Sarah Keating

SickKids, Toronto, Ontario, Canada

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Publications (77)203.09 Total impact

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    ABSTRACT: To determine the incidence of temporal lobe dysplasia (TLD) detected on prenatal ultrasound in thanatophoric dysplasia (TD) over an 11-year period in a tertiary referral centre. An 11-year retrospective review of perinatal autopsies was performed from 2002 to 2013 to identify cases of TD. The ultrasound images and corresponding reports of all TD cases were reviewed for TLD. The same set of images subsequently underwent a retrospective review by a perinatal radiologist with knowledge of the TLD feature to determine whether they could be identified. There were 31 TD cases that underwent perinatal autopsy. Prenatal ultrasound imaging was available to review in 24/31 (77%) cases. Mean gestational age (GA) of TD diagnosis was 21.3 weeks (range: 18-36 weeks). TLD was identified and reported in 6/24 (25%) cases; all six cases occurred after 2007. Retrospective interpretation of the ultrasound images identified features of TLD in 10 additional cases. In total, 16/24 (67%) cases displayed sonographic evidence of TLD. Temporal trends show that TLD features were present in 50% (5/10) of all TD cases from 2002-2006 and in 79% (11/14) of the cases from 2007-2013. Currently, the detection rate of TLD by ultrasound is low but may be increased by modified brain images that enhance visualization of the temporal lobes. Prenatal identification of TLD may help in the prenatal diagnosis of TD and thus provide more accurate prenatal counseling and guide molecular investigations to confirm the specific diagnosis of TD.
    Ultrasound in Obstetrics and Gynecology 02/2014; · 3.56 Impact Factor
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    ABSTRACT: To describe the prenatal sonographic features and the results of DNA analysis on three fetuses with Dyssegmental Dysplasia, Silverman-Handmaker Type (DD-SH). A retrospective review of three fetuses with confirmed DD-SH was conducted. The fetal ultrasound findings, radiological characteristics and results of the mutation analysis of the HSPG2 gene were reviewed. There were 3 cases in two families with DD-SH diagnosed prenatally. The main prenatal ultrasound and radiological features of DD-SH were severe limb shortening and vertebral segmentation and fusion defects (anisospondyly). DNA analysis of the HSPG2 gene showed that the two affected fetuses in a non-consanguineous family had a compound heterozygote for the c.646G > T transversion in exon 7 and a c.5788C > T transition in exon 46. The fetus born to the consanguineous couple had a homozygous mutation c.1356-27_1507 + 59del. DD-SH can be diagnosed prenatally using fetal ultrasound as early as 13 weeks. Fetal X-rays and DNA analysis of the HSPG2 gene are important for confirmation of the diagnosis and for pre-implantation and prenatal diagnosis in pregnancies at risk. This article is protected by copyright. All rights reserved.
    Prenatal Diagnosis 07/2013; · 2.68 Impact Factor
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    ABSTRACT: Severely-growth discordant monochorionic (MC) twins offer a unique opportunity to study fetal and placental growth based on a similar genetic background and maternal host environment where the healthy twin serves as an ideal control. Differences in development of monochorionic twins may therefore be due to differential epigenetic regulation of genes involved in placental development and function. Growth-discordant twins are known for abnormal angio-architecture in the placenta of the smaller twin. Since the reasons for this phenotype are mostly unknown this study was aimed to investigate expression and regulation of genes known to be involved in angiogenesis.We studied 10 severely growth-discordant monochorionic twin placentas (birth weight difference≥20%) without twin-twin-transfusion syndrome (TTTS) and 5 growth-concordant monochorionic twin placentas. Growth discordant twin placentas were phenotyped by histology. Placental mRNA expression of 88 angiogenesis related genes were measured by PCR array. Enzyme-linked immuno-sorbent assay (ELISA) and immuno-histochemistry were used to confirm PCR results. EpiTYPTER for DNA methylation was used to determine if methylation ratios were responsible for differential gene expression.The PCR array analysis showed significant mRNA up-regulation in the placental share of the smaller twin for several genes. These included Leptin (24.6 fold, p=0.017), Flt1 (fms-like tyrosine kinase 1, 2.4 fold, p=0.016) and Eng (Endoglin, 1.86 fold, p= 0.078). None of the other 84 angiogenesis related genes showed significant differences. ELISA confirmed significantly increased Leptin protein expression (49.22 vs. 11.03 pg/mL, p=0.049) in the smaller twin of the discordant growth cohort. Leptin expression in smaller twins' placentas was associated with elevated DNA methylation of the Leptin promotor region suggesting the inhibition of binding of a transcriptional activator / inhibitor in that region. We attempted to overcome the limitation of sample size by careful patient selection. We minimized any bias in placental sampling by random sampling from two different sites and by avoiding sampling from areas with grossly visible abnormalities using a standardized sampling protocol.In conclusion, the smaller twin's placenta is characterized by differentially-increased gene expressions for Flt1 and Eng mRNA that may be causally-associated with the villous pathology driven by abnormal feto-placental angiogenesis. The substantial up-regulation of Leptin mRNA may be epigenetically conferred and relevant to the post-natal risk of metabolic syndrome in IUGR offspring with placental pathology. Growth discordant MC twins offer unique insights into the epigenetic basis of perinatal programming.
    Molecular Human Reproduction 07/2013; · 4.54 Impact Factor
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    ABSTRACT: OBJECTIVES: To review the association between associated ultrasound findings, placental pathology and prognosis in pregnancies complicated by massive subchorionic thrombo-hematoma(MTH)/Breus' mole. METHOD: We identified 14 cases of MTH from January 2004 to December 2012. MTH was defined by: > 1 cm thickness hematoma, and extensive (≥ 50%) involvement of the fetal surface of the placenta. Patient information, details of initial presentation and perinatal outcome were obtained from the manual and electronic chart records. Ultrasound findings were related to pregnancy outcomes and associated placental pathology. Participants were stratified based on birth outcome into survivors (live births, n = 7) and non-survivors (NND or IUFD/TOP, n = 7). RESULTS: All 14 cases of MTH were suspected on ultrasound and confirmed by pathology assessment. All cases in the non-survivors group had abnormal umbilical artery Doppler waveforms compared to none in the survivors (p = 0.02). All cases in the non-survivor group had extreme preterm deliveries (p = 0.02). Birth weight was significantly reduced in the non-survivor group (p = 0.001), and 5/7 cases were diagnosed with severe intrauterine growth restriction, compared to none in the survivor group (p = 0.02). CONCLUSION: MTH/Breus' mole may be diagnosed in the second trimester by ultrasound assessment of the placenta. Normal fetal growth and umbilical artery Doppler waveforms are associated with perinatal survival. This article is protected by copyright. All rights reserved.
    Prenatal Diagnosis 06/2013; · 2.68 Impact Factor
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    ABSTRACT: OBJECTIVE: To report 3 different antenatal therapeutic approaches for fetal lung masses associated with hydrops. METHODS: Three prospectively followed cases are described and all 17 previously published minimally invasive cases of fetal therapy for hydropic lung masses are reviewed. RESULTS: Three hydropic fetuses with large intra-thoracic lung masses presented at 17, 21 and 24 weeks gestation, respectively. An aortic feeding vessel was identified in each case and thus a broncho-pulmonary sequestration (BPS) was suspected. Under ultrasound guidance, the feeding vessel was successfully occluded with: (1) interstitial laser; (2) thrombogenic coil embolisation and (3) radio-frequency ablation (RFA). Complete (1&3) or partial (2) resolution of the lung mass and hydrops was observed in all cases. An healthy infant was born at term after laser therapy (1), and the involved lung lobe was resected at day on day 2 of life. Despite technical success in complete vascular occlusion with coils, a stillbirth ensued 2 days after embolisation. In case 3, hydrops resolved completely following RFA, but an iatrogenic congenital diaphragmatic hernia and abdominal wall defect became apparent 4 weeks later. The neonate died from sepsis following spontaneous preterm labour at 33 weeks. CONCLUSIONS: The natural history of large microcystic or echogenic fetal chest masses associated with hydrops is dismal. This has prompted attempts at treatment by open fetal surgery, with mixed results, high risk of premature labor and consequences for future pregnancies. We have demonstrated the possibility of improved outcome following ultrasound-guided laser ablation of the systemic arterial supply. Despite technical success, RFA and coil embolisation led to procedure related complications and need further evaluation.
    Ultrasound in Obstetrics and Gynecology 05/2013; · 3.56 Impact Factor
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    ABSTRACT: Nephronophthisis associated ciliopathies (NPHP-AC) are a group of phenotypically related conditions that include Joubert syndrome, Meckel syndrome, nephronophthisis (NPHP), and Senior-Loken syndrome. We report on a male fetus with prenatal ultrasound findings at 24 weeks of gestation of anhydramnios, large and echogenic kidneys and situs inversus totalis. Histopathology revealed nephronophthisis and tracheal mucosa electron microscopy revealed ciliary dysgenesis. DNA analysis of the NPHP genes showed a previously unreported homozygous mutation, p.Arg603* (c.1078+1G>A), in the INVS/NPHP2 gene. This mutation is thought to abolish the splice donor site for exon 8, which likely disrupts the normal splicing of the INVS/NPHP2 gene. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 05/2013; · 2.30 Impact Factor
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    ABSTRACT: Objective: To assess the effectiveness of a multidisciplinary team approach to reduce severe maternal morbidity in women with invasive placenta previa. Methods: We conducted a prospective study of 33 women with placenta previa and increta-percreta (diagnosed by ultrasound and/or magnetic resonance imaging) delivering at Mount Sinai Hospital, Toronto, following the introduction in January 2008 of a team-based approach to women with this condition. We included women who delivered by June 2012. We reviewed antenatal outpatient and inpatient records for use of six pre-defined team components by the attending staff obstetrician: (1) antenatal maternal-fetal medicine consultation, (2) surgical gynaecology consultation, (3) antenatal MRI, (4) interventional radiology consultation and preoperative placement of balloon catheters in the anterior divisions of the internal iliac arteries, (5) pre-planned surgical date, and (6) surgery performed by members of the invasive placenta surgical team. Antenatal course, delivery, and postpartum details were recorded to derive a five-point composite severe maternal morbidity score based on the presence or absence of: (1) ICU admission following delivery, (2) transfusion > 2 units of blood, (3) general anaesthesia start or conversion, (4) operating time in highest quartile (> 125 minutes), and (5) significant postoperative complications (readmission, prolonged postpartum stay, and/or pulmonary embolism). Results: All 33 women survived during this time period. Two thirds (22/33) had either five or six of the six components of multidisciplinary care. Increasing use of multidisciplinary team components was associated with a significant reduction in composite morbidity (R2 = 0.228, P = 0.005). Conclusion: Team-based assessment and management of women with invasive placenta previa is likely to improve maternal outcomes and should be encouraged on a regional basis.
    Journal of obstetrics and gynaecology Canada: JOGC = Journal d'obstetrique et gynecologie du Canada: JOGC 05/2013; 35(5):417-25.
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    ABSTRACT: Objectives: To determine the pathologic basis and clinical associations of excessively thick placentas observed at second-trimester ultrasound examinations. Methods: Maximum sonographic placental thickness was correlated with clinical outcomes, maximum placental thickness after delivery and placental pathologic findings in a retrospective cohort of 19 singleton high-risk pregnancies noted to have a placental length to thickness ratio ≤ 2.0, in the second trimester. Findings were compared with an intermediate group of 21 high risk pregnancies, and a control group of 18 low-risk pregnancies. Increased maximum placental thickness (>28 mm) and abnormal placental deflation following delivery (pathology-sonography maximum thickness below -2mm) were defined by the upper and lower quartile values respectively in the control group. Results: The study group exhibited significantly more adverse outcomes and gross pathological placental features as compared to both the intermediate and control groups. Despite increased sonographic placental thickness (median 55mm [range 41 to 75] vs. 27 [21.7 to 41], p<0.0001 vs. 26 [23 to 36], p<0.0001) study and control placentas had similar maximal thickness following delivery (median 24mm [range 10 to 50] vs. 27 [15 to 40], p=0.82 vs. 28.5 [18 to 44], p=0.42). Placental pathology-sonography difference (<-2mm) in the study group (median -30 [-41 to 0]) was significantly greater than either the intermediate (-2 [-11 to 9], p<0.0001) or control (1.5 [-10 to 18], p<0.0001) groups and was significantly associated with abnormal development of the gas-exchanging placental villi (distal villous hypoplasia) (p=0.0001). Conclusions: Increased second trimester sonographic placental thickness represents a pathologic finding associated with severe adverse perinatal outcomes. This observation is due to over-inflation of the inter-villous space by maternal blood rather than by adaptive formation of functional placental tissue. Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.
    Ultrasound in Obstetrics and Gynecology 01/2013; · 3.56 Impact Factor
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    ABSTRACT: We report on a child with prenatal onset of overgrowth associated with thick, excessive wrinkled skin and other abnormalities including cleft palate, Chiari malformation and polymicrogyria. His clinical features do not resemble any of the known reported overgrowth syndromes. Genetic evaluations, including karyotype, oligoarray, methylation-sensitive multiplex ligation-dependent probe amplification (MLPA) for 11p11.2 region, CDKN1C sequencing, GPC3 sequencing and dosage analysis, and HRAS sequencing, have been un-revealing. Immunohistochemistry done on the patient's cultured skin fibroblasts showed normally assembled elastic fibers and normal pattern of chondroitin sulfate deposition with defective deposition of Collagen I fibers. In addition, there were high levels of immuno-detectable metalloproteinase 3 (MMP3) and undetectable tissue inhibitor of metalloproteinase 1 (TIMP1). The defective collagen deposition in the fibroblast culture could be reversed by the broad spectrum MMP inhibitor, doxycycline. We also present evidence that the fibroblasts of this patient have an increased rate of cellular proliferation. We propose that this is a previously unrecognized overgrowth syndrome associated with increased cellular proliferation and defective collagen I deposition due to an imbalance between MMP and TIMP in fibroblasts. © 2012 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 09/2012; 158A(10):2373-81. · 2.30 Impact Factor
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    ABSTRACT: To determine the utility of measuring maximum placental length in the second trimester to predict a small for gestational age placenta by weight at delivery in clinically high-risk women. Placental dimensions determined by 2-dimensional (2-D) real-time ultrasound at 19-23 weeks' gestation were compared to post-natal placental weights and pathology in 95 high-risk patients with singleton pregnancies. Maximum placental length <10.0 cm performed poorly (false positive rate 25.5%) for the detection of a small placenta by weight at delivery. Placental pathology examination revealed eccentric cord insertion to be an important explanation for poor screening test result, since this finding was significantly more common in the false negative group (length ≥10.0 cm, weight <10th percentile) compared with the true negative group (length ≥10.0 cm, weight ≥10th percentile) (15/28 vs. 9/38, Fisher's exact test, p = 0.005). Prediction of reduced placental weight by 2-D ultrasound determination of maximum placental length in clinically high-risk pregnancies confounded by the phenomenon of asymmetric chorion regression. Refinement of 2-D ultrasound methods to include orthogonal plane measurements, or replacement by 3-D techniques is predicted to significantly improve the effectiveness of diagnosing small placentas in-utero.
    Placenta 07/2012; 33(10):845-9. · 3.12 Impact Factor
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    ABSTRACT: Distal villous hypoplasia is a form of placental villous maldevelopment that has the potential to cause significant intrauterine growth restriction with adverse consequences for fetal viability, neurodevelopmental outcome and adult cardiovascular health. It is characterized by a sparse, poorly developed distal villous tree with abnormally shaped, elongated, slender villi and widening of the intervillous space. Generally, villi show widespread trophoblast abnormalities with thinning of the villous trophoblast layer, reduction in cytotrophoblast numbers, evidence of a widespread increase in syncytiotrophoblast nuclear senescence and wave-like syncytial knots. Investigation of pregnancies with false positive serum screening tests for fetal aneuploidy/structural defects can help identify pregnancies at risk of placental insufficiency, particularly when combined with ultrasound assessment of placental morphology at 19–22 weeks. Identification of pregnancies with multiple abnormal tests of placental function permits high-risk specialist referral to optimize maternal-fetal outcome.
    Diagnostic Histopathology. 05/2012; 18(5):195–200.
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    ABSTRACT: Since pregnancies with a male fetus have higher perinatal complications attributed to placental dysfunction, including severe pre-eclampsia and intrauterine growth restriction, the objective of our study was to formally evaluate placental pathology for a placental origin of these sex-specific differences. Retrospective study at Mount Sinai Hospital in Toronto, Canada. Identification of 262 singleton pregnancies affected by severe pre-eclampsia and/or intrauterine growth restriction who delivered between 22 and 32 weeks' gestation from 2000 to 2010. Detailed placental pathology was reviewed, and data from 140 pregnancies with male fetuses were compared with 122 pregnancies with female fetuses. A comparison group of 40 unaffected pregnancies who delivered in the same gestational range was used to determine baseline rates of placental pathology. Detailed placental pathology, including placental development/differentiation, velamentous umbilical cord insertion, maternal-fetal interface pathology, villous infarction, hemorrhagic lesions, villous development, and fetal vascular under-perfusion. Impaired placental development and differentiation was equally common amongst males (73/140, 52.1%) and females (69/122, 56.6%). Male placentas exhibited significantly higher rates of chronic deciduitis (17.9% vs. 9.0%; relative risk [RR] 1.98, 95% confidence interval [CI] 1.02-3.86) and velamentous umbilical cord insertion (9.5% vs. 1.7%; RR 5.66, 95% CI 1.30-24.6), and a significantly lower frequency of villous infarction (55.4% vs. 73.7%; RR 0.75, 95% CI 0.62-0.90) than female placentas. No significant differences were noted for other lesions. Fetal sex exerts a differential effect on the placental pathology that mediates severe pre-eclampsia and/or IUGR. Placental pathology at birth may provide insight into the mechanisms linking adverse in utero events with long-term adult disease since, for example, a male tendency to an inflammatory pathology at the maternal-fetal interface may be linked to the excess risk of coronary artery disease.
    Placenta 04/2012; 33(7):568-71. · 3.12 Impact Factor
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    ABSTRACT: The placental microvasculature is essential for efficient transfer of gases, nutrients and waste between the mother and fetus. Microvascular hypoplasia of the terminal villi is a common pathology in severe Intra Uterine Growth Restriction (IUGR). We used novel methods to obtain placental micro-vascular endothelial cells (PlMEC) from preterm control placentas (n = 3) and placentas from pregnancies with severe IUGR (n = 6) with absent or reversed end-diastolic velocity in the umbilical artery. Distal placental villous tissue was collected to enrich for intermediate and terminal villi. Tissue was digested and PlMEC positively selected using tocosylated magnetic Dynabeads labeled with Human Endothelial Antigen lectin. The purity of the PlMEC (94 ± 2 SD %) was assessed by CD31 and vimentin immunocytochemistry. RNA was extracted from the PlMEC samples and subjected to Affymetrix microarray analysis (U133Plus2 array chips). Comparison of preterm and IUGR PlMEC gene expression profiles identified BTNL9 and NTRK2 transcripts to be upregulated and SAA1 and SLAMF1 transcripts to be downregulated in all 6 IUGR cases relative to preterm controls. A third downregulated gene GNAS was identified to be near significance. Changes were demonstrated to be significant at the mRNA level by Real Time PCR in the PlMEC samples. Changes in the IUGR endothelium were confirmed at the protein level by immunohistochemistry for the 3 with available antibodies. We used a tissue microarray constructed from an independent cohort of placental samples from severe IUGR (n = 7), preeclamptic (n = 7), preterm control (n = 6) and term control (n = 6) pregnancies. Results confirmed differential endothelial expression of BTNL9, NTRK2 and SLAMF1 in IUGR versus preterm and term samples. These studies are the first to characterize PlMEC gene expression profiles thus we have advanced our understanding of the molecular basis of placental micro-vascular pathophysiology in fetal growth restriction.
    Placenta 04/2012; 33(4):285-93. · 3.12 Impact Factor
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    ABSTRACT: To conduct a pilot randomized controlled trial of unfractionated heparin (UFH) in women considered at high risk of placental insufficiency in the second trimester. Women with either false-positive first trimester (pregnancy-associated placental protein-A [PAPP-A] < 0.35 MoM) or second trimester (alpha-fetoprotein [AFP] > 2.0 MoM, inhibin > 3.0 MoM, human chorionic gonadotropin > 4.0 MoM) serum screening tests or medical/obstetric risk factors were screened for placental insufficiency by sonographic evaluation of the placenta and uterine artery Doppler between 18 and 22 weeks. Thrombophilia screen-negative women with two or three abnormal test categories were randomized by 23+6 weeks to self-administration of subcutaneous unfractionated heparin (UFH) 7500 IU twice daily until birth or 34 weeks, or to standard care. Maternal anxiety and other maternal-infant outcomes were determined. Thirty-two out of 41 eligible women consented, with 16 women randomized to UFH and 16 to standard care. There was no statistically significant difference identified between the two treatment groups (standard care vs. UFH) for the following: maternal anxiety score (mean [standard deviation]), 14.2 [± 1.6] vs. 14.0 [± 1.8]; birth weight (median [range]), 1795 [470-3295]g vs. 1860 [730-3050]g; perinatal death, 3 vs. 0; severe preeclampsia, 2 vs. 6; placental weight < 10th percentile, 7 vs. 4; or placental infarction, 4 vs. 3. Our study design identified women at high risk of adverse maternal-infant outcomes attributable to placental insufficiency. Women with evidence of placental insufficiency were willing to undergo randomization and self-administration of UFH without increased maternal anxiety.
    Journal of Thrombosis and Haemostasis 06/2011; 9(8):1483-92. · 6.08 Impact Factor
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    ABSTRACT: Seckel syndrome is a rare autosomal recessive disorder characterized by intrauterine growth retardation, dwarfism, microcephaly and mental retardation. Pathological descriptions of fetal stage Seckel syndrome are rare and pre-date the evolving understanding of the genetic and molecular mechanisms involved. The autopsy findings in a case of fetal Seckel syndrome at 30 weeks gestation are presented, with detailed description of the neuropathological findings. Severe neurological abnormalities in a male fetus were observed that included microencephaly, cortical neuronal migration disorder, white matter tract hypoplasia/aplasia, premature depletion of the germinal matrix with cystic transformation and patchy absence of the external granular cell layer of the cerebellum. The striking neuropathological finding in this case was evidence of failure of the developing brain's germinal elements, providing rare morphological insight into the abnormal development of the Seckel syndrome fetal brain. The selective failure of this proliferating cell population correlates with the emerging molecular evidence that Seckel syndrome is caused by defects in ATR-dependent DNA damage signaling with resultant premature death of proliferating cells.
    Brain & development 06/2011; 34(3):238-43. · 1.74 Impact Factor
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    ABSTRACT: The ZIC3 gene encodes a zinc finger protein which functions as a transcription factor in early stages of left-right body axis formation. Mutations in this X-linked gene cause a variety of clinical manifestations including heterotaxy, complex or isolated heart defect as well as other midline urogenital and hindgut malformations. We report a four generation family with X-linked heterotaxy associated with a deletion of the ZIC3 gene at Xq26.3. The index fetus of our proband showed classical features of heterotaxy while her maternal uncle and one brother had imperforate anus and her other brother had features suggestive of VACTERL-H without heterotaxy. A 1.4 Mb deletion in Xq26.3 including the ZIC3 gene was found in the fetus. Six females in the family were found to be asymptomatic carriers. Our report indicates that some of the cases with VACTERL-H syndrome may be caused by a mutation or deletion of the ZIC3 gene.
    American Journal of Medical Genetics Part A 04/2011; 155A(5):1123-8. · 2.30 Impact Factor
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    ABSTRACT: Neonates with birthweights below the tenth percentile for gestational age are considered small for gestational age (SGA). Such infants have an increased risk for perinatal mortality and morbidity as well as an increased lifetime risk for adult onset disorders. Low birth weight percentile is etiologically heterogeneous and may result from maternal, fetal, placental and environmental factors. However, the molecular determinants of human SGA are not well elucidated. We proposed that fetal growth potential could be negatively impacted by the epigenetic dysregulation of specific genes in the placenta. Using methyl DNA immunoprecipitation coupled with Agilent CpG island microarrays, we analyzed the differences in DNA methylation between placentas of eight SGA neonates and eight controls with birthweight percentiles above the tenth percentile. We identified several candidate genomic regions with differential DNA methylation between the two groups. The DNA methylation differences identified in the promoter of the WNT2 gene were prioritized for further study in an extended cohort of 170 samples given the important function of this gene in mouse placental development and its high expression in human placenta. High WNT2 promoter methylation (WNT2PrMe) was found only in placental tissue and not in the cord blood of the fetus. It was significantly associated with reduced WNT2 expression in placenta and with low birthweight percentile in the neonate. Our results show that WNT2 expression can be epigenetically downregulated in the placenta by DNA methylation of its promoter and that high WNT2PrMe is an epigenetic variant that is associated with reduced fetal growth potential. Note: All of the array data in the manuscript can be accessed from the Gene Expression Omnibus (GEO) NCBI database under GEO accession number GSE22326.
    Epigenetics: official journal of the DNA Methylation Society 04/2011; 6(4):440-9. · 4.58 Impact Factor
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    ABSTRACT: Germline mutations in the PTPN11 gene have been associated with Noonan syndrome (NS) and LEOPARD syndrome. Both germline and somatic mutations in this gene have been reported in association with malignancies. However, the T507K mutation in the PTPN11 gene, has only been reported in malignancies and in a fetus with hydrops fetalis but not in a live patient with NS. We report the autopsy findings in a fetus with the T507K mutation who presented prenatally with hydrops fetalis, cystic hygroma and 46, XX karyotype. On autopsy, the patient was found to have testes, male external genitalia, but absent Wolffian ducts.
    American Journal of Medical Genetics Part A 04/2011; 155A(5):1136-9. · 2.30 Impact Factor
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    ABSTRACT: To estimate the relative importance of positive maternal thrombophilia testing compared with additional pathological evidence of abnormal placentation with placental infarction. We performed a retrospective cohort study over a 10-year period in 180 singleton high-risk pregnancies (delivery at 22-34 6/7 weeks of gestation) that had histologic evidence of placental infarction. The rate of positive maternal tests for antiphospholipid syndrome, factor V Leiden, and prothrombin gene mutation were compared with the rate of detection of one or more gross or histological features of abnormal placentation (impaired placental development or differentiation, maternal vascular underperfusion, fetal vascular underperfusion, chronic inflammation, or intervillous thrombosis). Only 14 of 108 (13.0%) of placentas with documented infarction were associated with a positive maternal thrombophilia result. In contrast, 67 of 108 (62.3%) placentas showed features of abnormal placental development or differentiation and 85 of 108 (78.7%) had evidence of noninfarct-related maternal vascular underperfusion (P<.001). Only four of 108 (3.7%) infarcted placentas had no other pathologic lesions. Our data indicate that gross and histologic features of abnormal placentation associate strongly with placental infarction in comparison with maternal thrombophilia tests. II.
    Obstetrics and Gynecology 04/2011; 117(4):929-34. · 4.80 Impact Factor
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    ABSTRACT: Within the placenta, most centrally placed intervillous thrombi are thought to form at sites of foetomaternal haemorrhage, while parabasally located intervillous thombi have been linked to maternal vascular disease. To determine whether parabasally located haemorrhagic lesions were morphologically heterogeneous, the authors performed a retrospective review of 25 placentas with thrombohaematomas occurring in the vicinity of the basal plate. Using morphological criteria, two lesions were distinguished: (1) the parabasally located intervillous thrombus, which had all the morphological features of more centrally located intervillous thrombi; and (2) the rounded intraplacental haematoma. Rounded intraplacental haematomas form as a result of disruption of vasculopathic decidual arterioles in a setting of maternal vascular underperfusion and are thus aetiologically distinct from classically described intervillous thrombi.
    Journal of clinical pathology 03/2011; 64(8):729-32. · 2.43 Impact Factor

Publication Stats

511 Citations
146 Downloads
203.09 Total Impact Points

Institutions

  • 2008–2013
    • SickKids
      Toronto, Ontario, Canada
    • University of British Columbia - Vancouver
      • Department of Radiology
      Vancouver, British Columbia, Canada
  • 2005–2013
    • Mount Sinai Hospital, Toronto
      • • Department of Pathology and Laboratory Medicine
      • • Department of Obstetrics and Gynecology
      • • Department of Medical Imaging
      Toronto, Ontario, Canada
    • Case Western Reserve University School of Medicine
      • Department of Pathology
      Cleveland, OH, United States
  • 2006–2012
    • University of Toronto
      • • Department of Obstetrics and Gynaecology
      • • Department of Laboratory Medicine and Pathobiology
      Toronto, Ontario, Canada
  • 2011
    • KK Women's and Children's Hospital
      • Department of Pathology and Laboratory Medicine
      Singapore, Singapore
  • 2007
    • Hebrew University of Jerusalem
      • Human Genetics Center
      Jerusalem, Jerusalem District, Israel
  • 2003–2004
    • Mount Sinai Hospital
      New York City, New York, United States