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Background and ObjectivesClinical manifestations in STXBP1 developmental and epileptic encephalopathy (DEE) vary in severity and outcome, and the genotypic spectrum is diverse. We aim to trace the neurodevelopmental trajectories in individuals with STXBP1-DEE and dissect the relationship between neurodevelopment and epilepsy.MethodsRetrospective standardized clinical data were collected through international collaboration. A composite neurodevelopmental score system compared the developmental trajectories in STXBP1-DEE.ResultsForty-eight patients with de novo STXBP1 variants and a history of epilepsy were included (age range at the time of the study: 10 months to 35 years, mean 8.5 years). At the time of inclusion, 65% of individuals (31/48) had active epilepsy, whereas 35% (17/48) were seizure free, and 76% of those (13/17) achieved remission within the first year of life. Twenty-two individuals (46%) showed signs of developmental impairment and/or neurologic abnormalities before epilepsy onset. Age at seizure onset correlated with severity of developmental outcome and the developmental milestones achieved, with a later seizure onset associated with better developmental outcome. In contrast, age at seizure remission and epilepsy duration did not affect neurodevelopmental outcomes. Overall, we did not observe a clear genotype-phenotype correlation, but monozygotic twins with de novo STXBP1 variant showed similar phenotype and parallel disease course.DiscussionThe disease course in STXBP1-DEE presents with 2 main trajectories, with either early seizure remission or drug-resistant epilepsy, and a range of neurodevelopmental outcomes from mild to profound intellectual disability. Age at seizure onset is the only epilepsy-related feature associated with neurodevelopment outcome. These findings can inform future dedicated natural history studies and trial design.

Introduction We aimed to identify maternal and fetal complications and investigate post-natal and long-term outcomes of fetal hydrothorax (FHT) treated with pleuro-amniotic shunting (shunt). Methods Single-center retrospective observational cohort of shunt cases performed from 2000 to 2021. Risk factors for maternal complications, fetal demise, neonatal death (NND), and post-natal outcomes were identified. Results Out of 88 cases, 70 (79.5%) were complicated by hydrops, with an average gestational age (GA) at diagnosis of 27 weeks (range 16–34). In 16 cases, definitive etiology of FHT was identified; five cases of Noonan syndrome and three cases of monogenic disorders diagnosed by whole exome sequencing (EPHB4, VEGFR3, RASA1). Shunt was performed at an average GA of 28 weeks (20–34), with a dislodgement in 10 cases (11.4%). Maternal complications occurred in three cases; survival rate was 76.1% (67/88). Follow-up data were available for 57/67 (85.1%) children. Incidence of severe neurodevelopmental impairment and pneumopathy (broncho dysplasia, persistent pulmonary hypertension of newborn, and asthma) was 5.3% and 8.8%, respectively. Post-treatment persistence of hydrops, FHT associated with genetic syndromes, and GA at birth were risk factors for fetal demise, NND, and post-natal complications. Conclusion In truly isolated FHT, whenever indicated, pleuro-amniotic shunting is a safe procedure associated with good survival rate and long-term outcome.

Data about the neurological prognosis of isolated cerebellar hypoplasia in utero are scant and inconsistent. In this monocentric retrospective study, we describe the neurodevelopmental outcomes in a series of children with isolated cerebellar hypoplasia of presumably hemorrhagic origin prenatally detected with fetal magnetic resonance imaging (fMRI). We retrospectively reviewed the charts of all the pregnant women who were referred for a neurological consultation, diagnosed with fetal encephalic malformation/disruption between 2010 and 2020 in the Fetal Therapy Unit of our institution. Fetal MRI (fMRI) was performed in all the pregnancies. Fetuses with cerebellar hypoplasia presumably of hemorrhagic origin were selected for the study. Fetuses exposed to alcohol or with additional malformations in other cerebral or body areas were excluded. All the infants received the postpartum follow-up care adopted in our center, including post-natal MRI, serial neurological examinations, standardized neurodevelopmental tests, and regular parental interviews. Cognitive functions were tested with GRIFFITHS II, WPPSI-III, and WISC-IV according to the child's age. A total of 14 pregnant women out of 479 fetal consultations were eligible and included in the study group. In 57% of cases, the etiology of the hemorrhage was unknown. In 21% of cases, it was attributed to a blood transfusion, while in the remaining ones, it was attributed to maternal predisposing factors. Among the survivors, two infants were excluded for prematurity, and two were lost to follow-up. Ten patients were thus included in the study. Six patients had normal neurodevelopment and cognition, and three presented mild-moderate neurological signs, i.e., mild dyspraxia and visuoperceptual impairment. Only one child had a severe outcome, i.e., autism spectrum disorder. The cerebellum is particularly vulnerable to disruptions throughout its prolonged development. Extreme caution must be used in prenatal counseling considering that in the acute phase, lesion extension and vermis involvement can be overestimated with fMRI. In cases of uncertainty, performing an additional fMRI could be advisable after 4-8 weeks. However, in our series, infants with isolated cerebellar hypoplasia tended to have a favorable prognosis. Nevertheless, a long-term follow-up is needed and should include a postnatal brain MRI, serial neurological examinations, and neurodevelopmental tests at least up to school age.

Objective To the best of our knowledge, there have not been studies to address the issue of long-term follow-up of patients with prenatal diagnosis of isolated complete septum pellucidum agenesis (SPA). The aim of this study was to acquire information about the school-age outcome of such patients as a resource for counseling parents receiving this prenatal finding. Methods From a large fetal magnetic resonance (MR) database, we selected only those cases with isolated complete SPA as confirmed by two senior pediatric neuroradiologists in consensus; we then gathered information from the parents of those children who had reached the school age. Results None among the 12 cases (mean age at follow-up: 8.7 years, range: 6–13 year) of the resulting final cohort presented visual or stature deficits; only one required special teaching assistance in school. All other 11 children resulted without any notable academic issue. Conclusion Our report may provide information of practical value about the school-age outcome of fetuses detected by prenatal MR imaging to carry isolated complete SPA.

Background Adverse neurodevelopmental outcomes and MRI alterations are reported in infants born after fetal growth restriction (FGR). This study evaluates the additional role of FGR over prematurity in determining brain impairment. Methods Retrospective observational study comparing 48 FGR and 36 appropriate for gestational age infants born between 26 and 32 weeks' gestation who underwent a cerebral MRI at term equivalent age. Exclusion criteria were twins, congenital anomalies, and findings of overt brain lesions. Main outcomes were total maturation score (TMS) and cerebral areas independently measured by two neuro-radiologists and Griffiths or Bayley scale III scores at median age of 2 years. Results TMS was not significantly different between the groups. Inner calvarium and parenchyma's areas were significantly smaller in FGR cases. There were no significant differences in the average quotient scores. A positive correlation between parenchyma area and cognitive score was found (r = 0.372, p = 0.0078) and confirmed after adjusting for sex, gestational age, and birth weight (p = 0.0014). Among FGR, the subgroup with umbilical arterial Doppler velocimetry alterations had significantly worse gross motor scores (p = 0.005). Conclusions FGR plays additional role over prematurity in determining brain impairment. An early structural dimensional MRI evaluation may identify infants who are at higher risk. Impact Fetal growth-restricted infants showed smaller cerebral parenchymal areas than preterm controls. There is a positive correlation between the parenchyma area and the cognitive score. These results highlight the already known link between structure and function and add importance to the role of a structural dimensional MRI evaluation even in the absence of overt brain lesions.

The COVID-19 pandemic is a global traumatic experience for citizens, especially during sensitive time windows of heightened plasticity such as pregnancy and neonatal life. Pandemic-related stress experienced by mothers during pregnancy may act as an early risk factor for infants’ regulatory capacity development by altering maternal psychosocial well-being (e.g., increased anxiety, reduced social support) and caregiving environment (e.g., greater parenting stress, impaired mother–infant bonding). The aim of the present longitudinal study was to assess the consequences of pandemic-related prenatal stress on infants’ regulatory capacity. A sample of 163 mother–infant dyads was enrolled at eight maternity units in northern Italy. They provided complete data about prenatal stress, perceived social support, postnatal anxiety symptoms, parenting stress, mother–infant bonding, and infants’ regulatory capacity at 3 months of age. Women who experienced emotional stress and received partial social support during pregnancy reported higher anxious symptoms. Moreover, maternal postnatal anxiety was indirectly linked to the infants’ regulatory capacity at 3 months, mediated by parenting stress and mother–infant bonding. Dedicated preventive interventions should be delivered to mothers and should be focused on protecting the mother–infant dyad from the detrimental effects of pandemic-related stress during the COVID-19 healthcare emergency.

Objectives: To evaluate incidence of cerebral injury and outcome in a large series of monochorionic (MC) twin survivors after spontaneous single fetal demise. Methods: Retrospective analysis of all MC pregnancies with single fetal demise diagnosed at, or referred to, the Fetal Therapy Unit “U. Nicolini,” V. Buzzi Children’s Hospital, Milan, Italy, from 2004 to 2015. Survivors evaluation protocol included detailed ultrasound (US) of intracranial anatomy, Doppler investigation of peak systolic velocity in the middle cerebral artery (MCA-PSV), and magnetic resonance (MR). Data were collected on pregnancy characteristics, postnatal brain scan, and MR and neurological follow-up. Results: Seventy-eight consecutive MC pregnancies were analyzed. Median gestational age (GA) at single fetal demise was 22 weeks (range 15–36); median interval between single demise and live birth was 105 days (range 1–175), with a median GA at birth of 36 weeks (range 23–41). Prenatal MR was performed in 57 of 78 cases (73%). Cerebral injury affected 14/78 (18%) co-twins, 2 of whom were born immediately after single demise, with postnatal diagnosis of cerebral injury; of the other 12 fetuses that were studied before birth, 10 had a prenatal diagnosis of lesion both with US and MR, one only with MR, and in one case, a grade III intraventricular hemorrhage was reported only after delivery, which occurred at 25 weeks, 5 weeks after the single demise. Signs of fetal anemia (MCA-PSV value above 1.55 MoM) were related to a higher risk of prenatal cerebral injury; cases with postnatal diagnosis of lesion were delivered at lower GA. Conclusions: Cerebral injury affects 18% of co-twin survivors after single fetal demise in MC twin pregnancies, and evaluation and follow-up of these cases can improve detection rate of such damage.

Background The costs and benefits of full lockdown measures are debated. Neurologically impaired children are a vulnerable population with specific needs in terms of protection against infection and access to health services. Objectives We investigated the effects of lockdown on the health of children with neurological disorders and on their access to care during lockdown. Methods Data from 514 children (282 males – 232 females) were collected through physician-administered interviews to investigate: the occurrence of viral-like physical symptoms, the correlation between the risk of developing such symptoms and several demographic and clinical variables, the occurrence of any worsening of the children's neurological conditions during lockdown, and their access to care services during this period. Results 49.1% experienced at least one symptom during the study period, but no child developed severe complications. The prevalence of symptoms was significantly lower during lockdown than during the previous two months. The underlying neurological condition worsened in 11.5% of the patients. Children who regularly left the home during lockdown were greater risk of exhibiting symptoms. During lockdown, 67.7% had a specialist appointment cancelled, 52.6% contacted their paediatrician, and 30.9% contacted their child neuropsychiatrist. Among patients who usually receive rehabilitation, 49.5% continued remotely. Conclusion Lockdown protected children from infections. Telemedicine and telerehabilitation constituted a valid alternative for the care and treatment of these children, but they should not become a widespread and definitive model of care. COVID-19 and other emergency response plans must take into account the specific needs of children with disabilities.

The COVID-19 pandemic represents a collective trauma that may have enduring stress effects during sensitive periods, such as pregnancy. Prenatal stress may result in epigenetic signatures of stress-related genes (e.g., the serotonin transporter gene, SLC6A4) that may in turn influence infants’ behavioral development. In April 2020, we launched a longitudinal cohort study to assess the behavioral and epigenetic vestiges of COVID-19-related prenatal stress exposure in mothers and infants. COVID-19-related prenatal stress was retrospectively assessed at birth. SLC6A4 methylation was assessed in thirteen CpG sites in mothers and infants’ buccal cells. Infants’ temperament was assessed at 3-month-age. Complete data were available from 108 mother-infant dyads. Greater COVID-19-related prenatal stress was significantly associated with higher infants’ SLC6A4 methylation in seven CpG sites. SLC6A4 methylation at these sites predicted infants’ temperament at 3 months.

Background and ObjectivesPurine-rich element-binding protein A (PURA) gene encodes Pur-α, a conserved protein essential for normal postnatal brain development. Recently, a PURA syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients.MethodsData on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained.ResultsA cohort of 142 patients was included. Characteristics of the PURA syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epileptic abnormalities. Lennox-Gastaut was the most common epilepsy syndrome. Drug refractoriness was common: 33.3% achieved seizure freedom. We found 97 pathogenic variants in PURA without any clear genotype-phenotype associations.DiscussionThe PURA syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations.

Adverse neurodevelopmental outcomes and MRI alterations are reported in infants born after fetal growth restriction (FGR). This study evaluates the additional role of FGR over prematurity in determining brain impairment.Retrospective observational study comparing 48 FGR and 36 appropriate for gestational age infants born between 26 and 32 weeks' gestation who underwent a cerebral MRI at term equivalent age. Exclusion criteria were twins, congenital anomalies, and findings of overt brain lesions. Main outcomes were total maturation score (TMS) and cerebral areas independently measured by two neuro-radiologists and Griffiths or Bayley scale III scores at median age of 2 years.TMS was not significantly different between the groups. Inner calvarium and parenchyma's areas were significantly smaller in FGR cases. There were no significant differences in the average quotient scores. A positive correlation between parenchyma area and cognitive score was found (r = 0.372, p = 0.0078) and confirmed after adjusting for sex, gestational age, and birth weight (p = 0.0014). Among FGR, the subgroup with umbilical arterial Doppler velocimetry alterations had significantly worse gross motor scores (p = 0.005).FGR plays additional role over prematurity in determining brain impairment. An early structural dimensional MRI evaluation may identify infants who are at higher risk.Fetal growth-restricted infants showed smaller cerebral parenchymal areas than preterm controls. There is a positive correlation between the parenchyma area and the cognitive score. These results highlight the already known link between structure and function and add importance to the role of a structural dimensional MRI evaluation even in the absence of overt brain lesions.

ObjectiveTo estimate the prevalence of Joubert syndrome (JS) in Italy applying standards of descriptive epidemiology and to provide a molecular characterization of the described patient cohort.MethodsWe enrolled all patients with a neuroradiologically confirmed diagnosis of JS who resided in Italy in 2018 and calculated age and sex prevalence, assuming a Poisson distribution. We also investigated the correlation between proband chronological age and age at diagnosis and performed next-generation sequencing (NGS) analysis on probands' DNA when available.ResultsWe identified 284 patients with JS: the overall, female- and male-specific population-based prevalence rates were 0.47 (95% confidence interval [CI] 0.41–0.53), 0.41 (95% CI 0.32–0.49), and 0.53 (95% CI 0.45–0.61) per 100,000 population, respectively. When we considered only patients in the age range from 0 to 19 years, the corresponding population-based prevalence rates rose to 1.7 (95% CI 1.49–1.97), 1.62 (95% CI 1.31–1.99), and 1.80 (95% CI 1.49–2.18) per 100,000 population. NGS analysis allowed identifying the genetic cause in 131 of 219 screened probands. Age at diagnosis was available for 223 probands, with a mean of 6.67 ± 8.10 years, and showed a statistically significant linear relationship with chronological age (r2 = 0.79; p < 0.001).ConclusionsWe estimated for the first time the age and sex prevalence of JS in Italy and investigated the patients’ genetic profile. The obtained population-based prevalence rate was ≈10 times higher than that available in literature for children population.

Background: The coronavirus disease of 2019 (Covid-19) represents an unprecedented threat for human health worldwide that may have profound stress effects Pregnancy is a sensitive period for adverse parenting effects on infants’ development and epigenetic mechanisms (DNA methylation) may play a pivotal role Here we present the study protocol of the MOM-COPE project Methods: Mothers and infants will be enrolled in twelve neonatal units in Northern Italy, a dramatic hotspot for Covid-19 contagion in Europe Maternal covid-related stress will be assessed with an ad-hoc questionnaire At birth, newborns and mothers’ salivary samples will be obtained to estimate target genes’ methylation (BDNF, FKBP5, NR3C1, SLC6A4, and OXTR) Post-natal bonding and infants’ temperament will be assessed through maternal reports at 3, 6 and 12 months Maternal sensitivity and infants’ emotional regulation will be assessed during remote videotaped mother-infant interaction at 12 months Results: The study has obtained approval of the Ethics Committee and is going to start by May 15th Hypotheses and anticipated results will be discussed according to the available behavioral epigenetic literature on parenting, pregnancy and large-scale disasters Discussion: This multi-centric study will provide evidence about the effect of pandemic-related prenatal stress exposure on the health and well-being of mothers and infants from birth to 12 months of age Moreover, the longitudinal nature of the study will allow to assess the relative role of epigenetic regulation of specific target genes in mediating the effect of this precocious adverse exposure on short- and long-term outcomes

Objective The aim of our study was to determine the outcome of fetuses with isolated mild ventriculomegaly, with prenatal imaging work-up, prenatal consultation, delivery and clinical follow-up performed in a single tertiary referring center. Methods Fetuses with isolated and non-progressive mild ventriculomegaly (10–15 mm) were included in the study. Inclusion criteria were as follows: singleton pregnancies, normal chromosomal analysis, normal serological evaluation of TORCH, fetal ultrasound and MRI excluding additional CNS or extra-CNS malformations. The prenatal consultation consisted in discussing the prognosis of ventriculomegaly, according to the literature. The postnatal follow-up protocol included a neuroradiological investigation (cranial ultrasound or MRI), neurological and pediatric examinations. The Griffiths Scales were used to assess the neurodevelopmental outcome. Results Thirty newborns were included in follow-up. The postnatal neuroradiological investigations confirmed the ventriculomegaly as an isolated finding in all cases except one. Nineteen children were available for formal neurodevelopmental testing. In our case series, 93.3% of the children had a favorable outcome or mild anomalies. Two children (6.6%) with mild ventriculomegaly were diagnosed as having rare genetic conditions. The Griffiths developmental quotients were normal (mean General Quotient 98.3) at the latest assessment (mean age 20.8 months) in all but one case. Discussion Most children in our case series had a favorable outcome, as described in the literature. Even though a large quantity of data is now available on ventriculomegaly, fetal consultation remains challenging and requires caution. The diagnostic work-up of pregnancies diagnosed with mild ventriculomegaly must be very meticulous and include TORCH evaluation, microarray, serial ultrasounds to exclude progression, and a fetal MRI. However, despite accurate screening, there are more complex conditions in which ventriculomegaly can be the only non-specific finding in fetal life, making postnatal follow up mandatory.

Monochorionic twins, resulting from a single fertilized egg giving rise to two separate embryos, are monozygotic and considered genetically identical. However, discordant phenotypes have been reported in monozygotic twins. We analyzed a retrospective cohort of 155 monochorionic pregnancies (312 twins) with major discordant structural anomalies coded by the ICD-10 system in order to describe the spectrum of anomalies, the management of the pregnancies, and the perinatal outcome. Treatment options included conservative management, selective feticide with bipolar cord coagulation, or complete termination. All survivors underwent at least 24 months of postnatal follow-up. Discordancy was complicated by twin-to-twin transfusion syndrome in eight pregnancies (5%) and by selective intrauterine growth restriction in 41 (26%). Major structural anomalies affected one system in 139 cases (90%) and multiple systems in 16 (10%). Median gestational age at diagnosis was 19.1 weeks (IQR 16.4–21.3). The most frequent single-system anomalies involved the nervous and circulatory systems. In total, 72 anomalous twins (46%) and 116 normal co-twins (74%) were delivered at a median gestational age of 34.6 weeks (IQR 31.0–36.3). Neonatal/infant death of the anomalous twin occurred in 22 cases (14%), with an overall survival rate of 32% (50/155). Surviving anomalous twins underwent major surgery in 22/50 cases (44%), four of whom (8%) now suffer from severe neurologic morbidity. This study shows that a wide spectrum of major discordant structural anomalies can be found in monochorionic pregnancies. The outcome for the anomalous twin is poor, while the survival rate for the normal co-twin was 71%, with a favorable overall prognosis.

Background The COVID-19 pandemic represents a collective trauma that may have enduring stress effects during sensitive periods, such as pregnancy. Prenatal stress may result in epigenetic signatures of stress-related genes (e.g., the serotonin transporter gene, SLC6A4) that may in turn influence infants’ behavioral development. Methods In April 2020, we launched a longitudinal cohort study to assess the behavioral and epigenetic vestiges of COVID-19-related prenatal stress exposure in mothers and infants. COVID-19-related prenatal stress was retrospectively assessed at birth. SLC6A4 methylation was assessed in infants’ buccal cells. Infants’ temperament was assessed at 3-month-age. Results Complete data were available from 108 mother-infant dyads. Greater COVID-19-related prenatal stress was significantly associated with higher infants’ SLC6A4 methylation (RR =.07, p =.007, B =.16 [.05;.29]). SLC6A4 methylation at these sites predicted infants’ temperament at 3 months (RR =.05, p =.027, B = -.45 [-.92;-.06]). Conclusion Indirect effects of the pandemic may alter the trajectories of behavioral development infants. Appropriate prevention and care acts need to be adopted by healthcare systems.

Rett syndrome (RTT) is a neurodevelopmental disorder, affecting 1 in 10,000 girls. Intellectual disability, loss of speech and hand skills with stereotypies, seizures and ataxia are recurrent features. Stringent diagnostic criteria distinguish classical Rett, caused by a MECP2 pathogenic variant in 95% of cases, from atypical girls, 40–73% carrying MECP2 variants, and rarely CDKL5 and FOXG1 alterations. A large fraction of atypical and RTT-like patients remain without genetic cause. Next Generation Sequencing (NGS) targeted to multigene panels/Whole Exome Sequencing (WES) in 137 girls suspected for RTT led to the identification of a de novo variant in STXBP1 gene in four atypical RTT and two RTT-like girls. De novo pathogenic variants—one in GABRB2 and, for first time, one in GABRG2—were disclosed in classic and atypical RTT patients. Interestingly, the GABRG2 variant occurred at low rate percentage in blood and buccal swabs, reinforcing the relevance of mosaicism in neurological disorders. We confirm the role of STXBP1 in atypical RTT/RTT-like patients if early psychomotor delay and epilepsy before 2 years of age are observed, indicating its inclusion in the RTT diagnostic panel. Lastly, we report pathogenic variants in Gamma-aminobutyric acid-A (GABAa) receptors as a cause of atypical/classic RTT phenotype, in accordance with the deregulation of GABAergic pathway observed in MECP2 defective in vitro and in vivo models.

In this chapter, the peculiar aspects of the normal neonatal EEG are discussed, alongside with the recording modalities and the characteristic and age-specific electroencephalographic physiological patterns of the newborn, from preterm birth to the end of the neonatal period. In the iconographic material the physiological markers of electrogenesis maturation have been highlighted; in the Appendix, the terms utilized to describe the neonatal EEG will be defined. The knowledge of normal EEG patterns is a prerequisite for the interpretation of the abnormal neonatal EEG.

The distinctive features of the normal neonatal EEG pattern have been described in the first part of this Manual. This chapter will be dedicated to the description of the most characteristic artifacts and the abnormal EEG findings in the neonatal age. Particular attention has been devoted to the iconographic material..Both EEG backgroud abnormalities and ictal epileptiform discharges are the milestones in the knowledge of abnormal neonatal electroencephalography. The caption of the figures will report the anamnestic, clinical, and instrumental data related to the clinical cases described, in order to underline and confirm the importance of a complete integration among clinical, neurophysiological, and neuroimaging data in the approach of newborns with neurological impairments.

This paper aims to investigate if the dyadic interactive behaviours were influenced by parental stress and feelings both in preterm and full-term mother-child dyads.45 mothers (age = 35.29 ± 5.38) and fathers (age = 36.77 ± 6.89) of preterm infants (GA = 30.25 ± 2.95; BW = 1288.02 ± 488.76), and 36 mothers (age = 32.60 ± 4.56) and fathers (age = 35.54 ± 5.16) of full-term (GA = 39.88 ± 1.38; BW = 3156.39 ± 493.81) were involved. Parents filled out the Impact of Event Scale Revised (IES-R), Profile of Mood States (POMS) and Parenting Stress Index Short Form (PSI-SF) and interactive behaviours (Global Rating Scale) was videotaped after 3 months.Mothers of preterm children showed higher level of Intrusiveness (MOur results underline that preterm birth could be a risk factor for the co-construction of interactive exchanges between mother and premature baby. This study could help practitioners to better consider parental roles and to carry out specific supportive interventions for both parents and children.

Rett syndrome (RTT) is a neurodevelopmental disorder, affecting 1 in 10,000 girls. Intellectual disability, loss of speech and hand skills with stereotypies, seizures and ataxia are recurrent features. Stringent diagnostic criteria distinguish classical Rett, caused by a MECP2 pathogenic variant in 95% of cases, from atypical girls, 40&ndash, 73% carrying MECP2 variants, and rarely CDKL5 and FOXG1 alterations. A large fraction of atypical and RTT-like patients remain without genetic cause. Next Generation Sequencing (NGS) targeted to multigene panels/Whole Exome Sequencing (WES) in 137 girls suspected for RTT led to the identification of a de novo variant in STXBP1 gene in four atypical RTT and two RTT-like girls. De novo pathogenic variants&mdash, one in GABRB2 and, for first time, one in GABRG2&mdash, were disclosed in classic and atypical RTT patients. Interestingly, the GABRG2 variant occurred at low rate percentage in blood and buccal swabs, reinforcing the relevance of mosaicism in neurological disorders. We confirm the role of STXBP1 in atypical RTT/RTT-like patients if early psychomotor delay and epilepsy before 2 years of age are observed, indicating its inclusion in the RTT diagnostic panel. Lastly, we report pathogenic variants in Gamma-aminobutyric acid-A (GABAa) receptors as a cause of atypical/classic RTT phenotype, in accordance with the deregulation of GABAergic pathway observed in MECP2 defective in vitro and in vivo models.

Objective To review the experience of performing selective feticide with bipolar cord coagulation (BCC) in complicated monochorionic (MC) twin pregnancies at a single center. Methods This was a retrospective analysis of BCC performed using 3-mm bipolar forceps under ultrasound control in cases complicated by twin-to-twin transfusion syndrome, selective growth restriction, discordant anomaly or twin reversed arterial perfusion sequence. Results The series comprised 118 cases with a median gestational age at the time of the procedure of 22 (range, 16–30) weeks. There were 14 (12%) intrauterine deaths of the cotwin, eight (7%) miscarriages and one (1%) termination of pregnancy. When BCC was performed before 19 weeks of gestation, the rate of miscarriage was 45%, whereas it was 3% (P

Objective: To report the incidence of fetal and maternal complications after selective fetoscopic laser surgery for twin-to-twin transfusion syndrome (TTTS). Methods: A total of 150 cases of TTTS were treated from January 2004 to June 2009 (period 1, 2004–2006, 62 cases; period 2, 2007 to June 2009, 88 cases). Fetal complications (double and single intrauterine fetal death, recurrence of TTTS, twin anemia-polycythemia sequence (TAPS), reversal of TTTS, cerebral lesions in one twin) and maternal complications were recorded, and retrospectively analyzed. Results: Nineteen (12.6%), 58 (38.7%), 61 (40.7%) and 12 cases (8.0%) were classified preoperatively as Quintero stage I, II, III and IV, respectively. The anterior placenta was described in 73 cases (48.6%). Double and single fetal death occurred overall in 7.3 and 36.0% of cases, respectively. The rate of recurrence was 11.3%, of TAPS 3.3%, and of reversal of TTTS 1.3%. Cerebral lesions were diagnosed in 3 donors (2.0%). Eighteen cases (12.0%) of fetal complications had a second procedure (6 repeat laser, 4 serial amnioreduction, 8 bipolar cord coagulation). Pregnancies undergoing a second procedure delivered at a median gestational age of 30.2 weeks compared to 32.1 weeks for those not repeating (p = 0.04). Perinatal survival of at least one twin improved from 66.1 to 79.5% (p = 0.06) in the two consecutive periods. For every 10 laser surgeries performed, there was an average improvement of 1.5% in the predicted percentage of survival of at least one twin (OR 1.09, 95% CI 1.00–1.19). Major maternal complications occurred in 9 cases (6.0%), 3 of which required admission to intensive care unit. Conclusions: Fetal complications are common after fetoscopic laser surgery. In this experience, an increasing number of procedures improved the performance of a new fetoscopic laser center.

Rare intrachromosomal triplications producing partial tetrasomies have been reported for a number of chromosomes. A detailed molecular characterization, necessary to define the mechanism of their formation, has so far been lacking. We report on the detailed clinical, cytogenetic, and molecular characterization of two triplications, one de novo involving chromosome 18q, the other familial on chromosome Xp. The clinical phenotype of the patient with 18q triplication, very likely due to overexpression of one or more of the genes in the region, consists mainly of facial dysmorphisms and developmental delay. The familial Xp triplication does not cause an increase in the number of copies of any gene and is almost certainly a polymorphism. The rearrangements are actually complex duplications/triplications. In both patients, their proximal breakpoints are located within complex segmental duplications, one containing the VCX gene cluster on chromosome Xp, the other the TCEB3 genes on chromosome 18q. A proximal duplicated region is also present in both patients. All junctions we analyzed were formed by non-homologous end joining (NHEJ). The structural features shared between our patients suggest the involvement of a common mechanism in the genesis of interstitial intrachromosomal triplications. © 2011 Wiley Periodicals, Inc.

Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic overlap, being allelic at several loci. One of the most interesting gene is TMEM67, encoding the transmembrane protein meckelin. We performed mutation analysis of TMEM67 in 341 probands, including 265 JSRD representative of all clinical subgroups and 76 MKS fetuses. We identified 33 distinct mutations, of which 20 were novel, in 8/10 (80%) JS with liver involvement (COACH phenotype) and 12/76 (16%) MKS fetuses. No mutations were found in other JSRD subtypes, confirming the strong association between TMEM67 mutations and liver involvement. Literature review of all published TMEM67 mutated cases was performed to delineate genotype-phenotype correlates. In particular, comparison of the types of mutations and their distribution along the gene in lethal versus non lethal phenotypes showed in MKS patients a significant enrichment of missense mutations falling in TMEM67 exons 8 to 15, especially when in combination with a truncating mutation. These exons encode for a region of unknown function in the extracellular domain of meckelin.

Leber's congenital amaurosis (LCA) is a clinically and genetically heterogeneous disorder characterized by severe loss of vision at birth. It accounts for 10-18% of cases of congenital blindness. Some patients exhibit only blindness of retinal origin whereas others show evidence of a multi-systemic involvement. We review the literature relating to this severe disorder, highlighting unresolved questions, in particular the nature of the association of LCA with mental retardation and with systemic findings and syndromic pictures. In recent years, genetic advances in the diagnosis of LCA have opened up new horizons, also from a therapeutic point of view. A better understanding of this pathology would be valuable for paediatric neurologists.

Ciliopathies are an expanding group of rare conditions characterized by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS), Senior-Loken syndrome and isolated Leber congenital amaurosis (LCA). Although these conditions are recessively inherited, in a subset of patients only one CEP290 mutation could be detected. To assess whether genomic rearrangements involving the CEP290 gene could represent a possible mutational mechanism in these cases, exon dosage analysis on genomic DNA was performed in two groups of CEP290 heterozygous patients, including five JSRD/ MKS cases and four LCA, respectively. In one JSRD patient, we identified a large heterozygous deletion encompassing CEP290 C -terminus that resulted in marked reduction of mRNA expression. No copy number alterations were identified in the remaining probands. The present work expands the CEP290 genotypic spectrum to include multiexon deletions. Although this mechanism does not appear to be frequent, screening for genomic rearrangements should be considered in patients in whom a single CEP290 mutated allele was identified.

Previous studies described how early electroencephalogram patterns in neonatal hypoxic-ischemic encephalopathy seem to correlate with the severity of the clinical picture and provide prognostic information. This study evaluated whether electroencephalograms of newborns with severe perinatal hypoxic-ischemic encephalopathy, treated with hypothermia, provide information on clinical outcomes. Twenty-three newborns treated with hypothermia underwent electroencephalogram monitoring within 48 hours of age, and were enrolled in a follow-up with sequential electroencephalogram and neurologic controls (at ages 1 week, 1 month, 3-6 months, and 1 year). An inactive electroencephalogram pattern in the first 48 hours of age was associated with death or major neurologic sequelae. At age 1 week, a low-voltage, continuous pattern indicated a worse prognostic value when compared with other patterns. The persistence of electroencephalogram abnormalities at age 1 month was associated with a higher risk of neurologic sequelae. Background electroencephalogram abnormalities, detected in the first days of life after hypoxic-ischemic encephalopathy, can provide prognostic information, even in patients treated with hypothermia. After 1 month of age, the information on clinical outcomes provided by electroencephalograms usually decreases because of the natural trend toward electroencephalogram normalization.

This case describes a boy with pure partial trisomy of the long arm of chromosome 7. The only prenatal finding on the boy was cerebral ventricular enlargement. After birth, mild facial dysmorphic features and cardiac malformations (pulmonary valve dysplasia, interatrial and interventricular septal defects) were detected. The boy developed severe psychomotor retardation, failure to thrive, and poor interaction with the environment. Focal seizures occurred in the neonatal period. Left frontotemporal abnormalities were observed in the subsequent electroencephalograms. An area of subependymal nodular heterotopia in the right frontal region was detected. Eighteen cases of 7q pure trisomy have been described in the literature over the years. The present study confirms that, in 7q trisomy cases, there are several common, yet nonspecific, features: macrocephaly, frontal bossing, failure to thrive, psychomotor delay, low-set ears, short neck, and genital—urinary tract abnormalities. Shortened life span seems associated only with duplication of the entire arm, and correlation phenotype—genotype seems questionable.

An epidemiological investigation of behavior disorders in a population of 434 students (52.3% males, 47.7% females) ranging from 16 to 19 years of age has been carried out. Possible correlations between eating disturbances, drug addiction related behaviors, suicide attempts and former sexual abuses have been discussed. An anonymous self administered questionnaire, prepared by the authors, had been used. The statistical analysis was carried out with the SPSS/PC Factor software.This study revealed the presence of adolescents with unstable or quantitatively not adequate eating behaviors, which are expressed by borderline symptoms and not by clear syndromes. Distorted attitudes towards weight, body and food, related to disturbances of body image, were pointed out. In particular, girl seemed to be unhappy with their own body. There was a correlation between abnormal eating behaviors (borderline bulimia) and low level of selfesteem. "Anorexic behavior" and "bulimic behavior" had a significant correlation to suicide attempts. A relationship between "bulimic behavior" and use/abuse of drugs and/or alcohol was found. In our population several kinds of violence were found (2.6% sexual abuse with physical contact; 13.5% sexual abuse without physical contact; 9.4% physical abuse) experienced inside or outside families. The adolescent victims of sexual abuse showed abnormal eating behavior, mostly a tendency to a "bulimic behavior".This study seems to confirm that there are significant correlations and several conduct disorders. Moreover the presence of a correlation between eating disturbances, even if borderline and traumatic events of sexual nature is confirmed.