Spectrum of genes for inherited hearing loss in the Israeli Jewish population, including the novel human deafness gene ATOH1.

Mutations in more than 150 genes are responsible for inherited hearing loss, with thousands of different, severe causal alleles that vary among populations. The Israeli Jewish population includes communities of diverse geographic origins, revealing a wide range of deafness-associated variants and enabling clinical characterization of the associated phenotypes. Our goal was to identify the genetic causes of inherited hearing loss in this population, and to determine relationships among genotype, phenotype, and ethnicity. Genomic DNA samples from informative relatives of 88 multiplex families, all of self-identified Jewish ancestry, with either non-syndromic or syndromic hearing loss, were sequenced for known and candidate deafness genes using the HEar-Seq gene panel. The genetic causes of hearing loss were identified for 60% of the families. One gene was encountered for the first time in human hearing loss: ATOH1 (Atonal), a basic helix-loop-helix transcription factor responsible for autosomal dominant progressive hearing loss in a five-generation family. Our results show that genomic sequencing with a gene panel dedicated to hearing loss is effective for genetic diagnoses in a diverse population. Comprehensive sequencing enables well-informed genetic counseling and clinical management by medical geneticists, otolaryngologists, audiologists, and speech therapists and can be integrated into newborn screening for deafness.

When genotype is not predictive of phenotype: implications for genetic counseling based on 21,594 chromosomal microarray analysis examinations.

PurposeTo compare the frequency of copy-number variants (CNVs) of variable penetrance in low-risk and high-risk prenatal samples and postnatal samples.MethodsTwo cohorts were categorized according to chromosomal microarray analysis (CMA) indication: group I, low-risk prenatal-women with uneventful pregnancy (control group); group II, high-risk prenatal-women whose fetuses had congenital malformations; and group III, postnatal-individuals with unexplained developmental delay/intellectual disability, autism spectrum disorders, or multiple congenital anomalies. CNVs were categorized based on clinical penetrance: (i) high (>40%), (ii) moderate (10-40%), and (iii) low (<10%).ResultsFrom 2013 to 2016, 21,594 CMAs were performed. The frequency of high-penetrance CNVs was 0.1% (21/15,215) in group I, 0.9% (26/2,791) in group II, and 2.6% (92/3,588) in group III. Moderate-penetrance CNV frequency was 0.3% (47/15,215), 0.6% (19/2,791), and 1.2% (46/3,588), respectively. These differences were statistically significant. The frequency of low-penetrance CNVs was not significantly different among groups: 0.6% (85/15,215), 0.9% (25/2,791), and 1.0% (35/3,588), respectively.ConclusionHigh-penetrance CNVs might be a major factor in the overall heritability of developmental, intellectual, and structural anomalies. Low-penetrance CNV alone does not seem to contribute to these anomalies. These data may assist pre- and posttest CMA counseling.

Chromosomal microarray findings in pregnancies with an isolated pelvic kidney.

Objective To examine the risk for abnormal chromosomal microarray analysis (CMA) results among fetuses with an apparently isolated pelvic kidney. Methods Data from all CMA analyses performed due to an isolated pelvic kidney reported to the Israeli Ministry of Health between January 2013 and September 2016 were retrospectively obtained. Risk estimation was performed comparing the rate of abnormal observed CMA findings to the general population risk, based on a systematic review encompassing 9272 cases and on local data of 5541 cases. Results Of 120 pregnancies with an isolated pelvic kidney, two gain-of-copy number variants suggesting microduplication syndromes were demonstrated (1.67%). In addition, three variants of unknown significance were detected (2.5%). Conclusion The risk for clinically significant CMA findings among pregnancies with an isolated single pelvic kidney was not significantly different compared to both control populations. The results of our study question the practice of routine CMA analysis in fetuses with an isolated pelvic kidney.

The impact of third-trimester genetic counseling.

OBJECTIVE: To evaluate the impact of genetic counseling (GC) during the third trimester by analyzing changes in pregnancy management and the correlation with postnatal findings. METHODS: This was a retrospective study. Pregnancy course and neonatal follow-up were analyzed according to the reason for referral and implementation of recommendations. RESULTS: The records of neonates born to 181 women were retrieved. Fifty-two women (group 1-29%) qualified for pregnancy termination under Israeli guidelines and laws, and 129 (group 2-71%) were not at the time they were referred. By another division: 104 women (group 3-57%) followed the physician's diagnostic recommendations completely after counseling including amniocentesis, fetal MRI, targeted ultrasound scans, fetal echocardiography. Seventy-seven declined amniocentesis (group 4-43%). Additional abnormalities were detected postpartum in all groups without statistically difference: 3/52 (10%) in group 1, 9/129 (7%) in group 2, 6/104 (6%) in group 3, and 6/77 (8%) in group 4). CONCLUSION: GC in the third trimester of pregnancy provided the couple with a sharper more focused picture and assisted them to perceive the significance of new, significant fetal findings which attest to the value of the GC.

The association between maternal serum first trimester free ßhCG, second trimester intact hCG levels and foetal growth restriction and preeclampsia.

The purpose of this study was to analyse the association between free beta hCG (fßhCG) increased levels and pregnancy complications (PC), foetal growth restriction (FGR) and preeclampsia (PE). This connection was evaluated in two stages (i) investigating the association between those PC with first trimester fßhCG and second trimester intact hCG (ihCG), and (ii) studying the association between these two analytes in the same pregnancy. This was a retrospective study in two settings: medical centre that provided data on fßhCG and ihCG levels in pregnancies with FGR and PE, and central laboratory that provided fßhCG and ihCG levels that were compared in the same pregnancy. No association was found between those PC and the hCG analytes, except for elevated ihCG levels and FGR. Elevated fßhCG (>3.00 MoM) was found in 570/16,849 (3.4%) women. However, only 14% of whom had elevated second trimester ihCG. A positive correlation was found between the magnitude of first trimester fßhCG levels and the percentage of women who had elevated second trimester ihCG. This association was determined by the magnitude of the elevation of fßhCG levels. Impact statement What is already known on this subject: The two analytes, first trimester fßhCG and second trimester ihCG, are independently produced and parameters of the biochemical screening during pregnancy. What the results of this study add: Referring to 3.00 MoM as cut-off levels, most pregnancies with elevated levels of first trimester fßhCG will have normal ihCG second trimester levels. What the implications are of these findings for clinical practice and/or further research: The risk of developing pregnancy complications, FGR and PE should be associated with second trimester ihCG levels. About 3.5% of women had high fßhCG levels during the first trimester. However, only 14% also had increased ihCG levels, defined as >3.00 MoM; additional studies are needed to explore the association between increased first trimester fßhCG levels and the risk of developing pregnancy complications, independent of ihCG levels in the second trimester.

The magnitude of elevated maternal serum human chorionic gonadotropin and pregnancy complications.

This study assessed the correlation between the magnitude of the elevation in maternal serum human chorionic gonadotropin (MShCG) levels and pregnancy complications. Among 80,716 screened pregnancies, 120 with moderately elevated MShCG (3.00-5.99 MoM) were compared to 84 with extremely elevated MShCG >6.00 MoM. A control series of 120 women with normal MShCG (<3.00 MoM) were matched. Rates of intrauterine growth restriction, preterm labour, antepartum foetal death (APFD), pre-eclampsia, and placental abruption were analysed. We found that the study group had more adverse outcomes than the control group (73/204 [36%] vs. 18/120 [15%]; p < .0001). The rate was higher in the extremely elevated group than in the moderately elevated group (43/84 [51%] vs. 30/120 [25%]; p < .0001). All 12 cases of APFD (14%) occurred among the extremely elevated series. In conclusion, adverse pregnancy outcomes are more common in women with extremely elevated MShCG. The patients should receive counselling regarding this trend and undergo close pregnancy monitoring. Impact statement • What is already known on this subject?In addition to its contribution to Down syndrome (DS) screening, maternal serum human chorionic gonadotropin (MShCG) levels are a marker for pregnancy complications such as intrauterine growth restriction (IUGR), preterm labour (PTL), antepartum fatal death (APFD), pre-eclampsia (PE), placental abruption (PA) and fetal malformations with or without chromosomal aberrations. • What the results of this study add? We found that in the presence of elevated MShCG levels, the incidence of IUGR and PTL increased. PE increased clinically, but statistical significance was seen only when MShCG was extremely elevated (≥ 6.00 MoM). APFD and PA were associated with very high MShCG levels only. • What the implications are of these findings for clinical practice and/or further research? Women with high MShCG levels should be counselled. In case of very high levels (≥ 6.00 MoM), the risk of APFD and PA should be discussed. The pregnancy should be monitored for IUGR, PTL and PE. In view of the limited number of enrolled patients with very high levels of MShCG, the experience of other institutions is needed to corroborate these findings.

Is the ratio of maternal serum to amniotic fluid AFP superior to serum levels as a predictor of pregnancy complications?

PURPOSE: The use of maternal serum alpha fetoprotein (MSAFP) levels as a predictor of pregnancy complications (PC) is well established. We hypothesized that the ratio between the MSAFP/AFAFP levels (RATIO) will more accurately predict PC than MSAFP levels alone. METHODS: Women who had a MSAFP test followed by amniocentesis were divided into two groups: those who had PC comprised the study group and those who had an uneventful pregnancy served as the control group. Data regarding pregnancy and delivery course were collected. The RATIO between the study and the control groups was compared. RESULTS: 166 women were included in the study, of which 24 had PC. A significant correlation was found between the RATIO and intrauterine growth restriction (IUGR) and week of delivery. Six pregnancies had elevated MSAFP levels; two with RATIO below 2 had uneventful pregnancies. Among the other four pregnancies with RATIO above two, one had IUGR and the other, placental abruption. CONCLUSION: Our data suggest that the RATIO might serve as a predictor of IUGR and week of delivery. Although the number of patients in the current study was relatively small, the novelty of the proposed simple marker implies that a larger scale study is warranted. Such studies may confirm this finding and a possible advantage of using this RATIO instead of or in addition to MSAFP values for better prediction of pregnancies at risk for PC.

Telomere length and telomerase reverse transcriptase mRNA expression in patients with hepatitis C.

BACKGROUND/AIMS: Shortened telomeres reflect genetic instability that might lead to increased aneuploidy and malignant transformations. Chronic hepatitis C (HCV) viral infection is considered a pre-neoplastic condition that might progress to hepatocellular carcinoma. We evaluated telomere length and elongation, in patients with different stages of HCV to study the correlation between telomere length and the progression of HCV. METHODOLOGY: We analyzed peripheral lymphocytes from 10 patients with chronic active HCV, 10 patients with HCV infection in a remission stage, and 10 healthy, age-matched patients, as controls. The expression of hTERT mRNA, which is correlated with elongation of telomeres was measured using RT-PCR and telomere length was analyzed using Q-FISH and a novel computerized technique. RESULTS: hTERT mRNA was significantly decreased in patients with active HCV and slightly decreased in patients who were in remission, compared to healthy individuals. Telomere length was shorter in patients with chronic active HCV and in patients in remission, compared to the healthy controls. CONCLUSIONS: There is a correlation between telomerase reverse transcriptase mRNA expression and telomere length in patients with different stages of HCV infection that might be related to the risk of malignant transformation.

Mutation of TBCE causes hypoparathyroidism-retardation-dysmorphism and autosomal recessive Kenny-Caffey syndrome.

The syndrome of congenital hypoparathyroidism, mental retardation, facial dysmorphism and extreme growth failure (HRD or Sanjad-Sakati syndrome; OMIM 241410) is an autosomal recessive disorder reported almost exclusively in Middle Eastern populations. A similar syndrome with the additional features of osteosclerosis and recurrent bacterial infections has been classified as autosomal recessive Kenny-Caffey syndrome (AR-KCS; OMIM 244460). Both traits have previously been mapped to chromosome 1q43-44 (refs 5,6) and, despite the observed clinical variability, share an ancestral haplotype, suggesting a common founder mutation. We describe refinement of the critical region to an interval of roughly 230 kb and identification of deletion and truncation mutations of TBCE in affected individuals. The gene TBCE encodes one of several chaperone proteins required for the proper folding of alpha-tubulin subunits and the formation of alpha-beta-tubulin heterodimers. Analysis of diseased fibroblasts and lymphoblastoid cells showed lower microtubule density at the microtubule-organizing center (MTOC) and perturbed microtubule polarity in diseased cells. Immunofluorescence and ultrastructural studies showed disturbances in subcellular organelles that require microtubules for membrane trafficking, such as the Golgi and late endosomal compartments. These findings demonstrate that HRD and AR-KCS are chaperone diseases caused by a genetic defect in the tubulin assembly pathway, and establish a potential connection between tubulin physiology and the development of the parathyroid.

Correlation between prenatal and postnatal penile and clitoral measurements.

BACKGROUND: A correlation between prenatal and postnatal penile and clitoral sizes has not been reported. These data would substantiate the ability of prenatal ultrasound (US) scan to predict postnatal measurements. The aims were to correlate prenatal and postnatal penile and clitoral measurements and to ascertain the possible advantage of using prenatal penile width rather than length to predict postnatal measurements. METHODS: This was a longitudinal study. Fetal penis and clitoris were measured by high-resolution US between gestational weeks 14 and 29. Postnatal measurements of external genitalia were performed during the first postnatal week. All measurements were performed twice consecutively. A correlation between the measurements sets was sought. RESULTS: Paired prenatal and postnatal measurements were performed on 46 males and 48 females. Prenatal penile and clitoral length values correlated significantly with postnatal length at p < 0.05 each. CONCLUSIONS: Prenatal US findings appear to be reliable indicators of postnatal penile and clitoral length measurements. Penile width measurement did not add new information.

Telomere aggregates in amniocytes with karyotype of balanced chromosomal rearrangements.

Telomeres are TTAGGG repetitions at the ends of chromosomes. Functioning telomeres are essential for normal segregation and maintenance of chromosomes during mitotic and meiotic divisions. Dysfunctional telomeres support the survival of aneuploid cells, a characteristic of many human malignancies. In contrast to the non-overlapping nature of telomeres in normal nuclei, telomeres of tumor nuclei tend to form aggregates. In this study, our objective was to evaluate the number of telomere aggregates (TAs) in karyotype-balanced structural rearrangements. This is an additional parameter of genetic instability, which might suggest a possible increased risk for diseases related to genomic instability, such as cancer. Twenty-six amniotic fluid cell cultures were established following genetic amniocentesis. Telomere FISH protocol was applied to the samples. Telomere aggregates were counted using a 2D microscope. The results were statistically tested by analysis of variance (ANOVA) and Kruskal-Wallis tests. More telomere aggregates in the structural balanced rearrangements were found in both study groups (balanced translocations and inversions) compared to the control group (P < 0.05). The persistence of TAs in cells is probably related to Breakage-Bridge-Fusion (BBF) cycles, a mechanism of TAs described by Muller and McClintock, resulting in end-to-end fusion that contributes to the onset of genomic instability. BBF cycles contribute to deletions, gene amplification, non-reciprocal translocations, and overall genetic changes associated with tumor genesis. According to our studies, the individuals who are carriers of balanced structural chromosomal rearrangements show some of the genetic instability parameters that appear in other circumstances, such as premalignant and malignant conditions.

Based on a cohort of 52,879 microarrays, recurrent intragenic FBN2 deletion encompassing exons 1-8 does not cause Beals syndrome.

INTRODUCTION: Congenital contractural arachnodactyly (CCA) is a rare connective tissue disorder, associated with heterozygous mutations in the FBN2 gene. The objective of this study was to evaluate the prevalence of an intragenic deletion encompassing exons 1-8 of FBN2 gene in Israeli population. MATERIALS AND METHODS: A search for intragenic FBN2 microdeletions was performed in two databases of chromosomal microarray analysis (CMA) - genetic laboratory of a tertiary medical center (the primary cohort) and one of the largest Israeli health maintenance organizations (replication cohort). RESULTS: Overall, 52,879 microarray tests were searched for FBN2 microdeletions. The primary cohort constituted of 18,301 CMA tests, among which 33 intragenic FBN2 microdeletions in unrelated individuals were found (0.18%). Prenatal prevalence of this variant was 0.23% (28/12,604), and specifically in low risk pregnancies - 0.29% (22/7464). Of the 28 cases with known parental origin, 27 (96.4%) were of full or partial Ashkenazi Jewish ethnic background. The approximate allele incidence in the Ashkenazi Jewish origin was 0.4% (18/4961). Combined with the 34,578 CMA tests in the replication cohort, the overall frequency of FBN2 microdeletions was 0.24% (125/52,879). None of the pre- or postnatal cases had any clinical manifestations of CCA. DISCUSSION: Intragenic FBN2 microdeletions are found in one of every 420 CMA analyses in Israeli population, and in particular one of every 340 low-risk pregnancies. Due to high allele incidence in Ashkenazi Jewish population (1:275), we suggest that FBN2 gene deletion detected by CMA among Ashkenazi Jews should be interpreted as benign copy number variant.

Maternal serum triple marker levels in immigrants to Israel from Ethiopia.

OBJECTIVES: To determine if Ethiopian immigrants have similar triple marker levels as the general Israeli population. MATERIAL AND METHODS: Second-trimester maternal serum results on 346 Ethiopians were obtained from records of 36,309 women. Two series were constructed for comparison among patients screened between 2000 and 2001 ('old group') and 2005 and 2007 ('new group'). RESULTS: The median and 95% confidence intervals (CI) were: alpha-fetoprotein (AFP) 1.080 multiples of median (MoM) (95% CI 1.03-1.13); human chorionic gonadotrophin (hCG) 0.895 MoM (95% CI 0.82-0.97), and unconjugated estriol (uE(3)) 1.050 MoM (95% CI 1.00-1.10). The differences between the AFP and hCG medians for the old and new series were not statistically significant (p = 0.06 and 0.20) whilst the uE(3) difference was significant (p = 0.04). There was a general tendency for the levels to be closer to 1 MoM over time. CONCLUSIONS: Triple marker serum levels of AFP and hCG among Ethiopian patients may need to be slightly corrected, particularly for hCG.

Who should be offered fetal echocardiography? One center's experience with 3965 cases.

BACKGROUND: Although the comprehensive evaluation of the fetal heart includes echocardiography by an experienced pediatric cardiologist, economic constraints sometimes dictate the need to select patients. OBJECTIVES: To analyze the usefulness of fetal echocardiography in the detection of congenital heart disease according to the referral indication. METHODS: This retrospective survey relates to all 3965 FE studies performed in our center from January 2000 to December 2004. The diagnosed cardiac anomalies were classified as significant and non-significant malformations. All FE studies were done by a single operator (A.L.) at Meir Medical Center, a referral center for a population of about 400,000. The 3965 FE studies were performed for the following indications: abnormal obstetric ultrasound scans, maternal and family history of cardiac malformations, medication use during the pregnancy, and maternal request. The relative risk of detecting CHD was calculated according to the various referral indications. RESULTS: Overall, 228 (5.8%) cases of CHD were found. The most common indication for referral was suspicion of CHD during a four-chamber view scan in a basic system survey or during a level II ultrasound survey. No correlation was found between maternal age and gestational age at the time of scanning and the likelihood of finding CHD. CONCLUSIONS: Our data suggest that a suspicious level II ultrasound orthe presence of polyhydramnios is an important indication for FE in the detection of significant CHD.

The yield of the prenatal work-up in intrauterine growth restriction and the spectrum of fetal abnormalities detected postnatally †.

OBJECTIVE: To evaluate the yield of work-up in intrauterine growth restriction (IUGR) pregnancies and their outcomes. MATERIALS AND METHODS: Retrospective data regarding prenatal work-up (serology, genetic testing and imaging), and neonatal outcomes of 198 IUGR pregnancies (estimated fetal weight <10th percentile) were analyzed. RESULTS: IUGR was isolated in 72 cases. Work-up performed in 158 (80%) cases was positive in 4 (2.5%). No abnormalities were detected in prenatal genetic testing. Echocardiogram performed in 27 cases was abnormal in 3 (11.1%). Serological testing performed in 150 pregnancies (75.8%) detected 1 case (0.7%) of cytomegalovirus (CMV) infection. Thirteen neonates (6.5%) were diagnosed with significant health problems. A positive work-up and significant postnatal health problems were not correlated with IUGR severity, symmetry or additional concurrent findings. CONCLUSION: The yield of IUGR work-up is not clear and is probably highest for fetal echocardiography. The rate of significant adverse outcomes after birth is increased in IUGR pregnancies.

Yemenite-Jewish families with Machado-Joseph disease (MJD/SCA3) share a recent common ancestor.

In 1994, a kindred from Yemen was described as the first Jewish family with Machado-Joseph disease (MJD/SCA3), a dominant ataxia caused by the expansion of a (CAG)n above 61 repeats, in ATXN3. MJD is spread worldwide due to an ancient variant of Asian origin (the Joseph lineage). A second, more recent, independent expansion arose in a distinct haplotype (Machado lineage); other possible origins are still under study. We haplotyped 46 MJD patients and relatives, from 6 Israeli Yemenite families, and 100 normal chromosomes from that population, for 30 SNPs spreading 15 kb around the (CAG)n, and 8 STRs and 1 indel in the flanking regions. All six families shared an extended haplotype, showing no variants or recombination after a common origin, but differing in two SNPs (rs12895357 and rs12588287) from the Joseph lineage. To test for a new mutational origin in this population, we searched for the presence of that haplotype in Yemenite-Jewish controls. Only one (1%) normal (CAG)32 allele showed an extended STR-haplotype genetically closer to MJD than normal haplotypes (genetic distance, DA, 0.43 versus 0.53). That normal allele could be explained either by (1) the introduction of both normal and expanded alleles carrying this "Joseph-like" haplotype into the genetic pool of the Yemenite population; or by (2) a large contraction from the expanded CAG range. Based on the lack of STR diversity in MJD Yemenite-Jewish families, and on high frequency of this Joseph-like haplotype among African controls (23.2%), expanded alleles seem to have been introduced very recently (<400 years ago) from Africa.

Non-visualization of fetal gallbladder in microarray era - a retrospective cohort study and review of the literature.

OBJECTIVE: The objective of this study is to examine the frequency of abnormal Chromosomal Microarray (CMA) analyses among fetuses with isolated non-visualization of fetal gallbladder. METHODS: Data from CMA analyses performed due to isolated non-visualization of fetal gallbladder between January 2013 and September 2016 were retrospectively acquired from a computerized database of the Israeli Ministry of Health. The results were compared with the rate for clinically significant CMA findings in general population, based on a large cohort of 5541 pregnancies undergoing CMA due to maternal request, and a systematic review of 9272 cases with normal ultrasound. RESULTS: Of 45 pregnancies with isolated non-visualization of fetal gallbladder, CMA testing yielded one (2.22%) gain-of-copy-number variant at 16p11.2, categorized as "pathogenic". In addition, one finding of unknown significance was demonstrated. The risk for clinically meaningful CMA findings among pregnancies with isolated absent gallbladder was not significantly increased compared to control population. CONCLUSIONS: To the best of our knowledge, this study is the first report describing the rate of pathogenic CMA results in fetuses with isolated non-visualization of fetal gallbladder. The results, in conjunction with previous studies, show that the risk for abnormal CMA results in pregnancies diagnosed with non-visualized gallbladder is not significantly different from pregnancies with normal ultrasound.

Four USH2A founder mutations underlie the majority of Usher syndrome type 2 cases among non-Ashkenazi Jews.

Type 2 Usher syndrome (USH2) is a recessively inherited disorder, characterized by the combination of early onset, moderate-to-severe, sensorineural hearing loss, and vision impairment due to retinitis pigmentosa. From 74% to 90% of USH2 cases are caused by mutations of the USH2A gene. USH2A is composed of 72 exons, encoding for usherin, an extracellular matrix protein, which plays an important role in the development and maintenance of neurosensory cells in both retina and cochlea. To date, over 70 pathogenic mutations of USH2A have been reported in individuals of various ethnicities. Many of these mutations are rare private mutations segregating in single families. The aim of the current work was to investigate the genetic basis for USH2 among Jews of various origins. We found that four USH2A mutations (c.239-240insGTAC, c.1000C>T, c.2209C>T, and c.12067-2A>G) account for 64% of mutant alleles underlying USH2 in Jewish families of non-Ashkenazi descent. Considering the very large size of the USH2A gene and the high number of mutations detected in USH2 patients worldwide, our findings have significant implications for genetic counseling and carrier screening in various Jewish populations.

Adverse outcome of pregnancies with extremely high levels of maternal serum human chorionic gonadotropin.

BACKGROUND: The associated risk of elevated levels of maternal serum human chorionic gonadotropin (MShCG) with pregnancy complications was reported in many studies. However, the outcome of pregnancies with extremely high levels of MShCG was never independently studied. METHODS: We report on 6 out of 45,990 studied patients with extremely high levels of MShCG (>15 multiples of the medians) analyzed during the second trimester. RESULTS: Although our patient population was composed of more Jewish than Arab pregnant women, all those patients were Arabs. Overall, the prognosis of those pregnancies was poor. In 1 case, an antepartum fetal death occurred, 2 had premature deliveries (one of the newborns had severe failure to thrive), and 2 delivered small for gestational age babies. In 5 of these 6 cases, no specific diagnosis was established. One case was complete hydatidiform mole with a coexisting normal fetus. CONCLUSIONS: We recommend that these patients undergo counseling in which the predicted outcome will be described. In addition, a follow-up of high-risk pregnancy should be implemented: sonographic evaluation should be performed, initially to rule out a molar gestation. The patients should then be followed for growth restriction and they should be monitored to rule out other pregnancy complications such as premature labor and antepartum fetal death. Finally, the overrepresentation of Arabs among our affected patients raises the question of a possible genetic tendency for increased MShCG levels especially in the extreme level group.

The mid-gestation triple test profile among women diagnosed with vasa previa.

PURPOSE: To assess the mid-trimester triple test biomarkers among women diagnosed with vasa previa (VP). METHODS: The study included 43 singleton pregnancies diagnosed with vasa previa between the years 1988 and 2011. The mid-gestation screening test for Down syndrome was calculated from the combination of triple serum markers and maternal age, and expressed as a multiple of the gestation specific normal mean (MoM). Reference MoM values were calculated from the local population. The levels of mid-gestation maternal serum alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG), and unconjugated estriol (uE3) of patients with VP were compared with control reference group. RESULTS: The mean hCG and αFP levels of women diagnosed with VP was significantly higher compared to control reference group (1.42 versus 0.99 MoM; p < .002 and 1.24 versus1.01 MoM; p < .001, respectively). In contrast, there was no significant difference in uE3 levels between these two groups (0.99 versus 0.98 MoM; p = .71). CONCLUSIONS: Our findings suggest that increased mid-gestation hCG and AFP were found among pregnancies complicated with VP. Clinicians should consider targeted scanning of pregnant women with risk factors for VP, including unexplained high maternal levels of hCG and αFP of the triple test, while conducting mid-gestation anomaly scan.