Intractable diarrhea in infancy and molecular analysis: We are beyond the tip of the iceberg.

BACKGROUND: Intractable diarrhea (ID) could be defined as a syndrome of severe chronic diarrhea associated with malnutrition not easily resolved by conventional management. AIMS: To provide an overview on etiology and management of ID patients in Italy in the last 12 years. METHODS: The members of Italian Society for Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP) enrolled all ID patients seen between January 1, 2011 and December 31, 2022. RESULTS: 69 children were enrolled (49 M, 20 F; median age at ID onset 9.5 days) from 7 tertiary care pediatric centers. Overall 62 patients had genetic diseases; 3 had infantile Inflammatory Bowel Disease and 1 autoimmune enteropathy in absence of genetic mutations; 2 undefined ID. Defects of intestinal immune-related homeostasis caused ID in 29 patients (42 %). CONCLUSION: ID is a rare but challenging problem, although the potential for diagnosis has improved over time. In particular, molecular analysis allowed to identity genetic defects in 90 % of patients and to detect new genetic mutations responsible for ID. Due to both the challenging diagnosis and the treatment for many of these diseases, the close relationship between immune system and digestive tract should require a close collaboration between pediatric immunologists and gastroenterologists, to optimize epidemiologic surveillance and management of ID.

Teduglutide in pediatric intestinal failure: A position statement of the Italian society of pediatric gastroenterology, hepatology and nutrition (SIGENP).

In recent years, the spectrum of possible treatments for Intestinal Failure (IF)-Short Bowel Syndrome (SBS) has been enriched by the implementation of GLP-2 analogues. In Italy, teduglutide (Ted), an analogue of GLP-2, was approved in January 2021 by the Italian Regulatory Agency for Drugs (AIFA) for IF-SBS patients ≥1 year old. According to the Agency indications, Ted can now be prescribed by regional reference centers, with costs fully charged to the National Health Service. Following pediatric-use approval in our country and in light of scarce evidence in childhood, the pediatric network for IF of the Italian Society for Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP) planned to share management methods of Ted in pediatric IF. The main purpose was to identify the best candidates from a cost-effective perspective. Thus, focusing on available literature and on expert opinions, the present position statement provides consensus-based recommendations on the use of Ted for pediatric gastroenterologists and nutritionists treating children with SBS.

Cholelithiasis management in a third-level pediatric center: case series and literature review.

Pediatric cholelithiasis is being increasingly diagnosed owing to the widespread use of ultrasonography, raised pediatric obesity and use of long-time parenteral nutrition. Clinical presentation is variable and complicated onset could lead to severe consequences. The aim of this study is to present a 15-years-experience of a pediatric third-level-center in treating cholelithiasis. A retrospective study collecting children with gallstone operated on between 2006 and 2020 is presented. Demographic data, clinical presentation, sonographic findings, risk factors, surgery, complications, follow-up were evaluated. 199 patients were included. Twenty-nine patients (14.5%) with cholelithiasis had a complicated onset. Patients with cholelithiasis older than 10 years had a higher rate of symptomatic/complicated onset. Hemolytic disease was the most frequent co-morbidity (16.1%). Laparoscopic cholecystectomy was performed in 192 cases (96.5%) with a conversion rate of 1.6%. Nearly 1% showed a major post-operative complication after cholecystectomy. Cholelithiasis in patients older than 10 years can be safely treated with laparoscopic cholecystectomy, especially if one or more co-morbidities are present. Laparoscopic splenectomy can be easily associated in the same procedure depending on medical indication. Definition of pediatric surgical timing guidelines would be of quite interest in the field.

Different renal manifestations associated with very early onset pediatric inflammatory bowel disease: case report and review of literature.

BACKGROUND: Inflammatory bowel diseases are characterized by chronic inflammation of the gastrointestinal tract. In particular, Crohn disease and ulcerative colitis represent the two most common types of clinical manifestations. Extraintestinal manifestations of inflammatory bowel diseases represent a common complications, probably reflecting the systemic inflammation. Renal involvement is reported in 4-23% of cases. However, available data are limited to few case series and retrospective analysis, therefore the real impact of renal involvement is not well defined. CASE PRESENTATION: We report the case of a 10-years old male affected by very early onset unclassified-Inflammatory bowel diseases since he was 1-year old, presenting with a flare of inflammatory bowel diseases associated with acute kidney injury due to granulomatous interstitial nephritis. Of interest, at 7-year-old, he was treated for IgA nephropathy. To our knowledge, no previous reports have described a relapse of renal manifestation in inflammatory bowel diseases, characterized by two different clinical and histological phenotypes. CONCLUSIONS: The link between the onset of kidney injuries with flares of intestinal inflammation suggest that nephritis maybe considered an extra-intestinal manifestation correlated with active inflammatory bowel disease. However, if granulomatous interstitial nephritis represents a cell-mediated hypersensitivity reaction than a true extraintestinal manifestation of inflammatory bowel diseases is still not clarified. We suggest as these renal manifestations here described may be interpreted as extraintestinal disorder and also considered as systemic signal of under treatment of the intestinal disease.

Italian pediatric nutrition survey.

INTRODUCTION: the prevalence of malnutrition in children and its impact on clinical outcomes is underrecognized by clinicians in Italy as well as worldwide. A novel definition of pediatric malnutrition has been recently proposed by a working group of the Academy of Nutrition and Dietetics and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.), based on the correlation between illness and the use of zscores of anthropometric measurements. AIM: to investigate the prevalence of malnutrition and related nutritional support among hospitalized children in Italy, in a nationwide survey performed in a single day (16/4/2015). METHODS: an open access website (http://nday.biomedia.net) was used to collected data from 73 hospitals and 101 wards in 14 Italian regions (1994 patients). Anonymous information was collected on hospitals' characteristics, patient's anthropometry, admission diagnosis, presence of chronic diseases and use of nutritional support: oral nutritional supplements (ONS), enteral nutrition (EN) or parenteral nutrition (PN). Z-scores of anthropometric measurements, calculated with Epi Info 7.1.5, defined nutritional status: wasting was identified by BMI or Weight-for-Length z-score (<-1 mild, <-2 moderate, <-3 severe), stunting by Height-for-Age Z-score <-2. WHO 2006 and CDC 2000 growth charts were used respectively for children younger and older than 2 years old. RESULTS: 1790 complete records were obtained for hospitalized patients aged 0-20 years, with median age 6.16 (0.1-20 years and 53.3% males). 52.9% were aged 0-6 years and 58.8% of children suffered from chronic diseases. Wasting was detected in 28.7% of the total sample with higher occurrence observed in age ranges 0-6 and 14-20 years, while 17.3% of patients showed stunting; surprisingly almost 27% of them were aged 0-2. A ranking of the admission diagnosis with the highest rate of malnutrition was complied. The prevalence of wasting was significantly (p < 0.005) higher amongst children with chronic diseases (34.1% vs. 27.1%); stunting prevalence tripled in patients with chronic disease (24.5% vs. 8.3%). Only 23.5% of malnourished children (17%, 25.6% and 36.7%, respectively mild, moderate and severe malnutrition) received nutritional support: 11.7% received oral nutrition supplements (ONS, modular or complete), 11.5% enteral nutrition (EN, 6.4% via nasogastric tube, 5.1% via gastrostomy) and 6.8 % received parenteral nutrition (PN); in some patients a combination of two. Nutritional support is more commonly used among stunting patients, 39.5% of children under treatment. CONCLUSION: Malnutrition of any grade was observed in nearly 1/3 and stunting in 17% of the reported hospitalized children, and it is likely to be underrecognized as the nutritional support reached only a small part of the malnourished children.

Is perioperative cholangiography necessary in children undergoing elective laparoscopic cholecystectomy?

BACKGROUND: The necessity of carrying out pre- or intra-operative imaging of the biliary tree to rule out a possible anatomical abnormality or the presence of common bile duct (CBD) stones in patients undergoing laparoscopic cholecystectomy (LC) is debated. We prospectively assessed the risk of developing symptoms related to bile duct injury or CBD stones after LC in children not receiving peri-operative cholangiography. MATERIALS AND METHODS: All patients

Necessity for surgery in children with gastrooesophageal reflux and supraoesophageal symptoms.

BACKGROUND/PURPOSE: The majority of gastrooesophageal reflux (GER) manifestations in children are supraoesophageal, and "spitting/posseting" is "the tip of the iceberg" because most reflux episodes are not regurgitated. Aim of the present study was to prospectively evaluate the incidence of gastrooesophageal reflux and the incidence of antireflux surgery in patients with difficult-to-treat respiratory symptoms. PATIENTS AND METHODS: Five hundred and ninety-five children with difficult-to-treat respiratory symptoms were prospectively enrolled in a blind study looking for the correlation between clinical presentation (asthma or non-asthma), oesophageal pH monitoring, X-ray barium meal, broncho-alveolar lavage, necessity for surgery, and outcome. RESULTS: pH monitoring was anomalous in 47% of patients with asthma (group A) and in 43% of those who did not have asthma as main symptom (group B). Overall, 48 patients finally underwent anti-reflux surgery (8%) as anti-reflux medical treatment did not ensure stable benefits. No major surgical complications were experienced. Postoperatively, respiratory symptoms improved strongly (Visick 1) in 69% of cases, moderately (Visick 2) in 27%, while clinical worsening (Visick 4) was observed in 4%. CONCLUSIONS: The results of this study stress the importance of symptoms, clinical response to anti-reflux medical treatment and broncho-alveolar lavage compared to classical pH parameters in the decision-making process for patients with difficult-to-treat supraoesophageal symptoms. To date no single tool alone has proved to be diagnostic in these patients. Fundoplication is recommended only when a relationship between supraoesophageal symptoms and gastrooesophageal reflux is strongly suspected.

Results of the laparoscopic Heller-Dor procedure for pediatric esophageal achalasia.

BACKGROUND: Esophageal achalasia is not a frequent disorder in children and different treatments have been proposed during past decades. This study reviews the results of the laparoscopic Heller-Dor procedure performed in pediatric patients in two different surgical units. METHODS: We included the patients aged <14 years with a minimum follow-up of 6 months operated on in the period 1994-2001. A single longitudinal anterior esophageal myotomy (Heller) and a 180 degrees anterior gastropexy (Dor) were laparoscopically performed. The patients were checked to detect intra- or postoperative complications and recurrence. RESULTS: Twenty children were operated on. Mean follow-up was 45 months (range 6-102). Postoperative clinical score was Visick 1 in 15 cases and Visick 2 in five. CONCLUSIONS: As complication and recurrence rates are very low we consider modified Heller myotomy and Dor gastropexy through a laparoscopic approach our first choice to treat esophageal achalasia in the pediatric population.

The use of ciclosporin in paediatric inflammatory bowel disease: an Italian experience.

AIM: To asses the efficacy and safety of ciclosporin in a paediatric population with inflammatory bowel disease. PATIENTS AND METHODS: Twenty-three Italian children treated with ciclosporin were studied retrospectively. The indications for treatment were severe unresponsive colitis, chronic active colitis or severe fistulizing Crohn's disease. The treatment duration, follow-up and causes of drug discontinuation were assessed. RESULTS: Sixteen patients were treated intravenously for a mean time of 10 +/- 7 days (1-24 days) and 19 orally for a mean time of 133 days (17-660 days). The mean follow-up of all patients was 13.2 months. Ciclosporin was totally ineffective, being discontinued for surgery, in nine of 23 patients (39%); it was discontinued for partial response in three patients (13%). During treatment, clinical remission was achieved in eight children (35%) and maintained after drug withdrawal in four (17%). In severe unresponsive colitis, urgent colectomy was avoided in 12 (85%) of 14 patients who tolerated the drug. Side-effects appeared in six of 23 patients (26%), and three (13%) required ciclosporin to be discontinued due to neurotoxicity. CONCLUSIONS: Ciclosporin shows disappointing long-term results in the treatment of refractory inflammatory bowel disease, but can play an important role in preventing urgent surgery in unresponsive severe colitis. Severe side-effects can occur.

Laparoscopic vs open approach for the treatment of gastroesophageal reflux in children.

BACKGROUND: The laparoscopic approach has become increasingly popular for fundoplication over the last few years; however many surgeons are skeptical about its real advantages. METHODS: We conducted a prospective comparative study of children operated on for gastroesophageal reflux (GER). Exclusion criteria included age <1 YEAR AND >14 years, previous surgery on the esophagus or stomach, and neurologic impairment. We compared two groups of patients who met the same inclusion/exclusion criteria. One group was treated via a laparotomic approach between January 1993 and December 1997; the other was treated via a laparoscopic approach between September 1998 and December 2000. A 360 degrees wrap was performed in each group. RESULTS: Group 1 (laparotomic approach) included 17 patients; mean operative time was 100 min and postoperative time was 7 days. Group 2 comprised 49 children operated on via a laparoscopic approach; mean operative time was 78 min and postoperative time was 48 hours. No major complications were encountered in either group. In postoperative period, two patients in group 1 had complications. One had a prolonged bout of gastroplegia, which required nasogastric drainage, and then recovered spontaneously after 20 days; the other had stenosis of the wrap, which required dilation. No relapses occurred during a follow-up of 6 months. Long-term follow-up data are not presented. Comparative analysis of the short-term functional results indicated that there were no differences between the two groups. CONCLUSION: This study confirms that the minimally invasive approach is safe and effective for the treatment of primary gastroesophageal reflux disease in children.

Severe attack of ulcerative colitis in children: retrospective clinical survey.

AIM: To obtain clinical data concerning severe attacks of ulcerative colitis in children. PATIENTS AND METHODS: A retrospective chart review of 37 children with ulcerative colitis was carried out in order to assess the prevalence, risk factors, timing of presentation, and outcome of severe attacks of ulcerative colitis. RESULTS: A total of 20 severe attacks occurred in 15 out of the 37 patients. No difference in the occurrence of severe attacks was detected in relation to age or disease extent at diagnosis. The mean interval between disease diagnosis and a severe attack was 9.1 months (range 0-30). Of the 20 severe attacks, 11 were resolved with medical treatment in a mean time of 1 1 +/- 4.6 days while 9 out of 20 needed urgent surgery in a mean time of 7.4 +/- 4.8 days. Of 10 out of the 15 patients who recovered from the first attack 4 required colectomy after a mean time of 6.7 months, another 4 are still in remission at a mean period of 40.7 months, one needed elective surgery after 25 months and one was lost to follow-up. CONCLUSIONS: Severe attacks of ulcerative colitis had a high prevalence rate [40%); age and disease extent at presentation were not predictors of their occurrence. Approximately half the attacks resolved with medical treatment alone, while the other half required emergency surgery. After successful medical treatment of the first attack, 40% of children maintained long-term remission, while 40% required early colectomy

Medium-term results after cholecystectomy in patients younger than 10 years.

BACKGROUND: Gallbladder stones are a well-known and widely studied problem in children. Hematological disorders are the most common diseases that can cause cholelithiasis. However, in the last few years, the proportion of children with idiopathic cholelithiasis has increased 50%. Herein, we present a prospective study on laparoscopic cholecystectomy in a selected group of patients aged < 10 years. METHODS: Fifty-eight patients aged < 10 years underwent laparoscopic cholecystectomy for stones in the period 1992-99. The female/male ratio was 1.5, the mean age was 8 years (range, 2-10), and the mean weight was 30 kg. In all patients, parenteral nutrition, fasting state, and prolonged use of antibiotics had been suspended for > or = 6 months, and conservative treatment had been tried for > or = 12 months in the absence of symptoms of stone migration. All the patients were followed up after surgery: clinically at 1,6,12, and 36 months and by ultrasound at 1, 12, and 36 months. Liver function and hematological tests were performed in case of symptoms or if hemolytic disorders were the cause of stones. RESULTS: The mean operative time was 63 min (range, 30-120) in children undergoing cholecystectomy alone and 150 min in children undergoing associated splenectomy. There were no major complications or reoperations. Minor complications included bleeding from accessory cystic artery (n = 3) and insufflation of the omentum (n = 2). One case was converted to an open procedure due to technical problems. All the children were followed up and no complications were observed. CONCLUSION: We consider the laparoscopic approach the gold standard for cholecystectomy in children. This procedure does not have a complication rate any higher than open cholecystectomy, and patient follow-up is as good as that of open surgery. Previous abdominal surgery is not a contraindication to laparoscopy.

A girl with severe fistulizing Crohn's disease.

We report the case of a girl with a severe perianal fistulizing Crohn's disease who during intravenous infusion of cyclosporine developed headache, general seizures and cortical blindness. Head magnetic resonance imaging showed spread, cortical-subcortical nonenhancing signal changes. Full neurological recovery was achieved in 24 hours. Cyclosporine was stopped and a single dose of infliximab was infused with rapid improvement of the fistula that at 7 months' follow-up is still closed.

Mutations in the glucose-6-phosphatase gene of 53 Italian patients with glycogen storage disease type Ia.

Type Ia glycogen storage disease (GSD1a) is an autosomal recessive metabolic disorder caused by a deficiency in glucose-6-phosphatase (G6Pase). Recent cloning of the G6Pase gene and the subsequent identification of several disease-causing mutations have shown an ethnic molecular heterogeneity. Using SSCP analysis and DNA sequencing, we characterized the G6Pase gene of 53 unrelated Italian patients. The two most common mutations, R83C and Q347X, accounted for 66.9% of the mutant alleles. Eight novel mutations and three rare mutations were identified in 15.7% of disease alleles. These results suggest that a DNA-based method can be used as an initial screening in Italian patients clinically suspected of having GSD1a, avoiding liver biopsy for enzymatic diagnosis. In particular, a noninvasive diagnosis is a suitable method for the Italian subpopulation coming from Sicily, where the R83C mutation is present in 80% of mutant alleles. Molecular carrier detection and prenatal diagnosis can be provided to GSD1a families with identified mutation in the propositus.

99mTc-white cell scanning to detect gut inflammation in children with inflammatory bowel diseases or spondyloarthropathies.

OBJECTIVE: Gut inflammation is a common feature shared by inflammatory bowel diseases (IBD) and the spondyloarthropathies (SpA). The aim of the present study was to compare the reliability of a number of non-invasive investigations for the detection of an inflammatory process of the intestine. METHODS: Forty-two children were studied: (i) patients with a previous diagnosis of IBD (group A); (ii) patients with suspected IBD (group B); and (iii) patients with predominantly rheumatological manifestations associated with gastrointestinal symptoms (group C). All the patients were studied using 99mTechnetium-HMPAO labelled white cell scanning (99mTc-WCS), and abdominal ultrasound (US). In addition the ESR, serum class A immunoglobulins, faecal occult blood (OB) and faecal alpha 1-antitripsin level (F alpha 1-AT) were determined. Colonoscopy plus multiple biopsies and radiological study of the intestine were used as gold standards. RESULTS: 99mTc-WCS showed the highest sensitivity (85%) and specificity (100%) in detecting the presence of gut inflammation. This was followed by ESR and faecal occult blood (63% sensitivity, 44% specificity), F alpha 1-AT (43% sensitivity, 44% specificity) and IgA (42% sensitivity, 88% specificity). Ultrasound was informative in 28% of the active/affected patients, with a specificity of 75%. CONCLUSION: Although ileo-pancolonscopy remains the gold standard for the histological characterisation of gut inflammation, 99mTc-WCS represents the most reliable non-invasive test for its detection.

Multiple congenital anomalies, brain hypomyelination, and ocular albinism in a female with dup(X) (pter-->q24::q21.32-->qter) and random X inactivation.

We report on an 18-month-old girl with multiple congenital anomalies (prominence of the metopic suture, fine hair, club foot, absence of the 12th rib, brachydactyly) and severe mental retardation. The funduscopic examination showed diffuse retinal hypopigmentation. Brain magnetic resonance image (MRI) showed signs of diffuse hypomyelination. On cytogenetic and molecular evidence, the karyotype was 46,X,dirdup(X) (pter-->q24::q21.32-->qter). The duplication of the PLP gene, involved in Pelizaeus-Merzbacher disease, was confirmed by fluorescent in situ hybridization (FISH). Both cytogenetic and molecular studies on the X chromosome inactivation status indicated a random pattern in lymphocytes and fibroblasts. This patient appears to be the first case of a female bearing a large duplication of Xq with a random X inactivation. The phenotype of this patient is compared to that of previously reported cases with Xq duplication.

[Chronic idiopathic hypertransaminasemia]. / Ipertransaminasemia cronica idiopatica.

The elevation of aminotransferase serum levels is frequently encountered in pediatric practice. We have retrospectively evaluated the clinical patterns of 108 patients with chronic, so called "idiopathic", alterations of aminotransferases, by sending a questionnaire to 11 Italian Pediatric Centers. The average period of follow-up was 22 months. Patients, whose ages ranged through all pediatric ages, were mostly asymptomatic and with a rather insignificant physical examination. The average rise of aminotransferases value was generally limited within 2 times the upper normal level and the highest value, during the period of follow-up, never exceeded 5 times the upper normal level. Other liver function tests did not result generally altered significant. Just 25,9% of the patients normalized aminotransferases serum level during the follow-up period. All maintained good physical status with no clinical signs of liver disease. A muscular cause of hyper-transaminasemia was excluded in all the cases. Possible infective causes (HBV and HCV) autoimmune hepatitis, Wilson disease, alfa1 antitripsine deficiency and hyperammoniemia were excluded. Ultrasound investigation did not seem to be a sensitive investigation, resulting negative in 54/82. Histologic liver examination was more informative. This evaluation, performed in 46/108 patients, showed infarct metabolic alterations (steatosis, nucleus glucogenic degeneration, cytoplasmatic clarification) in 65% of cases and inflammatory findings in only 13% of cases. In conclusion, our results suggest the opportunity to enclose liver histologic study in the diagnostic approach of children with hepatic idiopathic chronic hypertransaminasemia. This approach may address the clinician, in a more aimed way, towards further investigations.

Report on two patients with Costello syndrome and sialuria.

We report on 2 unrelated patients with Costello syndrome. The first is a 5-year-old girl with "coarse" face, nasal papillomata, redundant skin of feet and hands, hyperextensible hand and finger joints, curly hair, feeding problems due to oral motor apraxia, growth and psychomotor retardation. The second is a 3-year-old boy with "coarse" face, loose skin on hands and feet, curly hair, oral motor apraxia, severe growth and psychomotor retardation. In both patients urine sialic acid levels were found to be repeatedly high. The meaning of this biochemical abnormality is discussed.