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Introduction and objectives Surrogate biomarkers of liver fibrosis developed in tertiary care are increasingly used in general populations. We evaluated the association between liver stiffness (LS) and five continuous (AST/ALT, APRI, Forns Index, FIB-4, GGT) and two discrete biomarkers (BARD, BAAT) in a general population. Patients and methods 636 (29%) of the 2159 citizens of the Bagnacavallo Study had LS measured by transient elastography. Using linear regression with univariate multiple imputation, we evaluated the association of LS with the above biomarkers in the total sample of 2159 citizens. Results The mean change of LS between the 5th and 95th internal percentile of any continuous biomarker was ≤1 kPa. The mean change of LS between scores 0 and 3 of BARD and scores 0 and ≥3 of BAAT was >1 kPa but of doubtful clinical relevance. Conclusion We found a modest association between LS and seven biomarkers of liver fibrosis in a general population.

We present the clinical and follow-up data of a female infant with Perlman syndrome from birth to the age of 9 years. Main features of Perlman syndrome include polyhydramnios, fetal overgrowth, neonatal macrosomia, macrocephaly, dysmorphic facial features, visceromegaly, nephroblastomatosis, and a predisposition for Wilm's tumor. In our patient, the nephromegaly with nephroblastomatosis was not present at birth or during the neonatal period; it became evident in the first months of postnatal life. A Wilm's tumor was diagnosed when she was about 1 year old. Long term follow-up documents the natural history of Perlman syndrome and allows us to establish the long-term prognosis of the affected individuals. © 2005 Wiley-Liss, Inc.

A newnborn admitted to NICU showed a severe clinical profile

Background: The published colorectal cancer (CRC) outcomes after bariatric surgery (BS) are conflicting, with some anecdotal studies reporting increased risks. The present nationwide survey CRIC-ABS 2020 (Colo-Rectal Cancer Incidence-After Bariatric Surgery-2020), endorsed by the Italian Society of Obesity Surgery (SICOB), aims to report its incidence in Italy after BS, comparing the two commonest laparoscopic procedures—Sleeve Gastrectomy (SG) and Roux-en-Y gastric bypass (GBP). Methods: Two online questionnaires—first having 11 questions on SG/GBP frequency with a follow-up of 5–10 years, and the second containing 15 questions on CRC incidence and management, were administered to 53 referral bariatric, high volume centers. A standardized incidence ratio (SIR—a ratio of the observed number of cases to the expected number) with 95% confidence intervals (CI) was calculated along with CRC incidence risk computation for baseline characteristics. Results: Data for 20,571 patients from 34 (63%) centers between 2010 and 2015 were collected, of which 14,431 had SG (70%) and 6140 GBP (30%). 22 patients (0.10%, mean age = 53 ± 12 years, 13 males), SG: 12 and GBP: 10, developed CRC after 4.3 ± 2.3 years. Overall incidence was higher among males for both groups (SG: 0.15% vs 0.05%; GBP: 0.35% vs 0.09%) and the GBP cohort having slightly older patients. The right colon was most affected (n = 13) and SIR categorized/sex had fewer values < 1, except for GBP males (SIR = 1.07). Conclusion: Low CRC incidence after BS at 10 years (0.10%), and no difference between procedures was seen, suggesting that BS does not trigger the neoplasm development.

Introduction In 1973, Petrea Jacobsen described the first patient showing dysmorphic features, developmental delay and congenital heart disease (atrial and ventricular septal defect) associated to a 11q deletion, inherited from the father. Since then, more than 200 patients have been reported, and the chromosomal critical region responsible for this contiguous gene disorder has been identified. Patients’ presentation We report on two unrelated newborns observed in Italy affected by Jacobsen syndrome (JBS, also known as 11q23 deletion). Both patients presented prenatal and postnatal bleeding, growth and developmental delay, craniofacial dysmorphisms, multiple congenital anomalies, and pancytopenia of variable degree. Array comparative genomic hybridization (aCGH) identified a terminal deletion at 11q24.1-q25 of 12.5 Mb and 11 Mb, in Patient 1 and 2, respectively. Fluorescent in situ hybridization (FISH) analysis of the parents documented a de novo origin of the deletion for Patient 1; parents of Patient 2 refused further genetic investigations. Conclusions Present newborns show the full phenotype of JBS including thrombocytopenia, according to their wide 11q deletion size. Bleeding was particularly severe in one of them, leading to a cerebral hemorrhage. Our report highlights the relevance of early diagnosis, genetic counselling and careful management and follow-up of JBS patients, which may avoid severe clinical consequences and lower the mortality risk. It may provide further insights and a better characterization of JBS, suggesting new elements of the genotype-phenotype correlations.

Summary Background Vancomycin is the most widely used antibiotic for neonatal Gram-positive sepsis, but clinical outcome data of dosing strategies are scarce. The NeoVanc programme comprised extensive preclinical studies to inform a randomised controlled trial to assess optimised vancomycin dosing. We compared the efficacy of an optimised regimen to a standard regimen in infants with late onset sepsis that was known or suspected to be caused by Gram-positive microorganisms. Methods NeoVanc was an open-label, multicentre, phase 2b, parallel-group, randomised, non-inferiority trial comparing the efficacy and toxicity of an optimised regimen of vancomycin to a standard regimen in infants aged 90 days or younger. Infants with at least three clinical or laboratory sepsis criteria or confirmed Gram-positive sepsis with at least one clinical or laboratory criterion were enrolled from 22 neonatal intensive care units in Greece, Italy, Estonia, Spain, and the UK. Infants were randomly assigned (1:1) to either the optimised regimen (25 mg/kg loading dose, followed by 15 mg/kg every 12 h or 8 h dependent on postmenstrual age, for 5 ± 1 days) or the standard regimen (no loading dose; 15 mg/kg every 24 h, 12 h, or 8 h dependent on postmenstrual age for 10 ± 2 days). Vancomycin was administered intravenously via 60 min infusion. Group allocation was not masked to local investigators or parents. The primary endpoint was success at the test of cure visit (10 ± 1 days after the end of actual vancomycin therapy) in the per-protocol population, where success was defined as the participant being alive at the test of cure visit, having a successful outcome at the end of actual vancomycin therapy, and not having a clinically or microbiologically significant relapse or new infection requiring antistaphylococcal antibiotics for more than 24 h within 10 days of the end of actual vancomycin therapy. The non-inferiority margin was −10%. Safety was assessed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov ( NCT02790996 ). Findings Between March 3, 2017, and July 29, 2019, 242 infants were randomly assigned to the standard regimen group (n=122) or the optimised regimen group (n=120). Primary outcome data in the per-protocol population were available for 90 infants in the optimised group and 92 in the standard group. 64 (71%) of 90 infants in the optimised group and 73 (79%) of 92 in the standard group had success at test of cure visit; non-inferiority was not confirmed (adjusted risk difference −7% [95% CI −15 to 2]). Incomplete resolution of clinical or laboratory signs after 5 ± 1 days of vancomycin therapy was the main factor contributing to clinical failure in the optimised group. Abnormal hearing test results were recorded in 25 (30%) of 84 infants in the optimised group and 12 (15%) of 79 in the standard group (adjusted risk ratio 1·96 [95% CI 1·07 to 3·59], p=0·030). There were six vancomycin-related adverse events in the optimised group (one serious adverse event) and four in the standard group (two serious adverse events). 11 infants in the intention-to-treat population died (six [6%] of 102 infants in the optimised group and five [5%] of 98 in the standard group). Interpretation In the largest neonatal vancomycin efficacy trial yet conducted, no clear clinical impact of a shorter duration of treatment with a loading dose was demonstrated. The use of the optimised regimen cannot be recommended because a potential hearing safety signal was identified; long-term follow-up is being done. These results emphasise the importance of robust clinical safety assessments of novel antibiotic dosing regimens in infants. Funding EU Seventh Framework Programme for research, technological development and demonstration.

Necrotizing enterocolitis (NEC) is a typical disorder of preterm newborns, with a high mortality and morbidity rate. The therapeutic and nutritional management of disease depends on several factors. Its prognosis is linked, in addition to the severity of the disease and the need for surgery, to a correct enteral feeding in these patients. This study aims to identify the clinical characteristics of 18 patients with NEC, evaluating the different therapeutic paths undertaken, the type of formula used and the survival rate of this population. Average time of enteral nutrition before the NEC onset was 11,3 ± 11,6 days, with an average fasting period since the onset of 24 ± 18.9 days. 77.8% of patients received surgery and resumed enteral nutrition 17.7 ± 17.9 days after the intervention. The overall survival rate of our cohort was 55.5%. More prospective studies are needed to evaluate the long-term outcomes of survived children with NEC.

SARS-COV-2 is a severe medical condition. Old patients are very vulnerable, but they have been studied only as institutionalized patients. During the lock-down, little attention is dedicated to old, demented patients who lived at home. This study wants to examine their behavioral reactions by video-phone follow-up. We conducted a longitudinal study in subcortical vascular dementia (sVAD) patients. We enrolled 221 sVAD, not institutionalized patients. We divided sVAD patients into low-medium grade sVAD (A) and severe sVAD (B), based on neuroimaging severity degree and executive alterations. At baseline, at the end of lock-down, and two months later, global behavioral symptoms were recorded for each patient. We found significantly higher scores of general behavioral deterioration, anxiety, delusions, hallucinations and apathy after controlling for sVAD severity. The direct consequence was a drastic increment of psychotropic drugs prescribed and employed during the lock-down. Moreover, caregivers’ stress has been evaluated, together with their anxiety and depression levels. During the lock-down, their scores increased and reflected a severe worsening of their behavior. Our data demonstrate that social isolation induces a severe perception of loneliness and abandonment, these fears can exacerbate behavior disturbances in old-aged frail persons. Thus, these can be considered as indirect victims of SARS-COV-2.

Objective: The aim of this study was to characterize the liver involvement in infants who have both neonatal asphyxia and neonatal cholestasis. Methods: We describe four asphyctic newborn infants (three born at term) who developed early (age 3.8 ± 2.1 days) intrahepatic neonatal cholestasis and in whom tests for causes of neonatal liver damage were negative. Results: The clinical picture and course were benign and similar to that of sporadic 'idiopathic' neonatal hepatitis. Clinical signs and abnormal liver function tests tended to normalize within the first year of life in all. Conjugated bilirubin became normal at 6 months after the onset of cholestasis, while liver enzymes tended towards normal values thereafter, within 1 year of follow-up. Liver biopsy (taken in one patient) showed a typical picture of giant cell hepatitis; ultrastructure was non-specific. Significance: Our results suggest that isolated asphyxia should be taken into account as a potential causal factor in term or pre-term asphyctic newborns who develop early 'idiopathic' neonatal cholestasis.

In this paper we describe an additional newborn patient with craniofacial dysmorphisms, congenital heart disease, hypotonia and a 2q13 deletion of 1.7 Mb, whose clinical and genomic findings are consistent with the diagnosis of 2q13 microdeletion syndrome.

Objective Methemoglobinemia (MetHb) is a rare congenital or acquired cause of infantile cyanosis. We examined the role of MetHb in a neonatal intensive care unit (NICU). Study Design A retrospective observational study was conducted reviewing blood gas analyses of hospitalized newborns over a 2-year period. MetHb-positive patients (MetHb >1.8%) were matched with a control group for gestational age, weight, disease, and illness severity at admission. Maternal, neonatal, clinical, and laboratory parameters were collected and analyzed in both groups. Results MetHb incidence was 6%. The mean MetHb in the case group was 7.2%, and the first positive samples were observed at a mean of 22 days of life, 6 days prior to clinical or culture-proven sepsis. We identified low maternal age (31 vs. 34 years; p = 0.038), sepsis (90 vs. 45%; p = 0.022), and protracted parenteral nutrition (46 vs. 23 days; p = 0.013) as risk factors for MetHb, and early minimal enteral feeding as protective factor (12th vs. 9th day; p = 0.038). Conclusion MetHb has a high occurrence in NICU and can be a helpful prognostic indicator of an infectious process. Understanding and prompt identification of MetHb can allow pediatricians to implement a life-saving therapy.

BackgroundAntimicrobial resistance in neonatal intensive care unit (NICU) patients is a threat, due to the frequent use of antimicrobial treatment and invasive devices in fragile babies. Since 2014 an active surveillance program of multidrug-resistant Gram-negative bacteria (MDR-GNB) carriage has been in place in the five NICUs of Palermo, Italy. In 2017 an increase in the prevalence of MDR-GNB, and in particular of extended-spectrum β-lactamases-producingKlebsiella pneumoniae(ESBL-KP), was observed in “Civico” hospital NICU.AimTo assess the impact of a coordinated intervention strategy in achieving long-lasting reduction of MDR-GNB prevalence in the NICU.MethodsRectal swabs were obtained monthly and processed to detect MDR-GNB using standard methods. MDR-GNB were characterized by pulsed-field gel electrophoresis (PFGE). Since November 2017 the following intervention measures were applied: (a) two-months intensification of sample collection; (b) stakeholders meetings; (c) improvement of prevention measures and antimicrobial policies.FindingsDuring the intensified microbiological surveillance MDR-GNB and ESBL-KP were detected in rectal swabs (34.8%; 23.2%), nasal swabs (24.6%; 14.5%), oral swabs (14.5%; 5.4%), milk samples (32.1%; 17.9%), pacifiers swabs (30.8%; 17.9%) and from sub-intensive room surfaces. Thirteen ESBL-KP strains isolated from clinical and environmental samples showed identical PFGE patterns. The prevalence of MDR-GNB and ESBL-KP carriage significantly decreased in the year after intervention compared to the previous year (20.6% vs 62.2%;p p p ConclusionsMDR-GNB broadly circulate in NICU setting, they can colonize different body sites and spread through various vehicles. A coordinated strategy of multiple interventions with active cooperation between epidemiologists and clinicians in the NICU can effectively reduce their circulation and in particular the carriage of the most dangerous ESBL-KP strains.

Infections represent a serious health problem in neonates. Invasive Candida infections (ICIs) are still a leading cause of mortality and morbidity in neonatal intensive care units (NICUs). Infants hospitalized in NICUs are at high risk of ICIs, because of several risk factors: broad spectrum antibiotic treatments, central catheters and other invasive devices, fungal colonization, and impaired immune responses. In this review we summarize 19 published studies which provide the prevalence of previous surgery in neonates with invasive Candida infections. We also provide an overview of risk factors for ICIs after major surgery, fungal colonization, and innate defense mechanisms against fungi, as well as the roles of different Candida spp., the epidemiology and costs of ICIs, diagnosis of ICIs, and antifungal prophylaxis and treatment.

Background Genetic diseases are chronic conditions with relevant impact on the lives of patients and their families. In USA and Europe it is estimated a prevalence of 60 million affected subjects, 75% of whom are in developmental age. A significant number of newborns are admitted in the Neonatal Intensive Care Units (NICU) for reasons different from prematurity, although the prevalence of those with genetic diseases is unknown. It is, then, common for the neonatologist to start a diagnostic process on suspicion of a genetic disease or malformation syndrome, or to make and communicate these diagnoses. Many surveys showed that the degree of parental satisfaction with the methods of communication of diagnosis is low. Poor communication may have short and long-term negative effects on health and psychological and social development of the child and his family. We draw up recommendations on this issue, shared by 6 Italian Scientific Societies and 4 Parents’ Associations, aimed at making the neonatologist’s task easier at the difficult time of communication to parents of a genetic disease/malformation syndrome diagnosis for their child. Methods We used the method of the consensus paper. A multidisciplinary panel of experts was first established, based on the clinical and scientific sharing of the thematic area of present recommendations. They were suggested by the Boards of the six Scientific Societies that joined the initiative: Italian Societies of Pediatrics, Neonatology, Human Genetics, Perinatal Medicine, Obstetric and Gynecological Ultrasound and Biophysical Methodologies, and Pediatric Genetic Diseases and Congenital Disabilities. To obtain a deeper and global vision of the communication process, and to reach a better clinical management of patients and their families, representatives of four Parents’ Associations were also recruited: Italian Association of Down People, Cornelia de Lange National Volunteer Association, Italian Federation of Rare Diseases, and Williams Syndrome People Association. They worked from September 2019 to November 2020 to achieve a consensus on the recommendations for the communication of a new diagnosis of genetic disease. Results The consensus of experts drafted a final document defining the recommendations, for the neonatologist and/or the pediatrician working in a fist level birthing center, on the first communication of genetic disease or malformation syndrome diagnosis. Although there is no universal communication technique to make the informative process effective, we tried to identify a few relevant strategic principles that the neonatologist/pediatrician may use in the relationship with the family. We also summarized basic principles and significant aspects relating to the modalities of interaction with families in a table, in order to create an easy tool for the neonatologist to be applied in the daily care practice. We finally obtained an intersociety document, now published on the websites of the Scientific Societies involved. Conclusions The neonatologist/pediatrician is often the first to observe complex syndromic pictures, not always identified before birth, although today more frequently prenatally diagnosed. It is necessary for him to know the aspects of genetic diseases related to communication and bioethics, as well as the biological and clinical ones, which together outline the cornerstones of the multidisciplinary care of these patients. This consensus provide practical recommendations on how to make the first communication of a genetic disease /malformation syndrome diagnosis. The proposed goal is to make easier the informative process, and to implement the best practices in the relationship with the family. A better doctor-patient/family interaction may improve health outcomes of the child and his family, as well as reduce legal disputes with parents and the phenomenon of defensive medicine.

In late December 2019, a novel coronavirus (lately referred to as SARS-CoV-2) spread in the city of Wuhan, China, causing an outbreak of unusual viral pneumonia. In many people, the disease is mild and self-limiting, but in a considerable number of patients, the disease may present more severe or even fatal. Therefore, determining which patients are at higher risk of developing a more severe disease is critical. Some studies have been focused on serum and fecal calprotectin to evaluate COVID-19 disease progression and possible complications. Some assumptions can be made: (1) serum calprotectin may efficiently predict the prognosis of COVID-19 patients; (2) fecal calprotectin may appear high in COVID-19 patients due to the double hit mechanism to the intestine (inflammatory and ischemic); (3) a relationship between the complement system and neutrophil activation contributes to the procoagulant status seen in COVID-19 patients; (4) some patients may develop severe gastro-intestinal complications and fecal calprotectin can be used to monitor intestinal disease activity levels.

INTRODUCTION: Since the beginning of the 2020 Sars-CoV-2 Italian outbreak, healthcare workers have been among the most exposed categories. There is little information about community pharmacists' on occupational exposure, symptoms development, and testing practices in the community pharmacist cohort. METHODS: Between April 30th and May 10th, a questionnaire was administered through social media to Italian community pharmacists. From 67000 pharmacists currently working in community pharmacies, 1632 answered the survey. RESULTS: The survey population reflected the general Italian community pharmacists population in terms of age, gender, and number of co-workers. Protective measures were adopted in up to 99.9% of pharmacies. 624 pharmacists (38.2%) developed at least one COVID-19 related symptom in the period between February 28th and May 10th. Also, 102 pharmacists (6.2%) were tested for COVID-19 and 15, the 15% of the tested population and 0.92% of the whole survey population, resulted positive on nasopharyngeal swab. However, while the number of symptomatic pharmacists decreased, a higher number of tests were performed, thus COVID-19 prevalence among community pharmacists could have been underestimated and is probably intermediate between other healthcare workers and the general population (0.31%). CONCLUSION: Community pharmacists have probably been one of the first categories to experience increased contact risk to SARS-CoV-2. COVID-19 prevalence among pharmacists could have been underestimated. In addition, the rates of protection measures adoption might have helped to reduce the spread of COVID-19 among co-workers and the community.

Objective To describe a case of thrombophlebitis associated with Candida infection and to analyze other published reports to define clinical characteristics, prognostic data, diagnostic and therapeutic strategies. Study design A computerized search was performed without language restriction using PubMed and Scopus databases. An article was considered eligible for inclusion if it reported cases with Candida thrombophlebitis. Our case was also included in the analysis. Results A total of 16 articles reporting 27 cases of Candida thrombophlebitis were included in our review. The median age of patients was 4 years. In 10 cases there was a thrombophlebitis of peripheral veins; in the remaining cases the deep venous circle was interested. Candida albicans was the most frequently involved fungal species. The most recurrent risk factors were central venous catheter (19/28), broad spectrum antibiotics (17/28), intensive care unit (8/28), surgery (3/28), mechanical assisted ventilation (5/28), total parenteral nutrition (8/28), cancer (2/28), premature birth (6/28), cystic fibrosis (2/28). Fever was the most frequent clinical feature. All children with peripheral and deep thrombophlebitis were given antifungal therapy: amphotericin B was the most used, alone or in combination with other antifungal drugs. Heparin was most frequently used as anticoagulant therapy. Illness was fatal in two cases. Conclusion Candida thrombophlebitis is a rare but likely underdiagnosed infectious complication in pediatric critically ill patients. It is closely connected to risk factors such as central venous catheter, hospitalization in intensive care unit, prematurity, assisted ventilation, chronic inflammatory diseases. Antifungal therapy and anticoagulant drugs should be optimized for each patient and surgical resection is considered in the persistence of illness.

Introduction Autosomal recessive polycystic kidney disease (ARPKD; MIM#263200) is one of the most frequent pediatric renal cystic diseases, with an incidence of 1:20,000. It is caused by mutations of the PKHD1 gene, on chromosome 6p12. The clinical spectrum is highly variable, ranging from late-onset milder forms to severe perinatal manifestations. The management of newborns with severe pulmonary insufficiency is challenging, and causes of early death are sepsis or respiratory failure. In cases of massive renal enlargement, early bilateral nephrectomy and peritoneal dialysis may reduce infant mortality. However, there is no conclusive data on the role of surgery, and decision-making is driven by patient’s clinical condition and expertise of the center. Patient presentation We hereby describe a preterm female newborn with perinatal, rapid and bilateral, abnormal growth of both kidneys, respiratory failure and initial signs of liver disease. She was subsequently confirmed to be affected by a rare and severe homozygous mutation of the PKHD1 gene, inherited from both her consanguineous parents. Our patient died 78 days after birth, due to a fungal sepsis which worsened her respiratory insufficiency. Conclusions This patient report shows some of the clinical and ethical issues of neonatal ARPKD, and the need of multidisciplinary approach and good communication with the family. Target next generation sequencing (NGS) techniques may guide and support clinicians, as well as guarantee to these patients the most appropriate clinical management, avoiding unnecessary and/or disproportionate treatments.

Background Persistent neonatal hypoglycemia, owing to the possibility of severe neurodevelopmental consequences, is a leading cause of neonatal care admission. Hyperinsulinemic hypoglycemia is often resistant to dextrose infusion and needs rapid diagnosis and treatment. Several congenital conditions, from single gene defects to genetic syndromes should be considered in the diagnostic approach. Kabuki syndrome type 1 (MIM# 147920) and Kabuki syndrome type 2 (MIM# 300867), can be associated with neonatal hyperinsulinemic hypoglycemia. Patient presentation We report a female Italian (Sicilian) child, born preterm at 35 weeks gestation, with persistent hypoglycemia. Peculiar facial dysmorphisms, neonatal hypotonia, and cerebellar vermis hypoplasia raised suspicion of Kabuki syndrome. Hyperinsulinemic hypoglycemia was confirmed with glucagon test and whole-exome sequencing (WES) found a novel heterozygous splicing-site mutation (c.674-1G > A) in KMT2D gene. Hyperinsulinemic hypoglycemia was successfully treated with diazoxide. At 3 months corrected age for prematurity, a mild global neurodevelopmental delay, postnatal weight and occipitofrontal circumference growth failure were reported. Conclusions Kabuki syndrome should be considered when facing neonatal persistent hypoglycemia. Diazoxide may help to improve hyperinsulinemic hypoglycemia. A multidisciplinary and individualized follow-up should be carried out for early diagnosis and treatment of severe pathological associated conditions.

Sarcopenia is an increasingly frequent syndrome characterized by generalized and progressive loss of muscle mass, reduction in muscle strength, and resultant functional impairment. This condition is associated with increased risk of falls and fractures, disability, and increased risk of death. When a sarcopenic patient undergoes major surgery, it has a higher risk of complications and postoperative mortality because of less resistance to surgical stress. It is not easy to recognize a sarcopenic patient preoperatively, but this is essential to evaluate the correct risk to benefit ratio. The role of sarcopenia in surgical patients has been studied for both oncological and non-oncological surgery. For correct surgical planning, data about sarcopenia are essential to design a correct tailored treatment.

Background Mitochondrial diseases, also known as oxidative phosphorylation (OXPHOS) disorders, with a prevalence rate of 1:5000, are the most frequent inherited metabolic diseases. Leigh Syndrome French Canadian type (LSFC), is caused by mutations in the nuclear gene (2p16) leucine-rich pentatricopeptide repeat-containing (LRPPRC). It is an autosomal recessive neurogenetic OXPHOS disorder, phenotypically distinct from other types of Leigh syndrome, with a carrier frequency up to 1:23 and an incidence of 1:2063 in the Saguenay-Lac-St Jean region of Quebec. Recently, LSFC has also been reported outside the French-Canadian population. Patient presentation We report a male Italian (Sicilian) child, born preterm at 28 + 6/7 weeks gestation, carrying a novel LRPPRC compound heterozygous mutation, with facial dysmorphisms, neonatal hypotonia, non-epileptic paroxysmal motor phenomena, and absent sucking-swallowing-breathing coordination requiring, at 4.5 months, a percutaneous endoscopic gastrostomy tube placement. At 5 months brain Magnetic Resonance Imaging showed diffuse cortical atrophy, hypoplasia of corpus callosum, cerebellar vermis hypoplasia, and unfolded hippocampi. Both auditory and visual evoked potentials were pathological. In the following months Video EEG confirmed the persistence of sporadic non epileptic motor phenomena. No episode of metabolic decompensation, acidosis or ketosis, frequently observed in LSFC has been reported. Actually, aged 14 months corrected age for prematurity, the child shows a severe global developmental delay. Metabolic investigations and array Comparative Genomic Hybridization (aCGH) results were normal. Whole-genome sequencing (WGS) found a compound heterozygous mutation in the LRPPRC gene, c.1921–7A > G and c.2056A > G (p.Ile686Val), splicing-site and missense variants, inherited from the mother and the father, respectively. Conclusions We first characterized the clinical and molecular features of a novel LRPPRC variant in a male Sicilian child with early onset encephalopathy and psychomotor impairment. Our patient showed a phenotype characterized by a severe neurodevelopmental delay and absence of metabolic decompensation attributable to a probable residual enzymatic activity. LRPPRC is a rare cause of metabolic encephalopathy outside of Québec. Our patient adds to and broaden the spectrum of LSFC phenotypes. WGS analysis is a pivotal genetic test and should be performed in infants and children with hypotonia and developmental delay in whom metabolic investigations and aCGH are normal.

Background Aplasia cutis congenita (ACC), classified in nine groups, is likely to be underreported, since milder isolated lesions in wellbeing newborns could often be undetected, and solitary lesions in the context of polymalformative syndromes could not always be reported. Regardless of form and cause, therapeutic options have in common the aim to restore the deficient mechanical and immunological cutaneous protection and to limit the risk of fluid leakage or rupture of the exposed organs. We aimed to review our institutional prevalence, comorbidities, treatment and outcome of newborns with ACC. Methods We conducted a retrospective study including all newborns affected by ACC and admitted at the University Mother-Child Department from October 2010 to October 2019. Anthropometric and clinical characteristics of ACC1 versus a non-isolated ACC group were analyzed. Results We encountered 37 newborns, 16 with ACC1 versus 21 with non-isolated ACC. The incidence rate of 0.1% in ACC1 was higher than expected, while 19% of cases showed intrafamilial autosomal dominant transmission. Higher birth weight centile, though lower than reference population, being adequate for gestational age, normal Apgar score and euglycemia characterizing ACC1 resulted associated to a rapid tissue regeneration. Non-isolated ACC, in relation to concomitant congenital anomalies and higher prematurity rate, showed more surgical and medical complications along with the risk of neonatal death. Specifically, newborns with ACC4 were characterized by the frequent necessity of abdominal wall defect repair, responsible for the occurrence of an abdominal compartment syndrome. Conclusion Prompt carefully assessment of the newborn with ACC in order to exclude concomitant other congenital malformations, provides clues to the underlying pathophysiology, and to the short-term prognosis. Family should be oriented toward identification of other family members affected by similar pathology, while obstetric history should exclude initial multiple pregnancy with death of a co-twin, placental anomalies and drug assumption. Molecular-genetic diagnosis and genetic counseling are integrative in individualized disease approach.

Objective: This study aimed to investigate clinical, surgical, and genetic data of neonates with anorectal malformation (ARM). Study design: A retrospective observational study was conducted on neonates with ARM as an isolated type (group 1), with ≤2 (group 2), and with ≥3 associated malformations (group 3), born between 2009 and 2020. Distribution of ARM, associated abnormalities and genetic testing were analyzed, and risk factors for adverse outcomes were identified. Results: The 45 ARM cases (36% females) were divided as follows: 13 neonates belonging to group 1 (29%), 8 to group 2 (18%), and 24 to group 3 (53%). Cases were equally distributed over 11years. Krickenbeck anatomy was: without fistula/imperforate anus (18%), perineal fistula (36%), rectourethral fistula (4%), rectovesical fistula (2%), vestibular fistula (4%), cloaca (4%), and rare ARMs (31%). Groups showed differences in anthropometric data, Krickenbeck anatomy, and intensive care burden. Additional major congenital abnormalities were prevalent specific of VATER/VACTERL spectrum (vertebral/anorectal/cardiac/tracheoesophageal/renal/limb defects), but also Hirschsprung disease was found in 3/20 biopsies (15%). The most frequent minor abnormality was a single umbilical artery. In group 3, we identified four de novo microdeletions at 8p23.2, 8q13.3, Xp22.31–p22.2, Xq28, four de novo microduplications at 1p36.32, 6p24.1–p23, 13q14.11, 15q11.2, one microdeletion at 9q33.1 inherited from the affected mother, one microdeletion at 7q35 inherited from the unaffected father, one structurally uncharacterized rearrangement involving 9p23–q34.3. Thus, we attributed the Xq28 deletion with inactivated FAM58A gene in one girl to the X-linked dominant STAR syndrome (toe syndactyly-telecanthus-anogenital/renal malformations). Conclusions: Despite the great physical and social burden on ARM patients and their parents, in the majority of cases, the etiology is largely unknown and attributed to be multifactorial. In females, STAR syndrome should be part of the differential diagnosis. Associated malformations of other organ systems interact in outcome parameters.

Background and Aims: T helper 17 [Th17] cells are crucially involved in the immunopathogenesis of inflammatory bowel diseases in humans. Nevertheless, pharmacological blockade of interleukin 17A [IL17A], the Th17 signature cytokine, yielded negative results in patients with Crohn's disease [CD], and attempts to elucidate the determinants of Th17 cells' pathogenicity in the gut have so far proved unsuccessful. Here, we aimed to identify and functionally validate the pathogenic determinants of intestinal IL-17-producing T cells. Methods: In vivo-generated murine intestinal IL-17-producing T cells were adoptively transferred into immunodeficient Rag1-/-recipients to test their pathogenicity. Human IL-17, IFN gamma/IL-17, and IFN gamma actively secreting T cell clones were generated from lamina propria lymphocytes of CD patients. The pathogenic activity of intestinal IL-17-producing T cells against the intestinal epithelium was evaluated. Results: IL-17-producing cells with variable colitogenic activity can be generated in vivo using different experimental colitis models. The pathogenicity of IL-17-secreting cells was directly dependent on their IFN gamma secretion capacity, as demonstrated by the reduced colitogenic activity of IL-17-secreting cells isolated from IFN gamma(-/-) mice. Moreover, IFN gamma production is a distinguished attribute of CD-derived lamina propria Th17 cells. IFN gamma secretion by CD-derived IL-17-producing intestinal clones is directly implicated in the epithelial barrier disruption through the modulation of tight junction proteins. Conclusions: Intestinal Th17 cell pathogenicity is associated with IFN gamma production, which directly affects intestinal permeability through the disruption of epithelial tight junctions.

Introduction and Objectives: This study aims to measure the values of spleen stiffness (SS) in healthy subjects, the inter-operator agreement in SS measurement, and to detect statistically significant correlations between SS and age, sex, weight, BMI, portal vein dynamics and splenic dimensions. Materials and methods: The study included 100 healthy volunteers who had no substantial alcohol intake (

Background: Cytomegalovirus is the most common cause of congenital infection in the developed countries. Gastrointestinal involvement has been extensively described in both adult and paediatric immunocompromised patients but it is infrequent in congenital or perinatal CMV infection. Case presentation: We report on a case of coexistent congenital Cytomegalovirus infection with intestinal malrotation and positive intestinal Cytomegalovirus biopsy. At birth the neonate showed clinical and radiological evidence of intestinal obstruction. Meconium passed only after evacuative nursing procedures; stooling pattern was irregular; gastric residuals were bile-stained. Laparatomy revealed a complete intestinal malrotation and contextually gastrointestinal biopsy samples of the appendix confirmed the diagnosis of CMV gastrointestinal disease. Intravenous ganciclovir was initiated for 2 weeks, followed by oral valgancyclovir for 6 month. Conclusion: CMV-induced proinflammatory process may be responsible of the interruption of the normal development of the gut or could in turn lead to a disruption in the normal development of the gut potentiating the mechanism causing malrotation. We suggest the hypothesis that an inflammatory process induced by CMV congenital infection may be responsible, in the early gestation, of the intestinal end-organ disease, as the intestinal malrotation. CMV infection should always be excluded in full-term infants presenting with colonic stricture or malrotation.

Background Neonatal units’ volume of activity, and other quantitative and qualitative variables, such as staffing, workload, work environment, care organization and geographical location, may influence the outcome of high risk newborns. Data about the distribution of these variables and their relationships among Italian neonatal units are lacking. Methods Between March 2010-April 2011, 63 neonatal intensive care units adhering to the Italian Neonatal Network participated in the SONAR Nurse study. Their main features and work environment were investigated by questionnaires compiled by the chief and by physicians and nurses of each unit. Twelve cross-sectional monthly-repeated surveys on different shifts were performed, collecting data on number of nurses on duty and number and acuity of hospitalized infants. Results Six hundred forty five physicians and 1601 nurses compiled the questionnaires. In the cross-sectional surveys 702 reports were collected, with 11082 infant and 3226 nurse data points. A high variability was found for units’ size (4–50 total beds), daily number of patients (median 14.5, range 3.4-48.7), number of nurses per shift (median 4.2, range 0.7-10.8) and number of team meetings per month. Northern regions performed better than Central and Southern regions for frequency of training meetings, qualitative assessment of performance, motivation within the unit and nursing work environment; mean physicians’ and nurses’ age increased moving from North to South. After stratification by terciles of the mean daily number of patients, the median number of nurses per shift increased at increasing volume of activity, while the opposite was found for the nurse-to-patient ratio adjusted by patients’ acuity. On average, in units belonging to the lower tercile there was 1 nurse every 2.5 patients, while in those belonging to the higher tercile the ratio was 1 nurse every 5 patients. Conclusions In Italy, there is a high variability in organizational characteristics and work environment among neonatal units and an uneven distribution of human resources in relation to volume of activity, suggesting that the larger the unit the greater the workload for each nurse. Urgent modifications in planning and organization of services are needed in order to pursue more efficient, homogeneous and integrated regionalized neonatal care systems.

Background: Respiratory support in very preterm infants is often a life-saving procedure and several techniques are available. There is lack of data on the current use of these techniques. Methods and aim: We analyzed a cohort of infants

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

Pulsus alternans was observed in a child with left ventricular dysfunction secondary to systemic hypertension. The Echo-Doppler of supravalvular aorta and a simultaneous electrocardiographic trace (ECG) clearly demonstrated the mechanism of an apparent abrupt halving of pulse frequency compared with the ECG, similar to an electromechanical dissociation 2: 1. Besides the extreme pulsus alternans, a P wave and a PP cycle length change were also observed. Both mechanical and electrical alternans disappeared with afterload reduction by nitroprusside treatment.

OBJECTIVES: We compared the relative effect of hypertensive disorders of pregnancy and chorioamnionitis on adverse neonatal outcomes in very preterm neonates, and studied whether gestational age (GA) modulates these effects. METHODS: A cohort of neonates 23 to 30 weeks' GA, born in 2008 to 2011 in 82 hospitals adhering to the Italian Neonatal Network, was analyzed. Infants born from mothers who had hypertensive disorders (N = 2096) were compared with those born after chorioamnionitis (N = 1510). Statistical analysis employed logistic models, adjusting for GA, hospital, and potential confounders. RESULTS: Overall mortality was higher after hypertension than after chorioamnionitis (odds ratio [OR], 1.39; 95% confidence interval [CI], 1.08–1.80), but this relationship changed across GA weeks; the OR for hypertension was highest at low GA, whereas from 28 weeks' GA onward, mortality was higher for chorioamnionitis. For other outcomes, the relative risks were constant across GA; infants born after hypertension had an increased risk for bronchopulmonary dysplasia (OR, 2.20; 95% CI, 1.68–2.88) and severe retinopathy of prematurity (OR, 1.48; 95% CI, 1.02–2.15), whereas there was a lower risk for early-onset sepsis (OR, 0.25; 95% CI, 0.19–0.34), severe intraventricular hemorrhage (OR, 0.65; 95% CI, 0.48–0.88), periventricular leukomalacia (OR, 0.70; 95% CI, 0.48–1.01), and surgical necrotizing enterocolitis or gastrointestinal perforation (OR, 0.47; 95% CI, 0.31–0.72). CONCLUSIONS: Mortality and other adverse outcomes in very preterm infants depend on antecedents of preterm birth. Hypertension and chorioamnionitis are associated with different patterns of outcomes; for mortality, the effect changes across GA weeks.

The purpose of the present study was to assess the presence and the time-course of contrast-enhancement in the pituitary gland and pituitary stalk of 24 patients with isolated growth hormone (GH) deficiency and multiple pituitary hormone deficiency. The patients were evaluated clinically (auxological measurements), endocrinologically (spontaneous GH secretion and GH stimulation tests) and with conventional MRI scans. In addition, fast-framing dynamic magnetic resonance imaging (MRI) with Gd-DTPA enhancement was used to quantitate the time course of contrast enhancement within the neurohypophysis, pituitary stalk, postero-superior adenohypophysis and antero-inferior adenohypophysis. In 3 patients without evidence of abnormalities at normal conventional MRI scans (normal anterior lobe and pituitary stalk, normal posterior lobe) and a high response to the GRF provocation test, sequential time-resolved Gd-enhanced MRI demonstrates reduced contrast enhancement in the pituitary stalk. These findings are consistent with impairment in stalk vasculature, presumably located at the level of the portal venous system, and could play a role in the pathogenesis of pituitary hormonal deficiency.

Sotos syndrome is included among the overgrowth disorders, most of which have an increased risk of neoplasms. Sotos syndrome does not appear to be related to a specific tumor type, but rather to the development of solid tumors of ectodermal or mesodermal origin in general. We report on two Sotos syndrome patients who developed a non-Hodgkin lymphoma and an acute lymphoblastic leukaemia, respectively. Our experience suggests that there may exist a high frequency of lymphoproliferative disorders in Sotos syndrome, and points out the importance of a long-term follow-up of Sotos syndrome patients, to detect a possible neoplastic evolution. ©1996 Wiley-Liss, Inc.

Background Hypospadias is a congenital displacement of the urethral meatus in male newborns, being either an isolated defect at birth or a sign of sexual development disorders. The aim of this study was to assess the prevalence rate of hypospadias in different Districts of Italy, in order to make a comparison with other countries all over the world. Methods We reviewed all the newborns file records (years 2001–2004) in 15 Italian Hospitals. Results We found an overall hypospadias prevalence rate of 3.066 ± 0.99 per 1000 live births (82.48% mild hypospadias, 17.52% moderate-severe). In newborns Small for Gestational Age (birthweight < 10th percentile) of any gestational age the prevalence rate of hypospadias was 6.25 per 1000 live births. Performing multivariate logistic regression analysis for different degrees of hypospadias according to severity, being born SGA remained the only risk factor for moderate-severe hypospadias (p = 0.00898) but not for mild forms (p > 0.1). Conclusion In our sample the prevalence of hypospadias results as high as reported in previous European and American studies (3–4 per 1000 live births). Pathogenesis of isolated hypospadias is multifactorial (genetic, endocrine and environmental factors): however, the prevalence rate of hypospadias is higher in infants born small for gestational age than in newborns with normal birth weight.

Prenatal exposure to antiepileptic drugs (AEDs) increases the risk of major congenital malformations (MCM) in the fetus. AED-related abnormalities include heart and neural tube defects, cleft palate, and urogenital abnormalities. Among the various congenital anomalies of the kidney and urinary tract (CAKUT), multicystic dysplastic kidney (MCDK) disease is one of the most severe expressions. Although prenatal ultrasound (US) examination has increased the prenatal diagnosis of MCDK, the pathogenesis is still unclear. We report on four cases of MCDK in infants of epileptic women treated with AEDs during pregnancy. From October 2003 to June 2006, we observed four infants with unilateral MCDK born to epileptic women. Three patients were considered to have typical features of multicystic dysplastic kidney, and one infant was operated because of a cystic pelvic mass in the absence of a kidney in the left flank. The macroscopic appearance of this mass showed an ectopic multicystic kidney confirmed by histological findings. All patients have been studied by US scans, voiding cystourethrogram (VCUG), and radionuclide screening isotope imaging. The prenatal exposure to AEDs increases the risk of major congenital malformations from the background risk of 1-2% to 4-9%. AEDs may determine a defect in apoptosis regulation that could lead to abnormal nephrogenesis, causing MCDK. Carbamazepine (CBZ) and phenobarbital (PHB) during pregnancy should be used at the lowest dosage compatible with maternal disease. The reduction, or even suspension, of drug dosage should be achieved from the periconceptional period to the first 8 weeks of gestation to avoid any interference with organogenesis.

A newborn with an unusual association of hepatic mesenchymal hamartoma and mesenchymal stem villous hyperplasia of the placenta is presented. At birth, the large hepatic mass caused severe respiratory distress necessitating early surgical intervention. This report on the association of hepatic mesenchymal hamartoma and mesenchymal stem villous hyperplasia of the placenta strongly suggests a common pathogenetic origin of the 2 lesions.

Background In Down syndrome there is an increased prevalence of coeliac disease, but the reasons for this association are yet unknown. Aims To evaluate a possible correlation between TNFα, IFNγ and IL-10 genotype polymorphisms with the susceptibility to coeliac disease in Down syndrome patients. Methods Single nucleotide polymorphisms of TNFα (−308G → A promoter region), IFNγ (+874T → A promoter region) and IL-10 (−1082G → A promoter region) have been studied in 10 Down patients with coeliac disease, in 40 Down patients without coeliac disease and in 220 healthy controls. Clinical features were also studied in coeliac disease–Down syndrome patients. Results The 10 coeliac disease–Down syndrome patients had a biopsy proven coeliac disease afterward a serological testing positive to antigliadin, antiendomysium and antitransglutaminase antibodies. Intestinal biopsy showed total atrophy in 6/10 and partial villous atrophy in 4/10 of them. All coeliac disease–Down syndrome patients had silent forms of coeliac disease and classical trisomy 21. No significant differences were observed for the IFNγ and IL-10 polymorphisms in the studied groups. A significant trend for increase of TNFα −308A positive frequency was observed in coeliac disease–Down syndrome patients compared to healthy controls (p = 0.043). Conclusions Single nucleotide polymorphisms of IFNγ and IL-10 do not play a role in predisposing Down syndrome patients to coeliac disease, while the TNFα −308 allele could be an additional genetic risk factor for coeliac disease in trisomy 21.

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To date, the combination of microcephaly and radio-ulnar synostosis has not been recognized as a distinct clinical and genetic entity. We report on 4 familial cases with this previously undescribed combination of defects, showing autosomal dominant inheritance (Fig. 1). © 1994 Wiley-Liss, Inc.