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ObjectivesTo assess the prevalence of antiepileptic drug (AED) exposure in pregnant women and the comparative risk of terminations of pregnancy (TOPs), spontaneous abortions, stillbirths, major birth defects (MBDs), neonatal distress and small for gestational age (SGA) infants following intrauterine AED exposure in the Emilia Romagna region, Italy (4 459 246 inhabitants on 31 December 2011).MethodsWe identified all deliveries and hospitalised abortions in Emilia Romagna in the period 2009–2011 from the certificate of delivery assistance registry (Certificato di Assistenza al Parto— CedAP) and the hospital discharge card registry, exposure to AEDs from the reimbursed drug prescription registries, MBDs from the regional registry of congenital malformations, and Apgar scores and cases of SGA from the CedAP. Records from different registries were linked.ResultsWe identified 145 243 pregnancies: 111 284 deliveries, 16 408 spontaneous abortions and 17 551 TOPs. Six hundred and eleven pregnancies (0.42%; 95% Cl 0.39 to 0.46) were exposed to AEDs. In the AED-exposed group 21% of pregnancies ended in TOPs vs 12% in the non-exposed women (OR: 2.24; 95% CI 1.41 to 3.56). Rates of spontaneous abortions, stillbirths, neonatal distress and SGA were comparable. Three hundred and fifty-three babies (0.31%; 95% CI 0.28 to 0.35) were exposed to AEDs during the first trimester. MBD rates were 2.3% in the exposed vs 2.0% in the non-exposed pregnancies (OR: 1.12, 95% CI 0.55 to 2.55).ConclusionThe Emilia Romagna prevalence of AED exposure in pregnancy was 0.42%, comparable with previous European studies. Rates of spontaneous abortions, stillbirths, neonatal distress, SGA and MBDs following AED exposure were not significantly increased. The rate of TOPs was significantly higher in the AED-exposed women.

Silver–Russell syndrome (SRS) is a clinically and genetically heterogeneous syndrome characterized by severe intrauterine and postnatal growth retardation, facial dysmorphism and body asymmetry. One of the main molecular mechanisms leading to the syndrome involves methylation abnormalities of chromosome 11p15. In the last decades, an increase of imprinting disorders have been reported in children born from assisted reproductive technology (ART); however there is currently little evidence linking SRS and ART. Only few infants with SRS born using ART, supported by molecular analysis, have been described. We report on a twin-girl conceived using intracytoplasmic sperm injection (ICSI) diagnosed with SRS. Molecular studies revealed a hypomethylation of the paternal H19/IGF2 Imprinting Control Region. Her twin sister had a normal prenatal and postnatal growth and a normal methylation pattern of the chromosome 11p15. This is the second reported case of a twin infant with SRS conceived using ART with hypomethylation of H19/IGF2; it provides additional evidence of a possible relationship between ART procedures and methylation defects observed in SRS. Given the clinical heterogeneity of SRS, and the increased risk of multiple and preterm births in the ART-conceived children, it is possible that a number of cases of SRS remains undiagnosed in this population. Future studies should investigate the possible link between ART and SRS, in order to better understand the causes of epimutations in ART pregnancies, and to help clinicians to adequately counsel parents who approach to ART and to assess the opportunity of a long-term follow-up of children conceived using ART. © 2013 Wiley Periodicals, Inc.

Down Syndrome (DS) is characterized by a wide spectrum of clinical signs, which include segmental premature aging of central nervous and immune systems. Although it is well established that the causative defect of DS is the trisomy of chromosome 21, the molecular bases of its phenotype are still largely unknown. We used the Infinium HumanMethylation450 BeadChip to investigate DNA methylation patterns in whole blood from 29 DS persons, using their relatives (mothers and unaffected siblings) as controls. This family-based model allowed us to monitor possible confounding effects on DNA methylation patterns deriving from genetic and environmental factors. Although differentially methylated regions (DMRs) displayed a genome-wide distribution, they were enriched on chromosome 21. DMRs mapped in genes involved in developmental functions, including embryonic development (HOXA family) and haematological (RUNX1 and EBF4) and neuronal (NCAM1) development. Moreover, genes involved in the regulation of chromatin structure (PRMD8, KDM2B, TET1) showed altered methylation. The data also showed that several pathways are affected in DS, including PI3K-Akt signaling. In conclusion, we identified an epigenetic signature of DS that sustains a link between developmental defects and disease phenotype, including segmental premature aging.

This work investigates the role of metabolite levels in the intellectual impairment of subjects with Down syndrome (DS). Homocysteine, folate, vitamin B12, uric acid (UA), creatinine levels and MTHFR C677T genotype were analyzed in 147 subjects with DS. For 77 subjects, metabolite levels were correlated with cognitive tests. Griffiths-III test was administered to 28 subjects (3.08–6.16 years) and WPPSI-III test was administered to 49 subjects (7.08–16.08 years). Significant correlations were found among some metabolite levels and between homocysteine levels and MTHFR C677T genotype. Moreover, homocysteine, UA and creatinine levels resulted increased with age. We did not find any correlation between metabolites and cognitive test score in the younger group. Homocysteine showed statistically significant correlation with WPPSI-III subtest scores when its level is ≥ 7.35 µmol/L, remaining correlated in higher thresholds only for non-verbal area scores. Vitamin B12 showed correlations with all WPPSI-III subtest scores when its level is

Among Down syndrome (DS) children, 40-50% have congenital heart disease (CHD). Although trisomy 21 is not sufficient to cause CHD, three copies of at least part of chromosome 21 (Hsa21) increases the risk for CHD. In order to establish a genotype-phenotype correlation for CHD in DS, we built an integrated Hsa21 map of all described partial trisomy 21 (PT21) cases with sufficient indications regarding presence or absence of CHD (n=107), focusing on DS PT21 cases. We suggest a DS CHD candidate region on 21q22.2 (0.96Mb), being shared by most PT21 cases with CHD and containing three known protein-coding genes (DSCAM, BACE2, PLAC4) and four known non-coding RNAs (DSCAM-AS1, DSCAM-IT1, LINC00323, MIR3197). The characterization of a DS CHD candidate region provides a useful approach to identify specific genes contributing to the pathology and to orient further investigations and possibly more effective therapy in relation to the multifactorial pathogenesis of CHD.

Background: Hidradenitis suppurativa (HS) is a chronic, inflammatory, recurrent skin disease of the pilosebaceous unit characterized by protean manifestations. Several studies have found an increased incidence and earlier presentation of this disease in patients carrying trisomy 21. Patients with Down syndrome (DS) have a higher risk of developing a wide range of cutaneous manifestations, including HS and chronic folliculitis. Recently, disseminate recurrent folliculitis (DRF) has been reported as an atypical monosymptomatic feature of HS at its onset. Objective: To assess the prevalence of HS and DRF by comparing a cohort of patients carrying trisomy 21 vs pediatric controls. Methods: A retrospective 2-year monocentric clinical study was performed by collecting clinical data of 131 patients with DS, aged 4-36 years, followed at the Dermatology Unit and Down Syndrome Regional Center of Bologna University. Data were matched with those coming from 12,351 pediatric controls. Results: In DS patients, DRF and HS showed a prevalence of, respectively, 6.8% and 24.4%, while 5.3% of patients presented both diseases. In the control group the prevalence for HS+ and DRF+ was 0.5% and 1.2%, respectively, with a 0.14% of overlap cases. The association between HS and DRF proved to be statistically significant in both groups (P < 0.05). In the DS cohort the mean age of symptoms onset was 15.67 (SD: 2.29) years for HS and 13.11 (SD: 4.93) years for DRF. Buttocks were the most frequently affected body area for DRF followed by the inguinocrural area, while in HS buttocks were less frequently involved than groins and upper thighs. Conclusions: Because of the later onset of HS, patients with DRF at an early age should be monitored for the possible onset of HS in the apocrine-bearing areas.

Trisomy 21 causes Down syndrome (DS), the most common human genetic disorder and the leading genetic cause of intellectual disability. The alteration of one-carbon metabolism was described as the possible metabolic cause of the intellectual disability development in subjects with DS. One of the biochemical pathways involved in the one-carbon group transfer is the folate cycle. The cytotoxic drug methotrexate (MTX) is a folic acid (FA) analogue which inhibits the activity of dihydrofolate reductase enzyme involved in the one-carbon metabolic cycle. Trisomy 21 cells are more sensitive to the MTX effect than euploid cells, and in 1986 Jerome Lejeune and Coll. demonstrated that MTX was twice as toxic in trisomy 21 lymphocytes than in control cells. In the present work, the rescue effect on MTX toxicity mediated by FA and some of its derivatives, tetrahydrofolate (THF), 5-formyl-THF, and 5-methyl-THF, in both normal and trisomy 21 skin fibroblast cells, was evaluated. A statistically significant rescue effect was obtained by 5-formyl-THF, 5-methyl-THF, and their combination, administered together with MTX. In conclusion, trisomy 21 fibroblast cell lines showed a good response to the rescue effects of 5-formyl-THF and 5-methyl-THF on the MTX toxicity almost as normal cell lines.

Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith-Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways. Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith-Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways.

PURPOSE: Mowat-Wilson syndrome (MWS) is a genetic disease characterized by distinctive facial features, moderate to severe intellectual disability, and congenital malformations, including Hirschsprung disease, genital and eye anomalies, and congenital heart defects, caused by haploinsufficiency of the ZEB2 gene. To date, no characteristic pattern of brain dysmorphology in MWS has been defined.METHODS: Through brain magnetic resonance imaging (MRI) analysis, we delineated a neuroimaging phenotype in 54 MWS patients with a proven ZEB2 defect, compared it with the features identified in a thorough review of published cases, and evaluated genotype-phenotype correlations.RESULTS: Ninety-six percent of patients had abnormal MRI results. The most common features were anomalies of corpus callosum (79.6% of cases), hippocampal abnormalities (77.8%), enlargement of cerebral ventricles (68.5%), and white matter abnormalities (reduction of thickness 40.7%, localized signal alterations 22.2%). Other consistent findings were large basal ganglia, cortical, and cerebellar malformations. Most features were underrepresented in the literature. We also found ZEB2 variations leading to synthesis of a defective protein to be favorable for psychomotor development and some epilepsy features but also associated with corpus callosum agenesis.CONCLUSION: This study delineated the spectrum of brain anomalies in MWS and provided new insights into the role of ZEB2 in neurodevelopment.Genet Med advance online publication 10 November 2016Genetics in Medicine (2016); doi:10.1038/gim.2016.176.

We undertook a population-based study to assess the comparative risk of spontaneous abortions, terminations of pregnancy (TOPs), major birth defects (MBDs), preterm births and small for gestational age (SGA) infants following intrauterine antiepileptic drug (AED) exposure in the Emilia Romagna region, Northern Italy (4 million inhabitants) over a 3-year period (2009–2011). The study was approved by the Local Ethical Committee and authorised by the Hospital Management Executive. Data were obtained from official regional registries: Certificates of Delivery Assistance (CedAP) for deliveries (>99% coverage of live births and stillbirths) and Hospital Discharge Cards collecting the International Classification of Diseases (ICD) codes of all the discharge diagnoses, for abortions . AED exposure was based on reimbursed prescription databases as AEDs are supplied and reimbursed by medical prescription in Italy; all drugs registered as AEDs and redeemed with ATC code N03 were considered. MBDs were taken from the Registry of Congenital Malformations (IMER) recording MBDs detected by paediatricians in stillbirths and in live births during the first week of the infant’s life (coverage >95% of births). Each recording from the first three registries contains a unique anonymous code identifying each citizen and linking information among registries. Recordings from the IMER are routinely linked to the CeDAP and consequently to the others, using an additional procedure (correct linkage >98% of the sample). All data were anonymised at the regional source of data to protect patient privacy according to Italian legislation. For the deliveries cohort, the exposure period was based on the date of delivery and gestational age. For the …

A 'Down Syndrome critical region' (DSCR) sufficient to induce the most constant phenotypes of Down syndrome (DS) had been identified by studying partial (segmental) trisomy 21 (PT21) as an interval of 0.6-8.3 Mb within human chromosome 21 (Hsa21), although its existence was later questioned. We propose an innovative, systematic reanalysis of all described PT21 cases (from 1973 to 2015). In particular, we built an integrated, comparative map from 125 cases with or without DS fulfilling stringent cytogenetic and clinical criteria. The map allowed to define or exclude as candidates for DS fine Hsa21 sequence intervals, also integrating duplication copy number variants (CNVs) data. A highly restricted DSCR (HR-DSCR) of only 34 kb on distal 21q22.13 has been identified as the minimal region whose duplication is shared by all DS subjects and is absent in all non-DS subjects. Also being spared by any duplication CNV in healthy subjects, HR-DSCR is proposed as a candidate for the typical DS features, the intellectual disability and some facial phenotypes. HR-DSCR contains no known gene and has relevant homology only to the chimpanzee genome. Searching for HR-DSCR functional loci might become a priority for understanding the fundamental genotype-phenotype relationships in DS.

Pallister-Killian syndrome (PKS) is a rare sporadic multi-systemic developmental disorder caused by a mosaic tetrasomy of the short arm of chromosome 12. A wide range of clinical characteristics including intellectual disability, seizures, and congenital malformations has previously been described. Individuals with PKS show a characteristic facial phenotype with frontal bossing, alopecia, sparse eyebrows, depressed nasal bridge, long philtrum, telecanthus, and posteriorly rotated ears. Oro-dental features, such as "Pallister lip," macroglossia, delayed eruption of primary teeth, high arched-palate, prognathism, and cleft palate have been occasionally reported in the medical literature. The aim of the study was to assess the oro-dental phenotype of PKS and to describe the oral health status in a cohort participating in the First European Workshop on PKS. A clinical dental examination was performed in 21 Caucasian probands and data regarding medical and dental history collected. Twelve probands (57%) showed an atypical dental pattern, with multiple missing teeth (primarily the first permanent molars) and 2 (10%) a double teeth. The severity of gingivitis and dental caries increased with age and gingival overgrowth was a common finding. A characteristic occlusive phenotype was found: a high-arched palate with mandibular prognathism associated with an anterior openbite and crossbite and with posterior crossbite (unilateral or bilateral). The prevalence of oral habits (non-nutritive sucking, mouth breathing, bruxism) was high, even in older probands. This study suggests that individuals affected by PKS should be observed closely for oro-dental diseases and a multidisciplinary approach is needed to implement the right preventive measures. © 2016 Wiley Periodicals, Inc.

Beckwith–Wiedemann syndrome (BWS) is the most common (epi)genetic overgrowth-cancer predisposition disorder. Given the absence of consensual recommendations or international guidelines, the Scientific Committee of the Italian BWS Association ( www.aibws.org ) proposed these recommendations for the diagnosis, molecular testing, clinical management, follow-up and tumor surveillance of patients with BWS. The recommendations are intended to allow a timely and appropriate diagnosis of the disorder, to assist patients and their families, to provide clinicians and caregivers optimal strategies for an adequate and satisfactory care, aiming also at standardizing clinical practice as a national uniform approach. They also highlight the direction of future research studies in this setting. With recent advances in understanding the disease (epi)genetic mechanisms and in describing large cohorts of BWS patients, the natural history of the disease will be dissected. In the era of personalized medicine, the emergence of specific (epi)genotype–phenotype correlations in BWS will likely lead to differentiated follow-up approaches for the molecular subgroups, to the development of novel tools to evaluate the likelihood of cancer development and to the refinement and optimization of current tumor screening strategies. Conclusions: In this article, we provide the first comprehensive recommendations on the complex management of patients with Beckwith–Wiedemann syndrome.

Bladder exstrophy (BE) is a complex congenital anomaly characterized by a defect in the closure of the lower abdominal wall and bladder. We aimed to provide an overview of the literature and conduct an epidemiologic study to describe the prevalence, and maternal and case characteristics of BE. We used data from 22 participating member programs of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR). All cases were reviewed and classified as isolated, syndrome, and multiple congenital anomalies. We estimated the total prevalence of BE and calculated the frequency and odds ratios for various maternal and case characteristics. A total of 546 cases with BE were identified among 26,355,094 births. The total prevalence of BE was 2.07 per 100,000 births (95% CI: 1.90-2.25) and varied between 0.52 and 4.63 among surveillance programs participating in the study. BE was nearly twice as common among male as among female cases. The proportion of isolated cases was 71%. Prevalence appeared to increase with increasing categories of maternal age, particularly among isolated cases. The total prevalence of BE showed some variations by geographical region, which is most likely attributable to differences in registration of cases. The higher total prevalence among male cases and older mothers, especially among isolated cases, warrants further attention. (C) 2011 Wiley Periodicals, Inc.

This study describes the epidemiology of congenital amelia (absence of limb/s), using the largest series of cases known to date. Data were gathered by 20 surveillance programs on congenital anomalies, all International Clearinghouse for Birth Defects Surveillance and Research members, from all continents but Africa, from 1968 to 2006, depending on the program. Reported clinical information on cases was thoroughly reviewed to identify those strictly meeting the definition of amelia. Those with amniotic bands or limb-body wall complex were excluded. The primary epidemiological analyses focused on isolated cases and those with multiple congenital anomalies (MCA). A total of 326 amelia cases were ascertained among 23,110,591 live births, stillbirths and (for some programs) elective terminations of pregnancy for fetal anomalies. The overall total prevalence was 1.41 per 100,000 (95% confidence interval: 1.26-1.57). Only China Beijing and Mexico RYVEMCE had total prevalences, which were significantly higher than this overall total prevalence. Some under-registration could influence the total prevalence in some programs. Liveborn cases represented 54.6% of total. Among monomelic cases (representing 65.2% of nonsyndromic amelia cases), both sides were equally involved, and the upper limbs (53.9%) were slightly more frequently affected. One of the most interesting findings was a higher prevalence of amelia among offspring of mothers younger than 20 years. Sixty-nine percent of the cases had MCA or syndromes. The most frequent defects associated with amelia were other types of musculoskeletal defects, intestinal, some renal and genital defects, oral clefts, defects of cardiac septa, and anencephaly. (C) 2011 Wiley Periodicals, Inc.

Objective: To report recent data on the epidemiology of pregnancies affected by open spina bifida in the Emilia-Romagna region of Italy. Methods: All cases of open spina bifida diagnosed in the Emilia-Romagna region between 2001 and 2011 and reported to the IMER regional registry were included in the study group. The pregnancy outcome was retrospectively assessed. Results: In the study period out of 390,978 babies born in Emilia-Romagna 126 cases of open spina bifida were reported to the IMER registry, resulting in a global prevalence of 3.2 per 10,000 births. Prenatal diagnosis was achieved in the vast majority of these cases (105/126; 83.3%) and in a great proportion of those women (85/105; 80.9%) who opted for termination of pregnancy. Conclusions: In a wide region of northern Italy where ultrasound anomaly scan is routinely offered to the general population, the vast majority of cases of open spina bifida are diagnosed antenatally and terminated electively.

Mowat-Wilson syndrome (MWS) is characterized by moderate to severe intellectual disability and distinctive facial features in association with variable structural congenital anomalies/clinical features including congenital heart disease, Hirschsprung disease, hypospadias, agenesis of the corpus callosum, short stature, epilepsy, and microcephaly. Less common clinical features include ocular anomalies, craniosynostosis, mild intellectual disability, and choanal atresia. These cases may be more difficult to diagnose. In this report, we add 28 MWS patients with molecular confirmation of ZEB2 mutation, including seven with an uncommon presenting feature. Among the "unusual" patients, two patients had clinical features of charge syndrome including choanal atresia, coloboma, cardiac defects, genitourinary anomaly (1/2), and severe intellectual disability; two patients had craniosynostosis; and three patients had mild intellectual disability. Sixteen patients have previously-unreported mutations in ZEB2. Genotype-phenotype correlations were suggested in those with mild intellectual disability (two had a novel missense mutation in ZEB2, one with novel splice site mutation). This report increases the number of reported patients with MWS with unusual features, and is the first report of MWS in children previously thought to have CHARGE syndrome. These patients highlight the importance of facial gestalt in the accurate identification of MWS when less common features are present.

Objective To investigate the clinical manifestations at diagnosis and during follow-up in patients with 22q11.2 deletion syndrome to better define the natural history of the disease. Study design A retrospective and prospective multicenter study was conducted with 228 patients in the context of the Italian Network for Primary Immunodeficiencies. Clinical diagnosis was confirmed by cytogenetic or molecular analysis. Results The cohort consisted of 112 males and 116 females; median age at diagnosis was 4 months (range 0 to 36 years 10 months). The diagnosis was made before 2 years of age in 71% of patients, predominantly related to the presence of heart anomalies and neonatal hypocalcemia. In patients diagnosed after 2 years of age, clinical features such as speech and language impairment, developmental delay, minor cardiac defects, recurrent infections, and facial features were the main elements leading to diagnosis. During follow-up (available for 172 patients), the frequency of autoimmune manifestations ( P = .015) and speech disorders ( P = .002) increased. After a median follow-up of 43 months, the survival probability was 0.92 at 15 years from diagnosis. Conclusions Our data show a delay in the diagnosis of 22q11.2 deletion syndrome with noncardiac symptoms. This study provides guidelines for pediatricians and specialists for early identification of cases that can be confirmed by genetic testing, which would permit the provision of appropriate clinical management.