Davide Vecchio

The first case of myoclonic epilepsy in a child with a de novo 22q11.2 microduplication

Chromosome 22, particularly the q11.2 sub‐band, has long been recognized as responsible for multiple congenital anomaly disorders. In particular, its susceptibility to subtle microdeletions or, more rarely, microduplications has been attributed to the presence of several low‐copy repeats spanning the region as mediators of nonallelic homologous recombination that result in 22q11.2 rearrangements. While recent data suggest that the frequency of 22q11.2 microduplications could be approximately half of all deletions, now only 50 unrelated cases have been reported thus far. However, it is reasonable to suppose that microduplications of 22q11.2 may be largely undetected as a result of a less‐distinct, unpredictable, and/or milder phenotype ranging from normal to mild learning difficulties with/without other multiple defects. We report on the first case of myoclonic epilepsy in a 10‐year‐old boy carrying a de novo 22q11.2 microduplication. Emphasizing that this rare association could be one of the many unrecognized aspects underlying this new emerging syndrome and once again its clinical heterogeneity, we suggest further investigation of the function of the RAB36 gene and propose that in the screening of individuals with developmental delay, minor behavioral problems mild dysmorphology and seizures, investigation of 22q11.2 microduplications should be considered.

Communication about vaccination: A shared responsibility.

ABSTRACT Vaccine hesitancy is an important issue to be addressed, due to the risk of decrease of vaccination coverage and consequent control of preventable diseases. While it is not considered a specific determinant, poor or inadequate communication can contribute to vaccine hesitancy and negatively influence vaccination uptake. As a contribution to the ongoing discussion regarding this theme and in the perspective of the implementation of the upcoming national vaccination plan in Italy, the Erice Declaration was drafted by experts in the field of immunization following a 5-day residential, independent workshop regarding communication topics in vaccinology. The aim of the current letter is to present to the broader international audience such a contribution, proposing the identification of the main actions that should be taken into account and prioritized in order to improve communication in the domain of vaccination.

The Increasing Challenge of Multidrug-Resistant Gram-Negative Bacilli: Results of a 5-Year Active Surveillance Program in a Neonatal Intensive Care Unit

AbstractColonization and infection by multidrug-resistant gram-negative bacilli (MDR GNB) in neonatal intensive care units (NICUs) are increasingly reported.We conducted a 5-year prospective cohort surveillance study in a tertiary NICU of the hospital “Paolo Giaccone,” Palermo, Italy. Our objectives were to describe incidence and trends of MDR GNB colonization and the characteristics of the most prevalent organisms and to identify the risk factors for colonization. Demographic, clinical, and microbiological data were prospectively collected. Active surveillance cultures (ASCs) were obtained weekly. Clusters of colonization by extended spectrum &bgr;-lactamase (ESBL) producing Escherichia coli and Klebsiella pneumoniae were analyzed by conventional and molecular epidemiological tools.During the study period, 1152 infants were enrolled in the study. Prevalences of colonization by MDR GNB, ESBL-producing GNB and multiple species/genera averaged, respectively, 28.8%, 11.7%, and 3.7%. Prevalence and incidence density of colonization by MDR GNB and ESBL-producing GNB showed an upward trend through the surveillance period. Rates of ESBL-producing E coli and K pneumoniae colonization showed wide fluctuations peaking over the last 2 years. The only independent variables associated with colonization by MDR GNB and ESBL-producing organisms and multiple colonization were, respectively, the days of NICU stay (odds ratio [OR] 1.041), the days of exposure to ampicillin–sulbactam (OR 1.040), and the days of formula feeding (OR 1.031). Most clusters of E coli and K pneumoniae colonization were associated with different lineages. Ten out of 12 clusters had an outborn infant as their index case.Our study confirms that MDR GNB are an increasing challenge to NICUs. The universal once-a-week approach allowed us to understand the epidemiology of MDR GNB, to timely detect new clones and institute contact precautions, and to assess risk factors. Collection of these data can be an important tool to optimize antimicrobials use and control the emergence and dissemination of resistances in NICU.

Paternal uniparental disomy chromosome 14-like syndrome due a maternal de novo 160 kb deletion at the 14q32.2 region not encompassing the IG- and the MEG3-DMRs: Patient report and genotype-phenotype correlation.

The human chromosome 14q32 carries a cluster of imprinted genes which include the paternally expressed genes (PEGs) DLK1 and RTL1, as well as the maternally expressed genes (MEGs) MEG3, RTL1as, and MEG8. PEGs and MEGs expression at the 14q32.2‐imprinted region are regulated by two differentially methylated regions (DMRs): the IG‐DMR and the MEG3‐DMR, which are respectively methylated on the paternal and unmethylated on the maternal chromosome 14 in most cells. Genetic and epigenetic abnormalities affecting these imprinted gene clusters result in two different phenotypes currently known as maternal upd(14) syndrome and paternal upd(14) syndrome. However, only few patients carrying a maternal deletion at the 14q32.2‐imprinted critical region have been reported so far. Here we report on the first patient with a maternal de novo deletion of 160 kb at the 14q32.2 chromosome that does not involves the IG‐DMR or the MEG3‐DMR but elicits a full upd(14)pat syndromes phenotype encompassing the three mentioned MEGs. By the analysis of this unique genotype–phenotype correlation, we further widen the spectrum of the congenital anomalies associated to this rare disorder and we propose that the paternally expressed imprinted RTL1 gene, as well as its maternally expressed RTL1as antisense transcript, may play a prominent causative role.

Management of multiple pregnancy with an affected twin

Newborns from multiple pregnancies demonstrate a higher perinatal morbidity and mortality compared to singletons. Prematurity is more frequent in twins and therefore birth weight is significantly lower compared to singletons [1]. Thus, twins are more exposed to prematurity related diseases (respiratory, cardiovascular, infectious, etc.) and to long-term complications [2]. It is very difficult to estimate the increased risk of neonatal morbidity related to twinning independently to the increased risk of prematurity. Prematurity is the main reason for most neonatal diseases in twins, but other variables may play a role. Fetal growth restriction [3] and congenital malformationsare major issues in offspring of multiple pregnancies. Specific risks vary according tozigosity (monozygotic >dizygotic) and kind (genetic, vascular, multifactorial, etc.) and site (systems and organs involved) of malformation. Accurate risk assessment strategies and adequate obstetrical-neonatological management of multiple pregnancies may reduce the increasing need for neonatal intensive care and for health resources in the long-term follow-up that has been observed over the last decades. Careful analysis of both twins for a pathological condition is mandatory to address the most appropriate management. Twin discordance for the presence of a severe pathological condition raises serious concern in terms of bioethical and psychological impact on the parents and medical staff[4]. Different management choices can be considered: termination of pregnancy, selective embryo reduction of the affected twin, anticipation of delivery or natural course of the pregnancy. Each choicehides difficult clinical and legal implications. Accurate clinical, laboratory and ultrasonographic evaluation together with pregnancy follow-up are essential for reaching the correct diagnosis and consider prognosis and therapeutic options [5]. The risk of intrauterine death and potential risks for the other twin and the mother must be taken into account. Sometimes it is possible to wait until the natural end of pregnancy and then provide suitable treatment to the affected twin. Other times, parents opt to terminate the pregnancy and loose both twins. A selective reduction (after accurate evaluation of placentation) of the affected twin only carries a high risk of complication for the healthy twin, especially in monochorionic pregnancies. In the late third trimester of pregnancy, the option of a preterm delivery can be considered and may contribute to the increase of prematurity and prematurity related diseases in twins. The management of multiple pregnancies is a very complex task for medical staff and requires parental support with adequate counselling and psychological help [6].

A Snapshot on MRSA epidemiology in a neonatal intensive care unit network, Palermo, Italy

Objectives: We performed a 1-year prospective surveillance study on MRSA colonization within the five NICUs of the metropolitan area of Palermo, Italy. The purpose of the study was to assess epidemiology of MRSA in NICU from a network perspective. Methods: Transfer of patients between NICUs during 2014 was traced based on the annual hospital discharge records. In the period February 2014–January 2015, in the NICU B, at the University teaching hospital, nasal swabs from all infants were collected weekly, whereas in the other four NICUs (A, C, D, E) at 4 week-intervals of time. MRSA isolates were submitted to antibiotic susceptibility testing, SCCmec typing, PCR to detect lukS-PV and lukF-PV (lukS/F-PV) genes and the gene encoding the toxic shock syndrome toxin (TSST-1), multilocus variable number tandem repeat fingerprinting (MLVF), and multilocus sequence typing (MLST). Results: In the period under study, 587 nasal swabs were obtained from NICU B, whereas 218, 180, 157, and 95 from NICUs A, C, D, and E, respectively. Two groups of NICUs at high prevalence and low prevalence of MRSA colonization were recognized. Overall, 113 isolates of MRSA were identified from 102 infants. Six MLVF types (A–F) were detected, with type C being subdivided into five subtypes. Five sequence types (STs) were found with ST22-IVa being the most frequent type in all NICUs. All the MRSA molecular subtypes, except for ST1-IVa, were identified in NICU B. Conclusions: Our findings support the need to approach surveillance and infection control in NICU in a network perspective, prioritizing referral healthcare facilities.

Delineating a new critical region for juvenile myoclonic epilepsy at the 22q11.2 chromosome.

We read with great interest the article entitled “The unexpected role of copy number variations in juvenile myoclonic epilepsy” by Helbig I. et al. [1] published in the supplemental special issue “Juvenile myoclonic epilepsy: What is it really?” [July 2013] of this journal. We thought that it would be appropriate to report the 22q11.2 chromosome as an additional proposed critical region for juvenile myoclonic epilepsy (JME) in order to raise awareness that 22q11.2 distal rearrangements may not be so uncommon in populations with epilepsy and to suggest the need to further study individuals with both microdeletions and duplications at 22q11.2. In fact, epileptic seizures are frequent in chromosomal disorders, but only a few of these disorders are associated with specific seizure and EEG patterns [2–4]. Thus, it is assumed that causative chromosomal aberrations offer the opportunity to identify genes which may be involved in idiopathic epilepsies [3]. In patients with JME, several autosomal genes have been reported to show heterozygous (CACNB4, CLCN2, GABRA1, EFHC1) [5–8] and, in a single case, homozygous mutations (GABRD) [9]. Further loci have been linked to chromosomes 5q, 6p, and 15q [10–12]. However, most forms of JME seem to follow polyor oligogenic inheritance. The 22q11.2 chromosome has long been implicated in several genomic disorders with neurological impairment including DiGeorge/velocardiofacial syndrome (DGS/VCFS), der(22) syndrome, and cat-eye syndrome (CES), which are associated with either decreased or increased gene dosage [13–16]. Recent evidence presumes that these different congenital anomaly disorders share a physical region of overlap containing chromosome 22-specific lowcopy repeats (LCRs) composed of a complex modular structure with a high degree of sequence homology (N95%) over large stretches within the repeats. Low-copy repeats predispose to homologous recombination events andmediatemeiotic nonallelic homologous recombinations (NAHR) resulting in genomic rearrangements of the 22q11.2 chromosome, including microdeletion and duplication [16–18]. While the cat-eye and der(22) syndromes are rare disorders characterized by duplications (tetrasomy and trisomy, respectively) of part of 22q11.2; on the contrary, 22q11.2 microdeletions, associated with DGS/VCFS, occur more often in the general population with an estimated frequency of 1/4000–6000 live births [19]. Even though recent data suggest that the frequency of 22q11.2 microduplications could be approximately half that of the deletions, relatively few duplications have been detected among human genomic disorders. Up to now, about 100 patients have been reported, and a high frequency of familial duplications has been detected [20]. This discrepancy may be due, in part, to the remarkable phenotypic variability of the duplications [21,22], which may complicate the clinical recognition of the corresponding syndromes. So far, several studies focused on the potential connection between certain epilepsy phenotypes and the 22q11.2 locus. Kao et al. [23]

Esophageal atresia and Beckwith-Wiedemann syndrome in one of the naturally conceived discordant newborn twins: first report

Recent studies report a high incidence of monozygotic twinning in Beckwith–Wiedemann syndrome. A phenotypical discordance in monozygotic twins is rare. Twinning and Beckwith–Wiedemann syndrome show higher incidence in children born after assisted reproductive techniques. We report on the first observation of esophageal atresia and Beckwith–Wiedemann syndrome in one of the naturally conceived discordant monozygotic twins.

The burden of Candida species colonization in NICU patients: a colonization surveillance study

Fungal infections are an important cause of morbidity and mortality in neonatal intensive care units (NICUs). The identification of specific risk factors supports prevention of candidemia in neonates. Effective prophylactic strategies have recently become available, but the identification and adequate management of high-risk infants is still a priority. Prior colonization is a key risk factor for candidemia. For this reason, surveillance studies to monitor incidence, species distribution, and antifungal susceptibility profiles, are mandatory. Among 520 infants admitted to our NICU between January 2013 and December 2014, 472 (90.77%) were included in the study. Forty-eight out of 472 (10.17%) patients tested positive for Candida spp. (C.), at least on one occasion. All the colonized patients tested positive for the rectal swab, whereas 7 patients also tested positive for the nasal swab. Fifteen out of 472 patients (3.18%) had more than one positive rectal or nasal swab during their NICU stay. Moreover, 9 out of 15 patients tested negative at the first sampling, suggesting they acquired Candida spp. during their stay. Twenty-five of forty-eight (52.1%) colonized patients carried C.albicans and 15/48 (31.25%) C.parapsilosis. We identified as risk factors for Candida spp. colonization: antibiotic therapy, parenteral nutrition, the use of a central venous catheter, and nasogastric tube. Our experience suggests that effective microbiological surveillance can allow for implementing proper, effective and timely control measures in a highrisk setting.

The Coat-Hanger Angle Sign

Figure 1. Chest radiograph showing a small bell-shaped thorax with “coat-hanger” appearance of the ribs. A n infant boy, the second child of healthy parents, was born at 35.5 weeks of gestation by cesarean delivery performed in emergency because of fetal bradycardia and polyhydramnios. At birth his weight was 2770 g (62nd percentile), length 48.3 cm (69th percentile), and head circumference 33.5 cm (64th percentile). Findings of a physical examination showed a broad forehead, a depressed nasal bridge, anteverted nares, a long and protruding philtrum, a high arched palate, retrognathia, joint contractures, and an umbilical hernia. The Apgar score was 6/8 at 1/5 minutes. Because of progressive respiratory distress he required hospitalization and noninvasive support ventilation for the first 36 hours. At admission, a chest radiograph demonstrated a bell-shaped thorax with curved ribs and cupped anterior ends (Figure 1). These chest roentgenogram findings were further investigated by calculating the coat-hanger angle (CHA), which was 36 1 (Figure 2; available at www.jpeds. com). CHA refers to the average of the angles between the peak point of both sixth posterior ribs and the horizontal axis passing through their costovertebral articulations. If there is no peak point of the sixth posterior ribs, the center of the ribs is used instead. An upward angle is defined as +, and a downward angle as . The horizontal axis is defined as a line passing through 2 points of both sixth costovertebral junctions. If this value exceeds 34 (CHA sign), in patients with suggestive dysmorphic features, a paternal uniparental disomy 14 syndrome, recently named Kagami-Ogata syndrome (KOS), should be suspected. KOS results in a unique phenotype characterized by facial abnormalities, abdominal wall defects, placentomegaly, polyhydramnios, and a small bell-shaped thorax with “coathanger” appearance of the ribs constituting its prominent pathognomonic feature.We performed a segregation study by microsatellite analysis polymorphisms using the leukocyte genomic DNA of the patient and parents, which confirmed our clinical suspicion. There are several congenital disorders wherein thoracic hypoplasia is the sole radiological hallmark. The finding of a CHA sign is a well-characterized and simple feature that could suggest the diagnosis of KOS. This sign is described to be more severe than that seen in other genetic bone diseases and to persist from infancy through childhood/puberty. Because of a poor swallowing reflex, the patient required