Prenatal and postnatal findings in serpentine fibula polycystic kidney syndrome and a review of the NOTCH2 spectrum disorders.

Serpentine fibula polycystic kidney syndrome (SFPKS; OMIM600330) is a rare skeletal dysplasia with a characteristic phenotype that includes polycystic kidneys, S-shaped fibulas, and abnormal craniofacial features. SFPKS shares features with Alagille (AGS; OMIM) and Hajdu-Cheney (HCS; OMIM10250) syndromes. All three syndromes result from mutations in the gene that encodes NOTCH2, one of the receptors involved in Notch signaling. Notch signaling is a major developmental signaling pathway, as well as a key regulator of numerous cellular processes. In this report, we present the prenatal ultrasound and postnatal findings in a 23-week fetus with severe manifestations of SPKS and heterozygosity for a de novo mutation in exon 34 of NOTCH2. These findings expand the phenotypic spectrum of NOTCH2 mutations and demonstrate the findings in the prenatal period.

RETIRED: The use of magnetic resonance imaging in the obstetric patient.

This document has been archived because it contains outdated information. It should not be consulted for clinical use, but for historical research only. Please visit the journal website for the most recent guidelines.

Ce document a été archivé, car il contient des informations périmées. Il ne devrait pas être consulté pour un usage clinique, mais uniquement pour des recherches historiques. Veuillez consulter le site web du journal pour les directives les plus récentes.

Beckwith-Wiedemann syndrome in sibs discordant for IC2 methylation.

Genetically heterogeneous imprinting disorders include Beckwith-Wiedemann syndrome (BWS) and multiple maternal hypomethylation syndrome (MMHS). Using DNA sequencing, quantitative PCR, SNuPE, pyrosequencing, and hybridization to the Illumina GoldenGate Methylation Cancer Panel 1 array, we characterized the genomic DNA of two brothers with BWS who were discordant for loss of methylation at several differentially methylated regions (DMR), including imprinting center 2 (IC2) on chromosome band 11p15.5, which is often hypomethylated in BWS. In keeping with MMHS, the elder child had hypomethylation of SGCE and PLAGL1 as well as of IC2, whereas the younger brother demonstrated no loss of methylation at these DMRs. Although this discordance is consistent with the observation that 15-20% of individuals with BWS do not have detectable genetic or epigenetic alterations of 11p15.5, this is the first report of familial recurrence of BWS with discordance for chromosomal 11p15.5 alterations. We hypothesize that this apparent discordance arises either from mosaicism precluding identification of IC2 hypomethylation in blood or buccal mucosa DNA of the younger child, or from hypomethylation at a site not interrogated by our molecular studies.

Project SWAVE 2.0: An overview of the study design for multimodal placental image acquisition and alignment.

Development of non-invasive and in utero placenta imaging techniques can potentially identify biomarkers of placental health. Correlative imaging using multiple multiscale modalities is particularly important to advance the understanding of placenta structure, function and their relationship. The objective of the project SWAVE 2.0 was to understand human placental structure and function and thereby identify quantifiable measures of placental health using a multimodal correlative approach. In this paper, we present a multimodal image acquisition protocol designed to acquire and align data from ex vivo placenta specimens derived from both healthy and complicated pregnancies. Qualitative and quantitative validation of the alignment method were performed. The qualitative analysis showed good correlation between findings in the MRI, ultrasound and histopathology images. The proposed protocol would enable future studies on comprehensive analysis of placental anatomy, function and their relationship. ● An overview of a novel multimodal placental image acquisition protocol is presented. ● A co-registration method using surface markers and external fiducials is described. ● A preliminary correlative imaging analysis for a placenta specimen is presented.

SWAVE 2.0 Imaging of Placental Elasticity and Viscosity: Potential Biomarkers for Placenta-Mediated Disease Detection.

Pregnancy complications such as pre-eclampsia (PE) and intrauterine growth restriction (IUGR) are associated with structural and functional changes in the placenta. Different elastography techniques with an ability to assess the mechanical properties of tissue can identify and monitor the pathological state of the placenta. Currently available elastography techniques have been used with promising results to detect placenta abnormalities; however, limitations include inadequate measurement depth and safety concerns from high negative pressure pulses. Previously, we described a shear wave absolute vibro-elastography (SWAVE) method by applying external low-frequency mechanical vibrations to generate shear waves and studied 61 post-delivery clinically normal placentas to explore the feasibility of SWAVE for placental assessment and establish a measurement baseline. This next phase of the study, namely, SWAVE 2.0, improves the previous system and elasticity reconstruction by incorporating a multi-frequency acquisition system and using a 3-D local frequency estimation (LFE) method. Compared with its 2-D counterpart, the proposed system using 3-D LFE was found to reduce the bias and variance in elasticity measurements in tissue-mimicking phantoms. In the aim of investigating the potential of improved SWAVE 2.0 measurements to identify placental abnormalities, we studied 46 post-delivery placentas, including 26 diseased (16 IUGR and 10 PE) and 20 normal control placentas. By use of a 3.33-MHz motorized curved-array transducer, multi-frequency (80,100 and 120 Hz) elasticity measures were obtained with 3-D LFE, and both IUGR (15.30 ± 2.96 kPa, p = 3.35e-5) and PE (12.33 ± 4.88 kPa, p = 0.017) placentas were found to be significantly stiffer compared with the control placentas (8.32 ± 3.67 kPa). A linear discriminant analysis (LDA) classifier was able to classify between healthy and diseased placentas with a sensitivity, specificity and accuracy of 87%, 78% and 83% and an area under the receiver operating curve of 0.90 (95% confidence interval: 0.8-0.99). Further, the pregnancy outcome in terms of neonatal intensive care unit admission was predicted with a sensitivity, specificity and accuracy of 70%, 71%, 71%, respectively, and area under the receiver operating curve of 0.78 (confidence interval: 0.62-0.93). A viscoelastic characterization of placentas using a fractional rheological model revealed that the viscosity measures in terms of viscosity parameter n were significantly higher in IUGR (2.3 ± 0.21) and PE (2.11 ± 0.52) placentas than in normal placentas (1.45 ± 0.65). This work illustrates the potential relevance of elasticity and viscosity imaging using SWAVE 2.0 as a non-invasive technology for detection of placental abnormalities and the prediction of pregnancy outcomes.

Pre- and postnatal findings in a boy with duplication of the bladder and intestine: report and review.

We describe a boy with a septated bladder and dilated bowel loop found on prenatal ultrasonography. Subsequent prenatal MRI diagnosed a probable caudal duplication anomaly. Postnatal investigations and surgical findings confirmed duplication of bladder, urethra, and bowel from distal ileum to rectum. This is the first reported case of combined bladder and colon duplication suspected antenatally with thorough imaging investigations including fetal MRI. While diagnosis of bladder duplication has been described, prenatal diagnosis of intestinal duplication has not been documented previously. This report of prenatal imaging with surgical and pathological correlation contributes to our detailed understanding of the spectrum of anatomy seen in caudal duplication anomaly.

Steroid sulfatase deficiency and contiguous gene deletion syndrome amongst pregnant patients with low serum unconjugated estriols.

OBJECTIVE: To ascertain all prenatally diagnosed cases of Steroid Sulfatase (STS) deficiency in British Columbia between August 2002 and July 2007 to determine the incidence of this condition, the clinical and laboratory findings, and the risk of a contiguous gene deletion syndrome. METHODS: We reviewed the medical records of these patients to obtain detailed information about the maternal serum screening results, family history, investigations performed, and outcome of the pregnancy. RESULTS: Thirty pregnant patients were found to have a male fetus/infant with STS deficiency, giving a minimal estimated incidence of this condition of approximately 1 in 1513 males. In twenty nine cases, this condition was isolated. One patient was found to have a contiguous gene deletion syndrome. In cases of sporadic STS deficiency diagnosed prenatally, the frequency of contiguous gene deletion syndrome in this study was 1 out of 12 (8.3%). CONCLUSION: The clinical, cytogenetic and molecular data on this series of prenatally diagnosed cases of STS deficiency indicates that this is a common condition and in cases with no family history, the risk of contiguous gene deletion syndrome is significant, and warrants additional molecular genetic investigations of the mother and/or fetus.

Attenuation Coefficient Estimation of Normal Placentas.

Attenuation coefficient estimation has the potential to be a useful tool for placental tissue characterization. A current challenge is the presence of inhomogeneities in biological tissue that result in a large variance in the attenuation coefficient estimate (ACE), restricting its clinical utility. In this work, we propose a new Attenuation Estimation Region Of Interest (AEROI) selection method for computing the ACE based on the (i) envelope signal-to-noise ratio deviation and (ii) coefficient of variation of the transmit pulse bandwidth. The method was first validated on a tissue-mimicking phantom, for which an 18%-21% reduction in the standard deviation of ACE and a 14%-24% reduction in the ACE error, expressed as a percentage of reported ACE, were obtained. A study on 59 post-delivery clinically normal placentas was then performed. The proposed AEROI selection method reduced the intra-subject standard deviation of ACE from 0.72 to 0.39 dB/cm/MHz. The measured ACE of 59 placentas was 0.77 ± 0.37 dB/cm/MHz, which establishes a baseline for future studies on placental tissue characterization.

Schinzel-Giedion syndrome: report of splenopancreatic fusion and proposed diagnostic criteria.

We report on the 46th patient with Schinzel-Giedion syndrome (SGS) and the first observation of splenopancreatic fusion in this syndrome. In the antenatal period, a male fetus was found to have bilateral hydronephrosis. Postnatally, in keeping with a diagnosis of SGS, there were large fontanelles, ocular hypertelorism, a wide, broad forehead, midface retraction, a short, upturned nose, macroglossia, and a short neck. Other anomalies included cardiac defects, widened and dense long bone cortices, cerebral ventriculomegaly, and abnormal fundi. Splenopancreatic fusion, usually encountered in trisomy 13, was found on autopsy. Schinzel-Giedion syndrome is likely a monogenic condition for which neither the heritability pattern nor pathogenesis has yet been determined. A clinical diagnosis may be made by identifying the facial phenotype, including prominent forehead, midface retraction, and short, upturned nose, plus one of either of the two other major distinguishing features: typical skeletal abnormalities or hydronephrosis. Typical skeletal anomalies include a sclerotic skull base, wide supraoccipital-exoccipital synchondrosis, increased cortical density or thickness, and broad ribs. Other highly supportive features include neuroepithelial tumors (found in 17%), hypertrichosis, and brain abnormalities. Severe developmental delay and poor survival are constant features in reported patients.

Prenatal ultrasound and fetal MRI: the comparative value of each modality in prenatal diagnosis.

Fetal MRI is used with increasing frequency as an adjunct to ultrasound (US) in prenatal diagnosis. In this review, we discuss the relative value of both prenatal US and MRI in evaluating fetal and extra-fetal structures for a variety of clinical indications. Advantages and disadvantages of each imaging modality are addressed. In summary, MRI has advantages in demonstrating pathology of the brain, lungs, complex syndromes, and conditions associated with reduction of amniotic fluid. At present, US is the imaging method of choice during the first trimester, and in the diagnosis of cardiovascular abnormalities, as well as for screening. In some conditions, such as late gestational age, increased maternal body mass index, skeletal dysplasia, and metabolic disease, neither imaging method may provide sufficient diagnostic information.

Multiparametric QUS Analysis for Placental Tissue Characterization.

Multiparametric Quantitative Ultrasound (QUS) holds promise for characterizing placental tissue and detecting placental disorders. In this study, we simultaneously extract two qualitatively different QUS parameters, namely attenuation coefficient estimate (ACE) and shear wave speed from ultrasound radio frequency data acquired using a shear wave vibro elastography (SWAVE) method. The study comprised data from 59 post-delivery clinically normal placentas. The shear wave speed was found to be equal to 1.74 ± 0.13 m/s whereas the attenuation coefficient estimate was 0.57 ± 0.48 dB/cm-MHz. This provides a baseline for future studies of placental disorders.

Expanding the FANCO/RAD51C associated phenotype: Cleft lip and palate and lobar holoprosencephaly, two rare findings in Fanconi anemia.

Fanconi anemia is a rare chromosome instability disorder with a highly variable phenotype. In the antenatal and neonatal periods, the diagnosis is usually suggested by the presence of typical congenital abnormalities such as intrauterine growth retardation, microcephaly and radial ray defects. We report a newborn female with a prenatal diagnosis of Fanconi anemia, complementation group O (FANCO). Antenatal ultrasounds identified symmetrical intrauterine growth retardation, complex heart defect as well as brain anomalies, overlapping fingers and cleft lip and palate. Imperforate anus was detected after birth. Compound heterozygous RAD51C variants c. [571+5G > A]; [c.935G > A] were detected by prenatal whole exome sequencing and cellular hypersensitivity to DNA interstrand crosslinking agents (DEB, MMC) was confirmed after birth. With only one previously described homozygous RAD51C variant to date, our findings expand the phenotypic spectrum of FANCO and suggest it should be part of the antenatal differential diagnosis for trisomy 13 and 18, due to the presence of atypical findings such as cleft lip and palate, holoprosencephaly, growth restriction and overlapping fingers.

Advances in basic science methodologies for clinical diagnosis in female stress urinary incontinence.

We provide an overview of advanced imaging techniques currently being explored to gain greater understanding of the complexity of stress urinary incontinence (SUI) through better definition of structural anatomic data. Two methods of imaging and analysis are detailed for SUI with or without prolapse: 1) open magnetic resonance imaging (MRI) with or without the use of reference lines; and 2) 3D reconstruction of the pelvis using MRI. An additional innovative method of assessment includes the use of near infrared spectroscopy (NIRS), which uses non-invasive photonics in a vaginal speculum to objectively evaluate pelvic floor muscle (PFM) function as it relates to SUI pathology. Advantages and disadvantages of these techniques are described. The recent innovation of open-configuration magnetic resonance imaging (MRO) allows images to be captured in sitting and standing positions, which better simulates states that correlate with urinary leakage and can be further enhanced with 3D reconstruction. By detecting direct changes in oxygenated muscle tissue, the NIRS vaginal speculum is able to provide insight into how the oxidative capacity of the PFM influences SUI. The small number of units able to provide patient evaluation using these techniques and their cost and relative complexity are major considerations, but if such imaging can optimize diagnosis, treatment allocation, and selection for surgery enhanced imaging techniques may prove to be a worthwhile and cost-effective strategy for assessing and treating SUI.

SWAVE Imaging of Placental Elasticity and Viscosity: Proof of Concept.

The placenta is the interface between the fetus and the mother and is vital for fetal development. Ultrasound elastography provides a non-invasive way to examine in vivo the stiffness of the placenta; increased stiffness has previously been linked to fetal growth restriction. This study used a previously developed dynamic elastography method, called shear wave absolute vibro-elastography, to study 61 post-delivery clinically normal placentas. The shear wave speeds in the placenta were recorded under five different low-frequency mechanical excitations. The elasticity and viscosity were estimated through rheological modeling. The shear wave speeds at excitation frequencies of 60, 80, 90, 100 and 120 Hz were measured to be 1.23 ± 0.44, 1.67 ± 0.76, 1.74 ± 0.72, 1.80 ± 0.78 and 2.25 ± 0.80 m/s. The shear wave speed values we obtained are consistent with previous studies. In addition, our multi-frequency acquisition approach enables us to provide viscosity estimates that have not been previously reported.

Pregnancy with uterine vascular malformations associated with hemorrhagic hereditary telangiectasia: a case report.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant condition. It is rarely seen in pregnancy and even more rarely has uterine manifestations. CASE: A 29-year-old primigravid woman with HHT was noted to have vascular manifestations of her disease in the lower uterus, distal rectum, pelvis, and bladder before pregnancy. Prior to delivery, a case conference was held, involving representatives of the departments of vascular surgery, hematology, radiology, anaesthesiology, maternal-fetal medicine, neonatology, and laboratory medicine, and other appropriate health professionals. A successful elective Caesarean section was performed at term, with a good outcome for both mother and child. CONCLUSION: regnancies in women with HHT and associated uterine vascular manifestations have been rarely reported, and published information is minimal. We present a case of a successful operative delivery following careful multidisciplinary antepartum care.

Additional post-natal diagnoses following antenatal diagnosis of isolated cleft lip +/− palate.

INTRODUCTION: Cleft lip with or without palate (CLP) can be diagnosed antenatally through ultrasound, and may be categorised as apparently isolated versus associated with other malformations. Limited data exist on the long-term outcomes following antenatal diagnosis of apparently isolated CLP. AIM: This study examined the long-term post-natal outcomes of CLP when found in isolation antenatally, in order to determine the rates of unexpected additional anomalies, developmental delay or genetic syndromes. PATIENTS AND METHODS: A retrospective chart review of antenatal and post-natal medical charts was completed for a ten-year period between January 2000 and December 2009. At least 2 years of available post-natal clinical information was required for inclusion in the study. RESULTS: A total of 97 cases of antenatally isolated CLP were ascertained. Fifteen pregnancies were terminated. Follow-up data were available for 81 liveborns, though 4 were lost to follow-up prior to 2 years of age. Twelve of the 77 children meeting study criteria were identified to have other major malformations and/or developmental disability either later in the pregnancy or post-natally. Findings included familial clefting syndromes, trisomy 21, autism spectrum disorders, brain malformations, fetal alcohol syndrome and Kabuki syndrome, among other findings. Another 11 children had additional anomalies of minor impact. Examples of findings include a perimembranous ventricular septal defect, mild unilateral optic nerve hypoplasia, mild pulmonary artery stenosis with a small atrial septal defect, and transient delays in fine and gross motor skills. No children with clefting of the lip only had major additional diagnoses.

Granulomatous herpes simplex encephalitis in an infant with multicystic encephalopathy: a distinct clinicopathologic entity?

BACKGROUND: Herpes simplex virus encephalitis can manifest as a range of clinical presentations including classic adult, neonatal, and biphasic chronic-granulomatous herpes encephalitis. METHOD: We report an infant with granulomatous herpes simplex virus type 2 encephalitis with a subacute course and multicystic encephalopathy. CASE: A 2-month-old girl presented with lethargy and hypothermia. Computed tomography scan of the head showed multicystic encephalopathy and calcifications. Cerebrospinal fluid analysis by polymerase chain reaction testing for herpes simplex virus 1 and 2, enterovirus, and cytomegalovirus was negative. Normal cerebrospinal fluid interferon-α levels argued against Aicardi-Goutières syndrome. The patient died 2 weeks after presentation. At autopsy, multicystic encephalopathy was confirmed with bilateral gliosis, granulomatous inflammation with multinucleated giant cells, and calcifications. Bilateral healing necrotizing retinitis suggested a viral etiology, but retina and brain were free of viral inclusions and immunohistochemically negative for herpes simplex virus-2 and cytomegalovirus. However, polymerase chain reaction analysis showed herpes simplex virus-2 DNA in four cerebral paraffin blocks. Subsequent repeat testing of the initial cerebrospinal fluid sample using a different polymerase chain reaction assay was weakly positive for herpes simplex virus-2 DNA. CONCLUSION: Granulomatous herpes simplex virus encephalitis in infants can present with subacute course and result in multicystic encephalopathy with mineralization and minimal cerebrospinal fluid herpes simplex virus DNA load. Infectious etiologies should be carefully investigated in the differential diagnosis of multicystic encephalopathy with mineralization, in particular if multinucleated giant cells are present.