Edward R. Oliver

Ribosomal protein L24 defect in belly spot and tail (Bst), a mouse Minute.

Ribosomal protein mutations, termed Minutes, have been instrumental in studying the coordination of cell and tissue growth in Drosophila. Although abundant in flies, equivalent defects in mammals are relatively unknown. Belly spot and tail (Bst) is a semidominant mouse mutation that disrupts pigmentation, somitogenesis and retinal cell fate determination. Here, we identify Bst as a deletion within the Rpl24 riboprotein gene. Bst significantly impairs Rpl24 splicing and ribosome biogenesis. Bst/+ cells have decreased rates of protein synthesis and proliferation, and are outcompeted by wild-type cells in C57BLKS↔ROSA26 chimeras. Bacterial artificial chromosome (BAC) and cDNA transgenes correct the mutant phenotypes. Our findings establish Bst as a mouse Minute and provide the first detailed characterization of a mammalian ribosomal protein mutation.

ATOH7 mutations cause autosomal recessive persistent hyperplasia of the primary vitreous

The vertebrate basic helix-loop-helix (bHLH) transcription factor ATOH7 (Math5) is specifically expressed in the embryonic neural retina and is required for the genesis of retinal ganglion cells (RGCs) and optic nerves. In Atoh7 mutant mice, the absence of trophic factors secreted by RGCs prevents the development of the intrinsic retinal vasculature and the regression of fetal blood vessels, causing persistent hyperplasia of the primary vitreous (PHPV). We therefore screened patients with hereditary PHPV, as well as bilateral optic nerve aplasia (ONA) or hypoplasia (ONH), for mutations in ATOH7. We identified a homozygous ATOH7 mutation (N46H) in a large family with an autosomal recessive PHPV disease trait linked to 10q21, and a heterozygous variant (R65G, p.Arg65Gly) in one of five sporadic ONA patients. High-density single-nucleotide polymorphism analysis also revealed a CNTN4 duplication and an OTX2 deletion in the ONA cohort. Functional analysis of ATOH7 bHLH domain substitutions, by electrophoretic mobility shift and luciferase cotransfection assays, revealed that the N46H variant cannot bind DNA or activate transcription, consistent with structural modeling. The N46H variant also failed to rescue RGC development in mouse Atoh7-/- retinal explants. The R65G variant retains all of these activities, similar to wild-type human ATOH7. Our results strongly suggest that autosomal recessive persistent hyperplastic primary vitreous is caused by N46H and is etiologically related to nonsyndromic congenital retinal nonattachment. The R65G allele, however, cannot explain the ONA phenotype. Our study firmly establishes ATOH7 as a retinal disease gene and provides a functional basis to analyze new coding variants.

Imaging of the Female Pelvis through the Life Cycle

The appearance of the normal reproductive tract on radiologic images changes dramatically over the female patients life span, reflecting the influence of hormones on these organs. In female children and adolescents, the appearance of the reproductive tract reflects the stage of sexual maturation. In women of reproductive age, physiologic changes such as those occurring in the corpus luteum are routinely imaged and must be distinguished from pathologic conditions. In the postmenopausal years, as reproductive hormone levels diminish, the endometrium and ovaries undergo progressive involution. Imaging findings that might be considered physiologic in younger women may represent pathologic or even neoplastic changes in postmenopausal women. Although postpartum imaging is typically performed in symptomatic patients, including those with greater than expected vaginal bleeding, suspected obstetric trauma, thromboembolic disease, or infectious complications, clinicians who interpret these radiologic results should be familiar with expected findings in asymptomatic patients after childbirth. Familiarity with the spectrum of ultrasonographic, computed tomographic, and magnetic resonance imaging appearances of the normal female reproductive tract from birth through the postmenopausal years will ultimately help clinicians avoid misinterpreting these normal physiologic changes as pathologic conditions.

Low-Dose Fetal CT in the Prenatal Evaluation of Skeletal Dysplasias and Other Severe Skeletal Abnormalities

OBJECTIVE Prenatal diagnosis of skeletal dysplasia is often difficult and based on findings with ultrasound, a technique with 40-60% sensitivity. The purpose of this study was to evaluate a preliminary experience in assessing severe prenatal osseous abnormalities with low-dose fetal CT. The hypothesis was that use of CT may improve the prenatal diagnosis of skeletal dysplasia beyond the available capabilities of ultrasound. MATERIALS AND METHODS Retrospective search of a radiology database (July 2008-February 2011) yielded the records of unenhanced CT examinations of patients referred because of abnormal fetal bones. The original ultrasound and CT reports as interpreted at image acquisition were independently analyzed by two radiologists blinded to the final diagnosis and to the findings of the opposing imaging modality. Blinded review of the images was also performed. Correlation was made with the postmortem and postnatal findings. RESULTS According to the reports of the studies, 5 of 21 cases were interpreted correctly with CT and incorrectly with ultrasound. In 17 cases, CT revealed additional osseous findings not in the ultrasound report. There were no cases in which ultrasound findings were correct and CT findings were incorrect. Blinded review of the images revealed that CT outperformed ultrasound (p < 0.001). There were a total of four CT errors among 218 total measures recorded and a total of 19 ultrasound errors among 218 total measures. CONCLUSION Although low-dose fetal CT should never be used as the initial diagnostic modality in cases of suspected skeletal dysplasia, it is a powerful imaging adjunct that depicts the fetal bones in exquisite detail. Use of CT of fetuses at risk of skeletal dysplasia may provide clinicians with more accurate information for counseling of families regarding neonatal morbidity and mortality.

Sonographic Features of Rare Posterior Fetal Neck Masses of Vascular Origin

The purpose of this series is to describe the grayscale and color Doppler sonographic characteristics as well as the histopathologic features of rare solid posterior neck masses identified on prenatal sonography in pregnant patients. We conducted a retrospective review of detailed fetal sonographic examinations of second- and third-trimester pregnancies referred to the Center for Fetal Diagnosis and Treatment at the Childrens Hospital of Philadelphia for suspected fetal neck masses from June 1998 to December 2011. Eight predominately solid posterior neck masses were identified on 139 studies performed during the study period. Of the 7 cases in which follow-up was available, 6 were confirmed as hemangiomas, and 1 was confirmed as a kaposiform hemangioendothelioma with Kasabach-Merritt syndrome. The most common sonographic features were hypervascularity (7) and calcifications (5). Posterior solid fetal neck masses are rare anomalies. Hemangioma is the most common etiology and should be suggested as the likely diagnosis rather than teratoma, even in the presence of calcifications.

Right Congenital Diaphragmatic Hernias: Is There a Correlation between Prenatal Lung Volume and Postnatal Survival, as in Isolated Left Diaphragmatic Hernias

Objectives: Whereas left-sided congenital diaphragmatic hernias (L-CDH) have been extensively studied and their prognostic parameters delineated, right-sided hernias (R-CDH) have not. Published results remain inconclusive. The aim of this study is to evaluate if proven prognostic indicators of postnatal survival in the fetus with L-CDH apply to the fetus with R-CDH. Methods: Retrospective single-center study of R-CDH fetuses with available prenatal studies assessed for fetal lung volume by means of ultrasound-measured observed versus expected (O/E) lung area to head circumference (LHR) and magnetic resonance-calculated O/E total lung volume (TLV) in a 12-year time period. Percentage of herniated liver volume and postnatal use of extracorporeal membrane oxygenation (ECMO) were also evaluated. Results: In a cohort of 24 patients, O/E LHR, O/E TLV, percentage of herniated liver, and postnatal use of ECMO are not prognostic indicators of survival in the fetus with R-CDH. Cut-off values of O/E LHR of ≤45 or O/E TLV ≤25, known to select a population of severe cases for the L-CDH fetus, do not appear to extrapolate to the R-CDH fetus, as survival in both R-CDH groups is 60%. Conclusion: The findings in this study suggest that L- and R-CDH appear to behave differently, and that factors that make L-CDH fatal (low O/E TLV and O/E LHR, high-volume herniated liver) may not apply to the fetus with R-CDH.

Going With the Flow: An Aid in Detecting and Differentiating Bronchopulmonary Sequestrations and Hybrid Lesions

To assess the ability of prenatal ultrasound (US) in identifying systemic feeding arteries in bronchopulmonary sequestrations and hybrid lesions and report the ability of US in classifying bronchopulmonary sequestrations as intralobar or extralobar.

The gravid uterus: MR imaging and reporting of abnormal placentation

Appropriate placentation is critical to maternal and fetal outcomes. Abnormal placentation, including placenta previa and morbidly adherent placenta, is increasing in incidence and is associated with multiple risk factors including advanced maternal age and history of prior cesarean delivery. Magnetic resonance imaging (MRI) is increasingly used in assessing the type and extent of abnormal placentation, often leading to modifications in surgical approach. Here, we review the MRI features and appropriate reporting of placenta previa and the placenta accreta spectrum.

Twin Reversed Arterial Perfusion Sequence A New Method of Parabiotic Twin Mass Estimation Correlated With Pump Twin Compromise

The purpose of this study was to test the hypothesis that using the formula of a prolate ellipsoid to estimate parabiotic twin mass correlates better with findings of pump twin compromise than using the sonographic method of Moore et al (Am J Obstet Gynecol 1990; 163:907–912).

Prenatal growth characteristics and pre/postnatal management of bronchopulmonary sequestrations

PURPOSE The prenatal natural history of intralobar and extralobar bronchopulmonary sequestrations (BPSs), including lesion growth patterns and need for prenatal intervention, have not been fully characterized. We review our series of BPSs to determine their natural history and outcomes in the context of the need for prenatal intervention. METHODS A retrospective review of the pre/postnatal course of 103 fetuses with an intralobar (n=44) or extralobar BPS (n=59) managed at a single institution between 2008 and 2015 was performed. Outcomes included prenatal lesion growth trajectory, presence of hydrops, need for prenatal intervention, survival, and postnatal surgical management. RESULTS Most extralobar (71%) and intralobar BPSs (94%) decreased in size or became isoechoic from initial to final evaluation. Peak lesion size occurred at 26-28weeks gestation. Eight fetuses developed hydrothorax, four of which (all extralobar BPSs) also developed hydrops. All four hydropic fetuses received maternal betamethasone, and three hydropic fetuses underwent thoracentesis and/or thoracoamniotic shunt placement with subsequent hydrops resolution. All fetuses survived. Forty-one intralobar (93%) and 35 extralobar BPSs (59%) were resected after birth. CONCLUSIONS BPSs tend to decrease in size after 26-28weeks gestation and rarely require fetal intervention. Lesions resulting in hydrothorax ± hydrops can be effectively managed with maternal steroids and/or drainage of the hydrothorax. LEVEL OF EVIDENCE IV.