Complete hydatidiform mole and live fetus in a singleton pregnancy with confined placental mosaicism and fetomaternal hemorrhage: a case report.

BACKGROUND: Coexistence of complete mole and a live fetus is uncommon (1:22,000-100,000), more so with euploidy. CASE: We present a case of a molar pregnancy with a euploid fetus who had close fetal evaluation for second trimester bleeding. The patient presented at 29 weeks' pregnancy with decreased fetal movements, a result of fetomaternal hemorrhage. She underwent cesarean section and delivered a live infant. By close follow-up and a multidisciplinary approach, the appropriate diagnosis and a favorable outcome were achieved. Both mother and the child at 5 years of age are doing well. CONCLUSION: Detailed anatomic and molecular studies demonstrated a complete mole resulting from confined placental mosaicism, with molar tissue showing a single paternal allele at 8/8 informative loci, all shared with the fetus, thus this coexistent molar pregnancy was not that of a separate conceptus.

Digynic monoandric triploidy in the setting of recurrent pregnancy loss: a case report and literature review.

Triploidy is a genetic occurrence in which the chromosome count is 3n = 69 with a double (2n) chromosomal contribution to the conceptus from one parent. Such pregnancies are usually nonviable and are estimated to account for approximately 1% of recognized conceptions and 10% of recognized miscarriages. Majority opinion is that fetal losses due to triploidies are caused by the presence of 2 copies of paternal chromosomes. In this study, we present a digynic monoandric triploid miscarriage from a 32-year-old G7P1051 at approximately 13 weeks gestation, in which 2 copies of the maternal chromosomes are present in the fetus. This unusual phenomenon is supported by nonmolar placental histology, chromosomal microarray, and short tandem repeat assays, with the latter 2 being discussed in detail. Furthermore, this study includes discussion of recurrent miscarriage, recurrent triploidy, and long-term clinical follow-up of the patient.

The first reported case of double trisomy 10 and 20 in a product of conception.

BACKGROUND: Double trisomies are rare findings among products of conception and are often lethal to the developing embryo or fetus. METHODS: Here we describe a double trisomy case with symptoms of threatened miscarriage at 9 weeks gestation. Ultrasound revealed an anembryonic pregnancy. Pregnancy was terminated by dilation and curettage at gestational age 11 weeks and 6 days. Histologic examination and chromosome microarray were performed on a formalin-fixed product of conception (POC) sample to identify the cause of the anembryonic pregnancy. RESULTS: Chromosome microarray analysis revealed a female chromosome complement with double trisomies 10 and 20, arr(10,20)x3, consistent with a karyotype of 48,XX,+10,+20. CONCLUSION: To the best of our knowledge, this is the first reported case of double trisomy 10 and 20 in a POC. Due to nonspecific histopathological findings, chromosomal microarray is a powerful tool in identifying and differentiating chromosomal aneuploidies.

Oxyntic Gland Adenoma in a Patient With Refractory Reflux.

A 58-year-old African American male was referred for endoscopic evaluation due to a persistent nine-year history of reflux. Previous endoscopy nine years ago revealed a small hiatal hernia and chronic gastritis caused by Helicobacter pylori (H. pylori), which was treated with triple therapy. During the current endoscopic evaluation, findings consistent with reflux esophagitis were identified, along with the discovery of an incidental 6 mm sessile polyp in the gastric fundus. Pathological examination revealed the presence of an oxyntic gland adenoma (OGA). Otherwise, the stomach was found to be unremarkable endoscopically and histologically. OGA is a rare gastric neoplasm that is primarily observed in Japan, with very few reported cases in North America. Studies have suggested a potential association with antacids, while the role of H. pylori in the development of OGA remains controversial. Our patient's OGA was completely resected during the endoscopy, with no recurrence noted on the three-month follow-up.

Cervical Esophageal Adenocarcinoma Arising From Gastric Inlet Patch: A Benign Lesion With Malignant Potential.

Proximal esophageal adenocarcinoma is extremely rare. A gastric inlet patch is a lesion of ectopic gastric mucosa usually found in the cervical esophagus and is considered an incidental finding, but there is a risk for malignant transformation. We report the case of a 50-year-old male with gastroesophageal reflux disease with a 6-month history of progressive dysphagia and 20-pound weight loss. Upper endoscopy showed a malignant stricture with adjacent gastric inlet patch. Biopsies obtained from endoscopic ultrasonography showed adenocarcinoma. This case re-emphasizes careful examination of ectopic gastric mucosa and to consider biopsy if there is suspicion for malignant transformation.

A Lassa virus mRNA vaccine confers protection but does not require neutralizing antibody in a guinea pig model of infection.

Lassa virus is a member of the Arenaviridae family, which causes human infections ranging from asymptomatic to severe hemorrhagic disease with a high case fatality rate. We have designed and generated lipid nanoparticle encapsulated, modified mRNA vaccines that encode for the wild-type Lassa virus strain Josiah glycoprotein complex or the prefusion stabilized conformation of the Lassa virus glycoprotein complex. Hartley guinea pigs were vaccinated with two 10 µg doses, 28 days apart, of either construct. Vaccination induced strong binding antibody responses, specific to the prefusion conformation of glycoprotein complex, which were significantly higher in the prefusion stabilized glycoprotein complex construct group and displayed strong Fc-mediated effects. However, Lassa virus-neutralizing antibody activity was detected in some but not all animals. Following the challenge with a lethal dose of the Lassa virus, all vaccinated animals were protected from death and severe disease. Although the definitive mechanism of protection is still unknown, and assessment of the cell-mediated immune response was not investigated in this study, these data demonstrate the promise of mRNA as a vaccine platform against the Lassa virus and that protection against Lassa virus can be achieved in the absence of virus-neutralizing antibodies.

XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high-grade tumors.

Xenotropic murine leukemia virus-related virus (XMRV) was recently discovered in human prostate cancers and is the first gammaretrovirus known to infect humans. While gammaretroviruses have well-characterized oncogenic effects in animals, they have not been shown to cause human cancers. We provide experimental evidence that XMRV is indeed a gammaretrovirus with protein composition and particle ultrastructure highly similar to Moloney murine leukemia virus (MoMLV), another gammaretrovirus. We analyzed 334 consecutive prostate resection specimens, using a quantitative PCR assay and immunohistochemistry (IHC) with an anti-XMRV specific antiserum. We found XMRV DNA in 6% and XMRV protein expression in 23% of prostate cancers. XMRV proteins were expressed primarily in malignant epithelial cells, suggesting that retroviral infection may be directly linked to tumorigenesis. XMRV infection was associated with prostate cancer, especially higher-grade cancers. We found XMRV infection to be independent of a common polymorphism in the RNASEL gene, unlike results previously reported. This finding increases the population at risk for XMRV infection from only those homozygous for the RNASEL variant to all individuals. Our observations provide evidence for an association of XMRV with malignant cells and with more aggressive tumors.

Placental biomarkers of phthalate effects on mRNA transcription: application in epidemiologic research.

BACKGROUND: CYP19 and PPARgamma are two genes expressed in the placental trophoblast that are important to placental function and are disrupted by phthalate exposure in other cell types. Measurement of the mRNA of these two genes in human placental tissue by quantitative real-time polymerase chain reaction (qPCR) offers a source of potential biomarkers for use in epidemiologic research. We report on methodologic challenges to be considered in study design. METHODS: We anonymously collected 10 full-term placentas and, for each, sampled placental villi at 12 sites in the chorionic plate representing the inner (closer to the cord insertion site) and outer regions. Each sample was analyzed for the expression of two candidate genes, aromatase (CYP19) and peroxisome proliferator activated receptor protein gamma (PPARgamma) and three potential internal controls: cyclophilin (CYC), 18S rRNA (18S), and total RNA. Between and within placenta variability was estimated using variance component analysis. Associations of expression levels with sampling characteristics were estimated using mixed effects models. RESULTS: We identified large within-placenta variability in both transcripts (>90% of total variance) that was minimized to <20% of total variance by using 18S as an internal control and by modelling the means by inner and outer regions. 18S rRNA was the most appropriate internal control based on within and between placenta variability estimates and low correlations of 18S mRNA with target gene mRNA. Gene expression did not differ significantly by delivery method. We observed decreases in the expression of both transcripts over the 25 minute period after delivery (CYP19 p-value for trend = 0.009 and PPARgamma (p-value for trend = 0.002). Using histologic methods, we confirmed that our samples were comprised predominantly of villous tissue of the fetal placenta with minimal contamination of maternally derived cell types. CONCLUSION: qPCR-derived biomarkers of placental CYP19 and PPARgamma gene expression show high within-placental variability. Sampling scheme, selection of an appropriate internal control and the timing of sample collection relative to delivery can be optimized to minimize within-placenta and other sources of underlying, non-etiologic variability.

Adenocarcinoma of the pancreas undetected by multidetector CT, endoscopic ultrasound, or intraoperative ultrasound.

CONTEXT: Patients with known or suspected pancreatic adenocarcinoma are typically evaluated with noninvasive imaging studies and endoscopic ultrasound. Rarely, patients require intraoperative evaluation with intraoperative ultrasound to identify mass lesions. Some patients have pancreatic adenocarcinomas that cannot be detected using any of these methods. CASE REPORT: A-58-year old female presented with a distal common bile duct stricture seen on ERCP with negative brushings. Multiple endoscopic ultrasound and triple phase pancreatic protocol CT exams were negative for a mass lesion and revealed a normal pancreas. Intraoperative ultrasound of the pancreas was also felt to be normal. Intraoperative biopsy of the head of the pancreas revealed a small, moderately to poorly differentiated adenocarcinoma, not visible on any of her imaging studies. CONCLUSION: Some pancreatic adenocarcinomas may defy detection using modern imaging modalities. This case illustrates how extensive imaging failed to detect a malignancy prior to surgery. Patients with a high clinical suspicion for malignancy but no visualized mass should undergo operative evaluation with definitive tissue sampling.

False-positive quadruple screen test for trisomy 18 in a patient with a fetus with Bloom's syndrome.

In the literature, conflicting reports on the significance of false-positive maternal serum multiple marker testing for trisomy 18 are encountered; however, the biology of this finding is discussed infrequently. We present such a case in association with Bloom's syndrome in the fetus. The fetus had intrauterine growth restriction, seen early in the second trimester, oligohydramnios, and was delivered at 34 weeks of gestation for impending fetal compromise. We propose that the adverse outcome of the pregnancy with false-positive serum analyte testing for trisomy 18 might result from a small-sized placenta and perhaps pathology at receptor level.

Genomic profiling maps loss of heterozygosity and defines the timing and stage dependence of epigenetic and genetic events in Wilms' tumors.

To understand genetic and epigenetic pathways in Wilms' tumors, we carried out a genome scan for loss of heterozygosity (LOH) using Affymetrix 10K single nucleotide polymorphism (SNP) chips and supplemented the data with karyotype information. To score loss of imprinting (LOI) of the IGF2 gene, we assessed DNA methylation of the H19 5' differentially methylated region (DMR). Few chromosomal regions other than band 11p13 (WT1) were lost in Wilms' tumors from Denys-Drash and Wilms' tumor-aniridia syndromes, whereas sporadic Wilms' tumors showed LOH of several regions, most frequently 11p15 but also 1p, 4q, 7p, 11q, 14q, 16q, and 17p. LOI was common in the sporadic Wilms' tumors but absent in the syndromic cases. The SNP chips identified novel centers of LOH in the sporadic tumors, including a 2.4-Mb minimal region on chromosome 4q24-q25. Losses of chromosomes 1p, 14q, 16q, and 17p were more common in tumors presenting at an advanced stage; 11p15 LOH was seen at all stages, whereas LOI was associated with early-stage presentation. Wilms' tumors with LOI often completely lacked LOH in the genome-wide analysis, and in some tumors with concomitant 16q LOH and LOI, the loss of chromosome 16q was mosaic, whereas the H19 DMR methylation was complete. These findings confirm molecular differences between sporadic and syndromic Wilms' tumors, define regions of recurrent LOH, and indicate that gain of methylation at the H19 DMR is an early event in Wilms' tumorigenesis that is independent of chromosomal losses. The data further suggest a biological difference between sporadic Wilms' tumors with and without LOI.

Cell type-specific over-expression of chromosome 21 genes in fibroblasts and fetal hearts with trisomy 21.

BACKGROUND: Down syndrome (DS) is caused by trisomy 21 (+21), but the aberrations in gene expression resulting from this chromosomal aneuploidy are not yet completely understood. METHODS: We used oligonucleotide microarrays to survey mRNA expression in early- and late-passage control and +21 fibroblasts and mid-gestation fetal hearts. We supplemented this analysis with northern blotting, western blotting, real-time RT-PCR, and immunohistochemistry. RESULTS: We found chromosome 21 genes consistently over-represented among the genes over-expressed in the +21 samples. However, these sets of over-expressed genes differed across the three cell/tissue types. The chromosome 21 gene MX1 was strongly over-expressed (mean 16-fold) in senescent +21 fibroblasts, a result verified by northern and western blotting. MX1 is an interferon target gene, and its mRNA was induced by interferons present in +21 fibroblast conditioned medium, suggesting an autocrine loop for its over-expression. By immunohistochemistry the p78MX1 protein was induced in lesional tissue of alopecia areata, an autoimmune disorder associated with DS. We found strong over-expression of the purine biosynthesis gene GART (mean 3-fold) in fetal hearts with +21 and verified this result by northern blotting and real-time RT-PCR. CONCLUSION: Different subsets of chromosome 21 genes are over-expressed in different cell types with +21, and for some genes this over-expression is non-linear (>1.5X). Hyperactive interferon signaling is a candidate pathway for cell senescence and autoimmune disorders in DS, and abnormal purine metabolism should be investigated for a potential role in cardiac defects.

Ascending aortic aneurysm in a fetus due to a benign nodular myofibroblastic lesion.

A fetal echocardiogram at 20 weeks of gestation revealed a large ascending aortic aneurysm in the presence of a normal aortic root and normal intracardiac anatomy. No other abnormalities were noted in the fetus. Upon termination of pregnancy, histopathological examination revealed an isolated benign nodular myofibroblastic lesion of likely hamartomatous origin, a first description of such pathology contributing to the formation of an aneurysm in the ascending aorta.

Antenatal sonographic prediction of twin chorionicity.

OBJECTIVE: We sought to determine the accuracy of antenatal diagnosis of twin chorionicity at a single tertiary care center and assess the consequences of incorrect diagnoses. STUDY DESIGN: Twins with chorionicity diagnosed by ultrasound < or = 24 weeks' gestation were retrospectively reviewed. Chorionicity was assigned by sonographic findings including placental location(s), the lambda and T-signs, and/or fetal gender(s). Postnatal diagnosis was determined by placental histopathologic examination. Medical records of antenatal-postnatal discordant chorionicities were reviewed for adverse sequelae. RESULTS: Chorionicity was correctly assigned antenatally in 392/410 (95.6%) twins. The sensitivity, specificity, and positive and negative predictive values of monochorionicity assessed < or = 14 weeks were 89.8%, 99.5%, 97.8%, and 97.5%. Corresponding statistical values for the second trimester were 88.0%, 94.7%, 88.0%, and 94.7%. Two cases of inaccurate antenatal diagnoses affected patient counseling or were associated with adverse clinical outcomes. CONCLUSION: Antenatal assessment of chorionicity is accurate; however, incorrect diagnoses do occur and can affect reliable patient counseling and management.

Expression of mammalian paralogues of HRAD9 and Mrad9 checkpoint control genes in normal and cancerous testicular tissue.

Human and mouse paralogues of the evolutionarily conserved mammalian HRAD9 and Mrad9 cell cycle checkpoint control genes have been isolated and called HRAD9B and Mrad9B, respectively. HRAD9B encodes a protein that is 414 amino acids long and is 55% similar and 35% identical to the HRAD9 gene product. The Mrad9B protein is 398 amino acids long and is 50% similar and 35% identical to its paralogue. We demonstrate that the encoded human protein is nuclear and can physically interact with checkpoint proteins HRAD1, HRAD9, HHUS1, and HHUS1B, much like HRAD9. Northern blot analysis to detect tissue specificity indicates that the human and mouse genes are expressed predominantly in the testis. The abundance of HRAD9B RNA, as judged by quantitative reverse transcription-PCR, is very low in most testicular tumors, particularly those of germ cell origin, i.e., seminomas, relative to normal testis control, nonseminomas, or Leydig tumor cells. RNA levels corresponding to HRAD17, another checkpoint control gene, demonstrated a similar pattern, but in general, higher quantities of this message were detected in samples. Furthermore, normal/tumor tissue differences were not as dramatic or consistent from sample to sample, especially for the seminomas. Our results demonstrate for the first time that HRAD9 and Mrad9 are part of a gene family and reveal a new genetic element encoding a product that interacts with multiple, known cell cycle checkpoint control proteins. The findings also indicate that HRAD9B can serve as a biomarker in particular for testicular seminomas and might be causally related to the disease.

Fetomaternal Hemorrhage following Placement of an Intrauterine Pressure Catheter: Report of a New Association.

Fetomaternal hemorrhage (FMH) can be associated with significant perinatal mortality. Our review of the literature did not identify any cases of FMH following placement of an intrauterine pressure catheter (IUPC). In our case, an IUPC was inserted in a patient undergoing induction of labor at term. Fetal bradycardia ensued shortly after placement, warranting an emergent cesarean delivery. Severe neonatal anemia was identified, and evaluation of maternal blood was consistent with massive FMH. This is the first reported association between FMH and IUPC placement. If this relationship is validated in future reports, appropriate changes in clinical practice may be warranted.

Immunohistochemistry for the imprinted gene product IPL/PHLDA2 for facilitating the differential diagnosis of complete hydatidiform mole.

OBJECTIVE: To determine if immunohistochemistry for PHLDA2 (also known as IPL and TSSC3), the product of a paternally imprinted, maternally expressed gene, can be used as a tool in the differential diagnosis of molar gestations. STUDY DESIGN: Twenty-five cases (15 complete moles, 5 partial moles and five hydropic abortions) were stained by immunohistochemistry for PHLDA2 and scored (without knowledge of the diagnosis) for positivity in the villous cytotrophoblast and then compared to adjacent sections stained by p57KIP2 immunohistochemistry. RESULTS: All partial moles and hydropic abortions were positive for PHLDA2 and p57KIP2. There was strong PHLDA2 staining of the cytoplasm in virtually all cells of the villous cytotrophoblast, while p57KIP2 was localized to the nucleus in a subset of those cells. All complete moles were negative for both markers in the villous cytotrophoblast. CONCLUSION: Immunohistochemistry for PHLDA2 serves as a practical and reliable diagnostic marker for the discrimination of complete mole from partial mole and hydropic abortion. Since the immunohistochemical diagnosis of complete mole is based on a negative result, absence of staining, the use of both markers (PHLDA2 and p57KIP2) together could increase the level of confidence when making this prognostically important distinction.