Cerebello-oculo-renal syndromes (CORSs) and Joubert syndrome (JS) are clinically and genetically heterogeneous autosomal recessive syndromes that share a complex neuroradiological malformation resembling a molar tooth on brain axial images, a condition referred to as "molar tooth on imaging" (MTI) or the "molar tooth sign." The current literature on these syndromes is complex, with overlapping and incomplete phenotypes that complicate the selection of clinically homogeneous cases for genetic purposes. So far, only one locus (JBTS1 on 9q34) has been mapped, in two families with JS. Here, we describe a large consanguineous family with JS and nephronophthisis, representing a novel cerebello-renal phenotype. We have mapped this condition to the pericentromeric region of chromosome 11 and have named the locus "CORS2." The acronym "CORS" is proposed for all loci associated with JS, CORSs, and related phenotypes sharing the MTI, because this neuroradiological sign seems to be the unifying feature of these clinically heterogeneous syndromes.

Cardio-facio-cutaneous syndrome (CFCS) is a rare disease characterized by mental retardation, facial dysmorphisms, ectodermal abnormalities, heart defects and developmental delay. CFCS is genetically heterogeneous and mutations in the KRAS, BRAF, MAP2K1 (MEK1) and MAP2K2 (MEK2) genes, encoding for components of the RAS-mitogen activated protein kinase (MAPK) signaling pathway, have been identified in up to 90% of cases. Here we screened a cohort of 33 individuals with CFCS for MEK1 and MEK2 gene mutations to further explore their molecular spectrum in this disorder, and to analyze genotypephenotype correlations. Three MEK1 and two MEK2 mutations were detected in six patients. Two missense MEK1 (L42F and Y130H) changes and one in-frame MEK2 (K63_E66del) deletion had not been reported earlier. All mutations were localized within exon 2 or 3. Together with the available records, the present data document that MEK1 mutations are relatively more frequent than those in MEK2, with exons 2 and 3 being mutational hot spots in both genes. Mutational analysis of the affected MEK1 and MEK2 exons did not reveal occurrence of mutations among 75 patients with Noonan syndrome, confirming the low prevalence of MEK gene defects in this disorder. Clinical review of known individuals with MEK1/MEK2 mutations suggests that these patients show dysmorphic features, ectodermal abnormalities and cognitive deficit similar to what was observed in BRAF-mutated patients and in the general CFCS population. Conversely, congenital heart defects, particularly mitral valve and septal defects, and ocular anomalies seem to be less frequent among MEK1/MEK2 mutation-positive patients.

A 2 ½-year-old girl with multiple congenital anomalies and a de novo 5.6-Mb deletion on chromosome 13q12.11-13q12.13 is reported. She showed choanal atresia, scalp aplasia cutis, mild dysmorphic features, severe malformation of the hands and feet, Sylvian aqueductal stenosis, hydrocephalus, small cerebellum with pointed cerebellar tonsils, cervical, lumbar and sacral clefting, single central incisor and mild developmental delay. The girl's anomalies were compared with: (A) one boy reported by each of Der Kaloustian et al. [2011] and Tanteles et al. [2011] with similar, albeit smaller, 2.1 to 2.9 Mb deletions in which the abnormalities consisted of mild facial dysmorphism, mild malformations of the fingers and/or toes, and developmental delay; (B) one girl reported by Friedman et al. [2006] with similar, albeit larger, 5.7 Mb deletion with mild developmental delay and haematological abnormalities; (C) one girl reported by Slee et al. [1991] with a deletion of band q12.2 in chromosome 13, who had Moebius syndrome with facial dysmorphism, high arched palate, micrognathia, and small tongue with no abnormalities of the extremities; and (D) seven additional individuals recorded in the DECIPHER 6.0 database who all had dysmorphic features and developmental delay plus a spectrum of clinical manifestations including deafness, ataxia/oculomotor apraxia, spasticity, small testes, and mild fingers' anomalies. The deleted region hereby reported encompassed 34 known genes, including GJA3, GJB2, and GJB6, which are responsible for autosomal recessive deafness, FGF9, which plays crucial roles in embryonic neurological development, and ATP8A2, which causes a cerebellar ataxia and disequilibrium syndrome.

Joubert Syndrome Related Disorders (JSRDs) are autosomal recessive pleiotropic conditions sharing a peculiar cerebellar and brainstem malformation known as the "molar tooth sign" (MTS). Recently, mutations in a novel ciliary gene, RPGRIP1L, have been shown to cause both JSRDs and MeckelGruber syndrome. We searched for RPGRIP1L mutations in 120 patients with proven MTS and phenotypes representative of all JSRD clinical subgroups. Two homozygous mutations, the previously reported p.T615P in exon 15 and the novel c.2268_2269delA in exon 16, were detected in two out of 16 families with cerebello-renal presentation (~12%). Conversely, no pathogenic changes were found in patients with other JSRD phenotypes, suggesting that RPGRIP1L mutations are largely confined to the cerebello-renal subgroup, while they overall represent a rare cause of JSRD (<2%).

The aim of our study was to measure, at delivery, maternal and cord blood cadmium levels (by means of atomic absorption spectrometry) in 45 healthy non-smoking pregnant women exposed to a low cadmium challenge, and to evaluate the relationship between these cadmium levels and the birth weight of the infants. Our results showed fairly low cadmium levels in maternal blood, in accordance with the fact that all women enrolled in this study lived in areas with low toxic metal contamination and that they did not smoke during their pregnancy. Furthermore, a highly significant direct correlation was found between maternal and cord blood cadmium concentrations. Since cadmium concentration appeared of the same order of magnitudine both in cord and maternal serum, one could speculate that cadmium is transferred easily from the mother to the fetus through the placenta. Finally, we found that birth weight is inversely correlated with maternal and cord blood cadmium concentrations; thus birth weight might be negatively influenced by cadmium levels as a result of the toxic effects of the metal on the placenta. Although preliminary, our data show that (also not-predictable) prenatal exposure to even low cadmium levels might be a risk factor for developmental impairment in infants.