Widening the mutation spectrum of EVC and EVC2: ectopic expression of Weyer variants in NIH 3T3 fibroblasts disrupts Hedgehog signaling.

Autosomal recessive Ellis-van Creveld syndrome and autosomal dominant Weyer acrodental dysostosis are allelic conditions caused by mutations in EVC or EVC2. We performed a mutation screening study in 36 EvC cases and 3 cases of Weyer acrodental dysostosis, and identified pathogenic changes either in EVC or in EVC2 in all cases. We detected 40 independent EVC/EVC2 mutations of which 29 were novel changes in Ellis-van Creveld cases and 2 were novel mutations identified in Weyer pedigrees. Of interest one EvC patient had a T>G nucleotide substitution in intron 7 of EVC (c.940-150T>G), which creates a new donor splice site and results in the inclusion of a new exon. The T>G substitution is at nucleotide +5 of the novel 5' splice site. The three Weyer mutations occurred in the final exon of EVC2 (exon 22), suggesting that specific residues encoded by this exon are a key part of the protein. Using murine versions of EVC2 exon 22 mutations we demonstrate that the expression of a Weyer variant, but not the expression of a truncated protein that mimics an Ellis-van Creveld syndrome mutation, impairs Hedgehog signal transduction in NIH 3T3 cells in keeping with its dominant effect.

Risk of hypospadias in newborn infants exposed to valproic acid during the first trimester of pregnancy: a case-control study in Spain.

BACKGROUND: Hypospadias is one of the most frequently occurring genital anomalies described in infants prenatally exposed to valproic acid (VA). However, to our knowledge, only one publication has studied a potential causal relationship between VA and hypospadias, only estimating the unadjusted global risk. Here we present the results of a multivariate case-control study aimed at analysing and quantifying the specific risk of hypospadias in newborn infants exposed to VA during the first trimester of pregnancy. METHODS: The data analysed here were derived from the Spanish Collaborative Study of Congenital Malformations (ECEMC), an ongoing, hospital-based, case-control study and surveillance system in which collaborating paediatricians identify case and control infants. The paediatricians collect the same data for both case and control infants, blinded to information on any prenatal exposure. The information includes 312 items related to many prenatal exposures, including drug exposure, reproductive and family history, and other characteristics. The sample analysed included 2,393 infants with hypospadias and 12,465 male controls. RESULTS: The results showed that the unadjusted risk of hypospadias in infants prenatally exposed to VA was 5.23 (95% CI 2.31, 11.86; p < 0.00001). Once adjusted for 13 potential confounding factors using conditional logistic regression analyses, the value of the risk was of a similar magnitude (odds ratio = 5.71; 95% CI 1.78, 18.36; p = 0.003). In addition, the frequency of hypospadias in the study population was approximately 1.8/1000 births. This allowed us to calculate the specific risk for an infant with hypospadias to be born to an exposed mother, which was 1 child in 97 births to mothers using VA during the first trimester of pregnancy. We consider this information much more useful for risk assessment than the risk value itself. CONCLUSIONS: An alteration of placental gonadotrophic stimulation caused by changes in gonadotropin-releasing hormone release produced by the effects of VA on GABA is a possible pathogenic mechanism. Our results support the relationship between prenatal exposure to VA and hypospadias.

Renal defects and limb deficiencies in 197 infants: is it possible to define the "acrorenal syndrome"?

Dieker and Opitz in 1969 described the simultaneous occurrence of limb deficiencies (LDs) and renal anomalies (RAs) in three patients. Curran and Curran introduced in 1972 the term "acrorenal syndrome." Since then, the term "acrorenal syndrome" is used occasionally, but a well-circumscribed definition has never been established. On the other hand, the concept of an acrorenal polytopic developmental field defect was postulated by Opitz and others to explain the association between RAs and LDs. We undertook this study to investigate whether this acrorenal "syndrome" could be identified in a large group of cases with congenital RAs and a limb deficiency. Eleven birth defect registries that are part of the International Clearinghouse for Birth Defects Monitoring (i.e., registries of ICBDMS in Finland, France [Paris and Strasbourg], Israel, Italy [IPIMC and Emilia Romagna], Mexico, Northern Netherlands, South America, Spain, and the United States [Atlanta]) provided data on 815 infants who had a LD and at least one other major congenital anomaly. These 815 cases were ascertained among 5,163,958 births. We selected the 197 cases who had both a limb deficiency and a renal or urinary tract anomaly. In about 50% of these cases a diagnosis or a recognized phenotype was reported, with chromosomal aberrations and VACTERL being most frequent. In the group with no diagnosis or recognized phenotype (95 cases), we looked for (a) clustering of specific types of LDs and RAs, and (b) for clustering of associated anomalies, in order to find evidence for and be able to define better the term "acrorenal syndrome." Our data suggest that an association exists between LDs and RAs, possibly explained by the concept of the acrorenal polytopic developmental field defect. However, our dataset does not yield evidence for the existence of one distinct "syndrome," defined as a pattern of causally related multiple anomalies. Therefore, use of the term "acrorenal syndrome" should be avoided.