Identification of copy number variants in miscarriages from couples with idiopathic recurrent pregnancy loss.

Background: Recurrent pregnancy loss (RPL), defined as two or more miscarriages, affects 3-5% of couples trying to establish a family. Despite extensive evaluation, no factor is identified in ∼40% of cases. In this study, we investigated the possibility that submicroscopic chromosomal changes, not detectable by conventional cytogenetic analysis, exist in miscarriages with normal karyotypes (46,XY or 46,XX) from couples with idiopathic RPL.

Genomic changes detected by array CGH in human embryos with developmental defects.

Developmental abnormalities of human embryos can be visualized in utero using embryoscopy. Our previous embryoscopic and genetic evaluations detected developmental abnormalities in the majority of both euploid (74%) and aneuploid or polyploid (90%) miscarriages. Since we found the pattern of morphological changes to be similar in euploid and non-euploid embryos, we proposed that lethal submicroscopic changes, not detected by standard chromosome testing, may be responsible for miscarriage of euploid embryos.

Placental weight in pregnancies with trisomy confined to the placenta.

Objective: Mosaicism with trisomy confined to the placenta is present in ~1% of ongoing pregnancies at the time of chorionic villus sampling. Some studies have found reduced fetal growth in confined placental trisomy. The objective of this study was to assess placental weight and feto-placental weight ratio in pregnancies with trisomy confined to the placenta, and to correlate them with the level of trisomy in the three major placental lineages.

Autologous bone marrow transplantation for children with AML in first remission.

In Children's cancer group (CCG) 2891, newly diagnosed patients with AML were randomized between standard and intensive timing induction therapies. Patients in first remission who lacked an HLA matched family donor were randomized between an autologous bone marrow transplantation (ABMT) where marrow was purged with 4 hydroperoxycyclophosphamide and consolidation chemotherapy. One hundred and thirty seven patients received an ABMT.

Postnatal follow-up of prenatally diagnosed trisomy 16 mosaicism.

Objective: To determine the long-term outcome of pregnancies prenatally diagnosed with trisomy 16 and identify variables associated with the outcome.

Methods: We reviewed all published and our unpublished data from trisomy 16 pregnancies for which outcomes were available for children of greater than 1 year of age.

Results: Nineteen cases were diagnosed with trisomy 16 on chorionic villus sampling (CVS) and 17 cases at amniocentesis.

Frequency of chromosomal abnormalities in spontaneous abortions derived from intracytoplasmic sperm injection compared with those from in vitro fertilization.

No statistical difference was found for the total aneuploidy rate in the spontaneous abortions between intracytoplasmic sperm injection and IVF groups; however, differences in the distribution of chromosomal abnormalities between the two groups were seen.

Prenatally detected trisomy 20 mosaicism.

Background: Trisomy 20 is one of the more common mosaic trisomies detected on amniocentesis and presents with a normal outcome in over 90% of reported cases. Trisomic cells are almost never confirmed in newborn blood and are only rarely found in other fetal or placental samples. Nonetheless, some abnormal outcomes have been reported, including unexplained fetal demise, intrauterine growth restriction, and multiple congenital anomalies.

Abnormal embryonic development diagnosed embryoscopically in early intrauterine deaths after in vitro fertilization: a preliminary report of 23 cases.

Objective: To provide data about the phenotypic appearance of the embryo of early failed pregnancies after IVF.

Design: Clinical prospective descriptive study.

Setting: Tertiary care center.

Effects of triploidy on early human development.

Objective: The morphologic features of 18 triploid embryos are described.

Method: Embryoscopic examination of the embryo in cases of missed abortion before instrumental evacuation from the uterus. Cytogenetic and histologic analysis of the chorionic villi.

Allogeneic bone marrow transplantation for children with acute myelocytic leukemia in first remission demonstrates a role for graft versus leukemia in the maintenance of disease-free survival.

In Children's Cancer Group (CCG) study 2891, patients who were recently diagnosed with acute myelocytic leukemia (AML) were assigned randomly to standard- or intensive-timing induction chemotherapy. Patients in first complete remission (CR1) and who had a human leukocyte antigen (HLA)-identical, related donor or a donor disparate at a single class I or II locus were nonrandomly assigned to receive a bone marrow transplant (BMT) by using oral busulfan (16 mg/kg) and cyclophosphamide (200 mg/kg). Methotrexate only was given for graft-versus-host disease (GVHD) prophylaxis.

Transcervical fetoscopic diagnosis of structural defects in four first-trimester monochorionic twin intrauterine deaths.

Objective: While chromosomal abnormalities are often the cause of early failed pregnancies, other mechanisms could be involved in monochorionic twin intrauterine deaths, that might be screened for careful morphological analysis.

Methods: Transcervical fetoscopy prior to instrumental evacuation of the uterus was performed in four first-trimester monochorionic twin intrauterine deaths.

Results: We present fetoscopic and cytogenetic findings in four cases of monochorionic twin intrauterine deaths.

Embryoscopic and cytogenetic analysis of 233 missed abortions: factors involved in the pathogenesis of developmental defects of early failed pregnancies.

Background: While chromosomal abnormalities are often the cause of missed abortions, other defects could be involved, which might be screened for by transcervical embryoscopy.

Methods: A total of 272 patients with missed abortion underwent transcervical embryoscopy prior to dilatation and curettage, together with cytogenetic analysis of chorionic villi, using either standard G-banding cytogenetic techniques or comparative genomic hybridization in combination with flow cytometry analysis.

Results: Visualization of the embryo or early fetus (12 cases) was successful in 233 patients, and karyotyping in 221.

Morphology of the 45,X embryo: an embryoscopic study.

The morphology of monosomy X in embryos was documented by means of transcervical embryoscopy prior to evacuation in 24 cases of missed abortion. The embryos ranged in size from 13 mm to 26 mm CRL and were all developed beyond the sixth week of development. The embryonic phenotype varied from nearly normal to obviously abnormal with a combination of localized external developmental defects consisting of microcephaly, facial dysplasia, and retarded limb development.

Loss of 1p and 7p in radiation-induced meningiomas identified by comparative genomic hybridization.

Cytogenetic and molecular studies of radiation-induced meningiomas (RIM) are rare and controversial. While comparative genomic hybridization (CGH) analysis identified monosomy 22 as the predominant change in RIM, occurring in frequencies comparable to those found in spontaneous meningioma (SM), molecular genetic analysis shows infrequent loss of chromosome 22 DNA markers. We have performed CGH analysis of six additional cases of RIM and detected an unbalanced genome in five of 6 cases.

Clinical aspects, prenatal diagnosis, and pathogenesis of trisomy 16 mosaicism.

Introduction: Analysis of data from cases of trisomy mosaicism can provide insight for genetic counselling after prenatal diagnosis and for the elucidation of the pathogenesis of trisomy during pregnancy.

Methods: Statistical analysis was carried out on data from 162 cases of pregnancies with prenatal diagnosis of trisomy 16 mosaicism.

Results: The majority of cases resulted in live birth (66%) with an average gestational age of 35.

Skewed X-chromosome inactivation is associated with trisomy in women ascertained on the basis of recurrent spontaneous abortion or chromosomally abnormal pregnancies.

An increase in extremely skewed X-chromosome inactivation (XCI) (> or = 90%) among women who experienced recurrent spontaneous abortion (RSA) has been previously reported. To further delineate the etiology of this association, we have evaluated XCI status in 207 women who experience RSA. A significant excess of trisomic losses was observed among the women who had RSA with skewed XCI versus those without skewed XCI (P=.

Origin of amnion and implications for evaluation of the fetal genotype in cases of mosaicism.

Objective: To investigate presence of trisomy in amniotic epithelium (uncultured amnion) and mesenchyme (cultured amnion) from mosaic cases to understand the origins of these tissues and their relationship to pregnancy outcome.

Methods: Polymerase chain reaction (PCR) of microsatellite loci was used to determine the presence of trisomy (of meiotic origin only) in amnion samples from 33 placentas previously ascertained because of a prenatal diagnosis of trisomy mosaicism that was predominantly confined to the placental tissues.

Results: In 16 (48%) of 33 cases, trisomy was confirmed to be present by molecular analysis of uncultured amnion.

Molecular cytogenetics in reproductive pathology.

This chapter presents the summary of two molecular cytogenetic techniques--FISH and CGH--with their applications and limitations in the studies of pregnancy loss. These molecular techniques clearly represent a significant advantage over the traditional cytogenetic technique and likely will become the predominant cytogenetic techniques in reproductive cytogenetics of the future.

Evidence for imprinting on chromosome 16: the effect of uniparental disomy on the outcome of mosaic trisomy 16 pregnancies.

Although a number of infants with maternal uniparental disomy of chromosome 16 (upd(16)mat) have been reported, the evidence for imprinting on chromosome 16 is not yet conclusive. To test the hypothesis that upd(16)mat has a distinct phenotype, which would support the existence of imprinted gene(s) on chromosome 16, statistical analysis was performed on a large series (n = 83) of mosaic trisomy 16 cases with molecular determination of uniparental disomy status. The incidence of upd(16)mat was 40%, which is consistent with the expected one third from random chromosome loss during trisomy rescue (P = 0.

Generalized abnormal embryonic development in missed abortion: embryoscopic and cytogenetic findings.

A direct view of the embryo by means of transcervical embryoscopy prior to evacuation in 154 cases of missed abortion showed general embryonic maldevelopment in 48 cases (31%). A successful cytogenetic evaluation of these growth-disorganized embryos was performed in 37. Chromosomal abnormalities were found in 26 cases (70%), with autosomal trisomies in 24 cases (92%).

Interphase fluorescence in situ hybridization and DNA flow cytometry analysis of medulloblastomas with a normal karyotype.

Interphase fluorescence in situ hybridization (FISH) with chromosome 3 and 17 centromeric probes and DNA flow cytometry were used for a retrospective study of nine pediatric medulloblastomas with normal karyotypes after tissue culture. The FISH analysis of medulloblastoma touch preparations showed that in seven of nine tumors, a significant proportion of nuclei had an increased number of centromeric signals for the selected chromosomes. In six of seven cases, this increase was caused by the presence of triploid and tetraploid clones as established by flow cytometry of paraffin-embedded tumors.

Neural tube defects in missed abortions: embryoscopic and cytogenetic findings.

Transcervical embryoscopy, a new technique for direct visualization of the first trimester conceptus was carried out in 116 cases of missed abortion. Embryonic neural tube defects and other localized developmental defects, were diagnosed in 10 out of 99 cases in which a complete embryoscopic evaluation was possible. All eight successfully karyotyped cases had a numerical chromosomal abnormality.

Amnion rupture sequence in a first trimester missed abortion.

We report the diagnosis of amnion rupture sequence made by sonography and fetoscopy during the first trimester of gestation in a case of missed abortion. The investigation revealed a demised fetus with the characteristics of 9 weeks of development. The early fetus had an amnion adhesion at the tip of the nose and strands of amnion wrapped around the terminal phalanges of both feet.

Transcervical embryoscopy in missed abortion.

Purpose: The present study was conducted to determine the usefulness of transcervical embryoscopy in diagnosing localized and systemic defects in embryonic morphogenesis of missed abortions.

Methods: The study population consisted of 24 women with the final diagnosis of missed abortion. Prior to the instrumental evacuation of the uterus a rigid hysteroscope was passed transcervically into the amniotic cavity to obtain a detailed view of the embryo.