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Objectives To assess the incidence of sex chromosome aneuploidy (SCA) predicted by noninvasive prenatal testing (NIPT), assess test performance, and compare it with nuchal translucency (NT) screening among patients seen in our prenatal diagnosis center. Methods We identified suspected cases of SCA by reviewing results from all NIPT samples sent from our center to commercial laboratories offering analysis by cell-free DNA between 1 December 2012 and 31 July 2015. Records of pregnancies positive for SCA were reviewed for ultrasound findings, NIPT indications, and karyotype results on maternal, fetal, and postnatal samples. Other SCA cases presenting during this period regardless of NIPT status were identified from genetic counseling and cytogenetics laboratory logbooks. Results Noninvasive prenatal testing predicted SCA in 18/2851 patients (0.63%). All had diagnostic testing of fetal or newborn samples. No patients terminated pregnancies on the basis of NIPT. NIPT suggested triple X in five cases, two with elevated NT: all were confirmed on karyotype. Two Klinefelter syndrome cases were also accurately predicted by NIPT. NIPT indicated monosomy X in 11 cases. Only one was a true positive. Ten were false positives, with 46, XX found on fetal or newborn karyotype. Maternal karyotype was mosaic (45, X[4], 46, XX[26]) in one case. Over the same time period, four additional cases of 45, X were confirmed on fetal samples, all with cystic hygromas. One of these had had a false negative NIPT result. The remaining patients pursued only direct testing via CVS or amniocentesis. Conclusions Sex chromosome aneuploidy was frequently suspected on NIPT. False positive rate for monosomy X was surprisingly high (91%). Prediction of other SCA was more accurate. Diagnostic fetal chromosome analysis should be offered after abnormal NIPT or in the presence of cystic hygromas despite normal NIPT. NIPT limitations should be explained in pretest counseling. © 2017 John Wiley & Sons, Ltd.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder with variability in clinical manifestations and molecular causes. In most cases, patients with BWS have normal development. Cases with developmental delay are usually attributed to neonatal hypoglycemia or chromosome abnormalities involving copy number variation for genes beyond the critical BWS region at 11p15.5. Brain abnormalities have not previously been recognized within the BWS phenotypic spectrum. We report on seven cases of BWS associated with posterior fossa abnormalities. Of these, two cases presented with Blake's pouch cyst, two with Dandy-Walker variant (DWV; hypoplasia of the inferior part of the vermis), one with Dandy-Walker malformation (DWM) and one with a complex of DWM, dysgenesis of the corpus callosum and brain stem abnormality. In all these cases, molecular findings involved the centromeric imprinted domain on chromosome locus 11p15.5, which includes imprinting center 2 (IC2) and the imprinted growth suppressor gene, CDKN1C. Three cases had loss of methylation at IC2, two had CDKN1C mutations, and one had loss of methylation at IC2 and a microdeletion. In one case no mutation/methylation abnormality was detected. These findings together with previously reported correlations suggest that genes in imprinted domain 2 at 11p15.5 are involved in normal midline development of several organs including the brain. Our data suggest that brain malformations may present as a finding within the BWS phenotype when the molecular etiology involves imprinted domain 2. Brain imaging may be useful in identifying such malformations in individuals with BWS and neurodevelopmental issues.

Apert syndrome was diagnosed in a newborn with typical facial and digital features whose only detected prenatal abnormality had been agenesis of the corpus callosum. This prompted a review of the central nervous system findings in all cases of Apert syndrome treated at the Craniofacial Center Boston Children's Hospital between 1978 and 2004. Two of 30 patients with Apert syndrome had prenatal identification of mild dilatation of the lateral cerebral ventricles and complete agenesis of the corpus callosum (ACC) documented with both ultrasound and MRI. Both had the common S252W mutation of FGFR2. Though cranial and orbital malformations typical of Apert were eventually seen in these fetuses in the third-trimester, even in retrospect, these were not detectable at mid second-trimester, ultrasound screening for congenital malformations. Hand malformations also went undetected in the second-trimester despite extensive imaging by experienced radiologists. We conclude that prenatal ultrasonographic identification of mild ventriculomegaly or ACC should stimulate a careful search for features of Apert syndrome and prompt follow-up imaging to look for bony abnormalities that have later onset. Prenatal molecular testing for Apert mutations should be considered in cases of mild ventriculomegaly and ACC.

A 15q26 terminal chromosomal microdeletion was associated with markedly enlarged 1st trimester nuchal translucency in three of four pregnancies of a couple seen in our prenatal diagnosis unit. Nuchal translucency was normal in the couple's fourth pregnancy, which did not carry the microdeletion. The diagnosis of a 15q26.2→qter microdeletion was first made when the couple's affected daughter displayed significant postnatal growth delay and minor malformations consistent with this contiguous gene syndrome. The microdeletion was confirmed on archived material from the first pregnancy, and identified prospectively on chorionic villi in the third pregnancy. This is the second reported case of familial recurrence of this microdeletion syndrome. As in the other reported family, no deletion or chromosomal rearrangement was identified in either parent, suggesting gonadal mosaicism as a possible cause. First trimester ultrasound findings in 15q26 terminal deletion syndrome have not previously been described. This family illustrates the utility of performing prenatal chromosomal microarray testing in the presence of ultrasound findings of enlarged nuchal translucency or structural abnormalities.

Objectives The purpose of this study was to determine how often a low-lying placenta, defined as a placenta ending within 2 cm of the internal cervical os but not covering it, diagnosed sonographically in the second trimester resolves before delivery. Methods After Institutional Review Board approval was obtained, 1416 pregnancies with a sonographically diagnosed low-lying placenta between 16 and 24 weeks' gestation were identified from our ultrasound database over a 5-year period. We reviewed medical records to determine the gestational age at which the low-lying placenta was first diagnosed, the gestational age at which the placenta was no longer sonographically low lying or covering the cervix, and, of those whose placentas that never cleared the internal cervical os sonographically, how many went on to cesarean delivery as a result of placental location. Results In total, 1220 of 1240 low-lying placentas (98.4%) that had sonographic follow up resolved to no previa before delivery; 89.9% of placentas cleared the cervix by 32 weeks, and 95.9% cleared by 36 weeks. Twenty patients (1.6%) had persistent sonographic placenta previa or a low-lying placenta at or near term, including 5 complete previas, 7 marginal previas, 5 low-lying placentas, and 3 vasa previas; all had cesarean deliveries. Conclusions A low-lying placenta sonographically diagnosed in the second trimester typically resolves by the mid third trimester. Only rarely (1.6% of the time) does it persist to term or near term. Follow-up sonography is warranted to diagnose persistent placenta previa or vasa previa, a complication of a low-lying placenta.

Objectives Our purpose was to review the outcomes of singleton pregnancies in which an absent nasal bone was noted on first- or second-trimester sonography and aneuploidy was not present. Methods We identified singleton pregnancies from 2005 to 2011 in which an absent nasal bone was noted on sonography, aneuploidy was excluded, and newborn examinations were available for review. Sonographic reports were reviewed for anomalies, growth, and amniotic fluid volume. Newborn records were reviewed for physical examinations, complications, and radiologic or genetic tests. Results We identified 142 fetuses with a sonographic appearance of an absent nasal bone. We excluded 52 cases with aneuploidy and 33 in which newborn examination information was unavailable. Fifty-seven cases met inclusion criteria. For 3 euploid fetuses with an absent nasal bone on sonography, the presence of additional anomalies on second-trimester sonography ultimately signaled an adverse outcome: the presence of multiple congenital anomalies, a microdeletion syndrome, and a specific genetic diagnosis. Conclusions All cases with adverse outcomes had additional prenatal sonographic findings. For the remainder, normal newborn examination findings provide some reassurance, especially in the setting of otherwise normal second-trimester sonographic findings. A microarray as a test for microdeletion and duplication syndromes in this situation could be considered.

Hand malformations characterize many congenital syndromes, including mendelian disorders, skeletal dysplasias, and karyotype abnormalities. Although identification of a hand anomaly alters obstetrical management, evaluation of the fetal hands is not included in current ultrasonographic guidelines. We prospectively studied the utility of allotting up to 5 min to examine fetal hands during obstetrical ultrasonography. Both hands were visualized in 87% of patients (188 of 215). Eight hand abnormalities were present at delivery. Six had been identified antenatally, four during the study with ultrasonography. There were no false positives. Four fetuses with hand malformations were aneuploid. Fetal hands should be examined during a comprehensive obstetrical sonographic evaluation, especially when risk factors for aneuploidy are present.

To assess karyotypes and outcomes of monochorionic diamniotic (MCDA) twin pregnancies discordant for markedly enlarged nuchal translucency (NT) in the first trimester.Brigham and Women's Hospital's ultrasound database was queried to identify all MCDA gestations in which one twin had NT ≥ 3.5 mm and the co-twin had normal NT. Cytogenetic results, ultrasound findings, and pregnancy outcomes were reviewed.Of 162 MCDA twin pairs, 11 were discordant for NT ≥ 3.5. Chromosomal abnormalities were present in three cases: one twin pair was concordant for trisomy 18; one pair discordant for mosaic trisomy 2; and one pair discordant for confined placental mosaicism (CPM) (high frequency tetraploidy). Adverse outcomes for twins with euploid or unknown karyotypes included twin reverse arterial perfusion (TRAP) sequence, growth discordance, and esophageal atresia with tracheoesophageal fistula.Postfertilization nondisjunction leading to mosaicism in one fetus, discordant phenotypes yet concordant karyotypes, and discordance for CPM were documented phenomena, supporting karyotyping of both twins. In this case series, discordant NT was a marker for chromosome abnormalities, as well as for complications specific to monochorionic gestations, including TRAP sequence, amniotic fluid discordance, and structural anomalies. Nonetheless, normal fetal anatomy and karyotype were the most common outcomes.

Fabiola Quintero-Rivera, Caroline D. Robson, Rosemary E. Reiss, Deborah Levine, Carol B. Benson, John B. Mulliken, and Virginia E. Kimonis* Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts Department of Radiology, Children’s Hospital, Boston, Massachusetts Maternal Fetal Medicine, Brigham and Women’s Hospital, Boston, Massachusetts Department of Radiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts Department of Radiology, Brigham and Women’s Hospital, Boston, Massachusetts Division of Plastic Surgery, Children’s Hospital, Boston, Massachusetts Division of Genetics and Metabolism, Children’s Hospital, Boston, Massachusetts Harvard Medical School, Boston, Massachusetts

Although the majority of reported pericardial teratomas have been excised successfully in the postnatal period, the outcome of prenatally diagnosed pericardial teratomas remains less favorable. Two recent cases of prenatally diagnosed pericardial teratomas and a review of previously reported cases suggest a new management algorithm for those pericardial teratomas discovered in utero. Fetuses in whom hydrops does not develop may be safely followed up and treated postnatally. However, if hydrops develops, the fetus requires treatment with either aspiration of the pericardial effusion, or fetal surgery and resection.

The fetus as "patient" during labor and birth has become an increasingly important concept during the past 20 years. However, what is understood about fetal status during labor and how the fetus prepares for its approaching separation from its mother? Current information indicates that not only is the term fetus well prepared for the adaptation to extrauterine life, but this transition is facilitated by normal labor.

• Current ultrasound technology allows for accurate evaluation of the fetal heart. To evaluate the importance and accuracy of the routine clinical use of fetal echocardiography at our center, a consecutive series of 338 fetal cardiac studies of 323 patients was reviewed. Average gestational age was 24 weeks (range, 17 to 39 weeks). Forty-seven (15%) patients with abnormal conditions were detected. The most common indication for fetal cardiac scan was a family history of congenital heart disease (28%). Other indications were maternal diabetes mellitus (25%), fetal dysrhythmia (14%), other major defect (10%), drug exposure (10%), and obstetrician suspicion of fetal congenital heart disease on routine scan (10%). The highest yield of significant abnormal findings was among those referred for dysrhythmia (31%) and obstetrician suspicion of congenital heart disease (29%). Five fetuses with sustained supraventricular tachycardia and hydrops were successfully treated. The combination of fetal bradycardia and structural heart disease was the most ominous finding. Fifteen (4.6%) patients had clear changes in management based on the fetal echocardiogram. Our experience suggests that the routine use of fetal echocardiography is accurate and an important part of the overall management of the pregnancy considered at risk for producing an infant with congenital heart disease. ( AJDC . 1990;144:49-53)

CYSTINOSIS is an autosomal recessive disorder characterized by intracellular accumulation of cystine due to failure of the normal carrier-mediated system that transports cystine out of lysosomes.1 ...

A decrease in systemic blood pressure by midtrimester of normal pregnancy has been observed by many investigators. To examine the timing of onset of this decline and to study early behavior of blood pressure in pregnancies complicated by preeclampsia, we reviewed the outpatient charts of all patients with preeclampsia who received prenatal care at our clinics during the past 3 years. The 30 patients who met our criteria for preeclampsia were matched for age, race, and parity with normotensive control subjects. We found that in normal pregnancies, decline in blood pressure occurred before the second trimester and blood pressure remained low throughout gestation, rising insignificantly near term. Both systolic and diastolic blood pressures were significantly higher (p less than 0.05) for patients with preeclampsia than for normal control subjects beginning in the first trimester. This difference persisted throughout pregnancy and was also present at the 6-week postpartum visit (p less than 0.025).

Pregnancies in two patients with Hermansky-Pudlak syndrome, oculocutaneous albinism with hemorrhagic diathesis, are presented. Outcomes were good despite prior reports of postpartum hemorrhage in patients with this syndrome. This autosomal recessive disease is relatively common in parts of Puerto Rico. Suspected patients should be screened with platelet aggregation studies.