, or pulmonary valve stenosis with RASopathies. However, this is not always the case, and the approach to evaluation must include prenatal ultrasound findings as well as genetic testing and many other factors. Genetic testing that has been utilized for NIHF ranges from standard chromosomal microarray or karyotype to gene panels and broad approaches such as whole exome sequencing. Family and obstetric history, as well as pathology examination, can yield additional clues that are helpful in establishing a diagnosis. A systematic approach to evaluation can guide a more targeted approach to genetic evaluation, diagnosis, and management of NIHF.

Anal sphincter injury in vaginal deliveries complicated by shoulder dystocia.

INTRODUCTION AND HYPOTHESIS: Shoulder dystocia is an obstetric emergency that occurs in 0.2-3% of all cephalic vaginal deliveries. We hypothesized that because of the difficult nature of deliveries complicated by shoulder dystocia, the condition may be associated with anal sphincter injury. We sought to identify risk factors for obstetric anal sphincter injury in women with shoulder dystocia. METHODS: This retrospective analysis included all cases of shoulder dystocia from 2007 to 2011 at two large tertiary referral centers, in the USA and Ireland. Details of maternal demographics, intrapartum characteristics, and delivery outcomes in cases of shoulder dystocia were analyzed. Univariate and multivariate analyses were used to describe the association between shoulder dystocia and anal sphincter injury. RESULTS: There were 685 cases of shoulder dystocia, and the rate of shoulder dystocia was similar at both institutions. The incidence of anal sphincter injury was 8.8% (60 out of 685). The rate was 14% (45 out of 324) in nulliparas and 4.2% (15 out of 361) in multiparas. Women with sphincter injury were more likely to be nulliparous (75% [45 out of 60] vs 45% [279 out of 625]; p < 0.0001), have had an operative vaginal delivery (50% [30 out of 60] vs 36% [226 out of 625]; p = 0.03) and require internal maneuvers (50% [30 out of 60] vs 32% [198 out of 625], p = 0.004) than those with an intact sphincter. On multivariate regression analysis, these predictors of sphincter injury remained significant when adjusted for other risk factors. Episiotomy was negatively associated with sphincter injury on multivariate regression analysis. CONCLUSIONS: In a retrospective cohort of 685 women with shoulder dystocia, the risk of anal sphincter injury is 9%. Risk factors include nulliparity, operative vaginal delivery, and use of internal maneuvers, whereas episiotomy was found to have a protective effect against anal sphincter injury during cases of shoulder dystocia.

A prediction model of vaginal birth after cesarean in the preterm period.

BACKGROUND: A validated model exists that predicts the probability of vaginal birth after cesarean delivery in patients at term who are undergoing a trial of labor after cesarean delivery. However, a model that predicts the success of a vaginal birth after cesarean delivery in the preterm period has not been developed. OBJECTIVE: We sought to develop and validate a predictive model for vaginal birth after cesarean delivery for women undergoing a trial of labor after cesarean delivery during the preterm period. STUDY DESIGN: We performed a secondary analysis of a prospective cohort study designed to evaluate perinatal outcomes in women with a prior cesarean scar. We included women with 1 prior low transverse cesarean delivery undergoing a trial of labor after cesarean delivery with a vertex singleton pregnancy in the preterm period (26-36 weeks). Using multivariable logistic regression modeling, we constructed a predictive model for vaginal birth after cesarean delivery with information known at admission for preterm delivery. Using a 70% to 30% random split of the data, the model was developed in the training data and subsequently confirmed in the validation data. Predictions and area under the curve were based on a 10-fold cross-validated jackknife estimation and based on 1000 bootstrap resampling methods. The adequacy of all models was evaluated based on the Hosmer-Lemeshow goodness-of-fit test. RESULTS: One thousand two hundred ninety-five women met our criteria for analysis. The significant predictors of vaginal birth after cesarean delivery success were chronic hypertension, hypertensive disease of pregnancy (gestational hypertension or preeclampsia), prior vaginal delivery, dilation on cervical examination at admission, prior vaginal birth after cesarean delivery, a recurring indication in a prior cesarean delivery, and induction of labor as well as a 2-way interactions between dilation and hypertensive disease of pregnancy, dilation and diabetes mellitus (pregestational or gestational), and induction of labor and hypertensive disease of pregnancy. The area under the curve from the prediction model was 0.80 (95% confidence interval, 0.77-0.83) and the model fit the data well (Hosmer-Lemeshow P = .367). The bootstrap and 10-fold cross-validated jackknife estimates of the corrected area under the curve of the model were 0.78 (95% confidence interval, 0.74-0.82) and 0.77 (95% confidence interval, 0.73-0.82), respectively, following incorporation of regression shrinkage. CONCLUSION: A cross-validated predictive model was created for patients undergoing a trial of labor after cesarean delivery in the preterm period using 8 variables known on admission. These factors were notably different from factors used in the model for term patients. This new model can be used to counsel patients in the preterm period who want to undergo a trial of labor after cesarean delivery on their predicted vaginal birth after cesarean delivery success.

Venous Thromboembolism Prophylaxis During Antepartum Admissions and Postpartum Readmissions.

OBJECTIVE: To characterize the use of venous thromboembolism prophylaxis during antepartum and postpartum hospitalizations in the United States. METHODS: A retrospective cohort study using the Perspective database was performed to analyze temporal trends of mechanical and pharmacologic venous thromboembolism prophylaxis for patients hospitalized for antepartum and postpartum indications between 2006 and 2015. Delivery hospitalizations were excluded. The association between use of prophylaxis and medical and obstetric risk factors as well as patient demographic and hospital characteristics was evaluated with unadjusted and adjusted models accounting for demographic, hospital and medical, and obstetric risk factors. RESULTS: A total of 622,740 antepartum and 105,361 postpartum readmissions were identified and included in the analysis. Between 2006 and 2015, use of venous thromboembolism prophylaxis increased from 18.5% to 38.7% for antepartum admissions (adjusted risk ratio [RR] 1.94, 95% CI 1.88-2.01) and from 22.5% to 30.6% for postpartum readmissions (adjusted RR 1.31, 95% CI 1.21-1.43). Among women readmitted postpartum, 56.4% of prophylaxis was pharmacologic and 43.6% was mechanical. For antepartum admissions, 87.2% of prophylaxis was mechanical and 12.8% was pharmacologic. Significant regional and hospital-level variation was noted with prophylaxis most common in the South. In both unadjusted and unadjusted analyses, use of venous thromboembolism prophylaxis was more common for women with thrombophilia, ovarian hyperstimulation syndrome, a history of venous thromboembolism, and prolonged hospitalization. Factors associated with decreased rates of prophylaxis included hyperemesis and postpartum endometritis. CONCLUSION: Although antepartum and postpartum venous thromboembolism prophylaxis is becoming increasingly common, particularly in the setting of medical or obstetric risk factors, use of prophylaxis varies regionally and on a hospital level. Some risk factors for venous thromboembolism were associated with lower rates of prophylaxis. The heterogeneity of clinical approaches to venous thromboembolism prophylaxis for these patient populations may represent an opportunity to perform outcomes research to further clarify best practices.