Objective: We report features at birth, at presentation and at the last follow up of children with Extrahepatic Portal Vein Obstruction (EHPVO) in order to favour an early diagnosis and a best management of the disease.

Background:Early-onset (EO) pediatric inflammatory bowel diseases (IBD) seem to be more extensive than those with a later onset. To test this hypothesis, we examined the phenotype and disease course of patients with IBD diagnosis at 0 to 5 years, compared with the ranges 6 to 11 and 12 to 18 years.Methods:Anatomic locations and behaviors were assessed according to Paris classification in 506 consecutive patients: 224 Crohn's disease, 245 ulcerative colitis, and 37 IBD-unclassified.Results:Eleven percent of patients were in the range 0 to 5 years, 39% in 6 to 11 years, and 50% in 12 to 18 years. Ulcerative colitis was the most frequent diagnosis in EO-IBD and in 6- to 11-year-old group, whereas Crohn's disease was predominant in older children. A classification as IBD-unclassified was more common in the range 0 to 5 years compared with the other groups (P < 0.005). EO Crohn's disease showed a more frequent isolated colonic (P < 0.005) and upper gastrointestinal involvement than later-onset disease. Sixty-two percent of the patients in the 0 to 5 years range had pancolonic ulcerative colitis, compared with 38% of 6 to 11 years (P = 0.02) and 31% of 12-18 years (P = 0.002) range. No statistical difference for family history for IBD was found in the 3-year age groups. Therapies at the diagnosis were similar for all children. However, at latest follow-up, a significantly higher proportion of younger children were under steroids compared with older groups (P < 0.05). Surgical risk did not differ according to age.Conclusions:EO-IBD exhibits an extensive phenotype and benefit from aggressive treatment strategies, although surgical risk is similar to later-onset disease. A family history for IBD is not common in EO disease.

Klinefelter syndrome (KS, 47,XXY) is associated with low serum testosterone (T), long thought to arise from disturbed steroidogenesis in Leydig cells. However, intratesticular testosterone (ITT) concentrations were recently found to be normal in a KS mouse model (41,XXY*). So far, nothing was known about ITT concentrations in human patients with KS. Therefore, ITT, sex hormone-binding globulin (SHBG) and histological parameters were measured in human testicular biopsies of 11 KS patients, 30 azoospermic patients with Sertoli-cell-only syndrome and nine men with normal spermatogenesis as controls. ITT concentrations showed an overall pronounced excess over intratesticular SHBG in molar terms and were significantly increased in men with KS despite of reduced serum T levels. While the ratio of ITT/serum T was markedly increased in KS, the ITT/LH-ratio was comparable between all groups. After finding significantly increased ITT levels in men with KS, a finding even more striking than in the 41,XXY* KS mouse model, we set out to find a possible vascular' explanation for the lack of T release into the testicular blood stream. In testis biopsies from patients, reliable analysis of the vessels is, however, not possible because of the bias resulting from the dissection technique requiring avoidance of larger blood vessels to prevent bleeding. Consequently, the blood vessel constitution was evaluated in whole testis sections from adult male 41,XXY* and 40,XY* mice (n=5, each). Indeed, the blood vessel/testes surface ratio correcting for the smaller testes of XXY* mice was significantly lower in these mice compared with XY* controls. In conclusion, testicular T production does not seem to be impaired in men with KS. On the contrary, ITT concentrations are increased, but not because of increased SHBG activity. The data from the mouse model let us speculate that a reduced vascular bed might be involved in lower release of T into the bloodstream.

We report the outcome of liver transplantation (LT) in the only surviving patient with lathosterolosis, a defect of cholesterol biosynthesis characterized by high lathosterol levels associated with progressive cholestasis, multiple congenital anomalies and mental retardation. From her diagnosis at age 2 she had shown autistic behavior, was unable to walk unaided and her sight was impaired by cataracts. By age 7 she developed end-stage liver disease. After a soul-searching discussion within the transplantation team, she was treated with LT as this represented her only lifesaving option. At 1-year follow-up, her lathosterol levels had returned to normal (0.61 mg/dL from 13.04 ± 2.65) and her nutrition improved. She began exploring her environment and walking by holding onto an adult's hand and then independently. Her brain magnetic resonance imaging (MRI) had shown a normal picture at age 1, whereas a volume reduction of white matter with ex vacuo ventricular dilatation and defective myelinization were observed before transplant. At 5-year follow-up, a complete biochemical recovery, an arrest of mental deterioration and a stable MRI picture were achieved, with a return to her every day life albeit with limitations. Timely liver transplant in defects of cholesterol biosynthesis might arrest the progression of neurological damage.

Aims: Patients with Klinefelter syndrome (47,XXY = KS) as well as 41,XXY* mice suffer from low serum T levels. However, Leydig cells are hyperplastic and hyperactive in the KS mouse model and ITT concentrations are normal. We therefore analysed ITT in KS patients and tested the hypothesis that altered testicular vasculature might be the cause of low T release into circulation.

Non-classical congenital adrenal hyperplasia (NCAH) is a morbid condition sustained by the reduced function of one of the enzymes involved in the adrenal steroid biosynthesis pathway, mainly the 21-hydroxylase. Different degrees of enzyme activity impairment determine different clinical pictures, with childhood or post-pubertal onset. The aim of this study was to evaluate the relationship between genotype, phenotype, and adrenal hormonal levels in a group of 66 patients affected by NCAH attending outpatient pediatric or endocrinological Clinics. Our findings show that age at pubarche/menarche was significantly younger, height SD score) and Δ bone age-chronological age were significantly higher in patients with a more severe enzyme activity impairment, while cutaneous androgenization and menstrual irregularities in post-pubertal girls were not related to the grading of genotype.

Case report: We report the case of an 80-day-old infant referred to our department with refractory severe dermatitis, resembling Acrodermatitis Enteropathica (AE), associated with moderate failure to thrive. She had been hospitalized in a different clinic when she was 50 days old. During that time she was treated with oral steroids for suspected atopic dermatitis with no lasting benefits. The baby had been exclusively breast fed. At admission, the patient was well below the 3rd percentile for weight and at the 25th percentile for length, while the respective percentiles at birth were both at the 50th. Dermatological examination revealed erythematous, scaly plaques with crusts and ulcerations, predominantly in the diaper area, perioral area and extremities. Mucous membranes and nails were not involved. Laboratory tests revealed anemia, hypoalbuminemia and zinc deficiency. Laboratory abnormalities included the following: albumin minimum values of 16.2 and 19.2 g/dl (38–54 g/dl), haemoglobin minimum values of 5.5 and 6.7 g/dl (10–13 g/dl). Two albumin infusions and two blood transfusions were required. A sweat test was done but the amount of sweat collected was insufficient for an accurate result, influenced by the skin condition. However, stools were positive for fat analysis; steatocrit was 28% ( 5 U/g). With the suspect of CF pancreatic enzyme supplementation was started and was associated with clinical and laboratory findings improvement. The dermatitis showed a gradual resolution, preceded by an extensive desquamation. Finally, mutation analysis for CF showed homozygous mutation 508. After three months of therapy, the patient’s weight increased from the 3rd to the 25th percentile, the dermatitis had completely resolved and laboratory findings had improved. Conclusions: Skin manifestations of CF are under-estimated; however, dermatitis can be the presenting sign of the disease, prior to pulmonary and gastrointestinal symptoms. AE-like dermatitis may concur and allows a correct and early diagnosis in atypical presentations of CF, particularly in association with other symptoms such as failure to thrive or laboratory findings such as anemia and hypoalbuminemia. Even in cases of negative neonatal screening, further investigations such as the sweat test and/or genetic analysis may be required if there are symptoms suggestive of CF. It is important to offer genetic counselling to parents with a family history of CF so that they are aware of the possibility of performing CF carrier screening and prenatal diagnosis.

Background and Aim: Liver fibrosis is an important factor affecting organ survival in transplanted patients, but liver biopsy is an invasive technique to use in children without clinical or serological signs of graft damage.Transient elastography (TE) is a new noninvasive technique, validated in adults, that estimates the liver stiffness of a cylindrical section that is 100 fold that of a standard bioptic specimen.We evaluated the feasibility of TE in children after liver transplantation (LT) and we compared it with liver biopsy.Methods: 24 HCV/HBV negative paediatric liver transplant recipients with reliable TE (IQR <30% and success rate >60%) were enrolled in the study.All patients had TE and biopsy within a 1 year interval.Bioptic specimens (length range: 1-4.2 cm, at least 4 portal spaces) were evaluated according to the METAVIR score.The cut-off value to use for the identification of significant fibrosis (F ≥ 2) was obtained by the ROC curve analysis. Results:The METAVIR fibrosis stages were: F0 = 7, F1 = 9, F2 = 6, F3 = 1, F4 = 1; the average stiffness was calculated for all the histological fibrosis stages (F0 = 4.72±1.12kPa, F1 = 4.4±0.64kPa, F2 = 5.7±2.31kPa, F3 = 6.8 kPa, F4 = 10.1 kPa).There was a statistically significant correlation between TE and METAVIR (R = 0.571, p = 0.004).The diagnostic accuracy of TE for the diagnosis of fibrosis (F ≥ 2), which was calculated by a comparison between the liver stiffness and METAVIR as gold standard, measured as an area under the curve (AUROC), gave a result equal to 0.715, showing that the method had a good diagnostic performance.A stiffness cut-off of 6.6 kPa was identified as the best value associated with significant fibrosis (F ≥ 2) (sensitivity 62.5%, specificity 100%, PPV 100% and NPV 84.21%).Conclusions: TE is a simple, non-invasive, reliable tool to assess and monitor the progression of liver fibrosis in paediatric transplanted liver patients.If liver stiffness is <6.6 kPa a significant fibrosis can be excluded.Therefore, these results suggest that follow-up liver fibrosis biopsy could be reserved to selected cases with a liver stiffness of ≥6.6 kPa.Further studies are ongoing on larger cohorts.

Chylomicron retention disease is a recessive inherited disorder characterized by fat malabsorption and steatorrhea and is associated with failure to thrive in infancy. We describe a kindred carrying a mutation of Sara2 gene causing a chylomicron retention phenotype. The proband was a 5-month-old baby, born of consanguineous, apparently healthy parents from Morocco, with failure to thrive. There was a large quantity of fats in feces and malabsorption of fat-soluble vitamins. Intestinal biopsies showed a diffused enterocyte vacuolization with large cytosolic lipid droplets. Chylomicron retention disease or Anderson disease was hypothesized, and the Sara2 gene was analyzed by direct sequencing. Analysis of the Sara2 gene in the proband identified a 2-nucleotide homozygous deletion in exon 3 leading to a premature stop codon (c.75-76 del TG-L28fsX34). The father was heterozygous for the same mutation, whereas the proband's mother was homozygous, suggesting a variable phenotypic expression of the molecular defect. More studies are needed to understand the reasons of the phenotypic variability of the same molecular defect in the same family.

AIMS:To investigate the influence of genotype, age and gender on the thiopurine S-methyltransferase (TPMT) phenotype in healthy Italian-Caucasian subjects.MATERIALS & METHODS:The study investigated the TPMT genotype and the TPMT phenotype of 943 healthy Italian-Caucasian subjects of different age and gender (age range: 0.08-68 years; 623 males 320 females). TPMT red blood cell activity was measured in all samples and genotype was determined for the TPMT alleles *2, *3A, *3B and *3C.RESULTS:TPMT activity levels in our whole population ranged from 1.6 up to 75.2 U/gHb. Significant TPMT activity differences between wild-type and heterozygous subjects were observed. We divided our TPMT activity into four categories according to our frequency distribution: low (0.1%), intermediate (32.9%), normal (60%) and high (7%), with arbitrary cut-off values of 8.0, 19.4 and 37.0 U/gHb, respectively. The whole population had a total of 94.5% of homozygous wild-type subjects, 5.4% heterozygous variants and one (0.1%) compound heterozygous variant TPMT*3B/*3C. The overall concordance rate between TPMT genotypes and phenotypes was 71.6%. The TPMT activity was significantly higher in wild-type children (0.08-17 years) than in wild-type adults (aged 18-68 years). Moreover, it was noted that wild-type infants from 0.08 to 5 years had a 9% higher average TPMT activity than the other wild-type groups, and only in children from 0.08 to 2 years was the TPMT activity higher in males than in females.CONCLUSION:The data obtained in this study show that genetic factors seem to be the major aspect in TPMT phenotype variability in adults, whilst, in children, other physiological factors should be taken into consideration when assessing the TPMT phenotype, such as age and gender.

The aim of the study was to examine the effects of strenuous training on the hypothalamic-pituitary-adrenal axis activity. Exercise tests and saliva collections for analysis of awakening cortisol response (ACR) and midnight cortisol were performed before and after a 7-day period of intensified training in a group of 15 soccer players. Intensified training resulted in a performancedecrement as shown by the pre-post-training changes in maximal values of counter movement jump (CMJ) height ( p =0.008). Cortisol assessment during the first 30 min after awakening showed significant increases both before and after the 7-day period and post-training ACR higher than pre-training ACR ( p <0.001). Midnight cortisol also significantly increased after training (mean±SD, before: 3.0±0.7 nmol/l vs after: 5.9±3.3 nmol/l; p =0.017). The analysis of individual data showed an important inter-individual variability in the pre-post-training changes: several subjects increased post-awakening peak of cortisol, rate of cortisol increase from awakening to peak, and area under the curve (AUC) values, whereas other subjects showed no training-related increases. Significant correlations were observed between pre-post-training change in CMJ and in the following variables: awakening cortisol (r=0.74), post-awakening peak of cortisol (r=0.81), rate of cortisol increase (r=0.75), and AUC (r=0.79). Briefly, the lower the performance decrease, the higher the training-associated ACR increase. These data could indicate that a dys-regulated adaptation to exercise occurred in athletes who experienced a higher performance decrease after training and lower (or absent) hormonal changes. Future studies are needed to elucidate the physiological determinants which underlie the exercise-elicited changes in ACR and in midnight cortisol levels and their value in predicting impaired adaptations to exercise.

A 32 year-old asymptomatic male came to our attention with a 21-year history, documented elsewhere, of puzzling increases in his serum transaminase level. At first, very low serum ceruloplasmin level suggested Wilson disease. Two liver biopsies showed mild portal inflammation, steatosis and mild fibrosis. Further investigation revealed low levels of the glycoproteins AT III and clotting factor XI, leading to a diagnosis of congenital disorder of glycosylation (CDG) type II. Further studies as to the cause of this 'apparently new' CDG, are ongoing. On the basis of our data and a literature review, we suggest that subjects with asymptomatic hypertransaminasaemia be screened for CDG.

Background and aim. The emergence of variants unable to produce HBeAg (P-C mutants) may account for the persistence of HBV infection and disease in genotype D HBV infected children. We investigated the relationship of the longitudinal changes in P-C wild type and mutant populations with the virological and clinical outcomes.