Genomic imbalances in patients with a clinical presentation in the spectrum of Cornelia de Lange syndrome.

BACKGROUND: Cornelia de Lange syndrome (CdLS) is a rare autosomal-dominant disorder characterised by facial dysmorphism, growth and psychomotor developmental delay and skeletal defects. To date, causative mutations in the NIPBL (cohesin regulator) and SMC1A (cohesin structural subunit) genes account for > 50% and 6% of cases, respectively. METHODS: We recruited 50 patients with a CdLS clinical diagnosis or with features that overlap with CdLS, who were negative for mutations at NIPBL and SMC1A at molecular screening. Chromosomal rearrangements accounting for the clinical diagnosis were screened for using array Comparative Genomic Hybridisation (aCGH). RESULTS: Four patients were shown to carry imbalances considered to be candidates for having pathogenic roles in their clinical phenotypes: patient 1 had a 4.2 Mb de novo deletion at chromosome 20q11.2-q12; patient 2 had a 4.8 Mb deletion at chromosome 1p36.23-36.22; patient 3 carried an unbalanced translocation, t(7;17), with a 14 Mb duplication of chromosome 17q24.2-25.3 and a 769 Kb deletion at chromosome 7p22.3; patient 4 had an 880 Kb duplication of chromosome 19p13.3, for which his mother, who had a mild phenotype, was also shown to be a mosaic. CONCLUSIONS: Notwithstanding the variability in size and gene content of the rearrangements comprising the four different imbalances, they all map to regions containing genes encoding factors involved in cell cycle progression or genome stability. These functional similarities, also exhibited by the known CdLS genes, may explain the phenotypic overlap between the patients included in this study and CdLS. Our findings point to the complexity of the clinical diagnosis of CdLS and confirm the existence of phenocopies, caused by imbalances affecting multiple genomic regions, comprising 8% of patients included in this study, who did not have mutations at NIPBL and SMC1A. Our results suggests that analysis by aCGH should be recommended for CdLS spectrum cases with an unexplained clinical phenotype and included in the flow chart for diagnosis of cases with a clinical evaluation in the CdLS spectrum.

Dandy-Walker malformation masking the molar tooth sign: an illustrative case with magnetic resonance imaging follow-up.

Joubert syndrome is a disorder characterized by ataxia, developmental delay, oculomotor anomalies, and breathing irregularities, with cerebellar vermian and midbrain dysgenesis. The molar tooth sign, reflecting the midbrain dysgenesis of Joubert syndrome, is the neuroradiological hallmark and is an essential sign in the identification of this condition. Variable vermian agenesis, an expanded fourth ventricle, and a large posterior cranial fossa with a normal brainstem are typical of Dandy-Walker malformation. The authors report a case in which a Dandy-Walker malformation coexisted with Joubert syndrome, but initially prevented the ''molar tooth sign'' from being recognized because of an important cystic dilatation of the fourth ventricle. In this article, they discuss the importance of the re-examination of brain magnetic resonance features after decompression of the posterior cranial fossa in a patient with Dandy-Walker malformation and additional clinical neurological or systemic abnormalities typical of Joubert syndrome, to not miss the correct diagnosis.

Mild mental retardation in a child with a de novo interstitial deletion of 15q21.2q22.1: a comparison with previously described cases.

We report on a child with mild mental retardation, hypotelorism, blepharophimosis, face slight asymmetry and partial hypoplasia of corpus callosum, with an interstitial deletion of a chromosome 15. The deletion was molecularly characterized by array-CGH and FISH techniques. This rearrangement has a 7.18Mb extension and maps to 15q21.2q22.1. To date, there have been only six individuals reported with a deletion of 15q21; in three cases, the rearrangement was characterized by molecular cytogenetic techniques. After a comparison with these three cases, it appeared that the deletion we found is one of the smallest and it overlaps the distal portion of the ones taken into account. Finally, we tried to delineate the genotype-phenotype correlation in patients with a deletion of 15q21.

A study of the impact of agricultural pesticide use on the prevalence of birth defects in northeast Italy.

Pesticides are probably the most frequently deliberately released toxic chemicals into the environment. However, although the results of experimental studies indicate developmental toxicity hazards for several groups of chemicals used, the studies in humans are contradictory. There are specific regulations in the European Union (EU) regarding the use of pesticides and there is also considerable awareness about possible related health problems. In order to investigate whether, in the current EU situation, the use of certain pesticides could be associated with adverse health effects in the outcome of pregnancies, we have performed a 6-year study in an agricultural area in the Veneto Region of, northeastern Italy, where we have been able to define the exact quantity and type of pesticides as well as the exposed population, in order to quantify the risk of congenital malformations related to the use of pesticides. Data on congenital malformations were obtained from the northeast Italy Congenital malformation Registry, using several sources of ascertainment, while pesticide use were obtained through interviews with users and sellers. The municipalities of three contiguous provinces were divided into those with a high, low or intermediate use of pesticides. In the study period there was a total of 146,239 consecutive pregnancies terminating in birth or induced abortion because of congenital malformation. No significant differences in the prevalence of congenital malformations were observed between the three different areas (high, low, intermediate risk). Our study confirms that in countries such as Italy, where there is close control of the use of pesticides, there is no epidemiological evidence that pesticides have any effect on the prevalence of congenital malformations.