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Neonatal and infantile cholestasis (NIC) can represent the onset of a surgically correctable disease and of a genetic or metabolic disorder worthy of medical treatment. Timely recognition of NIC and identification of the underlying etiology are paramount to improve outcomes. Upon invitation by the Italian National Institute of Health (ISS), an expert working grouped was formed to formulate evidence-based positions on current knowledge about the diagnosis of NIC. A systematic literature search was conducted to collect evidence about epidemiology, etiology, clinical aspects and accuracy of available diagnostic tests in NIC. Evidence was scored using the GRADE system. All recommendations were approved by a panel of experts upon agreement of at least 75% of the members. The final document was approved by all the panel components. This position document summarizes the collected statements and defines the best-evidence diagnostic approach to cholestasis in the first year of life.

PurposeBinding proteins (G-proteins) mediate signalling pathways involved in diverse cellular functions and comprise Gα and Gβγ units. Human diseases have been reported for all five Gβ proteins. A de novo missense variant in GNB2 was recently reported in one individual with developmental delay/intellectual disability (DD/ID) and dysmorphism. We aim to confirm GNB2 as a neurodevelopmental disease gene, and elucidate the GNB2-associated neurodevelopmental phenotype in a patient cohort.MethodsWe discovered a GNB2 variant in the index case via exome sequencing and sought individuals with GNB2 variants via international data-sharing initiatives. In silico modelling of the variants was assessed, along with multiple lines of evidence in keeping with American College of Medical Genetics and Genomics guidelines for interpretation of sequence variants.ResultsWe identified 12 unrelated individuals with five de novo missense variants in GNB2, four of which are recurrent: p.(Ala73Thr), p.(Gly77Arg), p.(Lys89Glu) and p.(Lys89Thr). All individuals have DD/ID with variable dysmorphism and extraneurologic features. The variants are located at the universally conserved shared interface with the Gα subunit, which modelling suggests weaken this interaction.ConclusionMissense variants in GNB2 cause a congenital neurodevelopmental disorder with variable syndromic features, broadening the spectrum of multisystem phenotypes associated with variants in genes encoding G-proteins.

To comparatively assess the role of abdominal ultrasound (US) and magnetic resonance imaging (MRI) in predicting long-term medical outcome in native liver survivor patients with biliary atresia (BA) after Kasai portoenterostomy (KP). Twenty-four retrospectively enrolled patients were divided in two groups according to clinical and laboratory data at initial evaluation after KP (median follow-up = 9.7 years; range = 5–25 years) as with ideal (Group 1; n = 15) or non-ideal (Group 2; n = 9) medical outcome. All patients were re-evaluated for a period of additional 4 years using clinical and laboratory indices. US and MRI studies were qualitatively analyzed assessing imaging signs suggestive of chronic liver disease (CLD). At re-evaluation, 6 patients (40%) of Group 1 changed their medical outcome in non-ideal (Group 1A); the other 9 patients (60%) remained stable (Group 1B); the mean time to change the medical outcome in non-ideal status at re-evaluation was 43.5 ± 2.3 months. The area under the ROC curve was 0.84 and 0.87 for US and MRI scores to predict long-term medical outcome with the best cut-off value score > 4 for both modalities (p = 0.89). In Group 2, 6 (67%) patients showed a clinical progression (Group 2A) with a mean time of 39.8 ± 3.8 months; in the other 3 (33%) patients, no clinical progression was observed (Group 2B). In BA patients with ideal medical outcome after KP, US and MRI may both predict long-term outcome. US, non-invasive and widely available technique, should be preferred.

OBJECTIVES: Sofosbuvir/Ledipasvir (SOF/LDV) has been approved by the European Medicine Agency (EMA) for the treatment of children and adolescents (at least 3 years of age) with chronic hepatitis C (CHC) genotype 1, 3, and 4 infection. The aim of this study was to evaluate the efficacy and safety of SOF/LDV in adolescents (12 to

Alagille syndrome (ALGS) is a multisystemic disease caused by mutations in genes of Notch pathway, which regulates embryonic cell differentiation and angiogenesis. Clinically, ALGS is characterized by cholestasis, cardiac defects, characteristic facial features, skeletal and ophthalmologic abnormalities. The aim of this review is to illustrate neuroradiological findings in ALGS, which are less well-known and prevalent, including cerebrovascular anomalies (such as aneurysms, dolichoectasia, Moyamoya syndrome and venous peculiarities), Chiari 1 malformation, craniosynostosis, intracranial hypertension, and vertebral anomalies (namely butterfly vertebra, hemivertebra, and craniocervical junction anomalies). Rarer cerebral midline malformations and temporal bone anomalies have also been described.

Wilson's Disease (WD) is an autosomal recessive disorder caused by excessive copper deposition in liver, brain and other organs. The clinical picture is characterized by hepatic, psychiatric and neurological dysfunction. Movement disorders are the core neurological features, although non-motor symptoms (NMS), as cognitive/affective, autonomic and sleep disorders, may occur over time. We aimed to assess the frequency of NMS in WD patients compared with healthy subjects.Twenty-seven patients affected with genetically proven WD (12 F, 15 M) and 35 healthy controls (Ctrl; 17 F, 18 M), comparable for age and education, were enrolled. Eighteen patients presented with the neurological form of the disease (NV) and nine with the non-neurological variant (NNV). NMS were assessed in all subjects by the following clinical scales: Mini-Mental State Examination (MMSE), Non-Motor Symptoms Scale (NMSS), SCOPA-AUT Questionnaire, Apathy Evaluation Scale (AES), Beck Depression Inventory (BDI), Epworth Sleepiness Scale (ESS), Restless Legs Syndrome Rating Scale (RLSRS), REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ), Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease (QUIP-RS).We found that the patients showed more severe and frequent NMS and daytime sleepiness, and lower MMSE than Ctrl. In comparison to healthy subjects, NV subjects showed statistically significant higher ESS, NMSS, and RLSRS scores, and a lower MMSE score. Subtle and subclinical extrapyramidal/pyramidal signs and brain MRI signal abnormalities were detected in patients considered as asymptomatic for neurological disturbances.NMS are common among WD patient, in particular those with NV, likely due to the widespread pathological changes throughout the central nervous system.

Hepatic hydrothorax represents a rare complication of portal hypertension among adult cirrhotic patients. Here we describe a pediatric case of hepatic hydrothorax, observed in a biliary atresia infant. The child presented with recurrent right side pleural effusion, after a successful Kasai portoenterostomy with restoration of bile flow and without overt signs of hepatic failure. Recurrence of hepatic hydrothorax led the patient to liver transplant despite a low Pediatric End-stage Liver Disease value. Although rare, hepatic hydrothorax can also occur in children and should be suspected in patients with portal hypertension and respiratory distress. HH may be an indication for liver transplantation.

Wilson's disease (WD) is a disorder of copper metabolism that can cause hormonal alterations. The impact of WD and its therapies on fertility is not well defined. The aim of this study was to evaluate ovarian reserve and sperm parameters in long-term treated WD patients with hepatic onset.WD patients with hepatic onset treated for at least 5 years were compared with healthy controls. Men underwent spermiogram and sperm DNA fragmentation (SDF) analysis. Women were tested for serum FSH, anti-Müllerian hormone (AMH) and sonographic antral follicle count (AFC) in the early follicular phase. Ovulation was monitored with ultrasound and progesterone serum concentrations in the luteal phase.The WD group included 26 patients (12 males), the control group 19 subjects (9 males). All patients apart from four (one male) were responders to WD treatment. Sperm count and morphology were comparable between cases and controls. Sperm motility (total and after 1 h) was significantly lower in cases (44.78 ± 21.65%; 47.85 ± 21.52%) than controls (61.88 ± 11.03; 69.44 ± 11.02%, P = 0.03 and 0.01, respectively). The only non-responder had severe oligo-astheno-teratozoospermia. SDF values were normal in cases and controls. AMH, AFC and FSH did not differ between cases and controls. LH was significantly lower in cases (3.36 ± 1.65 mIU/ml) than controls (6.25 ± 1.03 mIU/ml, P 0.0001). A non-responder woman who developed neurological signs had a 7-year history of infertility.WD patients with hepatic onset, diagnosed early and treated, have no impairment in fertility potential even if males show reduced sperm motility and females lower LH values. Only patients with poor disease control have some evidence of impaired fertility.

In biliary atresia, infants left untreated, and in those with unsuccessful porto-enterostomy, hepatic condition and function worsen rapidly towards cirrhosis, malnutrition, portal hypertension with ascites, and variceal haemorrhage; many die within the first 3 years of life unless they benefit from liver replacement. We describe a girl with biliary atresia splenic malformation syndrome, who had portal vein cavernoma and microsplenia; she did not undergo porto-enterostomy. She survived with her native liver over the age of 3 years. Remarkably, she remained in satisfactory condition in absence of ascites or severe hepatic dysfunction, when 4 other similar patients-managed during the same period of time-all had the usual clinical deterioration and ascites, with the need for liver replacement. To our knowledge, there is no similar report in literature. Possible pathogenetic mechanisms and the role of portal hypertension as important factors are discussed.

Kasai portoenterostomy (KP) represents the first-line treatment for biliary atresia (BA). The purpose was to compare the accuracy of quantitative parameters extracted from laboratory tests, US imaging, and MR imaging studies using machine learning (ML) algorithms to predict the long-term medical outcome in native liver survivor BA patients after KP. Twenty-four patients were evaluated according to clinical and laboratory data at initial evaluation (median follow-up = 9.7 years) after KP as having ideal (n = 15) or non-ideal (n = 9) medical outcomes. Patients were re-evaluated after an additional 4 years and classified in group 1 (n = 12) as stable and group 2 (n = 12) as non-stable in the disease course. Laboratory and quantitative imaging parameters were merged to test ML algorithms. Total and direct bilirubin (TB and DB), as laboratory parameters, and US stiffness, as an imaging parameter, were the only statistically significant parameters between the groups. The best algorithm in terms of accuracy, sensitivity, specificity, and AUCROC was naive Bayes algorithm, selecting only laboratory parameters (TB and DB). This preliminary ML analysis confirms the fundamental role of TB and DB values in predicting the long-term medical outcome for BA patients after KP, even though their values may be within the normal range. Physicians should be alert when TB and DB values change slightly.

Binding proteins (G-proteins) mediate signalling pathways involved in diverse cellular functions and comprise Gα and Gβγ units. Human diseases have been reported for all five Gβ proteins. AWe discovered aWe identified 12 unrelated individuals with fiveMissense variants in

The role of Plasmodium in the etiology of acute diarrhea in developing countries remains controversial, and gastrointestinal (GI) symptoms are inconsistently reported in malaria. In this observational case–control study, we investigated the prevalence and risk factors for GI symptoms in hospitalized malarious children aged 1 month to 5 years in northern Uganda. Children with a diagnosis of Plasmodium falciparum malaria were enrolled as cases, and feverish children in whom malaria was excluded were enrolled as controls. Among 451 malarious children, 46.1% had GI symptoms at admission. Compared with controls, the frequency of diarrhea (24.8% versus 11.2%, P < 0.001) and vomiting (35.5% versus 17.5%, P < 0.001) was significantly higher in children with malaria, who had a higher chance of showing either vomiting (odds ratio [OR]: 3.22; 95% CI: 2.14–4.91) or diarrhea (OR: 3.14; 95% CI: 1.99–5.07) at hospital admission. A subgroup analysis performed in children with severe malaria, severe anemia, or high-grade fever confirmed these results. Diarrhea was more frequent in infants and children younger than 3 years than in older children. The analysis of 71 malarious children with diarrhea who received intravenous artesunate showed that the symptom resolved within the first 24 hours since the beginning of the treatment in 85.9% of cases. The 3-fold higher prevalence of diarrhea and vomiting in malarious children compared with febrile controls may provide rationale for incorporating malaria testing in the symptom-guided diagnostic approach of the young child with diarrhea and vomiting in malaria-endemic settings.

Background Biliary atresia (BA) is a rare obliterative cholangiopathy and Kasai portoenterostomy (KP) represents its first-line treatment; clinical and laboratory parameters together with abdominal ultrasound (US) are usually performed during the follow-up. Shear-wave elastography (SWE) is able to evaluate liver parenchyma stiffness; magnetic resonance imaging (MRI) has also been proposed to study these patients. Purpose To correlate US, SWE, and MRI imaging findings with medical outcome in patients with BA who are native liver survivors after KP. Material and Methods We retrospectively enrolled 24 patients. They were divided in two groups based on “ideal” (n = 15) or “non-ideal” (n = 9) medical outcome. US, SWE, and MRI exams were analyzed qualitatively and quantitatively for imaging signs suggestive of chronic liver disease (CLD). Results Significant differences were found in terms of liver surface ( P = 0.007) and morphology ( P = 0.013), portal vein diameter ( P = 0.012) and spleen size ( P = 0.002) by US, liver signal intensity ( P = 0.013), portal vein diameter ( P = 0.010), presence of portosystemic collaterals ( P = 0.042), and spleen size ( P = 0.001) by MRI. The evaluation of portal vein diameter (moderate, κ = 0.44), of portosystemic collaterals (good, κ = 0.78), and spleen size (very good, κ = 0.92) showed the best agreement between US and MRI. A significant ( P = 0.01) difference in liver parenchyma stiffness by SWE was also found between the two groups (cut-off = 9.6 kPa, sensitivity = 55.6%, specificity = 100%, area under the ROC curve = 0.82). Conclusion US, SWE, and MRI findings correlate with the medical outcome in native liver survivor patients with BA treated with KP.

Background Pseudo-ascites is a very rare condition in children and remains a challenging diagnosis. Targeted imaging may be helpful, but a high index of clinical suspicion is often necessary to guide the investigations, as pseudo-ascites may efficiently mimic true ascites. To date, still many cases of pseudo-ascites suffer diagnostic and therapeutic delay, and some are only diagnosed during surgical exploration. We report the case of a patient with a late laparoscopic diagnosis of pseudo-ascites. We retrospectively review our patient’s imaging findings and suggest new characteristic features which may help differentiate pseudo-ascites from true ascites. Case presentation A 7-month-old infant was referred for a progressive abdominal distention. Physical examination and initial ultra-sonographic findings evoked free ascites. An extensive diagnostic workup was then performed and was negative for hepatic, renal, cardiac, intestinal, pancreatic, inflammatory or infectious diseases, malignancy and congenital metabolic disorders. Pseudo-ascites was evoked and dedicated ultra-sonographic and magnetic resonance studies were repeated but could not confirm this diagnosis. Symptomatic diuretic treatment with spironolactone and furosemide was then started. A temporary and limited effect was noted but, with time, repeated paracenteses were necessary as the abdominal distention progressed causing discomfort and breathing difficulty. Last, because the patient’s quality of life deteriorated, a peritoneal-venous shunting was proposed; as the operation started with a diagnostic laparoscopy, a benign giant cystic mesenteric lymphangioma was identified and totally excised. The resolution of symptoms was immediate and the patient remained symptom-free throughout the subsequent observation period that lasted more than 1 year. Conclusions Increased awareness about pseudo-ascites is necessary, as the diagnosis is often overlooked, and treatment delayed. Targeted imaging may be helpful, as some specific, although not pathognomonic, features exist which may aid in the diagnosis.

Background: Hereditary fructose intolerance (HFI) is a rare genetic disorder of fructose metabolism due to aldolase B enzyme deficiency. Treatment consists of fructose, sorbitol, and sucrose (FSS)-free diet. We explore possible correlations between daily fructose traces intake and liver injury biomarkers on a long-term period, in a cohort of young patients affected by HFI. Methods: Patients&rsquo, clinical data and fructose daily intake were retrospectively collected. Correlations among fructose intake, serum alanine aminotransferase (ALT) level, carbohydrate-deficient transferrin (CDT) percentage, liver ultrasonography, genotype were analyzed. Results: We included 48 patients whose mean follow-up was 10.3 &plusmn, 5.6 years and fructose intake 169 &plusmn, 145.4 mg/day. Eighteen patients had persistently high ALT level, nine had abnormal CDT profile, 45 had signs of liver steatosis. Fructose intake did not correlate with ALT level nor with steatosis severity, whereas it correlated with disialotransferrin percentage (R2 0.7, p &lt, 0.0001) and tetrasialotransferrin/disialotransferrin ratio (R2 0.5, p = 0.0001). p.A150P homozygous patients had lower ALT values at diagnosis than p.A175D variant homozygotes cases (58 &plusmn, 55 IU/L vs. 143 &plusmn, 90 IU/L, p = 0.01). Conclusion: A group of HFI patients on FSS-free diet presented persistent mild hypertransaminasemia which did not correlate with fructose intake. Genotypes may influence serum liver enzyme levels. CDT profile represents a good marker to assess FSS intake.

BACKGROUND A transient dysfunction of the endocrine growth axis has been reported in celiac disease (CD). This apparent growth hormone deficiency (GHD) generally normalizes with the institution of a gluten-free diet (GFD). However, in few cases, the dysfunction of the GH axis persists despite a good adherence to the GFD. Aims of this study were to investigate pediatric patients with concurrent CD and GHD and to compare them with patients with isolated CD. METHODS Data regarding CD patients with and without associated GHD were retrospectively collected. Inclusion criteria were availability of anthropometric and laboratory data at baseline and regularly at the reference center up to a 2-year follow-up. In case of poor catch-up growth despite a good adherence to the GFD, endocrinological investigation was carried on. RESULTS Fifty-three patients with CD were included. Four (7.5%) out of 53 CD patients had a concurrent GHD. In two cases, firstly diagnosed with CD, GHD was suspected because of a poor catch-up growth despite a good adherence to the GFD. In two other cases, firstly diagnosed with GHD, gastrointestinal symptoms revealed the diagnosis of CD. Normalization of height velocity was achieved by GH treatment in all cases. No statistical significant difference between the two groups of patients was found as regard laboratory and histological features of CD. It is to note that 2 out of 4 patients with concomitant CD and GHD had thyroiditis compared to 6% of patients with isolated CD (P=0.004). CONCLUSIONS A high prevalence of CD and GHD association was found. CD patients with poor catch-up growth despite a good adherence to the GFD should be carefully investigated for endocrine disorders.

Background & aims Wilson's disease (WD) is a genetic disorder of copper metabolism causing dysfunctions of various organs, mostly the liver and brain. If untreated, WD is fatal, but early treatment results in a good prognosis, although the long-term neurological outcome has not yet been clarified. To address this issue, we evaluated the neurological status of early-treated WD patients without overt nervous system impairment using neurophysiological, neuropsychological and neuroimaging procedures at least 10 years after treatment onset. Methods Thirty-eight WD patients (18 females, aged 24.47 ± 7.50 years), who received an early diagnosis (in presymptomatic or mild/moderate liver disease stages without neurological involvement) and prompt treatment, were clinically evaluated with the Global Assessment Scale. Presentation was hepatic in 36 subjects (95%), while 2 patients (5%) were presymptomatic. A neurophysiological study was performed to explore the central motor conduction time of the upper and lower limbs, and motor cortex excitability using single pulses and paired-pulse transcranial magnetic stimulation. Neuroimages were obtained with brain magnetic resonance scans. Cognitive abilities, and psychiatric and behavioral disturbances were evaluated with neuropsychological tests. Results Patients were undergoing treatment with penicillamine (7 patients) or zinc salts (31 patients) with good adherence. They did not present any neurological signs at clinical evaluation or at specific scale of impairment, the mean Global Assessment Scale score was 0.3 ± 0.7. Magnetic resonance imaging, transcranial magnetic stimulation studies and neuropsychological/neuropsychiatric assessment ruled out subclinical involvement. Conclusions This study suggests that early diagnosis and treatment of WD may prevent the onset of neurologic damage, even at subclinical level.

We describe a case of Wilson's disease (WD) diagnosed at 5 years after routine biochemical test showed increased aminotransferases. Mutation analysis of the ATP7B gene revealed a 3039-bp deletion in the homozygous state spanning from the terminal part of intron 1 to nt position 368 of exon 2. This deletion results in the activation of 3 cryptic splice sites: an AG acceptor splice site in nt positions 578-579 producing a different breakpoint and removing the first 577 nts of exon 2, an acceptor and a donor splice site in nt positions 20363-4 and 20456-7, respectively, in intron 1, resulting in the activation of a 94-bp cryptic Alu exon being incorporated into the mature transcript. The resulting alternative transcript contains a TAG stop codon in the first amino acid position of the cryptic exon, likely producing a truncated, non-functional protein. This study shows that intron exonization can also occur in humans through naturally occurring gross deletions. The results suggest that the combination of DNA and RNA analyses can be used for molecular characterization of gross ATP7B deletions, thus improving genetic counseling and diagnosis of WD. Moreover these studies help to better establish new molecular mechanisms producing Wilson's disease.

Background Wilson’s disease (WD) evolves rapidly and is fatal if untreated. The treatment of WD patients with mild liver disease is not clearly defined. To address this issue, we evaluated long-term outcomes of three treatment regimens (D-penicillamine, zinc or both) in patients diagnosed in childhood. Methods We retrospectively evaluated efficacy, compliance and reasons for treatment discontinuation in 42 WD patients (median age at diagnosis: 6 years; median follow-up: 12 years) with mild liver disease. Treatment duration for each treatment block until a medication change or completion of follow-up was analyzed. Events of change of treatment were evaluated using Kaplan-Meier analysis. Results Total discontinuations due to treatment failure or adverse events were more frequent in patients receiving D-penicillamine (45%) or combination (36%) therapy than in patients receiving zinc (12%) (P = .001 and P = .02, respectively). Treatment failure was more frequent on D-penicillamine (28%) and combination therapy (36%) than on zinc (12%); the difference was statistically significant only between zinc and combination therapy (P = .03). First-line zinc monotherapy controlled WD-related liver disease in 13/15 patients (87%); the two subjects that failed on zinc were poor adherent. Zinc was effective in 3/5 (60%) patients that failed on D-penicillamine and combination regimens. All 15 D-penicillamine responders that switched to zinc had good control of liver disease at a median follow-up of 13.1 years. Among 6 D-penicillamine non-responders that switched to zinc, 4 (67%) responded. At follow-up completion, only 5/42 (12%) patients failed. Adverse event-induced discontinuation was significantly more frequent in patients on D-penicillamine than in patients receiving zinc (P = .03). Conclusions Zinc monotherapy is effective in controlling WD-related liver disease both as first-line and as maintenance treatment in patients with mild liver disease diagnosed in childhood.