Case report: Gastroenterological management in a case of cardio-facio-cutaneous syndrome.

Background: cardio-facio-cutaneous syndrome is a rare genetic disorder affecting less than 900 people in the world. It is mainly characterized by craniofacial, dermatologic and cardiac defects, but also gastroenterological symptoms may be present, ranging from feeding difficulties to gastroesophageal reflux and constipation.In this report we describe a case of this syndrome characterized by severe feeding and growth difficulties, with a particular focus on the management of gastroenterological complications. Case presentation: the patient was a caucasian male affected by Cardio-Facio-Cutaneous syndrome who presented feeding difficulties already a few hours after birth. These symptoms worsened in the following months and lead to a complete growth arrest and malnutrition. He was first treated with a nasogastric tube placement. Subsequently, a laparoscopic Nissen fundoplication and a laparoscopic Stamm gastrostomy were performed. The child was fed with nocturnal enteral nutrition and diurnal oral and enteral nutrition. Eventually the patient resumed feeding validly and regained adequate growth. Conclusion: this paper aims to bring to light a complex rare syndrome that infrequently comes to the attention of the pediatricians and whose diagnosis is not always straightforward. We also highlight the possible complications under a gastroenterologic point of view. Our contribution can be helpful to the pediatrician in the first diagnostic suspect of this syndrome. In particular, it is worth highlighting that -in an infant with Noonan-like features- symptoms like suction or swallowing problems, vomiting and feeding difficulties should orient towards the diagnosis of a Cardio-facio-cutaneous syndrome. It is also important to stress that its related gastroenterological issues may lead to severe growth failure and therefore the role of the gastroenterologist is key to manage supplemental feeding and to establish whether a nasogastric or gastrostomic tube placement is necessary.

Systemic corticosteroids could be used as bridge treatment in children with obstructive sleep apnea syndrome waiting for surgery.

PURPOSE: Local and systemic inflammatory markers and pro-inflammatory cytokines are increased in children with obstructive sleep apnea syndrome (OSAS). Therefore, systemic or topical anti-inflammatory agents are used to treat this syndrome. We evaluated the treatment with systemic corticosteroids in children with severe OSAS and adenotonsillar hypertrophy before surgery. METHODS: This was an unblinded open label study. Children with severe OSAS (diagnosed through polysomnography, obstructive apnea-hypopnea index [AHI] > 10 eV/h) were recruited. Exclusion criteria included age < 3 years, history of acute or chronic cardiorespiratory or neuromuscular or metabolic disease; major craniofacial abnormalities; and chromosomal syndromes and epilepsy. Computer-generated random numbers were used for simple randomization of subjects. All children were treated with intranasal beclomethasone spray, and 15 children additionally received oral betamethasone and 0.1 mg/kg per day for 7 days. Sleep clinical record (SCR) and pulsoximetry were performed before and after 7 days in all children. RESULTS: Among 28 children with severe OSAS mean age was 4.5 ± 1.8 years, AHI 20.4 ± 1.8 eV/h). In children treated with intranasal and oral corticosteroids, mean (95.3 ± 1.1 vs 97.0 ± 0.8%, p = 0.0001) and minimum oxygen saturation (78.8 ± 6.3 vs 89.2 ± 4.2, p = 0.001) improved, and the SCR score (12.6 ± 1.2 vs 8.3 ± 1.1, p = 0.0001) was reduced. Children treated only with intranasal beclomethasone spray showed no differences in outcome measures before and after treatments. When we considered the oximetry measures, after corticosteroid treatment, we obtained statistical differences between the 2 groups (p < 0.01). CONCLUSIONS: These results seem to suggest that a short course of oral betamethasone could be useful to treat children with severe OSAS and adenotonsillar hypertrophy waiting for surgery.

Chronic intestinal pseudo-obstruction: Progress in management?

Chronic intestinal pseudo-obstruction (CIPO) is a severe form of gastrointestinal dysmotility (often due to derangement of the innervation/smooth muscle/interstitial cells of Cajal) with recurrent episodes of intestinal subocclusion mimicking a mechanical obstruction. Because of its complexity and heterogeneity, CIPO is often misdiagnosed or remains unrecognized until advanced stages. Management is a critical aspect in CIPO patient care. So far, most prokinetic drugs have not proven efficacy in restoring intestinal propulsion, thus nutritional support, fluid/electrolyte replacement, and antibiotics are the mainstay of treatment. In this issue of the journal, Ohkubo et al showed promising data indicating that percutaneous endoscopic gastro-jejunostomy (PEG-J) can be proposed as a measure for intestinal decompression, thereby improving CIPO-associated abdominal symptoms, including pain. In addition to a concise update of clinical and diagnostic features, the present minireview tackles management options, with a major emphasis on PEG-J, for CIPO patients.

Chronic intestinal pseudo-obstruction in children and adults: diagnosis and therapeutic options.

BACKGROUND: Chronic intestinal pseudo-obstruction (CIPO) represents the most severe form of gastrointestinal dysmotility with debilitating and potentially lethal consequences. Symptoms can be non-specific, and result in this condition being diagnosed incorrectly or too late with consequences for morbidity and even mortality. PURPOSE: The present article aims to provide pediatric and adult gastroenterologists with an up to date review about clinical features, diagnosis and therapeutic options for CIPO. Although pediatric and adult CIPO share many clinical aspects distinctive features can be identified. There is no single diagnostic test or pathognomonic finding of CIPO, thus a stepwise approach including radiology, endoscopy, laboratory, manometry, and histopathology should be considered in the diagnostic work-up. Treatment of patients with CIPO is challenging and requires a multidisciplinary effort with participation of appropriately experienced gastroenterologists, pathologists, dieticians, surgeons, psychologists, and other subspecialists based on the presence of comorbidities. Current treatment options invariably involve surgery and specialized nutritional support, especially in children. Medical therapies are mainly aimed to avoid complications such as sepsis or intestinal bacterial overgrowth and, where possible, restore intestinal propulsion. More efficacious therapeutic options are eagerly awaited for such difficult patients.

Neuroimmune interactions at different intestinal sites are related to abdominal pain symptoms in children with IBS.

BACKGROUND: Neuroimmune interactions and inflammation have been proposed as factors involved in sensory-motor dysfunction and symptom generation in adult irritable bowel syndrome (IBS) patients. In children with IBS and healthy controls, we measured ileocolonic mast cell infiltration and fecal calprotectin and evaluated the relationships between these parameters and abdominal pain symptoms and stooling pattern. METHODS: Irritable bowel syndrome patients diagnosed according to Pediatric Rome III criteria and healthy controls kept a 2-week pain/stooling diary. Ileocolonic mucosal mast cells (MC) and MC in close proximity to nerve fibers (MC-NF) were identified immunohistochemically and quantified. Fecal calprotectin concentration was measured. KEY RESULTS: 21 IBS patients and 10 controls were enrolled. The MC-NF count was significantly higher in the ileum (p = 0.01), right colon (p = 0.04), and left colon (p < 0.001) of IBS patients compared with controls. No differences in fecal calprotectin concentration were noted. Abdominal pain intensity score correlated with ileal MC count (r(s) = 0.47, p = 0.030) and right colon MC-NF count (r(s) = 0.52, p = 0.015). In addition, children with IBS with >3 abdominal pain episodes/week had greater ileal (p = 0.002) and right colonic (p = 0.01) MC counts and greater ileal (p = 0.05) and right colonic (p = 0.016) MC-NF counts than children with less frequent pain. No relationship was found between MC and MC-NF and fecal calprotectin or stooling pattern. CONCLUSIONS & INFERENCES: Mast cells-nerve fibers counts are increased in the ileocolonic mucosa of children with IBS. Mast cells and MC-NF counts are related to the intensity and frequency of abdominal pain.

Size and dynamics of mucosal and peripheral IL-17A+ T-cell pools in pediatric age, and their disturbance in celiac disease.

Mucosal interleukin (IL)-17A-producing T cells contribute to protective antimicrobial responses and to epithelial barrier integrity; their role in celiac disease (CD) is debated. We analyzed the frequency and developmental dynamics of mucosal (intraepithelial lymphocytes (IEL)) and circulating (peripheral blood (PB)) IL-17A (T17) and/or interferon (IFN)-γ-producing (T1, T1/T17) T-cell populations in 86 pediatric controls and 116 age-matched CD patients upon phorbol myristate acetate/ionomycin or CD3/CD28 stimulation. T17 and T1/17 are physiologically present among IEL and PB populations, and their frequency is selectively and significantly reduced in CD IEL. The physiological age-dependent increase of Th17 IEL is also absent in CD, while IFN-γ-producing PB-T cells significantly accumulate with patient's age. Finally, the amplitude of IL-17A+ and IFN-γ+ T-cell pools are significantly correlated in different individuals; this relationship only applies to CD4+ T cells in controls, while it involves also the CD4- counterpart in CD patients. In conclusion, both size and dynamics of mucosa-associated and circulating IL-17A+ T-cell pools are finely regulated in human pediatric subjects, and severely disturbed in CD. The impaired IL-17A+ IEL-T pool may negatively impact on epithelial barrier efficiency, and contribute to CD mucosa damage; the disturbed dynamics of circulating IL-17A+ and IFN-γ+ T-cell pools may be involved in the extraintestinal autoimmune manifestations associated with CD.

Randomised clinical trial: the effectiveness of Lactobacillus reuteri ATCC 55730 rectal enema in children with active distal ulcerative colitis.

BACKGROUND: Intestinal microbiota manipulation, one of the pathogenetic components of inflammatory bowel disease (IBD), has become an attractive therapy for ulcerative colitis (UC). AIM: To assess in children with active distal UC the effectiveness of Lactobacillus (L) reuteri ATCC 55730 enema on inflammation and cytokine expression of rectal mucosa. METHODS: A total of 40 patients (median age: 7.2 years range 6-18) with mild to moderate UC were enrolled in a prospective, randomised, placebo-controlled study. They received an enema solution containing 10(10) CFU of L. reuteri ATCC 55730 or placebo for 8 weeks, in addition to oral mesalazine. Clinical endoscopic and histological scores as well as rectal mucosal expression levels of IL-10, IL-1ß, TNFα and IL-8 were evaluated at the beginning and at the end of the trial. RESULTS: Thirty-one patients accomplished the trial (17 males, median age 13 year, range 7-18). Mayo score (including clinical and endoscopic features) decreased significantly in the L. reuteri group (3.2 ± 1.3 vs. 8.6 ± 0.8, P < 0.01) compared with placebo (7.1 ± 1.1 vs. 8.7 ± 0.7, NS); furthermore, histological score significantly decrease only in the L. reuteri group (0.6 ± 0.5 vs. 4.5 ± 0.6, P < 0.01) (placebo: 2.9 ± 0.8 vs. 4.6 ± 0.6, NS). At the post-trial evaluation of cytokine mucosal expression levels, IL-10 significantly increased (P < 0.01) whereas IL-1ß, TNFα and IL-8 significantly decreased (P < 0.01) only in the L. reuteri group. CONCLUSIONS: In children with active distal ulcerative colitis, rectal infusion of L. reuteri is effective in improving mucosal inflammation and changing mucosal expression levels of some cytokines involved in the mechanisms of inflammatory bowel disease.

Use of macrogol 4000 in chronic constipation.

BACKGROUND: Chronic constipation is a common functional disorder of the gastrointestinal tract, affecting up to 35% of the general population, and especially the elderly. However, its definition as perceived by the patient can vary, making it difficult to understand the problem and find appropriate therapeutic measures. The approach to chronic constipation, thus, needs a thorough understanding of the patient's complaint and the main pathophysiological mechanism requiring treatment. Lifestyle changes do not usually meet with complete patient satisfaction. Other treatments include different types of laxatives. Of these, osmotic laxatives appear one of the most effective and are, therefore, frequently prescribed. DESIGN: This review will cover the topic of osmotic laxatives, specifically focusing on polyethylene glycol (PEG/macrogol 4000) in chronic constipation and as a key agent for bowel cleansing prior to colonoscopy. PEG formulations, including macrogol 4000, are safe, effective treatments for constipation, even in children and elderly patients. Macrogol 4000 may well be more palatable than combined formulations (macrogol 3350 with electrolytes), which could help improve adherence to the long-term treatment required for chronic constipation. CONCLUSIONS: PEG/macrogol is also recommended as an effective option for bowel cleansing prior to colonoscopy. The improved cost-effectiveness of macrogol over other commonly prescribed laxatives, such as lactulose, should be taken into consideration.

Methotrexate in paediatric ulcerative colitis: a retrospective survey at a single tertiary referral centre.

BACKGROUND: Patients with ulcerative colitis often receive thiopurines as immunomodulators (IMs) to maintain remission and avoid corticosteroids. If unresponsive or intolerant to these agents, patients are treated with methotrexate, an antimetabolite never assessed in paediatric ulcerative colitis. AIM: To describe the experience with methotrexate in children with ulcerative colitis. METHODS: Thirty-two patients (median age 13.9 years) received methotrexate. Pediatric Ulcerative Colitis Activity Index (PUCAI) and use of corticosteroids were the main outcomes evaluated at baseline and at 3, 6 and 12 months. RESULTS: Indications to methotrexate were azathioprine unresponsiveness in 18 patients, azathioprine intolerance/toxicity in 10 and spondyloarthropathy in four. Response or remission was achieved in 72%, 63% and 50% of patients at 3, 6 and 12 months respectively. Mean PUCAI were 49.5 ± 23.3 at baseline and 32.9 ± 21.9, 29.5 ± 21.8 and 29.4 ± 19.9 at 3, 6 and 12 months respectively (P: 0.03). At the beginning of methotrexate, 16 patients (50%) received corticosteroids that were discontinued in 13 of them (81%) by 6 months. At the end of the study, 11 patients (33%) needed short courses of corticosteroids for disease relapse. CONCLUSIONS: Methotrexate may be useful in treating children with ulcerative colitis, although large, controlled trials are warranted to define better its effectiveness.

JC Viral reactivation in a pediatric patient with Crohn's disease.

This is a report concerning human polyomavirus JC (JCV) reactivation in a pediatric patient with Crohn's disease (CD) during the treatment with 5-aminosalicylic acid (5-ASA), a non-steroidal anti-inflammatory drug (NSAID). We examined 9 bioptic samples from three different bowel districts (ileum, cecum, rectum) of this child. These samples were analyzed by Quantitative PCR (Q-PCR) to investigate the presence of JCV DNA. JCV DNA was detected in one rectum biopsy taken two months after 5-ASA treatment. Although our result must be validated in a larger group of subjects and with a longer follow-up period, it underlines the importance of JVC monitoring in CD patients.

Review article: molecular, pathological and therapeutic features of human enteric neuropathies.

BACKGROUND: Considerable information has been gathered on the functional organization of enteric neuronal circuitries regulating gastrointestinal motility. However, little is known about the neuropathophysiological mechanisms underlying gastrointestinal motor disorders. AIM: To analyse the most important pathological findings, clinical implications and therapeutic management of idiopathic enteric neuropathies. METHODS: PubMed searches were used to retrieve the literature inherent to molecular determinants, pathophysiological bases and therapeutics of gastrointestinal dysmotility, such as achalasia, gastroparesis, chronic intestinal pseudo-obstruction, Hirschsprung's disease and slow transit constipation, to unravel advances on digestive disorders resulting from enteric neuropathies. RESULTS: Current data on molecular and pathological features of enteric neuropathies indicate that degenerative and inflammatory abnormalities can compromise the morpho-functional integrity of the enteric nervous system. These alterations lead to a massive impairment in gut transit and result in severe abdominal symptoms with associated high morbidity, poor quality of life for patients and established mortality. Many pathophysiological aspects of these severe conditions remain obscure, and therefore treatment options are quite limited and often unsatisfactory. CONCLUSIONS: This review of enteric nervous system abnormalities provides a framework to better understand the pathological processes underlying gut dysmotility, to translate this knowledge into clinical management and to foster the development of targeted therapeutic strategies.

Postinfectious gastroparesis related to autonomic failure: a case report.

BACKGROUND AND AIM: Severe dysautonomia may be secondary to viral infections, resulting in impaired autoimmune, cardiovascular, urinary and digestive dysfunction. Herein, we present a case of a 31-year-old white female patient who had severe gastroparesis related to autonomic failure following an episode of acute gastroenteritis. This seems to be the first report providing thorough assessment of the enteric and autonomic nervous system by analysis of full-thickness small intestinal biopsies, cardiovagal testing and autopsy. HOSPITAL COURSE: This patient affected by a severe gastroparesis was treated with antiemetics, prokinetics, analgesics and gastric electrical stimulation to control symptoms. Nutritional support was made using jejunal feeding tube and, in the final stage of disease, with total parenteral nutrition. Autonomic studies revealed minimal heart rate variability and a disordered Valsalva manoeuvre although the enteric nervous system and the smooth muscle layer showed a normal appearance. Hospital courses were complicated by episodes of bacteraemia and fungemia. Serum antiphospholipid antibodies were noted but despite anticoagulation, she developed a pulmonary embolism and shortly thereafter the patient died. Autopsy revealed acute haemorrhagic Candida pneumonia with left main pulmonary artery thrombus. Sympathetic chain analysis revealed decreased myelinated axons with vacuolar degeneration and patchy inflammation consistent with Guillain-Barre syndrome. The evaluation of the enteric nervous system in the stomach and small bowel revealed no evidence of enteric neuropathy or myopathy. CONCLUSION: A Guillain-Barre-like disease with gastroparesis following acute gastroenteritis is supported by physiological and autonomic studies with histological findings.

Idiopathic achalasia is not allelic to alacrima achalasia adrenal insufficiency syndrome at the ALADIN locus.

BACKGROUND: Evidence indicates that patients with familial achalasia associated with Allgrove or triple-A syndrome (i.e. alacrima, achalasia and adrenocorticotropin-resistant adrenal insufficiency with neurological impairment) have mutations of the alacrima achalasia adrenal insufficiency syndrome (AAAS) gene. AIM: The present study was aimed at identifying possible AAAS gene mutations in patients with established idiopathic non-familial achalasia. METHODS: Genomic DNA of 41 patients was isolated from peripheral blood cells using standard methods. The 16 exons of the AAAS gene (or ALADIN) were screened for mutations using the denaturing high-performance liquid chromatography method. RESULTS: Four heterozygous nucleotidic variations have been identified in patients with idiopathic achalasia, among which three were exonic conservative polymorphisms [i.e. D138D (GAT-->GAC), L227L (TTG-->CTG) and F285F (TTC-->TTT) in exons 5, 7 and 9, respectively]. The fourth nucleotidic variation was located in intron 13 (IVS14-23delT). All variants have been regarded as polymorphisms resulting in a normal ALADIN protein since they are either conservative or lying outside the consensus splice sites. CONCLUSIONS: Our data do not support a pathogenetic role for common AAAS gene mutations in patients with idiopathic achalasia as seen in Allgrove syndrome. These findings suggest the participation of different mechanisms in the pathogenesis of idiopathic achalasia.

New therapeutic approach in the management of intestinal disease: probiotics in intestinal disease in paediatric age.

Current evidence supports the view that oral administration of probiotics may be of therapeutic usefulness in several clinical disorders by reestablishing normal flora in the gastrointestinal tract. These entities include inflammatory and infectious diseases of the gut as well as extraintestinal disorders (such as atopic eczema) in which a defective intestinal permeability plays a role. The probiotic effects are attributed to restoration to normal of increased intestinal permeability, unbalanced gut microecology, improved immunological gut barrier function, downregulation of the intestinal inflammatory responses with reduced generation of proinflammatory cytokines. Entities for which the impact of probiotic administration can be considered as proven are Rotavirus diarrhoea, Clostridium difficile diarrhoea, post-antibiotic diarrhoea, allergic diseases. On the other hand, entities for which administration of probiotics is considered under investigation are inflammatory bowel disease, necrotizing enterocolitis, cystic fibrosis, small bowel bacterial contamination, functional gastrointestinal disorders. The value of probiotics as therapy for a variety of gastrointestinal disorders in childhood still needs to be investigated in detail, through well controlled and rigorous studies, including a placebo group and strict criteria of randomisation. Much work needs to be done in this area by clearly defining indications, delivery system, costs, safety long-term effects.

Domperidone is more effective than cisapride in children with diabetic gastroparesis.

BACKGROUND: Disorders of gastrointestinal motility are commonly detected in patients with insulin-dependent diabetes mellitus and are associated with significant morbidity. They contribute to poor metabolic control of diabetes. AIM: To assess the effect of an 8-week course of domperidone or cisapride on gastric electrical activity, gastric emptying time and dyspeptic symptoms in children with insulin-dependent diabetes mellitus and gastroparesis. METHODS: Dyspeptic symptoms were assessed by a score system, gastric emptying time was measured by ultrasonography and gastric electrical activity was obtained by electrogastrography. Fourteen children received domperidone and 14 received cisapride. The median (range) ages were 11.6 years (5-15 years) and 12 years (6-16.9 years), respectively. Symptom assessment, ultrasonography and electrogastrography were repeated at the end of the trial. Fasting and fed (180 min after feeding) glycaemia and haemoglobin A, C (HbA1c) levels were also measured. RESULTS: At the end of the trial both groups showed a significant decrease in symptomatic score; however, the score was markedly lower in the domperidone group than in the cisapride group (P < 0.01). Domperidone was significantly more effective than cisapride in reducing the gastric emptying time (P < 0.05), normalizing gastric electrical activity (P < 0.05) and decreasing the prevalence of episodes of gastric dysrhythmia (P < 0.01). Domperidone was also more effective than cisapride in improving diabetic metabolic control. No potentially drug-related adverse effects occurred. CONCLUSIONS: In children with insulin-dependent diabetes mellitus complicated by dyspeptic symptoms and gastroparesis, domperidone is superior to cisapride in reversing gastric emptying delay and gastric electrical abnormalities, as well as in improving dyspeptic symptoms and diabetic metabolic control.

Role of drug therapy in the treatment of gastro-oesophageal reflux disorder in children.

Gastro-oesophageal reflux (GOR) is the effortless passage of gastric contents into the distal oesophagus. It can be classified as functional (or symptomatic), in which the infant remains free from disease, or a pathological (GOR disease, GORD), in which gastrointestinal, respiratory or neurobehavioural signs occur with intraoesophageal acidification and the development of oesophagitis. Functional or symptomatic GOR is successfully treated by conservative measures and does not require investigative diagnostic tools; however, both drug administration and an investigative approach are mandatory in patients with GORD. There is currently a great range of proven therapeutic options for GORD that are directed at counteracting the pathogenetic components of the disorder. In this report we discuss the role of different drug classes for treating GORD in children. The choice of therapy for GORD depends upon the severity of signs and the degree of oesophagitis. The presence of oesophagitis, as documented by endoscopy, suggests the use of antisecretory drugs; H2 receptor antagonists are the first-line agents. Nevertheless, individuals with refractory disease or those patients requiring potent inhibition of acid secretion (for example, GORD with respiratory involvement) can be given proton pump inhibitors. Other groups of patients who need potent inhibition of acid secretion are children with neurological dysfunction and those with Barrett's oesophagus. It is still unclear whether patients with frequent relapses are candidates for long term administration of antisecretory drugs or for surgical fundoplication.

[Pretreatment evaluation of CA 72.4 in patients with carcinoma of the stomach (0-IV stage) versus CEA, TPA, CA 19-9, FER]. / Valutazione pretrattamento del CA 72.4 in pazienti con carcinoma gastrico (stadio 0-IV) vs CEA, TPA, CA 19-9 FER.

Before surgical treatments, sera of 54 pts suffering from gastric cancer, histologically typed and clinically staged (from stage 0 to 4), were assayed to evaluate CEA, TPA, CA 19-9 and Ferritin versus a new tumoral marker called TAG-72, in order to determine the biological behaviour and the relation to the clinical stage of this last one. Starting from their results, Authors say that the new marker TAG 72 has an increasing sensibility according to the clinical stage (4 th more than 1 st), and that the association of the TAG-72 plus CEA and/or TPA is rather significant in order to evaluate the evolution of the gastric cancer than other markers.