Michiko Yamanaka

Losartan and fetal toxic effects

We report a case of maternal exposure to the antihypertensive drug losartan during weeks 20-31 of pregnancy. We saw the fetal toxic effects of oligohydramnios (decreased amniotic fluid), fetal pulmonary hypoplasia, fetal hypoplastic skull bones, and subsequent fetal death. This pattern of abnormalities is similar to those seen in exposure to angiotensin-converting-enzyme (ACE) inhibitors during pregnancy, and were probably caused by losartan.

Risk of Recurrence of Fetal Chromosomal Aberrations: Analysis of Trisomy 21, Trisomy 18, Trisomy 13, and 45,X in 1,076 Japanese Mothers

Objective: To evaluate the risk of recurrence of fetal chromosomal aberrations in women who had offspring with numeric chromosomal abnormalities.

Paternal uniparental disomy 14 and related disorders: Placental gene expression analyses and histological examinations

Although recent studies in patients with paternal uniparental disomy 14 [upd(14)pat] and other conditions affecting the chromosome 14q32.2 imprinted region have successfully identified underlying epigenetic factors involved in the development of upd(14)pat phenotype, several matters, including regulatory mechanism(s) for RTL1 expression, imprinting status of DIO3 and placental histological characteristics, remain to be elucidated. We therefore performed molecular studies using fresh placental samples from two patients with upd(14)pat. We observed that RTL1 expression level was about five times higher in the placental samples of the two patients than in control placental samples, whereas DIO3 expression level was similar between the placental samples of the two patients and the control placental samples. We next performed histological studies using the above fresh placental samples and formalin-fixed and paraffin-embedded placental samples obtained from a patient with a maternally derived microdeletion involving DLK1, the-IG-DMR, the MEG3-DMR and MEG3. Terminal villi were associated with swollen vascular endothelial cells and hypertrophic pericytes, together with narrowed capillary lumens. DLK1, RTL1 and DIO3 proteins were specifically identified in vascular endothelial cells and pericytes, and the degree of protein staining was well correlated with the expression dosage of corresponding genes. These results suggest that RTL1as-encoded microRNA functions as a repressor of RTL1 expression, and argue against DIO3 being a paternally expressed gene. Furthermore, it is inferred that DLK1, DIO3 and, specially, RTL1 proteins, play a pivotal role in the development of vascular endothelial cells and pericytes.

Pregnancy outcome of fetuses with trisomy 18 identified by prenatal sonography and chromosomal analysis in a perinatal center

To investigate the pregnancy outcome of fetuses affected with trisomy 18, we analyzed 63 cases diagnosed at our hospital from January 1993 to December 2004. Twenty‐nine were males and 34 were females. Fifty‐eight were prenatally diagnosed, and in 16 (27.6%) of them intrauterine fetal death (IUFD) occurred between 28 weeks and 41 weeks gestation (34.6 ± 3.9 weeks, Mean ± SD). Ten (17.2%) fetuses died during labor and their age ranged from 30 weeks to 40 weeks of gestation. The total number of cases ending in fetal demise was 26 (44.8%) and the mean gestational age at the time of fetal demise was 35.0 ± 3.6 weeks (Mean ± SD). All liveborn infants (n = 36) were born after 31 weeks gestation. In our study the preterm birth ratio for trisomy 18 is 34.8%, which is much higher than the ratio for the general population. Females are more likely than males to be long‐term survivors. These data are helpful in the counseling of parents faced with the difficult decision of whether or not to continue a pregnancy with a fetus affected with trisomy 18.

Origin and mechanisms of formation of fetus-in-fetu: two cases with genotype and methylation analyses.

Fetus‐in‐fetu (FIF) is a condition in which a host infant has a fetus‐like mass(es) within its body. We describe here results of molecular genetic analysis in two cases of FIF. In FIF‐1, a male host had two retroperitoneal fetiform masses each with a vertebral column, and in FIF‐2, a fetiform mass with vertebral column was present in the cranial cavity of a male host. Genotyping of each case using microsatellite markers showed that the host infant and its fetus(es) inherited one copy each of parental alleles and shared identical genotypes. These findings were confirmed by single nucleotide polymorphism (SNP) analysis using Affymetrix GeneChip Human Mapping 50K Array, and supported a monozygotic twin theory of FIF. Analysis of the methylation status was done in both cases at the differentially methylated region (DMR) within the human IGF2‐H19 locus after bisulfite treatment, methylation‐specific PCR, and cloning of PCR products. Normally, only the paternal allele is methylated and the maternal allele unmethylated in DMR. However, in FIF‐1, 7 (46.7%) of 15 clones from a fetiform mass and 6 (66.7%) of 9 clones from the other mass showed an unmethylated paternal allele, while the methylation status of a host infant and its fetiform mass in FIF‐2 was the same in all clones examined with normal patterns. These data suggest that in FIF‐1, two isolated blastocysts originated from one zygote, one of the two was implanted into (or included by) the other blastocyst during the process of methylation, and such abnormal implantation may have occurred in FIF‐2 after the establishment of methylation. This is the first case of FIF showing different methylation patterns between a host infant and fetiform mass.

A large interstitial deletion of 17p13.1p11.2 involving the Smith–Magenis chromosome region in a girl with multiple congenital anomalies

A 6‐month‐old girl had multiple congenital anomalies, including dysmorphic face; tetralogy of Fallot, pulmonary atresia and patent ductus arteriosus; congenital cystic adenomatoid malformation of the right upper lung, and hemilateral kidney defect. Chromosome analysis as well as flurorescence in situ hybridization (FISH) and polymorphic marker analyses in the girl and her parents revealed a de novo large interstitial deletion of 17p13.1‐p11.2 of the paternally derived chromosome 17. The deletion involved the Smith–Magenis chromosome region (SMCR). Lack of involvement of the Miller–Dieker syndrome region at 17p13.3 was confirmed by both FISH analysis and radiological examinations that showed no migrational abnormality. The girl died at age 7 months. This is the first report of a patient with a large interstitial deletion of 17p.

Prenatal findings of paternal uniparental disomy 14: Report of four patients†

Prenatal Findings of Paternal Uniparental Disomy 14: Report of Four Patients Michiko Yamanaka,* Hiroshi Ishikawa, Keisuke Saito, Yasuyo Maruyama, Katsuske Ozawa, Jun Shibasaki, Gen Nishimura, and Kenji Kurosawa Osaka Prefecture University, School of Nursing & Graduate School of Nursing, Osaka, Japan Division of Obstetrics and Gynecology, Kanagawa Children’s Medical Center, Yokohama, Japan Division of Neonatology, Kanagawa Children’s Medical Center, Yokohama, Japan Department of Radiology, Tokyo Metropolitan Kiyose Children’s Hospital, Tokyo, Japan Division of Medical Genetics, Kanagawa Children’s Medical Center, Yokohama, Japan

Sirenomelia with a de novo balanced translocation 46,X,t(X;16)(p11.23;p12.3).

We report a female fetus with sirenomelia with 46,X,t(X;16)(p11.23;p12.3) de novo. Fluorescence in situ hybridization (FISH) with bacterial artificial chromosomes were employed for narrowing down the breakpoint regions. On chromosome 16, the breakpoint was mapped in the region of RP11‐453F10 (19 920 640–20 118 153 bp from 16pter). On chromosome X, the breakpoint was mapped in the region of RP11‐794A15 (47 333 744–47 524 066 bp from Xpter). This is the first case report of sirenomelia associated with translocations. The abnormal phenotype, associated with a balanced translocation, was caused by deletion or breakage of dosage‐sensitive genes of the breakpoint, disruption of an imprinted gene, or uniparental disomy. Although the parental origin of normal 16 and der(16) remained undetermined, this case will provide insight into the pathogenetic mechanism of sirenomelia.

Fetus-in-fetu: Parasite or Neoplasm?

Introduction: Fetus-in-fetu is a rare congenital fetiform mass whose etiology is still controversial. We report two cases of fetus-in-fetu. Case 1: A fetal retroperitoneal cystic tumor including two masses was detected by ultrasonography at 26 gestational weeks. The masses showed distinctive structures resembling a vertebral axis and were prenatally diagnosed as fetus-in-fetu. A resected specimen revealed two fetiform masses. Case 2: An intracranial tumor with hydrocephalus was detected by ultrasonography at 19 gestational weeks. The pregnancy was terminated, and a postmortem examination revealed six fetiform masses with immature teratoma. Discussion: The tumors may possibly consist of parasitic monozygotic diamniotic twins or highly differentiated teratomas.

Pericardial hemangioma presenting fetal cardiac tamponade and postnatal bronchostenosis

A case of pericardial hemangioma is described which was resected in the neonatal period due to its effect on the cardiopulmonary system. Preoperative differential diagnosis of a teratoma was difficult. Surgical extirpation resulted in massive bleeding and postoperative bronchomalacia. These complications suggest that we should choose a conservative therapy as often as possible.