Ellis‐van Creveld syndrome (EvC) is a chondral and ectodermal dysplasia caused by biallelic mutations in the EVC, EVC2 and WDR35 genes. A proportion of cases with clinical diagnosis of EvC, however, do not carry mutations in these genes. To identify the genetic cause of EvC in a cohort of mutation‐negative patients, exome sequencing was undertaken in a family with 3 affected members, and mutation scanning of a panel of clinically and functionally relevant genes was performed in 24 additional subjects with features fitting/overlapping EvC. Compound heterozygosity for the c.2T>C (p.Met1?) and c.662C>T (p.Thr221Ile) variants in DYNC2LI1, which encodes a component of the intraflagellar transport‐related dynein‐2 complex previously found mutated in other short‐rib thoracic dysplasias, was identified in the 3 affected members of the first family. Targeted resequencing detected compound heterozygosity for the same missense variant and a truncating change (p.Val141*) in 2 siblings with EvC from a second family, while a newborn with a more severe phenotype carried 2 DYNC2LI1 truncating variants. Our findings indicate that DYNC2LI1 mutations are associated with a wider clinical spectrum than previously appreciated, including EvC, with the severity of the phenotype likely depending on the extent of defective DYNC2LI1 function.

Purpose: Intrapartum antibiotic prophylaxis (IAP) prevents group B streptococcus (GBS) early-onset disease (EOD). No European study evaluates the relative impact of risk factors (RFs) for EOD after a screening-based strategy and widespread IAP use We aimed to evaluate the risks of EOD in an Italian region where a screening-based strategy for preventing EOD was implemented. Materials and methods: Cases of EOD born at or above 35 weeks' gestation were reviewed and matched with controls. Results: There were 109 cases of EOD among 532,154 live births. Most cases had negative GBS prenatal screening (56/91, 61.5%) and were unexposed to IAP (86/109, 78.9%). At multivariate analysis, GBS bacteriuria (OR = 6.99), positive prenatal screening (OR = 13.7) and maternal intrapartum fever (OR = 188.3) were associated with an increased risk of EOD, whereas intrapartum beta-lactam antibiotics were associated with a decreased risk of EOD (>= 4 h: OR = 0.008; OR = 0.04). Neonates born to nonfebrile, GBS positive pregnant women, receiving beta-lactam antibiotics had very low probability of EOD, particularly if IAP was adequate. Conclusions: GBS positive prenatal screening, GBS bacteriuria and intrapartum fever are associated with EOD. Intrapartum beta-lactam antibiotics reduce the probability of EOD in neonates born to nonfebrile mothers.

Objective: Group B streptococcus (GBS) early-onset sepsis (EOS) has declined after widespread intrapartum antibiotic prophylaxis. However, strategies for preventing EOS may differ across countries. The analysis of their strategies allows to compare the effectiveness of prevention in different countries and suggests opportunities for improvement.Methods: We compared six western countries. Prevention strategies, incidence rates of EOS and approaches for managing neonates at-risk were analysed. Countries were selected because of availability of recommendations for prevention and sufficient epidemiological data for comparison.Results: Five of six countries recommend antenatal vagino-rectal screening. The decline of GBS cases is relevant in most countries, particularly in those with a screening-based strategy, which have reached incidence rates from 0.1 to 0.3/1000 live births and zero or close to zero mortality in full-term newborns. The recommendation for managing asymptomatic neonates at risk for EOS varies according to gestational age and ranges from observation only to laboratory testing plus empirical antibiotics. Chorioamnionitis (suspected or confirmed) is the main indication for carry out laboratory testing and for administering empirical antibiotics.Conclusions: Wide variations exists in preventing EOS. They depend on national epidemiology of GBS infections, compliance, cost, and feasibility of the strategy. The extreme variability of approaches for managing neonates at risk for EOS reflects the even greater uncertainty regarding this issue, and may explain the persisting, great use of resources to prevent a disease that has become very rare nowadays.

Background: Fungal colonisation by Candida spp. affects a high proportion of VLBW neonates in NICU. However, few data are available on the clinical characteristics of colonisation in preterm infants who are colonised at baseline via vertical transmission, compared to preterms who become colonised during their stay in NICU via horizontal transmission.Material and Methods: We reviewed the database of a multicentre, randomised trial of prophylactic fluconazole in VLBW neonates conducted in 8 Italian NICUs in the years 2004 and 2005 (Manzoni et al., NEJM 2007;356(24):2483-95). Per the protocol, all enrolled infants underwent weekly surveillance cultures from birth till discharge. We investigated the frequency of the two different modalities of Candida colonisation in this population, as well as the clinical and outcome characteristics possibly related to them.Results: Overall, Candida colonisation affected 54 of 336 infants (16.1%). Baseline (i.e., detected <3rd day of life) colonisation affected 16 (4.7%), and acquired 38 (11.4%), of the 54 colonised preterms. Infants with baseline colonisation had significantly higher birth weight (1229 28g vs. 1047g +/- 29, p=0.01) and gestational age (30.2 wks 2.7 vs. 28.5 wks 2.6, p=0.01), and were significantly more likely to limit progression from colonisation to invasive Candida infection when fluconazole prophylaxis was instituted (21.6% vs. 42.7%, p=0.009). Isolation of C. parapsilosis was significantly more frequent in infants with acquired colonisation.Conclusions: Infants with baseline and acquired colonisation differ for demographics characteristics and for their response to fluconazole prophylaxis. This information may be useful for targeting more accurate management strategies for these two different groups of colonised preterms in NICU. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

Background: Ethanol is the most widely used drug in the world and a human teratogen whose consumption among women of childbearing age has been steadily increasing. There are no Italian or Spanish statistics on ethanol consumption during pregnancy nor any information regarding prevalence of fetal alcohol syndrome (FAS) and fetal alcohol spectrum disorders (FASD). There is also a reasonable suspicion that these two diseases are underdiagnosed by professionals from the above-reported countries. The objectives of this study were: 1) to evaluate the experience, knowledge and confidence of Italian and Spanish neonatologists and paediatricians with respect to the diagnosis of FAS and FASD, and 2) to evaluate professionals awareness of maternal drinking patterns during pregnancy.Methods: A multiple-choice anonymous questionnaire was e-mailed to Italian neonatologists registered in the mailing list of the corresponding Society and administered to Italian and Spanish paediatricians during their National Congress.Results: The response rate was 16% (63/400) for the Italian neonatologists of the National Society while a total of 152 Spanish and 41 Italian paediatricians agreed to complete the questionnaire during National Congress. Over 90% of the surveyed physicians declared that FAS is an identifiable syndrome and over 60% of them identified at least one of the most important features of FAS. Although over 60% Italian responders and around 80% Spanish responders were aware that ethanol use in pregnancy is dangerous, approximately 50% Italian responders and 40% Spanish ones allowed women to drink sometimes a glass of wine or beer during pregnancy. Neonatologists and paediatricians rated confidence in the ability to diagnosis FAS and FASD as low, with over 50% responders feeling they needed more information regarding FAS and FASD identification in newborn and child.Conclusions: Italian and Spanish neonatologists and paediatricians do not feel confident about diagnosing FAS and FASD. More training is needed in order to accurately diagnose ethanol use during pregnancy and correctly inform pregnant women on the consequences on the newborn.

Late-onset sepsis (LOS) affects a large proportion of pre-term neonates in neonatal intensive care units (NICUs) worldwide, with high morbidity and related mortality, and frequent occurrence of severe late neurodevelopmental impairment. Due to the frequency, severity and difficulties in early diagnosis and prompt therapy, prevention is crucial for decreasing the burden of infection-related complications in NICUs.

Background and methods: Ring chromosomes are often associated with abnormal phenotypes because of loss of genomic material at one or both ends.In some cases no deletion has been detected and the abnormal phenotype has been attributed to mitotic ring instability.We investigated 33 different ring chromosomes in patients with phenotypic abnormalities by array based comparative genomic hybridisation (CGH) and fluorescence in situ hybridisation (FISH).Results: In seven cases we found not only the expected terminal deletion but also a contiguous duplication.FISH analysis in some of these cases demonstrated that the duplication was inverted.Thus these ring chromosomes derived through a classical inv dup del rearrangement consisting of a deletion and an inverted duplication.Discussion: Inv dup del rearrangements have been reported for several chromosomes, but hardly ever in ring chromosomes.Our findings highlight a new mechanism for the formation of some ring chromosomes and show that inv dup del rearrangements may be stabilised not only through telomere healing and telomere capture but also through circularisation.This type of mechanism must be kept in mind when evaluating possible genotypephenotype correlations in ring chromosomes since in these cases: (1) the deletion may be larger or smaller than first estimated based on the size of the ring, with a different impact on the phenotype; and (2) the associated duplication will in general cause further phenotypic anomalies and might confuse the genotype-phenotype correlation.Moreover, these findings explain some phenotypic peculiarities which previously were attributed to a wide phenotypic variation or hidden mosaicism related to the instability of the ring.

Cornelia de Lange syndrome (CdLS) is a rare multisystem disorder characterized by facial dysmorphisms, upper limb abnormalities, growth and cognitive retardation. About half of all patients with CdLS carry mutations in the NIPBL gene. The first Italian CdLS cohort involving 62 patients (including 4 related members) was screened for NIPBL mutations after a clinical evaluation using a quantitative score that integrates auxological, malformation and neurodevelopmental parameters. The patients were classified as having an overall ‘severe’, ‘moderate’ or ‘mild’ phenotype. NIPBL screening showed 26 mutations so classified: truncating (13), splice‐site (8), missense (3), in‐frame deletion (1) and regulatory (1). The truncating mutations were most frequently found in the patients with a high clinical score, whereas most of the splice‐site and all missense mutations clustered in the low‐medium score groups. The NIPBL ‐negative group included patients covering the entire clinical spectrum. The prevalence of a severe phenotype in the mutated group and a mild phenotype in the non‐mutated group was statistically significant. In terms of the isolated clinical signs, the statistically significant differences between the mutation‐positive and mutation‐negative individuals were pre‐ and post‐natal growth deficits, limb reduction, and delayed speech development. The proposed score seems to be a valuable means of prioritizing the patients with CdLS to undergo an NIPBL mutation test.

OBJECTIVE:Despite accumulating evidence that procedural pain experienced by preterm infants may have acute detrimental and even long-term effects on an infant's subsequent behavior and neurological outcome, neonates admitted to Neonatal Intensive Care Units still frequently experience acute and prolonged uncontrolled pain. Many invasive and surgical procedures are routinely performed at the bedside in the NICU without adequate pain management.AIM:To develop evidence-based guidelines and recommendations for pain control and prevention in Italian i.e. heel lancing, venipuncture and percutaneous venous line positioning, tracheal intubation, mechanical ventilation, lumbar puncture, chest tube positioning, for certain surgical procedures performed at the NICU, e.g. central venous cutdown, surgical PDA ligation, and cryotherapy, laser therapy for ROP, and for postoperative pain management.CONCLUSION:Adequate pain prevention and management should be an essential part of standard health care at the NICU, and recognizing and assessing sources of pain should be routine in the day-to-day practice of physicians and nurses taking care of the newborn. We hope these guidelines will contribute towards increasing the NICU caregiver's awareness and understanding of the importance of adequate pain control and prevention.

Sotos syndrome is characterized by pre- and post-natal overgrowth, typical craniofacial features, advanced bone age, and developmental delay. Some degree of phenotypic overlap exists with other overgrowth syndromes, in particular with Weaver syndrome. Sotos syndrome is caused by haploinsufficiency of the NSD1 (nuclear receptor SET domain containing gene 1) gene. Microdeletions involving the gene are the major cause of the syndrome in Japanese patients, whereas intragenic mutations are more frequent in non-Japanese patients. NSD1 aberrations have also been described in some patients diagnosed as Weaver syndrome. Some authors have suggested a certain degree of genotype-phenotype correlation, with a milder degree of overgrowth, a more severe mental retardation, and a higher frequency of congenital anomalies in microdeleted patients. Data on larger series are needed to confirm this suggestion. We report here on microdeletion and mutation analysis of NSD1 in 59 patients with congenital overgrowth. Fourteen novel mutations, two previously described and one microdeletion were identified. All patients with a NSD1 mutation had been clinically classified as "classical Sotos," although their phenotype analysis demonstrated that some major criteria, such as overgrowth and macrocephaly, could be absent. All patients with confirmed mutations shared the typical Sotos facial gestalt. A high frequency of congenital heart defects was present in patients with intragenic mutations, supporting the relevance of the NSD1 gene in the pathogenesis of this particular defect.

In an attempt to define the distinctive Wolf-Hirschhorn syndrome (WHS) phenotype, and to map its specific clinical manifestations, a total of eight patients carrying a 4p16.3 microdeletion were analyzed for their clinical phenotype and their respective genotypes. The extent of each individual deletion was established by fluorescence in situ hybridization, with a cosmid contig spanning the genomic region from MSX1 (distal half of 4p16.1) to the subtelomeric locus D4S3359. The deletions were 1.9-3.5 Mb, and all were terminal. All the patients presented with a mild phenotype, in which major malformations were usually absent. It is worth noting that head circumference was normal for height in two patients (those with the smallest deletions [1.9 and 2.2 Mb]). The currently accepted WHS critical region (WHSCR) was fully preserved in the patient with the 1.9-Mb deletion, in spite of a typical WHS phenotype. The deletion in this patient spanned the chromosome region from D4S3327 (190 b4 cosmid clone included) to the telomere. From a clinical point of view, the distinctive WHS phenotype is defined by the presence of typical facial appearance, mental retardation, growth delay, congenital hypotonia, and seizures. These signs represent the minimal diagnostic criteria for WHS. This basic phenotype maps distal to the currently accepted WHSCR. Here, we propose a new critical region for WHS, and we refer to this region as "WHSCR-2." It falls within a 300-600-kb interval in 4p16.3, between the loci D4S3327 and D4S98-D4S168. Among the candidate genes already described for WHS, LETM1 (leucine zipper/EF-hand-containing transmembrane) is likely to be pathogenetically involved in seizures. On the basis of genotype-phenotype correlation analysis, dividing the WHS phenotype into two distinct clinical entities, a "classical" and a "mild" form, is recommended for the purpose of proper genetic counseling.

We report two patients, one with sternal cleft, haemangiomas, supraumbilical midline raphe and the other with a sternal cleft, haemangiomas, coarctation of the aorta with a right aortic arch.

A case of trisomy 21 with congenital chylothorax is reported Congenital chylothorax is very rare in a trisomy 21 patient. this is the seventh case associating both conditions reported in the literature. We confirm that relationship between the two conditions may be not casual.