Multidisciplinary follow-up in a patient with Morgagni hernia leads to diagnosis of Marfan syndrome.

BACKGROUND: congenital diaphragmatic hernia (CDH) is a birth defect occurring in isolated or syndromic (chromosomal or monogenic) conditions. The diaphragmatic defect can be the most common one: left-sided posterolateral, named Bochdalek hernia; or it can be an anterior-retrosternal defect, named Morgagni hernia. Marfan syndrome (MFS) is a rare autosomal dominant inherited condition that affects connective tissue, caused by mutations in fibrillin-1 gene on chromosome 15. To date various types of diaphragmatic defects (about 30 types) have been reported in association with MFS, but they are heterogeneous, including CDH and paraesophageal hernia. CASE PRESENTATION: We describe the case of a child incidentally diagnosed with Morgagni hernia through a chest X-ray performed due to recurrent respiratory tract infections. Since the diagnosis of CDH, the patient underwent a clinical multidisciplinary follow-up leading to the diagnosis of MFS in accordance with revised Ghent Criteria: the child had typical clinical features and a novel heterozygous de novo single-base deletion in exon 26 of the FBN1 gene, identified by Whole-Exome Sequencing. MFS diagnosis permitted to look for cardiovascular complications and treat them, though asymptomatic, in order to prevent major cardiovascular life-threatening events. CONCLUSION: Our case shows the importance of a long-term and multidisciplinary follow-up in all children with diagnosis of CDH.

Exclusive human milk feeding and prevalence of early adiposity rebound in ELBW infants: a retrospective cohort study.

The purpose of the present study was to evaluate the prevalence of early adiposity rebound (EAR) and factors associated with its occurrence in a cohort of extremely low birth weight infants (ELBW). We conducted a retrospective longitudinal study including ELBW infants followed-up for up to 10 years after discharge. EAR was defined as occurring before 5 years of age. A multivariate binary logistic regression analysis was performed to evaluate maternal and perinatal variables independently associated with EAR. Out of 212 ELBW infants included in the analysis, 40.6% developed EAR and 21.5% showed it before 4 years of age. Only formula milk feeding at discharge was independently associated with a higher risk of EAR. The mean BMI of children with EAR was higher than that of children without EAR. Furthermore, the prevalence of overweight and obesity was higher in the EAR group than in the timely AR group.  Conclusions: ELBW infants in our cohort developed EAR in a relatively high percentage of cases. In this already at-risk population, EAR may represent a further risk factor for an adverse metabolic outcome. Monitoring preterm infants' growth within a long-term follow-up program and promoting and supporting human milk feeding is advisable. What is Known: • Preterm-born infants are at high risk for long-term adverse health outcomes, especially cardiovascular and metabolic. • The occurrence of early adiposity rebound (EAR) is associated with the risk of later obesity and metabolic syndrome. What is New: • The occurrence of EAR in ELBW infants may represent an additional risk factor for later adverse metabolic outcomes in an already vulnerable population. • Future preventive strategies should include a long-term follow-up and the promotion of exclusive breastfeeding.

To be born twin: effects on long-term neurodevelopment of very preterm infants-a cohort study.

Objective: To examine the effect of twin birth on long-term neurodevelopmental outcomes in a cohort of Italian preterm infants with very low birth weight. Study design: We performed a retrospective cohort study on children born in a tertiary care centre. We included children born between 1 January 2007 and 31 December 2013 with a gestational age (GA) of ≤32 weeks and birth weight of <1,500 g. The infants born from twin pregnancies complicated by twin-to-twin transfusion syndrome and from higher-order multiple pregnancies were excluded. The children were evaluated both at 2 years corrected age and 5 years chronological age with Griffiths mental development scales revised (GMDS-R). The linear mixed effects models were used to study the effect of being a twin vs. being a singleton on GMDS-R scores, adjusting for GA, being born small for gestational age, sex, length of NICU stay, socio-economic status, and comorbidity score (CS) calculated as the sum of the weights associated with each of the major morbidities of the infants. Results: A total of 301 children were included in the study, of which 189 (62.8%) were singletons and 112 (37.2%) were twins; 23 out of 112 twins were monochorionic (MC). No statistically significant differences were observed between twins and singletons in terms of mean general quotient and subscales at both 2 and 5 years. No effect of chorionicity was found when comparing scores of MC and dichorionic twins vs. singletons; however, after adjusting for the CS, the MC twins showed lower scores in the hearing and language and performance subscales at 5 years. Conclusion: Overall, in our cohort of children born very preterm, twin infants were not at higher risk of neurodevelopmental impairment compared with singletons at pre-school age.

Dose-dependent impact of human milk feeding on tidal breathing flow-volume loop parameters across the first 2 years of life in extremely low-birth-weight infants: a cohort study.

The purpose of this study is to test the hypothesis that higher consumption of human milk (HM) in preterm infants with birth weight (BW) <1000 g is associated with improved lung function in a dose-dependent manner over the first 2 years of corrected age (CA). This retrospective study at an academic medical center included infants with BW <1000g. They had lung function assessment by the tidal breathing flow-volume loop (TBFVL) follow-up visits at 0-3-, 3-6-, 6-12-, 12-18-, and 18-24-month CA. One hundred eighty infants were included in the study with a mean (SD) gestational age 26.5 (1.90) weeks and BW 772.4 (147.0) g, 50% were female, and 60% developed BPD. 62.8% of infants received HM during the NICU stay. According to a general linear model (including GA, being small for GA (SGA), sex, human milk percentage, sepsis, and BPD), on average, each week of GA resulted in a higher tPTEF/tE of 1.24 (p = 0.039) and being SGA in a lower tPTEF/tE of 5.75 (p = 0.013) at 0-3-month CA. A higher percentage of human milk out of the total enteral intake was associated with better tPTEF/tE z-scores at 0-3 months (p = 0.004) and 18-24 months of CA (p = 0.041). BPD diagnosis was associated with a relevantly worse tPTEF/tE z-score at 6-12 months of CA (p = 0.003). CONCLUSION: Preterm infants with higher consumption of HM had significantly less airway obstruction across the first 2 years, suggesting that human milk may contribute in a dose-dependent manner to improve lung function in early childhood in former preterm infants born ELBW. WHAT IS KNOWN: • Human milk feeding reduces the risk of prematurity-related morbidities, including necrotizing enterocolitis, sepsis, lower respiratory tract infections, and BPD. Both exclusive and partial human milk feeding appear to be associated with a lower risk of BPD in preterm infants. WHAT IS NEW: • This cohort study of 180 preterm infants with birth weight < 1000 g found that exposure to human milk during hospitalization improves airway obstruction markers tPTEF/tE z-score over the first 2 years of corrected age in a dose-dependent manner.

In-hospital growth and long-term neurodevelopmental outcomes of very low birth weight infants.

Background and Objectives: Very low birth weight infants (VLBW) are at risk for adverse growth and neurodevelopmental outcomes. We aimed to evaluate the association between growth during Neonatal Intensive Care Unit (NICU) stay and long-term neurodevelopmental outcomes in a cohort of preterm VLBW newborns. Methods: We conducted a longitudinal observational study in the Follow-up Service of our Clinic from January 2014 to April 2017. All preterm VLBW infants born at our hospital and enrolled in our follow-up program were considered eligible for the study. The neurodevelopmental assessment was performed using the Griffiths Mental Development Scales at 12 and 24 months corrected age. Results: Study population included 172 subjects (47.1% males) with a mean gestational age of 29 weeks and a mean birth weight of 1,117 g. A unitarian Δz-score increase in head circumference from birth to discharge was associated with a 1.6-point increase in General Quotient at 24 months corrected age. An association with subscales C and D was also found. Likewise, an increase in length Δz-score was associated with better 24-month subscale C scores although not reaching statistical significance. No relationship with the outcome at 24 months was found for weight gain. Conclusions: Growth during NICU stay appears to be related to a more favorable neurodevelopmental outcome at 24 months corrected age, especially in the hearing and language domain (subscale C). The longitudinal evaluation of auxological parameters during hospitalization can contribute to the identification of subjects at risk for adverse neurodevelopmental outcomes in the first years of life.

Chung-Jansen syndrome can mimic Cornelia de Lange syndrome: Another player among chromatinopathies?

Cornelia de Lange syndrome (CdLS) is a rare multisystem congenital neurodevelopmental disorder (NDD) characterized by distinctive facial anomalies, short stature, developmental delay, hirsutism, gastrointestinal abnormalities and upper limb reduction defects. CdLS syndrome is associated with causative variants in genes encoding for the cohesin complex, a cellular machinery involved in chromatid pairing, DNA repair and gene-expression regulation. In this report, we describe a familial case of a syndromic presentation in a 4-year-old patient (P1) and in his mother (P2). Trio-based Whole Exome Sequencing (WES) performed on P1 was first negative. Since his phenotypic evolution during the follow-up was reminiscent of the CdLS spectrum, a reanalysis of WES data, focused on CdLS-related genes, was requested. Although no alterations in those genes was detected, we identified the likely pathogenetic variant c.40G > A (p.Glu14Lys) in the PHIP gene, in the meanwhile associated with Chung-Jansen syndrome. Reverse phenotyping carried out in both patients confirmed the molecular diagnosis. CHUJANS belongs to NDDs, featuring developmental delay, mild-to-moderate intellectual disability, behavioral problems, obesity and facial dysmorphisms. Moreover, as here described, CHUJANS shows a significant overlap with the CdLS spectrum, with specific regard to facial gestalt. On the basis of our findings, we suggest to include PHIP among genes routinely analyzed in patients belonging to the CdLS spectrum.

Postnatal growth of small for gestational age late preterm infants: determinants of catch-up growth.

BACKGROUND: Failure to recover growth is a risk reported in late preterm population. This study aimed to evaluate the auxological outcome of late preterm infants and identify factors associated with failure to recover growth. METHODS: We enrolled late preterm infants with birth weight ≤10th percentile, followed up at High-Risk Infant Follow-up Service. We collected data at birth and at follow-up visits. A logistic regression analysis was performed to assess variables independently associated with growth failure. RESULTS: The population consisted of 175 preterms. The percentage of children showing no weight recovery was 34% at 36 months. At logistic regression analysis, infants who had not regained weight at 12 months had a higher risk of not regaining weight even at 36 months. The same risk factor was highlighted for length catch-up growth. Moreover, infants fed any human milk at discharge were protected from not achieving both weight and length catch-up growth at 36 months. CONCLUSION: These results indicate that children born late preterm and small for gestational age could fail to recover weight and stature growth in the first 36 months. The protective effect of human milk on failure to thrive highlights the importance of promoting breastfeeding in this population. IMPACT: A significant number of SGA late preterms show a failure to recover weight and statural growth. Having experienced intrauterine growth restriction is associated with a greater chance of achieving statural catch-up growth. Being born singleton represents a risk factor for slower weight and height growth velocity. Breastmilk has a protective effect on failure to recover adequate weight and length in preterm SGA infants. This finding highlights the importance of promoting breastfeeding in this population.

Congenital diaphragmatic hernia in Coffin Siris syndrome: Further evidence from two cases.

Coffin-Siris Syndrome (CSS) is a rare multi-system dominant condition with a variable clinical presentation mainly characterized by hypoplasia/aplasia of the nail and/or distal phalanx of the fifth digit, coarse facies, hirsutism/hypertrichosis, developmental delay and intellectual disability of variable degree and growth impairment. Congenital anomalies may include cardiac, genitourinary and central nervous system malformations whereas congenital diaphragmatic hernia (CDH) is rarely reported. The genes usually involved in CSS pathogenesis are ARID1B (most frequently), SMARCA4, SMARCB1, ARID1A, SMARCE1, DPF2, and PHF6. Here, we present two cases of CSS presenting with CDH, for whom Whole Exome Sequencing (WES) identified two distinct de novo heterozygous causative variants, one in ARID1B (case 1) and one in SMARCA4 (case 2). Due to the rarity of CDH in CSS, in both cases the occurrence of CDH did not represent a predictive sign of CSS but, on the other hand, prompted genetic testing before (case 1) or independently (case 2) from the clinical hypothesis of CSS. We provide further evidence of the association between CSS and CDH, reviewed previous cases from literature and discuss possible functional links to related conditions.

Short stature in PRMT7 Mutations: first evidence of response to growth hormone treatment.

Protein arginine methyltransferase 7 (PRMT7) pathogenetic variants have been associated with the human disorder of Short Stature, Brachydactyly, Intellectual Developmental Disability and Seizures syndrome (SBIDDS). Only 15 cases have been described in the literature. Here we report two female dizygotic twins with novel compound heterozygous deleterious variants of PRMT7 and describe the associated endocrine manifestations and short-term response to recombinant growth hormone (rGH) treatment. They were born at 36 + 3 weeks from a dichorionic diamniotic twin pregnancy. Twin A was appropriate for gestational age while Twin B was small for gestational age. Whole exome sequencing analyses showed the same novel compound heterozygous genetic defects in the PRMT7 gene (c.1220 G > A of maternal origin; c.1323 + 2 T > G of paternal origin, Fig. 1). Due to severe short stature and growth impairment, at six years of age, endocrine investigations were performed to rule out growth hormone (GH) deficiency, and revealed GH deficiency (GHD) in Twin A and an appropriate GH response in Twin B. Therefore, both started rGH, albeit at different dosages according to the underlying diagnosis. Both showed a satisfactory short-term response to treatment with height gain (∆HT) of +0.52 SDS (Twin A) and +0.88 SDS (Twin B) during the first year. In conclusion, our findings expand the knowledge about the endocrine manifestations associated with PRMT7 pathogenetic variants, including GH deficiency and rGH response. Further studies are needed to investigate long-term outcomes and establish whether PRMT7 genetic defects can be included among syndromic short stature treatable with rGH.

Case Report: Effect of Targeted Therapy With Carbamazepine in KCNQ2 Neonatal Epilepsy.

We present a family case of neonatal-onset KCNQ2-related epilepsy due to a novel intronic mutation. Three members of an Italian family (father and offspring) presented with neonatal-onset asymmetric tonic and clonic seizures with peculiar video-electroencephalography and aEEG features referring to sequential seizures. The father and the first son underwent standard of care treatments in line with current neonatal intensive care unit protocols, with a prolonged hospitalization before reaching full seizure control with carbamazepine. After the experience acquired with her family and the latest advances in the literature, the younger daughter was directly treated with carbamazepine, obtaining rapid seizure control and short hospitalization. They all had normal development. Carbamazepine is rarely administered as a first-line option in neonatal seizures. Recent evidence suggests that neonatal intensive care unit protocols should implement a trial with sodium channel blockers such as carbamazepine as first-option anti-seizure medication and a fast access to genetic testing in neonates with sequential seizures without structural brain injury or acute causes. Moreover, we report and discuss the laboratory studies performed on a novel causative intronic mutation in KCNQ2 (c.1525+5 G>A in IVS13), since pathogenicity may be difficult to prove for intronic variants.

Effect of human milk and other neonatal variables on lung function at three months corrected age.

OBJECTIVE: To evaluate the impact of human milk and different neonatal variables on tidal breathing flow-volume loop (TBFVL) parameters within three months' corrected age (CA) in infants born ≤32 wks or weighing <1500 g. METHODS: We retrospectively studied 121 infants with gestational age (GA) ≤ 32 weeks or birth weight (BW) <1500 gr who had lung function assessment within three months' CA by TBFVL analysis between June 2009 and April 2018. We investigated the impact of GA, gender, being Small for GA (SGA), sepsis, days of mechanical ventilation (MV) and human milk feeding (HMF) on later respiratory function, both in the entire group and according to BW ( ≤1000 g and >1000 g). RESULTS: The mean(SD) z-score for tidal volume (Vt) and time to peak expiratory flow to expiratory time (tPTEF/tE) were respectively -4.3 (2.5) and -0.8 (2.0) for the overall population with no significant differences between infants <1000 g or ≥1000 g. The mean(SD) Vt standardized for body weight was 6.2(2.0) ml/kg. Being female was associated with better Vt/Kg, whereas longer MV or being born SGA were associated with worst tPTEF/tE. For infants with BW < 1000 gr, tPTEF/tE was positively associated with HMF. CONCLUSION: An early TBFVL assessment within three months' CA already reveals lung function alteration in preterm infants. Being female is associated with better Vt/Kg, while longer duration of MV or being born SGA negatively affect tPTEF/tE. The positive association between HMF and better tPTEF/tE in infants with BW <1000 g has emerged, which deserves further investigation.

NeoAPACHE II. Relationship Between Radiographic Pulmonary Area and Pulmonary Hypertension, Mortality, and Hernia Recurrence in Newborns With CDH.

Congenital diaphragmatic hernia is a rare disease with high mortality and morbidity due to pulmonary hypoplasia and pulmonary hypertension. The aim of the study is to investigate the relationship between radiographic lung area and systolic pulmonary artery pressure (sPAP) on the first day of life, mortality, and hernia recurrence during the first year of life in infants with a congenital diaphragmatic hernia (CDH). A retrospective data collection was performed on 77 CDH newborns. Echocardiographic sPAP value, deaths, and recurrence cases were recorded. Lung area was calculated by tracing the lung's perimeter, excluding mediastinal structures, and herniated organs, on the preoperative chest X-ray performed within 24 h after birth. Logistic and linear regression analyses were performed. Deceased infants showed lower areas and higher sPAP values. One square centimeter of rising in the total, ipsilateral, and contralateral area was associated with a 22, 43, and 24% reduction in mortality risk. sPAP values showed a decreasing trend after birth, with a maximum of 1.84 mmHg reduction per unitary increment in the ipsilateral area at birth. Recurrence patients showed lower areas, with recurrence risk decreasing by 14 and 29% per unit increment of the total and ipsilateral area. In CDH patients, low lung area at birth reflects impaired lung development and defect size, being associated with increased sPAP values, mortality, and recurrence risk. Clinical Trial Registration: The manuscript is an exploratory secondary analysis of the trial registered at ClinicalTrials.gov with identifier NCT04396028.

Mind-mindedness and parenting stress in mothers of preterm and full-term infants: The moderating role of perceived social support.

The goal of this study was to examine the effects of preterm birth and maternal childbirth-related posttraumatic stress and parenting stress on maternal mind-mindedness (MM). The study also investigated the effects of perceived social support on parenting stress and MM. Sixty-five preterm (N = 32) and full-term (N = 33) mother-infant dyads were observed at 6 months. Measures of maternal MM were obtained from observations of mother-infant interaction. Mothers also provided ratings of their posttraumatic stress disorder (PTSD) symptoms, parenting stress, and perceived social support via an online survey. Experiencing a preterm birth did not affect mothers' use of mental state descriptors during mother-infant interaction. Neither childbirth-related posttraumatic stress nor parenting stress directly affected maternal ability to comment on the child's mental states appropriately. However, at medium and high levels of perceived social support, a negative association between parenting stress and MM was observed. Maternal perception of being emotionally supported by significant others promoted MM in mothers showing low or mild levels of parenting stress, but not in mothers experiencing high stress in parenting their infants. Results suggest that a proclivity to MM might be affected by the interaction between parenting stress and social support, rather than by childbirth-related variables, such as prematurity.

El propósito de este estudio fue examinar los efectos del nacimiento prematuro y el estrés materno postraumático relacionado con dar a luz, y el estrés de la crianza sobre la disposición de la mente (MM). El estudio también investigó los efectos que la percepción del apoyo social tiene en el estrés de la crianza y la disposición de la mente. Se observaron 65 díadas de madre-infantes prematuros (N = 32) y de gestación completa (N = 33) a los 6 meses. Las medidas de la disposición mental materna se obtuvieron de observaciones de la interacción madre-infante. Las madres también suministraron los puntajes de sus síntomas de PTSD, el estrés de la crianza y la percepción del apoyo social por medio de una encuesta electrónica. El experimentar un nacimiento prematuro no afectó el uso por parte de las madres de los factores de descripción del estado mental durante la interacción madre-infante. Ni el estrés postraumático relacionado con el dar a luz ni el estrés de la crianza directamente afectaron la habilidad materna para comentar de manera apropiada sobre los estados mentales del niño. Sin embargo, al nivel medio y alto de la percepción de apoyo social, se observó una asociación negativa entre el estrés de crianza y la disposición de la mente. La percepción materna de contar con el apoyo emocional de su pareja promovió la disposición mental de las madres que mostraban bajos o leves niveles de estrés de crianza, aunque no así en aquellas madres que experimentaban un nivel alto de estrés en la crianza de sus infantes. Los resultados sugieren que una propensión a la disposición mental pudiera ser afectada por la interacción entre el estrés de crianza y el apoyo social, en vez de las variables relacionadas con el dar a luz, tal como el nacimiento prematuro.

Le but de cette étude était d'examiner les effets du stress posttraumatique lié à la naissance avant terme et à l'accouchement maternel et le stress de parentage sur l'Etat d'esprit/Orientation mentale (abrégé ici EE/OM). L'étude s'est aussi penchée sur les effets du soutien social perçu du stress de parentage et de l'EE/OM maternel. Soixante-cinq dyades mères-bébés nés avant terme (N = 32) et à plein terme (N = 33) ont été observées à 6 mois. Les mesures d'EE/FM maternel ont été obtenues d'observations de l'interaction mère-bébé. Les mères ont aussi offert des évaluations de leurs propres symptômes ESPT, du stress de parentage, et du soutien social perçu au travers d'un questionnaire en ligne. Le fait d'avoir fait l'expérience d'une naissance avant terme n'a pas affecté l'utilisation de descripteurs de santé mentale des mères durant l'interaction mère-bébé. Ni le stress posttraumatique lié à l'accouchement ni le stress de parentage n'ont affecté directement la capacité maternelle à commenter les états mentaux de l'enfant de manière appropriée. Cependant, à des niveaux moyens et élevés de soutien social perçu, une association négative entre le stress de parentage et l'EE/OM a été observée. La perception maternelle d'être soutenue émotionnellement par leurs partenaires a promu l'EE/FM chez les mères faisant preuve de niveaux bas ou peu élevés de stress de parentage, mais pas chez les mères faisant preuve de stress élevé dans le parentage de leurs bébés. Les résultats suggèrent qu'une tendance à l'EE/OM peut être affectée par l'interaction entre le stress de parentage et le soutien social, plutôt que par des variables liées à l'accouchement, comme la prématurité.

Tidal Breathing Measurements in Former Preterm Infants: A Retrospective Longitudinal Study.

OBJECTIVES: To investigate, in infants born preterm with or without bronchopulmonary dysplasia (BPD), the trajectory of tidal breathing flow-volume (TBFV) parameters in the first 2 years of life; the association between TBFV parameters and perinatal risk factors; and the predictive value of TBFV parameters for rehospitalizations due to respiratory infections and wheeze. STUDY DESIGN: We retrospectively analyzed TBFV measurements performed at 0-6, 6-12, and 12-24 months of corrected age in 97 infants <32 weeks of gestation and <1500 g. We assessed the association between TBFV parameters and perinatal risk-factors using linear regressions and the predictive capacity for subsequent respiratory morbidity using logistic regressions. We used the area under the curve and likelihood ratio test (LRT) to compare nested models. RESULTS: Time to peak tidal expiratory flow/expiratory time ratio (tPTEF/tE) was lower than normal for the first 2 years of corrected age. Longer duration of oxygen supplementation, intubation, and respiratory support were associated with reduced tPTEF/tE at all time points. For each z-score increase in tPTEF/tE, the OR for rehospitalizations decreased by 0.70. tPTEF/tE added significantly to BPD classifications alone in predicting rehospitalizations (area under the receiver operating characteristic curve = 0.81 vs 0.76, P value for LRT = .0012), and wheeze (area under the receiver operating characteristic curve = 0.76 vs 0.71, P value for LRT <.001). CONCLUSIONS: Infants born preterm, with and without BPD, display persistent airway obstruction during the first 2 years of life. tPTEF/tE may identify infants at greater risk of severe respiratory morbidity.

The NeoAPACHE Study Protocol I: Assessment of the Radiographic Pulmonary Area and Long-Term Respiratory Function in Newborns With Congenital Diaphragmatic Hernia.

In newborns with congenital diaphragmatic hernia (CDH), the radiographic lung area is correlated with functional residual capacity (FRC) and represents an alternative method to estimate lung hypoplasia. In a cohort of newborn CDH survivors, we retrospectively evaluated the relationship between radiographic lung area measured on the 1st day of life and long-term respiratory function. As a secondary analysis, we compared radiographic lung areas and respiratory function between patients undergoing fetal endoscopic tracheal occlusion (FETO) and patients managed expectantly (non-FETO). Total, ipsilateral, and contralateral radiographic areas were obtained by tracing lung perimeter as delineated by the diaphragm and rib cage, excluding mediastinal structures and herniated organs. Tidal volume (VT), respiratory rate (RR), and their Z-Scores when compared to the norm were collected from pulmonary function tests (PFTs) performed at 12 ± 6 months of age. Linear regression analyses using the absolute Z-Score values for each parameter were performed. In CDH survivors, an increase in total and ipsilateral lung area measured at birth was related to a reduction in the absolute Z-Score for VT in PFTs (p = 0.046 and p = 0.023, respectively), indicating a trend toward an improvement in pulmonary volumes and VT normalization. Radiographic lung areas were not significantly different between FETO and non-FETO patients, suggesting a volumetric lung increase due to prenatal intervention. However, the mean Z-Score value for RR was significantly higher in the FETO group (p < 0.001), probably due to impaired diaphragmatic motility in the most severe cases. Further analyses are necessary to better characterize the role of the radiographic pulmonary area in the prognostic evaluation of respiratory function in patients with CDH. Clinical Trial Registration: This trial was registered at ClinicalTrials.gov with the identifier NCT04396028.

Is Fetal Endoscopic Tracheal Occlusion (FETO) a Predisposing Factor for Acid Gastro-Esophageal Reflux in Infants With Congenital Diaphragmatic Hernia?

Introduction: Various anatomical defects predispose patients with congenital diaphragmatic hernia (CDH) to develop gastroesophageal reflux disease (GERD). The fetal endoscopic tracheal occlusion (FETO) has increased the survival of patients with severe CDHs. The aim of this study was to study GERD in patients who underwent FETO. Materials and Methods: We included patients with CDH treated with or without FETO ("FETO" and "no-FETO" group, respectively) from 2013 to 2016. Data on gestational age (GA), birth weight (BW), initial observed/expected lung to head ratio (O/E LHR), final O/E LHR, duration of ventilation and hospitalization, maximal tracheal diameter, and pulmonary volume were collected. All patients underwent pH-metry after 1 year of life, and the results were compared between groups and correlated to risk factors. Results: Thirty-two patients were included in the study: 10 FETO and 22 no-FETO. No significant differences were observed in the pH-metric results of the two groups. No correlation was found between GA, BW, initial O/E LHR, maximal tracheal diameter, pulmonary volume, and pH-metric results. pH-metric results were correlated with the total duration of ventilation (R = 0.5, p = 0.003) and of hospitalization (R = 0.54, p = 0.001). Gastric herniation is associated with the worse pH-metric result. Conclusions: The FETO procedure does not seem to represent an independent risk factor for GERD. However, patients with the most severe CDH have the worst GERD.

Neurodevelopmental Outcome and Adaptive Behavior in Preterm Multiples and Singletons at 1 and 2 Years of Corrected Age.

BACKGROUND: Recent literature has investigated the role of multiple birth on neurodevelopmental outcomes of premature infants, especially extremely preterm ones. Multiple gestations are often associated to increased neurodevelopmental disability. Actually, research findings are controversial. OBJECTIVE: To compare the neurodevelopmental and behavioral outcomes of multiples and singletons in a cohort of preterm infants ≤28 weeks gestational age at 1 and 2 years of corrected age. METHODS: The study included 86 infants, born from January 2014 to September 2017 and enrolled in the follow-up program provided at authors' Institution. Exclusion criteria included: major brain lesions and malformations, severe neuro-sensorial deficits, genetic syndromes, single-twin survivors. Thirty four multiples were compared to 52 singletons, using the Griffiths Mental Development Scales and the Child Behavior Checklist 1½-5. Statistical analysis was based on ANOVA techniques to test group differences. A p < 0.05 was considered statistically significant. RESULTS: The neurodevelopmental outcomes of multiples and singletons at 1 and 2 years of corrected age did not significantly differ at a general level (p > 0.05). Multiples showed significantly lower mean scores than singletons at 1 year in Locomotor (87.15 ± 11.94 vs. 92.48 ± 11.59) and Personal-Social (84.88 ± 10.25 vs. 89.63 ± 8.19) subscales. Considering the behavioral outcomes, higher rates of externalizing problems were observed in multiples at 2 years (54.27 ± 9.64 vs. 49.31 ± 10.39). CONCLUSION: The slightly lower neurodevelopmental outcome showed by multiples, especially in the gross-motor and personal-social domains at 1 year, might be related to the specific environmental condition they experience. Multiple birth may affect mother's sensitivity to infant's needs and infant's acquisition of emotional and behavioral regulation. This affects the separation process and the acquisition of the independent walking and other gross-motor skills. Being multiples might also induce an hyperstimulation and this could explain their higher vulnerability to externalizing problems (impulsiveness, hyperactivity, attention deficits). Additionally, males are more affected by the multiple condition than females.

(Epi)genetic profiling of extraembryonic and postnatal tissues from female monozygotic twins discordant for Beckwith-Wiedemann syndrome.

BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder caused by defects at the 11p15.5 imprinted region. Many cases of female monozygotic (MZ) twins discordant for BWS have been reported, but no definitive conclusions have been drawn regarding the link between epigenetic defects, twinning process, and gender. Here, we report a comprehensive characterization and follow-up of female MZ twins discordant for BWS. METHODS: Methylation pattern at 11p15.5 and multilocus methylation disturbance (MLID) profiling were performed by pyrosequencing and MassARRAY in placental/umbilical cord samples and postnatal tissues. Whole-exome sequencing was carried out to identify MLID causative mutations. X-chromosome inactivation (XCI) was determined by HUMARA test. RESULTS: Both twins share KCNQ1OT1:TSS-DMR loss of methylation (LOM) and MLID in blood and the epigenetic defect remained stable in the healthy twin over time. KCNQ1OT1:TSS-DMRLOM was nonhomogeneously distributed in placental samples and the twins showed the same severely skewed XCI pattern. No MLID-causative mutations were identified. CONCLUSION: This is the first report on BWS-discordant twins with methylation analyses extended to extraembryonic tissues. The results suggest that caution is required when attempting prenatal diagnosis in similar cases. Although the causative mechanism underlying LOM remains undiscovered, the XCI pattern and mosaic LOM suggest that both twinning and LOM/MLID occurred after XCI commitment.

A case series of CHARGE syndrome: identification of key features for a neonatal diagnosis.

BACKGROUND: An early diagnosis of CHARGE syndrome is challenging, especially for the primary care physicians who often take care of neonates with multiple congenital anomalies. Here we report eight cases of CHARGE syndrome whose diagnosis was made early in life with the intent to identify the most helpful features allowing a prompt clinical diagnosis. METHODS: Medical records of patients with CHARGE syndrome whose diagnosis was made at the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico in Milan, Italy were retrospectively reviewed. RESULTS: Taken together, these patients reflect the considerable phenotypic variability of the syndrome; in one patient, the diagnosis was made immediately after birth because all the major criteria were met. In six patients, presenting with relatively nonspecific defects, a temporal bone computerized tomography scan was essential to achieve the correct diagnosis. In one patient, the diagnosis was made later than the others were. A careful examination revealed the presence of outer, middle, and inner ear anomalies: these elements, in the absence of any additional major criteria, represented for us an important diagnostic clue. CONCLUSIONS: This article suggests that an accurate evaluation of the ear should be made every time CHARGE syndrome is considered as a likely diagnosis even when the standard criteria are not fulfilled.