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Prolyl endopeptidase-like (PREPL) deficiency (MIM#616224) is a rare congenital disorder characterised by neonatal hypotonia and feeding difficulties, growth hormone (GH) deficiency and hypergonadotropic hypogonadism. This syndrome is an autosomal recessive disease resulting from mutations in the PREPL gene (MIM#609557). Herein we report a 7-year-old female patient with biallelic mutations in PREPL (c.1528C>T in one allele and a whole gene deletion in the other) with early growth impairment in infancy. Growth hormone deficiency was confirmed at 20 months of life. Recombinant growth hormone treatment was introduced with a good response. Her clinical features were similar to those of previously reported cases. The description of new patients with PREPL deficiency syndrome is essential to better delineate the phenotypic and genotypic spectrum of the disease.

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.

Purpose Thyroid dyshormonogenesis is a heterogeneous group of hereditary diseases produced by a total/partial blockage of the biochemical processes of thyroid-hormone synthesis and secretion. Paired box 8 (PAX8) is essential for thyroid morphogenesis and thyroid hormone synthesis. We aimed to identify PAX8 variants in patients with thyroid dyshormonogenesis and to analyze them with in vitro functional studies. Patients and Methods Nine pediatric patients with a eutopic thyroid gland were analyzed by the Catalan screening program for congenital hypothyroidism. Scintigraphies showed absent, low, or normal uptake. Only one patient had a hypoplastic gland. On reevaluation, perchlorate discharge test was negative or compatible with partial iodine-organization deficit. After evaluation, 8 patients showed permanent mild or severe hypothyroidism. Massive-sequencing techniques were used to detect variants in congenital hypothyroidism-related genes. In vitro functional studies were based on transactivating activity of mutant PAX8 on a TG-gene promoter and analyzed by a dual-luciferase assays. Results We identified 7 heterozygous PAX8 exonic variants and 1 homozygous PAX8 splicing variant in 9 patients with variable phenotypes of thyroid dyshormonogenesis. Five were novel and 5 variants showed a statistically significant impaired transcriptional activity of TG promoter: 51% to 78% vs the wild type. Conclusions Nine patients presented with PAX8 candidate variants. All presented with a eutopic thyroid gland and 7 had deleterious variants. The phenotype of affected patients varies considerably, even within the same family; but, all except the homozygous patient presented with a normal eutopic thyroid gland and thyroid dyshormonogenesis. PAX8 functional studies have shown that 6 PAX8 variants are deleterious. Our studies have proven effective in evaluating these variants.

Infant botulism (IB) is defined as a potentially life-threatening neuroparalytic disorder affecting children younger than 12 months. It is caused by ingestion of food or dust contaminated by Clostr...

Ceftriaxone is an antibiotic agent frequently used in paediatric hospital practice for the treatment of severe bacterial infections. The use of this agent can result in cholelithiasis and/or biliary sludge, more commonly in children than in adults. This systematic review was aimed at analysing available literature concerning ceftriaxone-associated biliary pseudolithiasis in paediatric patients, with a special emphasis on the clinical aspects. A literature analysis was performed using Medline and Embase electronic databases (articles published in English up to December 2019), with the search terms and combinations as follows:'ceftriaxone', 'cholelithiasis', 'biliary sludge' 'gallstones' 'neonates' 'children' 'clinical aspects' 'management'. Several case reports, case series and prospective/retrospective studies have documented a relationship between ceftriaxone treatment and biliary pseudolithiasis in the paediatric population, even though literature data regarding neonates and infants are scarce. Ceftriaxone-associated biliary pseudolithiasis is dose-dependent and usually asymptomatic but, sometimes, it may present with abdominal pain, nausea and emesis. Abdominal ultrasonography should be performed when this complication is suspected. Generally, ceftriaxone-associated cholelithiasis resolves over a variable period of time (days to months) after cessation of therapy. Therefore, a conservative approach to this condition is advocated, but a prolonged follow-up may be necessary. A personalized assessment of factors predisposing to ceftriaxone-associated biliary pseudolithiasis before prescribing the drug can allow to minimize the risk of developing it, with significant advantages in terms of human and economic costs.

AIM The etiopathogenesis of non-syndromic biliary atresia (BA) is obscure. The primary aim was to investigate intrahepatic bile duct cilia (IHBC) in BA at diagnosis and its correlation with clinical outcome. The secondary aim was to analyze IHBC in routine paraffin-embedded liver biopsies using conventional scanning electron microscopy (SEM). METHODS Surgical liver biopsies taken at diagnosis from 22 BA infants (age range, 39-116 days) and from eight children with non-BA chronic cholestasis (age range, 162 days -16.8 years) were evaluated for IHBC by immunofluorescence (IF) and SEM. A minimum 18-month follow-up after surgery was available for all patients. RESULTS By IF, cilia were present in 6/8 (75%) non-BA but only in 3/22 (14%) BA cases, and cilia were reduced or absent in 19/22 (86%) BA and 2/8 (25%) non-BA livers (P 90% at 12 months, and >70% at 24 months post-surgery, were recorded regardless of cilia presence/absence at diagnosis. Electron microscopy was able to detect bile ducts and cilia in routine liver biopsies, revealing significant abnormalities in 100% BA livers. CONCLUSIONS The presence of IHBC in BA livers at the diagnosis was associated with resolution of cholestasis, although was not predictive of short-term survival with native liver. Scanning electron microscopy represents a powerful new tool to study routine liver biopsies in biliary disorders. Cilia dysfunction in BA pathogenesis and/or disease progression warrants further investigation.

Having a hepatitis B virus (HBV) or hepatitis C virus (HCV) infection places a child at higher risk for subsequent chronic hepatitis B (CHB) or chronic hepatitis C (CHC) infection. The risk of mother-to-child transmission is higher for HBV (20% to 90%) than for HCV (

Non-alcoholic fatty liver disease (NAFLD) in children is becoming a major health concern. A "multiple-hit" pathogenetic model has been suggested to explain the progressive liver damage that occurs among children with NAFLD. In addition to the accumulation of fat in the liver, insulin resistance (IR) and oxidative stress due to genetic/epigenetic background, unfavorable lifestyles, gut microbiota and gut-liver axis dysfunction, and perturbations of trace element homeostasis have been shown to be critical for disease progression and the development of more severe inflammatory and fibrotic stages [non-alcoholic steatohepatitis (NASH)]. Simple clinical and laboratory parameters, such as age, history, anthropometrical data (BMI and waist circumference percentiles), blood pressure, surrogate clinical markers of IR (acanthosis nigricans), abdominal ultrasounds, and serum transaminases, lipids and glucose/insulin profiles, allow a clinician to identify children with obesity and obesity-related conditions, including NAFLD and cardiovascular and metabolic risks. A liver biopsy (the "imperfect" gold standard) is required for a definitive NAFLD/NASH diagnosis, particularly to exclude other treatable conditions or when advanced liver disease is expected on clinical and laboratory grounds and preferably prior to any controlled trial of pharmacological/surgical treatments. However, a biopsy clearly cannot represent a screening procedure. Advancements in diagnostic serum and imaging tools, especially for the non-invasive differentiation between NAFLD and NASH, have shown promising results, e.g., magnetic resonance elastography. Weight loss and physical activity should be the first option of intervention. Effective pharmacological treatments are still under development; however, drugs targeting IR, oxidative stress, proinflammatory pathways, dyslipidemia, gut microbiota and gut liver axis dysfunction are an option for patients who are unable to comply with the recommended lifestyle changes. When morbid obesity prevails, bariatric surgery should be considered.

This report summarizes the clinical features and the indications for treating HCV infection in immunocompromised and transplanted patients in the Direct Acting Antiviral drugs era.

Hypovitaminosis D in childhood is a re-emerging public health problem in developed countries. New life style habits, current “epidemics” of obesity in children and adolescents worldwide, and other preventable risk factors may play a role in favoring the occurrence of vitamin D deficiency. In addition to skeletal consequences, hypovitaminosis D has been found to be involved in the development of serious health extra-skeletal problems in childhood, including atopy and autoimmunity. The increasing concerns about the global health impact of vitamin D deficiency make further research necessary to fill the gaps of knowledge in this field, and particularly to establish universally accepted “normal” serum 25(OH)D levels in the pediatric population, and to improve strategies for the screening, prevention and treatment of hypovitaminosis D. This review discusses the key points of hypovitaminosis D in childhood in the light of new knowledge, and highlights the limitations of current strategies to control this condition.

Primary adrenal insufficiency is life threatening and can present alone or in combination with other comorbidities. Here, we have described a primary adrenal insufficiency syndrome and steroid-resistant nephrotic syndrome caused by loss-of-function mutations in sphingosine-1-phosphate lyase (SGPL1). SGPL1 executes the final decisive step of the sphingolipid breakdown pathway, mediating the irreversible cleavage of the lipid-signaling molecule sphingosine-1-phosphate (S1P). Mutations in other upstream components of the pathway lead to harmful accumulation of lysosomal sphingolipid species, which are associated with a series of conditions known as the sphingolipidoses. In this work, we have identified 4 different homozygous mutations, c.665G>A (p.R222Q), c.1633_1635delTTC (p.F545del), c.261+1G>A (p.S65Rfs*6), and c.7dupA (p.S3Kfs*11), in 5 families with the condition. In total, 8 patients were investigated, some of whom also manifested other features, including ichthyosis, primary hypothyroidism, neurological symptoms, and cryptorchidism. Sgpl1-/- mice recapitulated the main characteristics of the human disease with abnormal adrenal and renal morphology. Sgpl1-/- mice displayed disrupted adrenocortical zonation and defective expression of steroidogenic enzymes as well as renal histology in keeping with a glomerular phenotype. In summary, we have identified SGPL1 mutations in humans that perhaps represent a distinct multisystemic disorder of sphingolipid metabolism. ispartof: Journal of Clinical Investigation vol:127 issue:3 pages:942-953 ispartof: location:United States status: published

Hepatitis E virus (HEV) was discovered in the 1980s and has been considered as being confined to developing countries. The purpose of this critical review was to determine the reported HEV seroprevalence rates in Italy, to identify predisposing factors and individuals at risk and to assess possible importation of HEV by immigrants. A critical review of 159 articles published in PubMed from 1994 to date was done. Only 27 original reports of 50 or more subjects, written in the English or Italian language, were included. Over three decades, the HEV seroprevalence varied from 0.12% to 49%, with the highest rates being reported from the central region of Italy. Risk factors included ingestion of raw pork or potentially contaminated food. The seroprevalence among immigrants ranged from 15.3% to 19.7% in Apulia. Italy has a population of 60 656 000; the total number of individuals surveyed was only 21.882 (0.036%). A national epidemiological survey program is needed to capture more comprehensive seroprevalence data. Keywords: Hepatitis E infection, Epidemiology, Seroprevalence, Risk factors, Immigrants, Italy

Diagnosis of de novo autoimmune hepatitis (AIH) after orthotopic liver transplantation (OLT) is challenging especially in the absence of hyper-γ-globulinemia. Circulating autoantibodies are not sensitive nor specific in de novo AIH but when positive increase the diagnostic probability. We report the discovery of novel liver microsomal (LM) autoantibodies against CYP-2C19 in a 9-year-old boy with “de novo” AIH developed 7 years after OLT. Graft dysfunction presented with hypertransaminasemia (up to 400 IU/L), while serum γ-globulins remained within the normal range for age. Liver histology and response to high dose prednisone (2 mg/kg/day) with the addition of azathioprine therapy further supported the diagnosis of de novo AIH. Autoantibodies investigation by indirect immunofluorescence (IF) on rodent tissues showed a novel staining pattern involving the pericentral liver zone and sparing the renal tissue. Human but not rat liver proteins immunoblotting allowed us to characterize the novel LM antibodies and to identify CYP-2C19 as human antigen. The finding offers insights into the controversial discussion about autoimmunity versus alloreactivity with regard to the pathogenesis of de novo AIH. Correct information on human versus rat tissue antigens tested by methods other than IF for antibodies detection may have significant implications for the correct diagnosis and management of patients followed up after OLT.

Recent studies have shown that infants with intrauterine growth restriction (IUGR) undergo catch-up growth during infancy. The aim of our study was to evaluate the postnatal growth in a cohort of IUGR infants born in a tertiary-level Obstetric University Hospital of Northern Sardinia. An observational retrospective study was conducted on 12 IUGR (group A) and 12 control infants (group B) by measuring the anthropometric parameters of weight (W), length (L) and head circumference (HC) from birth to the 3rd postnatal year. At birth, significant differences were found between group A and group B with regard to all the auxological parameters (W, mean 1846.6 versus 3170.8 g, p < 0.0001; HC, 30.1 versus 34.4 cm, p < 0.0001; L, mean 43.4 versus 49.4 cm, p < 0.0001). During the 1st year, 8 of 12 (70%) IUGR infants exhibited a significant catch-up growth in the 3 anthropometric parameters and a regular growth until the 3rd year of follow-up. The majority but not all infants born with IUGR in our series showed significant postnatal catch-up growth essentially during the first 12 months of life. An improved knowledge of the causes of IUGR will help to develop measures for its prevention and individualized treatment.

Background: The HLA DRB1*08 allele associated with primary biliary cholangitis (PBC) among Caucasians is of low frequency in the Sardinian population. Objective: The aim of our study was to type a cohort of PBC patients from the island of Sardinia for HLA class II antigens. Methods: Twenty Sardinian patients affected by PBC, 14 with autoimmune hepatitis (AIH) and 89 healthy controls (HCs) were typed for HLA class II alleles by dot-blot analysis. Results: The PBC-associated HLA DRB1*08 allele was detected in none of the studied individuals. The DRB1*0301–DQB1*0201 was the prevalent HLA haplotype, detected in 19 (47.5%) out of 40 PBC haplotypes (OR = 3.0; 95% CI 1.5–6.2) and in 11 (39.3%) out of 28 AIH haplotypes (OR = 2.2; 95% CI 0.94–5.0), but in only 41 (23%) out of 178 HC haplotypes. Moreover, PBC patients showed an increased frequency of homozygosity for the DQB1*0201 allele (35% compared with 6.7% of the HCs; OR = 7.5; 95% CI 2.2–25.7). The frequency of the DRB1*11 allele in the PBC group was about half of that seen in the Sardinian HCs (7.5% vs 15.7%) (p = ns). Conclusions: Our study confirmed the low frequency of the HLA DRB1*08 allele among Sardinians, either in the general population or PBC patients. The high prevalence of the HLA DRB1*0301–DQB1*0201 haplotype is a distinctive genetic feature of PBC among Sardinians. Our study strengthens the hypothesis that still unknown genetic, epigenetic, and environmental factors must be involved in the pathogenesis of different HLA-associated liver diseases, and it represents a pathfinder that warrants exploration in a future extensive study.

Biliary atresia is a severe and progressive inflammatory process of unknown cause, which initially involves the extrahepatic bile ducts but which quickly proceeds towards the intrahepatic bile tree leading rapidly to biliary cirrhosis. Biliary atresia is the major reason for liver transplantation during childhood. The extrahepatic bile ducts in biliary atresia become connective fibrotic cords which is irreversibly damaged.

Chronic hepatitis B (CHB) in children shows a variety of clinical presentations, which influence its natural course and treatment options. This report provides an overview of the ongoing strategies in pediatric CHB management. Interferon-α represents the first choice of treatment in children showing HBV replication and hepatic inflammation (immune active CHB), while the recommendation is to monitor inactive/immune-tolerant children (normal transaminases and low/absent viral replication). When circumstances preclude the use of Interferon-α and in cases of compensated/decompensated cirrhosis, entecavir for children above 2 years of age or tenofovir for children above 12 years of age are the nucleos(t)ide analogues recommended by the most recent guidelines.

Background: Retinol-binding protein 4 (RBP4) is known to be involved in obesity-associated insulin resistance. Aims: To study the relationships between the degree of adiposity, insulin resistance indices, plasma lipids, inflammatory parameters, glucose intolerance (GI) status and plasma RBP4 levels in obese children and adolescents. Patients and Methods: Prospective study comprising 199 obese patients (95 boys) aged 8–16 years (11.8 ± 1.9). Fifty-three subjects (23 boys) of similar mean age, 11.3 ± 2.1 years, served as controls. BMI, waist and hip circumferences, plasma lipids, and inflammatory parameters were measured and patients underwent an oral glucose tolerance test. Plasma RBP4 levels were determined by nephelometry. Results: Plasma RBP4 levels (pg/ml) in obese patients with GI (n = 15) were higher (45.0 ± 14.1) compared with those of obese patients without GI (35.9 ± 11.7, p = 0.02; n = 184) and controls (31.5 ± 12.3, p = 0.04) in a generalized linear model adjusted for age, sex, BMI and pubertal status. A negative correlation was found between the skeletal muscle insulin resistance index and RBP4; positive correlations were found between the RBP4 and BMI Z-score (r = 0.213, p < 0.001), waist circumferences (r = 0.135, p < 0.05), plasma triglycerides (r = 0.187, p = 0.005) and apolipoprotein B (0.187, p = 0.007). Conclusions: Our results suggest a direct relationship between circulating insulin and RBP4 levels, which indicates that this protein might contribute to the development of muscle insulin resistance.

Celiac disease (CD) is a T-lymphocyte-mediated small intestinal enteropathy triggered and maintained by dietary gluten, with a strong genetic component mapping to the HLA genes encoding for the class II DQ(alpha1*0501, beta1*02) molecule. Damage of the small intestine may cause a variety of clinical signs ranging from isolated long-standing iron-deficiency anemia refractory to iron supplementation to forms of severe malnutrition that may become life threatening. However, patients carrying the typical intestinal lesions of CD and presenting no symptoms at all (silent CD) are also a common clinical observation. Since it is commonly assumed that clinical signs and symptoms tend to correlate with the severity of the intestinal damage, the purpose of this study was to investigate whether particular HLA class II genotypes might also influence the extent of intestinal damage and consequently the clinical presentation of the disease.We retrospectively compared histological grading of celiac disease intestinal biopsies with HLA haplotype, age at onset of disease and clinical signs and symptoms.Our findings showed that homozygosis for the DQB1*0201 allele is associated with a higher severity of the histological score (p0.008). Of note for the clinician, this work also suggests that the same type 3c of intestinal damage causes a different clinical syndrome, depending on the patient's age.The genetic predisposition at the HLA-DQB1 locus influences the severity of the mucosal damage in a dose-dependent manner, but not the clinical presentation, of celiac disease.

The d3/fl-GH receptor (d3/fl-GHR, exon 3-deleted/full-length GHR) has recently been associated with responsiveness to GH therapy.The objective of the study was to evaluate whether the d3/fl-GHR genotypes influence the intensity of spontaneous and/or GH therapy-stimulated growth in small-for-gestational-age (SGA) patients.This was a 2-yr prospective, controlled, randomized trial.Thirty Spanish hospitals participated. Auxologic and GH secretion evaluation was hospital based, whereas molecular analyses and auxologic data computation were centralized.Patients included 170 short SGA children: 140 remained prepubertal and 30 entered puberty during the second follow-up year.Eighty-six were treated with GH (66 microg/kg.d) for 2 yr and 84 were not treated.Previous and 2-yr follow-up auxologic data were recorded at each hospital, d3/fl-GHR genotypes determined, and data analyzed for patients who remained prepubertal (group 1, 68 GH treated and 72 non-GH treated) and for all the patients (group 2).In group 1 GH-treated patients, growth velocity, and height-sd score during the first and second years, total 2-yr height gain (18.5 +/- 2.4 cm in d3/d3; 18.4 +/- 2.6 in d3/fl; 19.5 +/- 2.3 in fl/fl), Delta 2-yr height increase (9.1 +/- 2.4 cm in d3/d3; 9.4 +/- 3.0 in d3/fl; 10.4 +/- 2.1 in fl/fl), first-year growth prediction and studentized residual values (0.08 +/- 1.26 in d3/d3; 0.28 +/- 1.21 in d3/fl; 0.67 +/- 0.95 in fl/fl) did not differ among the d3/fl-GHR genotypes. In group 1 non-GH-treated patients, neither growth velocity nor height-sd score changed significantly, and values were similar in each d3/fl-GHR genotype. Results in all patients (group 2) were similar to those in group 1.In short non-GH-deficient SGA children, both spontaneous growth rate and responsiveness to 66 microg/k.d GH therapy were similar for each d3/fl-GHR genotype carried.

Thyroid function was evaluated in 75 healthy preterm infants, 30-35 weeks of gestational age. Serum thyrotropin (TSH), thyroxine (T(4)), triiodothyronine (T(3)), free T(4) (immunochemoluminescence) and reverse triiodothyronine (rT(3)) (radioimmunoassay) were measured in the mother and in the cord at delivery and in the preterm infants at 1 hour, 24 hours, 1 week, 3 weeks, 2 months, 4 months, 6 months, and 12 months of postnatal age. These values were compared to those of healthy full-term infants of the same postnatal age (22 at 24 hours from our hospital and from previously reported data at others times). Mean 24-hour TSH values were significantly lower (p < 0.001) in preterm than in full-term infant populations (12.38 +/- 6.13 microIU/mL versus 22.02 +/- 13.28 microIU/mL); however, all TSH values of preterm infants were in the range of the full-term values. Mean 24-hour free T(4) values were similar in preterm and full-term infants (1.88 +/- 0.46 ng/dL versus 2.01 +/- 0.54 ng/dL) and all preterm infants had free T(4) values within the range of those of full-term infants at 24 hours. Mean T(4) and T(3) values were significantly lower in preterm than in full-term neonates at 1 hour and 24 hours of age. Mean 24-hour rT(3) values were significantly higher in preterm than in full-term newborns. From 1 week onwards, all thyroid function values were in the same range in both populations. In conclusion, individual thyroid function was similar in healthy preterms and full-terms from the first 24 hours of life. Normative data in preterm infants during the first year of life applying the latest luminescence techniques currently used worldwide are reported.

Tissue transglutaminase enzyme-linked immunosorbent assay (tTG-ELISA) has recently been proposed as a simple and fast screening test for celiac disease (CD). The rate of false-positive and false-negative tests with tTG-ELISA, however, has not been definitively established. Therefore, the aim of our study was to investigate anti-tTG antibodies (TGA) not only in untreated patients with CD and in healthy controls, but also in a large group of patients with other autoimmune diseases.The presence of TGA was investigated in sera from 111 patients with untreated CD, 96 patients with other autoimmune conditions (28 with autoimmune liver disease, 46 with insulin-dependent diabetes mellitus, 10 with inflammatory bowel syndrome, 12 with type 1 polyglandular syndrome) and from 100 healthy controls using guinea pig tTG-ELISA (gp-TG/ELISA) and highly purified recombinant human tTG-ELISA (h-TG/ELISA). Western blotting with guinea pig tTG was also performed.Ninety-four patients with CD who tested positive for antiendomysial antibodies (AEA) and one who tested negative for AEA showed antibodies against the gp-TG. Among the controls, 50% of patients with autoimmune liver disease and 6.5% of patients with insulin-dependent diabetes mellitus tested positive with gp-TG/ELISA. Western blotting experiments revealed that the high rate of positive tests observed using ELISA among the control group sera is attributable to impurities in the gp-TG preparation. However, h-TG/ELISA tests were positive for the sera from all patients who tested positive for AEA and from one control who tested negative for AEA, whereas h-TG/ELISA tests were negative for all CD patients who tested negative for AEA and for other controls who tested negative for AEA.The frequency of false-negative and false-positive tests represents the major limit to the use of gp-tTG/ELISA. However, because h-TG/ELISA is both simple and fast, it could be used in large screening programs for CD.

To analyze the prevalence of acute asymptomatic group A and C rotavirus (RV-A and RV-C) infection in neonates with cholestasis.Participants were infants180 days of age with cholestasis (serum direct or conjugated bilirubin20% of total and ≥2 mg/dL) enrolled in the Childhood Liver Disease Research and Education Network during RV season (December-May). Forty infants with biliary atresia (BA), age 62 ± 29 days (range, 4.7-13 weeks) and 38 infants with cholestasis, age 67 ± 44 days (range, 3-15.8 weeks) were enrolled.At enrollment, RV-A IgM positivity rates did not differ between infants with BA (10%) vs those without (18%) (P = .349). RV-C IgM was positive in 0% of infants with BA vs 3% in those without BA (P = .49). RV-A IgG was lower in infants with BA: 51 ± 39 vs 56 ± 44 enzyme-linked immunoassay unit, P = .045 but this difference may lack biological relevance as maternal RV-A IgG titers were similar between groups. Infant RV-A IgM titers at 2-6 months follow-up increased markedly vs at presentation in both infants with BA (50 ± 30 vs 9 ± 9) and those without (43 ± 18 vs 16 ± 20 enzyme-linked immunoassay unit) (P.0001), without differences between groups.RV-A infection in the first 6 months of life is common in infants with cholestasis of any cause. RV-A could have different pathogenetic effects by initiating different hepatic immune responses in infants with vs without BA or could lack pathogenetic significance.

OBJECTIVE—To report the long-term follow-up of three nonpancreatectomized patients with persistent hyperinsulinemic hypoglycemia of infancy due to mutations in the ABCC8 gene. RESEARCH DESIGN AND METHODS—Oral glucose tolerance test (OGTT) and venous 24-h glucose-insulin profile were performed yearly from adolescence. RESULTS—Patient 1 (now aged 31 years) developed insulin-dependent diabetes at the age of 25 years. In patient 2 (now aged 17 years), impaired fasting glucose and a diabetic OGTT response with normal A1C values have been observed since the age of 10 years. In patient 3 (now aged 24 years), intolerant OGTT response and hyperglycemic episodes with normal A1C have been observed since the age of 16 years. All patients presented relatively low insulin levels during hyperglycemia, normal BMI, and negative autoantibodies (GAD antibody, insulinoma-associated protein 2, and islet cell antibody). CONCLUSIONS—Development of glucose metabolism impairment ranging from glucose intolerance to insulin-dependent diabetes is observed in the evolution of these patients.

To investigate the factors that may confer susceptibility or protection to hepatitis C virus (HCV) infection and to HCV-associated immunological disorders, we designed two studies on 420 Sardinian transfusion-dependent thalassemia patients followed in our department in Cagliari since 1974. The first one was an epidemiological survey aimed to evaluate the prevalence of HCV infection and HCV-associated immunological disorders. In the second study, the distribution of different HLA class II genes was examined by DNA analysis in 116 HCV positive patients, 30 HCV negative patients, and 606 healthy controls. Three hundred fourteen patients became infected with HCV (74.7%) after 5.6 +/- 2.8 years of regular transfusion program. Mixed cryoglobulinemia, purpura, arthritis, proteinuria, decreased complement levels, rheumatoid factor and anti-GOR, smooth muscle antibody (SMA), anti-nuclear antibody (ANA), and liver, kidney microsome (LKM) autoantibodies were significantly more represented in HCV positive patients than in negative ones (P.05). A significant increase of HLA class II DR2 subtype (DRB1*1601,DQB1*0502) was observed in a group of 30 HCV negative patients who despite 10.3 +/- 2.2 years in a regular blood transfusion program did not show any evidence of HCV infection (Pc.0092). Our results represent clear evidence for a relationship between HCV infection and immune extrahepatic abnormalities. A gene(s) located in the human major histocompatibility complex (MHC) region may play an important role in conferring protection against HCV infection.

The purpose of this study was to determine whether interferon-alfa (IFN-alpha) therapy benefits patients with transfusion-dependent thalassemia and chronic active hepatitis C, and whether their iron burden modifies the response to this therapy. We conducted a controlled trial of recombinant IFN-alpha (3 million units per square meter of body surface area, three times a week for 15 months) in 65 patients with thalassaemia major and chronic active hepatitis C; 14 of them were untreated control subjects. In 21 of the 51 treated patients, alanine aminotransferase values returned to normal within 6 months, and hepatitis C virus ribonucleic acid was no longer detected in serum; no changes were detected among control subjects. The response to IFN-alpha therapy was inversely related (p < 0.002) to the liver iron burden as assessed by atomic absorption, the histologic semiquantitative method, or both methods. During 3 years of follow-up, two responder patients had relapses. We conclude that IFN-alpha represents a useful therapeutic option for children with transfusion-dependent thalassemia and chronic active hepatitis C with a mild to moderate iron burden.

BACKGROUND A prospective study was conducted to evaluate low-density lipoprotein-cholesterol (LDL-C) lowering efficacy and tolerability of ezetimibe as monotherapy in children and adolescents with polygenic hypercholesterolemia (PH) or familial hypercholesterolemia (FH). METHODS AND RESULTS Children with PH (n=6) or FH (n=11) aged 5-15 years were consecutively enrolled to receive ezetimibe as monotherapy at 10 mg/day for 11.3 +/- 7.3 and 15.9 +/- 10.1 months, respectively. Plasma biochemical and lipid profiles were assessed before and after treatment. Ezetimibe significantly lowered total cholesterol (TC) and LDL-C in patients with PH and FH: TC from 260.5 +/- 12.4 to 180.0 +/- 21.6 mg/dl (p = 0.02) and from 315.3 +/- 41.8 to 233.3 +/- 36.8 mg/dl (p = 0.003), respectively, and LDL-C from 177.1 +/- 17.7 to 102.6 +/- 16.7 mg/dl (p = 0.02) and from 243.0 +/- 41.8 to 170.0 +/- 29.8 mg/dl (p = 0.003), respectively. However, high-density lipoprotein-cholesterol (HDL-C) only decreased significantly (from 58.1 +/- 10.0 to 49.3 +/- 9.1 mg/dl) (p < 0.01) in patients with FH and remained unaltered in patients with PH. Triglyceride levels remained unchanged in both groups. Biochemical profile (hemogram, transaminases, creatinine, calcium, phosphorus and liposoluble vitamins A and E) remained unchanged; no adverse effects were observed. CONCLUSIONS Our data show that ezetimibe as monotherapy significantly lowered TC and LDL-C in children with PH and FH.

Background Age at pubertal growth spurt (PGS) onset varies and is sex-dependent. We present anthropometric pubertal growth data for five 1-year interval age maturity groups: very early, early, intermediate, late and very late. Methods Longitudinal growth study of 458 healthy children (223 boys, 235 girls). Ages at PGS onset and at adult height attainment, total pubertal growth (TPG), and peak height velocity (PHV) were evaluated. PGS begins between the ages of 10 and 15 in boys and 8 and 13 in girls; children were allocated to the corresponding 1-year interval age maturity group. Results For each sex, the earlier the start of PGS onset, the higher were PHV and TPG gain. However, adult heights were similar among the five pubertal maturity groups. Height SDS values for mean values of the very early, early, late and very late maturity groups calculated according to data from the five pubertal maturity groups taken together as a single group differed from zero in both sexes, mainly during the pubertal years for the very early (> +1) and very late (> -1) maturers. These differences disappeared at adult height. Conclusions Our data might contribute to better clinical evaluation of pubertal growth according to individual pubertal maturity tempo.

Aim To assess thyroid function in 76 sick preterm infants 30-36 weeks gestational age. Patients and methods Measurement of serum TSH, T4, T3, free T4 and rT3 in the mother and cord at delivery, and in the infant at 1 and 24 hours, 1 and 3 weeks, 2, 4, 6 and 12 months of postnatal age. These values were compared with those of 75 healthy age-matched controls. Gestational age was 30 weeks in 24, 31 weeks in 23, 32 weeks in 13, 33 weeks in 13, 34 weeks in one, 35 weeks in one and 36 weeks in one. Hypothyroxinemia at each postnatal age was defined as serum free T4 values under -2 SD of the mean of controls. Results Forty-four patients were normothy-roxinemic at all times, and 32 presented hypothyroxinemia at 24 hours (29 patients), 1 week (seven patients) and 3 weeks (two patients). Follow-up of 31 patients who were normothyroxinemic at 24 hours of life showed that at one week three (9.7%) were hypothyroxinemic and at 3 weeks all were normothyroxinemic. At 24 hours of life, all patients with patent ductus arteriosus and all patients treated with dopamine were in the hypothyroxinemic range. Conclusion Hypothyroxinemia may be present in sick preterm infants 30-36 weeks of gestational age, particularly in those treated with dopamine and/or presenting patent ductus arteriosus.

Background: Maximum bone mass accretion in the fetal skeleton is acquired during the third trimester of gestation, and may he compromised in premature newborns. Objective: To ascertain the incidence and evolution of osteopenia, a longitudinal study was performed to evaluate areal bone mineral density (aBMD) in the lumbar spine in premature newborns followed during the first 2 years of life. Methods: aBMD values were assessed in lumbar spine (L2-L4) by DEXA and expressed as grams hydroxyapatite/cm 2 in 80 premature newborns, 41 boys and 39 girls, of gestational ages 24.5-35.7 weeks. aBMD values were evaluated at (mean ′ SD) 0.2 ′ 0.1 years (at discharge from the neonatal unit), 0.9 ′ 0.2 years and 2.0 ′ 0.5 years of postnatal age, and compared with those of age- and sex-matched full-term newborns with normal intrauterine and postnatal growth. Results: aBMD values recovered progressively from the first to the third evaluations, and were 0.139 ′ 0.06 g/cm 2 (-2.4 ′ 1.4 SDS) at 0.2 ′ 0.1, 0.270 ′ 0.06 g/cm 2 (-1.0 ′ 1.0 SDS) at 0.9 ′ 0.2 and 0.410 g/cm 2 (-0.08 ′ 1.0 SDS) at 2.0 ′ 0.5 years. Conclusions: Our data show a significant catch-up of aBMD, reaching values similar to those of full-term newborns at the age of 0.2 ′ 0.5 years, regardless of the gestational age at birth.

Background: Compulsory vaccination of children against hepatitis B virus (HBV) infection was introduced in Italy in 1991. Patients and Methods: To evaluate the current importance of pediatric HBV infection, we studied 359 HBsAg-positive children admitted to 16 centers in Italy from 1991 to 1998. 185 patients were natives of Italy and 174 (39 immigrants and 135 adopted) came from highly endemic countries (eastern Europe: 60.9%, Asia: 16.7%, Africa: 14.9% and Central and South America: 5.7%). Results: Transaminase levels were moderately altered in both Italian (mean 134 UI/l) and foreign children (mean 168 UI/l). In total, 77% of Italian children and 88% of foreign children tested HBeAg positive. High transaminase levels and HBeAg positivity were more frequent in adopted children. Follow-up of 317 patients showed that the incidence of HBeAg/anti-HBe serum conversion was similar in all cohorts, but in adopted children it occurred at an earlier age and was associated with HBsAg clearance in 5%. Conclusion: HBV is not frequent in Italian children today, but it is common among children coming from highly endemic areas. The vaccination of nonimmune native populations must be strongly recommended.

During an 8-year prospective study of post-transfusion hepatitis conducted at the Thalassemic Center of Cagliari (Italy), including 135 newly diagnosed thalassemic children on long-term transfusion maintenance, 83 children (61%) developed non-A, non-B hepatitis (NANBH). Resolution of NANBH was observed in 17 (20%) cases, and chronicity in 57 (69%), whereas the remaining 9 (11%) experienced one or two additional bouts of acute NANBH. Of the 83 children with NANBH, 75 (90%) showed anti-hepatitis C virus (HCV) seroconversion when tested by second-generation enzyme-linked immunosorbent assay (ELISA), whereas first-generation ELISA showed anti-HCV in only 59 (71%) cases (p = 0.003). Moreover, the newly developed assay allowed an earlier detection of anti-HCV response in most of the patients who seroconverted by both assays, reducing significantly the mean onset-seroconversion interval (5 +/- 9.4 weeks vs. 14.5 +/- 20.8 weeks, p < 0.05). It was significantly more sensitive for the identification of HCV infection, not only in resolving NANBH, but also in NANBH progressing to chronicity (79 vs. 35%, respectively, p = 0.008; and 93 vs. 79%, p = 0.028). The pattern of antibody response with first-generation assay was characterized by clearance of anti-HCV with time, in most of the patients who recovered, and by persistence of anti-HCV in the majority of those who progressed to chronicity, whereas second-generation ELISA usually showed persistence of anti-HCV over time, regardless to the outcome of the disease.(ABSTRACT TRUNCATED AT 250 WORDS)

North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Annual Meeting October 19Y22, 2006 Orlando, Florida

Zonulin, an intestinal tight junction modulator, is involved in the pathogenesis of type I diabetes