Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γH2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the α-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity

ORIGINAL RESEARCH ARTICLEPurpose: Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS. Methods:In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations.Results: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations. Conclusion:Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.

Although ribosomes are ubiquitously expressed and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein encoding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.

Many attempts have been made to obtain safe and effective analgesia in newborns. Oral glucose-water has been found to have analgesic properties in neonates. We investigated whether other sensory stimulation added to oral glucose provided more effective analgesia than oral glucose alone. In a randomized prospective double-blind trial, we studied 120 term newborns during heel prick. The babies were divided randomly into six groups of 20, and each group was treated with a different procedure during heel prick: A) control; B) 1 mL 33% oral glucose given 2 min before the heel prick; C) sucking; D) 1 mL 33% oral glucose plus sucking; E) multisensory stimulation including 1 mL 33% oral glucose (sensorial saturation); F) multisensory stimulation without oral glucose. Sensorial saturation consisted in massage, voice, eye contact, and perfume smelling during heel prick. Each heel prick was filmed and assigned a point score according to the Douleur Aiguë du Nouveau-né (DAN) neonatal acute pain scale. Camera recording began 30 s before the heel prick, so it was impossible for the scorers to distinguish procedure A (control) from B (glucose given 2 min before), C (sucking water) from D (sucking glucose), and E (multisensory stimulation and glucose) from F (multisensory stimulation and water) from the video. Procedure E (multisensory stimulation and glucose) was found to be the most effective procedure, and the analgesia was even more effective than that produced by procedure D (sucking glucose). We conclude that sensorial saturation is an effective analgesic technique that potentiates the analgesic effect of oral sugar. It can be used for minor painful procedures on newborns. Newborns feel pain (1, 2). Repeated painful stimuli lower their pain threshold (3, 4) by overstimulation of NMDA receptors, which may lead to excitotoxic brain damage (5). Until a few years ago, it was claimed that the word pain was inappropriate for newborns, as pain is a subjective experience that newborns, because of their age, cannot have (6). Until the 1980s, analgesics were rarely administered to newborns even in the case of surgery (7). Now we know that anesthesia reduces brain damage due to hypoxemia, hypertension, tachycardia, variations in heart rate, and increased intracranial pressure (8, 9), all of which are particularly dangerous because of immature cerebral vasoregulation in the premature (10).The number of painful stimuli needs to be kept to a minimum, and every effort should be made to render them less painful. Guidelines for neonatal analgesia have been suggested (11-15), especially for the most routine type of pain, blood sampling, which is usually performed by heel prick. To avoid the drawbacks of general and local analgesics (16 -21), types of nonpharmacologic analgesia have been proposed, including nonnutritional sucking and instillation of glucose or other sweet liquids on the newborn's tongue (22). The analgesic effect of glucose is thought to stimulate an increase in plasma concentrations of ␤-endorphin (23-27) by a preabsorptiv...