Meckel syndrome (MKS) is a rare autosomal recessive lethal condition characterized by central nervous system malformations, polydactyly, multicystic kidney dysplasia, and ductal changes of the liver. Three loci have been mapped (MKS1-MKS3), and two genes have been identified (MKS1/FLJ20345 and MKS3/TMEM67), whereas the gene at the MKS2 locus remains unknown. To identify new MKS loci, a genomewide linkage scan was performed using 10-cM-resolution microsatellite markers in eight families. The highest heterogeneity LOD score was obtained for chromosome 12, in an interval containing CEP290, a gene recently identified as causative of Joubert syndrome (JS) and isolated Leber congenital amaurosis. In view of our recent findings of allelism, at the MKS3 locus, between these two disorders, CEP290 was considered a candidate, and homozygous or compound heterozygous truncating mutations were identified in four families. Sequencing of additional cases identified CEP290 mutations in two fetuses with MKS and in four families presenting a cerebro-reno-digital syndrome, with a phenotype overlapping MKS and JS, further demonstrating that MKS and JS can be variable expressions of the same ciliopathy. These data identify a fourth locus for MKS (MKS4) and the CEP290 gene as responsible for MKS.

Background:The acronym CHARGE refers to a non-random cluster of malformations including coloboma, heart malformation, choanal atresia, retardation of growth and/or development, genital anomalies, and ear anomalies. This set of multiple congenital anomalies is frequent, despite rare patients with normal intelligence, and prognosis remains poor. Recently, CHD7 gene mutations have been identified in CHARGE patients; however, the function of CHD7 during development remains unknown. Methods: We studied a series of 10 antenatal cases in whom the diagnosis of CHARGE syndrome was suspected, considering that a careful pathological description would shed light on the CHD7 function during development. CHD7 sequence analysis and in situ hybridisation were employed. Results: The diagnosis of CHARGE syndrome was confirmed in all 10 fetuses by the identification of a CHD7 heterozygous truncating mutation. Interestingly, arhinencephaly and semi-circular canal agenesis were two constant features which are not included in formal diagnostic criteria so far. In situ hybridisation analysis of the CHD7 gene during early human development emphasised the role of CHD7 in the development of the central nervous system, internal ear, and neural crest of pharyngeal arches, and more generally showed a good correlation between specific CHD7 expression pattern and the developmental anomalies observed in CHARGE syndrome. Conclusions: These results allowed us to further refine the phenotypic spectrum of developmental anomalies resulting from CHD7 dysfunction.

Objective To evaluate the potential of three-dimensional ultrasound to predict outcome in congenital diaphragmatic hernia. Design Prospective observational study.Setting Tertiary care centre.Population Twelve cases of isolated congenital diaphragmatic hernia (11 left-sided, 1 right-sided) and 109 controls. Methods Fetal lung volume was assessed by three-dimensional ultrasound using the technique of rotation of the multiplanar imaging. In the control fetuses, a logistic transformation was performed to correlate fetal lung volume with gestational age, and the confidence interval was obtained with a bootstrap resampling. A mathematical equation was then obtained allowing calculation of the expected fetal lung volume as a function of gestational age. In fetuses with congenital diaphragmatic hernia, the observed/expected lung volume ratio was compared with postnatal outcome. Main outcome measures Neonatal mortality and pulmonary hypoplasia, which was defined as lung/body weight ratios less than 0.012. The observed/expected fetal lung volume ratio was also correlated with the postmortem lung/body weight ratio. Conclusion In isolated congenital diaphragmatic hernia, fetal lung volume measurement by three-dimensional ultrasound is a potential predictor for pulmonary hypoplasia and postnatal outcome.

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Objective The prognosis of fetal lower urinary tract obstruction (LUTO) depends upon renal function and also upon the underlying etiology. Precise identification

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Fetal sex prediction can be achieved using PCR targeted at the SRY gene by analysing cell-free fetal DNA in maternal serum. Unfortunately, the results reported to date show a lack of sensitivity, especially during the first trimester of pregnancy. Therefore, determination of fetal sex by maternal serum analysis could not replace karyotype analysis following chorionic villus sampling. A new highly sensitive real-time PCR was developed to detect an SRY gene sequence in maternal serum. Analysis was performed on 121 pregnant women during the first trimester of pregnancy (mean gestational age: 11.8 weeks). Among them, 51 had at least one previous male-bearing pregnancy. Results were compared with fetal sex. SRY PCR analysis of maternal serum was in complete concordance with fetal sex. Among the 121 pregnant women, 61 were bearing a male fetus and 60 a female fetus. No false-negative results were observed. Furthermore, no false-positive results occurred, even though 27 women carrying a female fetus during the current pregnancy had at least one previous male-bearing pregnancy. This study demonstrates that a reliable, non-invasive sex determination can be achieved by PCR analysis of maternal serum during the first trimester of pregnancy. This non-invasive approach for fetal sex prediction should have great implications in the management of pregnant women who are carriers of an X-linked genetic disorder. Prenatal diagnosis might thus be performed for male fetuses only, avoiding invasive procedures and the risk of the loss of female fetuses.

Objective To establish a correlation between prenatal ultrasound findings and postnatal outcome in neonates with gastroschisis (GS).Design Retrospective case-control study.Setting Prenatal ultrasound reports, labour and neonatal intensive care unit notes, and paediatric surgical clinic records were reviewed.Population Neonates with an antenatal diagnosis of isolated GS.Methods The neonates were divided into two groups: one with associated bowel complications including intestinal atresia, perforation, necrosis or volvulus ('complex' GS), and the second without bowel complication ('simple' GS). Prenatal ultrasound markers: small-for-gestational-age, intra-abdominal and extra-abdominal bowel dilatation (>6 mm), thickened intestinal wall and stomach dilatation were correlated with outcome.Main outcome measures Fetal or neonatal death in complex versus simple GS. Time on parenteral nutrition and duration of hospital stay were also noted.Results In all, 105 cases were eligible for analysis. Survival rate was 101/105 (96.2%). None of the ultrasound markers was predictive of fetal or neonatal death. Fourteen of 103 live-born babies (14.6%) had complex GS, which was associated with longer time on parenteral nutrition [8.0 (51.5-390) versus 33.5 (25.3-53.3) days, P < 0.001] and longer duration of hospital stay [85.3 (55.5-210) versus 41.5 (33.0-64.8) days, P < 0.001]. Infants with complex GS were more likely to require bowel resection and stoma placement (P < 0.05). Intra-abdominal bowel dilatation was the only predictive ultrasound marker of complex GS (odds ratio 4.13, 95% CI 1.32-12.90; P = 0.018). Receiver operating characteristic curve for observed/expected bowel diameter yielded 6 as the cutoff value for predicting complex GS (odds ratio 7.9, 95% CI 2.3-27.3; P = 0.001) with 54% and 88% for sensibility and specificity, respectively.Conclusions Intra-abdominal bowel dilatation is the only ultrasound marker predictive of complex GS but it is a strong marker.