Girolamo Mattioli

Hirschsprung disease and congenital anomalies of the kidney and urinary tract (CAKUT): a novel syndromic association.

Congenital anomalies of the kidney and urinary tract (CAKUT) can be associated with Hirschsprung disease (HSCR). Based on the common genetic background of enteric nervous system and kidney development, the reported association of CAKUT and HSCR seems underestimated. Therefore, we designed a prospective study aimed at determining the prevalence of CAKUT in HSCR patients and at identifying RET, glial cell line-derived neurotrophic factor (GDNF), and GDNF family receptor &agr;1 (GFR&agr;1) mutations or haplotypes associated with this subset of HSCR patients. Eighty-four HSCR patients consecutively admitted to our department between July 2006 and July 2007 underwent interviews, notes review, ultrasound screening (further investigation according to detected anomaly), urinalysis, and DNA extraction for molecular genetics study. Another 27 patients with isolated CAKUT were included as a control group for the molecular genetics study. Twenty-one patients (25%) with HSCR had associated CAKUT, with hydronephrosis and hypoplasia being the most frequent diagnoses. Nine of 21 CAKUT were symptomatic. Six additional patients had other non-CAKUT anomalies (for example, stones, Barter syndrome) that were excluded from association and molecular genetics analysis to avoid bias of inclusion criteria. RET mutations were found in 5 patients (4 HSCR, 1 HSCR + CAKUT, 0 CAKUT) and GDNF mutations in 3 (2 HSCR, 1 CAKUT, 0 HSCR + CAKUT). No GFR&agr;1 mutations were found. Finally, the HSCR-predisposing T haplotype of RET proto-oncogene was found in 64% of HSCR, 50% of HSCR + CAKUT, and in 24% of CAKUT patients. The incidence of CAKUT in HSCR patients is 4- to 6-fold higher than expected. Therefore, a patient with HSCR has a 3- to 18-fold higher risk of developing a CAKUT, particularly hydronephrosis or hypoplasia. If we consider that the proportion of predisposing haplotype in HSCR + CAKUT patients resembles that of other syndromic HSCR, we can conclude that HSCR + CAKUT has to be considered a novel syndromic association. These results need to be confirmed in a larger series. At present, we strongly suggest considering ultrasound screening of the urinary tract in every patient with a diagnosis of HSCR. Abbreviations: CAKUT = congenital anomalies of the kidney and urinary tract, GDNF = glial cell line-derived neurotrophic factor, GFR&agr;1 = glial cell line-derived neurotrophic factor family receptor &agr;1 gene, HSCR = Hirschsprung disease, HSCR + CAKUT = association of Hirschsprung disease and congenital anomalies of the kidney and urinary tract, L-HSCR = long form of Hirschsprung disease, S-HSCR = short or classic form of Hirschsprung disease, SNP = single nucleotide polymorphism.

Induction of RET Dependent and Independent Pro-Inflammatory Programs in Human Peripheral Blood Mononuclear Cells from Hirschsprung Patients

Hirschsprung disease (HSCR) is a rare congenital anomaly characterized by the absence of enteric ganglia in the distal intestinal tract. While classified as a multigenic disorder, the altered function of the RET tyrosine kinase receptor is responsible for the majority of the pathogenesis of HSCR. Recent evidence demonstrate a strong association between RET and the homeostasis of immune system. Here, we utilize a unique cohort of fifty HSCR patients to fully characterize the expression of RET receptor on both innate (monocytes and Natural Killer lymphocytes) and adaptive (B and T lymphocytes) human peripheral blood mononuclear cells (PBMCs) and to explore the role of RET signaling in the immune system. We show that the increased expression of RET receptor on immune cell subsets from HSCR individuals correlates with the presence of loss-of-function RET mutations. Moreover, we demonstrate that the engagement of RET on PBMCs induces the modulation of several inflammatory genes. In particular, RET stimulation with glial-cell line derived neurotrophic factor family (GDNF) and glycosyl-phosphatidylinositol membrane anchored co-receptor α1 (GFRα1) trigger the up-modulation of genes encoding either for chemokines (CCL20, CCL2, CCL3, CCL4, CCL7, CXCL1) and cytokines (IL-1β, IL-6 and IL-8) and the down-regulation of chemokine/cytokine receptors (CCR2 and IL8-Rα). Although at different levels, the modulation of these “RET-dependent genes” occurs in both healthy donors and HSCR patients. We also describe another set of genes that, independently from RET stimulation, are differently regulated in healthy donors versus HSCR patients. Among these “RET-independent genes”, there are CSF-1R, IL1-R1, IL1-R2 and TGFβ-1, whose levels of transcripts were lower in HSCR patients compared to healthy donors, thus suggesting aberrancies of inflammatory responses at mucosal level. Overall our results demonstrate that immune system actively participates in the physiopathology of HSCR disease by modulating inflammatory programs that are either dependent or independent from RET signaling.

Weakly acidic gastroesophageal refluxes are frequently triggers in young children with chronic cough.

To evaluate whether the proportion of acid and weakly acidic refluxes preceding cough bursts could be different in infants, preschool‐ and school‐aged children with chronic, unexplained cough.

Outcome of primary endorectal pull-through for the treatment of classic Hirschsprung disease.

INTRODUCTIONnEndorectal pull-through (ERPT) is a widely accepted procedure for the treatment of Hirschsprungs disease (HSCR). This study was aimed at presenting the long-term results of patients with classic HSCR who were operated on with a laparoscopic-assisted Georgeson procedure and to compare them to patients treated with a Soave-Boley procedure.nnnPATIENTS AND METHODSnPatients treated for Hirschsprung disease in the period 1997-2006 with a minimum follow-up of 6 months were prospectively included in this study. Demographic details, associated anomalies, surgical technique, length of aganglionosis, and postoperative complications were collected. A questionnaire was submitted to all families to assess general health, bowel adaptation, fecal and urinary continence, cosmetic results, and patients and parents perspective of overall outcome.nnnRESULTSnOverall, 162 patients underwent a pull-through procedure: 25 patients treated with Georgeson and 21 with Soave-Boley ERPT were eligible for this study. Conversion was required in 3 of 28 patients approached laparoscopically. Hospitalization was shorter for patients treated laparoscopically (P < 0.05), whereas length of surgery was comparable. Complication rate was similar for both groups, as well as growth that remained within normal ranges for age. Long-term outcome, in terms of bowel movements, was similar. None of the patients experienced fecal and/or urinary incontinence. Cosmetic results proved to be excellent to good in all patients undergoing the Georgeson and in 67% of patients undergoing the Soave-Boley procedure (P < 0.05). Patients perspective of overall outcome was excellent in more than 90% of patients from both groups.nnnCONCLUSIONSnOverall results proved to be similar. Likewise, long-term bowel function did not show significant differences. Nonetheless, if we consider hospitalization and cosmetic results, it becomes clear that the minimally invasive approach should be preferred, when possible, to improve patients comfort, perspective of overall health status, and psychologic acceptance.

Fast-track surgery of the colon in children.

INTRODUCTIONnThe aim of this study is to present the fast-track experience in children who underwent colon resection.nnnMATERIALS AND METHODSnForty-six children who underwent laparoscopic colon resection were prospectively included in the study. Anomalies of colon innervation and inflammatory bowel disease represented the main surgical indications.nnnRESULTSnLeft colon/sigmoid resection was performed in 37, total colon resection was done in 5, and right colon resection in 4 children. Total colon resection was always associated to ileostomy. Anastomosis was performed in 41 cases. Patients were postoperatively monitored for pain, return to normal activity, feeding, bowel movements, and complications. Stool passage and oral feeding were started on postoperative day 1, and all patients were discharged before postoperative day 4. One child was readmitted the day after discharge because of an anastomotic leak. No other major complications were recorded.nnnDISCUSSIONnMinimally invasive surgery is safe and effective in pediatric colonic surgery and allows a fast recovery time (fast-track).

Surgery for acute graft-versus-host disease of the bowel: description of a pediatric case.

Gastrointestinal acute graft-versus-host disease (GI-aGvHD) is still a common complication of allogeneic stem cell transplantation. Surgical management is an unusual approach, reserved for patients with intestinal occlusion, severe profuse rectal bleeding, or both. The authors describe a child with severe GI-aGvHD who did not respond to common immunosuppressive drugs and procedures and therefore underwent subtotal colectomy due to untreatable rectal bleeding. The bowel resection was followed by three surgical looks for occlusive intestinal episodes. In the end, a cholecystectomy for cholelithiasis was performed. The patient is still alive 41 months after stem cell transplantation, and although the terminal ileostomy is not closed yet, his quality of life is good. This experience suggests that surgery can be performed on children with severe, unresponsive GI-aGvHD.

Pediatric Gastric Volvulus: Diagnostic and Clinical Approach

Gastric volvulus is a significant, rare cause of non-bilious vomiting and consists of a pathological rotation of the stomach of more than 180° around the axis without obstruction of the gastrointestinal tract. A definitive diagnosis is made with upper radiological gastrointestinal studies. Treatment may be conservative or surgical with anterior and fundal gastropexy in patients with ingravescent symptoms. We describe the case of a 16-month-old female admitted to our hospital for recurrent and postprandial vomiting episodes which had started at 11 months of age. A history of gastroesophageal reflux was present until 1 year of age, in association with recurrent respiratory infections. The basic metabolic panel was normal. Barium study showed stomach rotation along a horizontal plane stomach. Esophagogastroduodenoscopy showed no mucosal alterations. The diagnosis was chronic organoaxial gastric volvulus. In our patient, the surgical procedure of gastropexy, both anterior and fundal, without fundoplication was performed. She showed good improvement after surgery, with resolution of symptoms and weight gain.

A prospective observational study of associated anomalies in Hirschsprung’s disease

BackgroundAssociated anomalies have been reported in around 20% of Hirschsprung patients but many Authors suggested a measure of underestimation. We therefore implemented a prospective observational study on 106 consecutive HSCR patients aimed at defining the percentage of associated anomalies and implementing a personalized and up-to-date diagnostic algorithm.MethodsAfter Institutional Ethical Committee approval, 106 consecutive Hirschsprung patients admitted to our Institution between January 2010 and December 2012 were included. All families were asked to sign a specific Informed Consent form and in case of acceptance each patient underwent an advanced diagnostic algorithm, including renal ultrasound scan (US), cardiologic assessment with cardiac US, cerebral US, audiometry, ENT and ophthalmologic assessments plus further specialist evaluations based on specific clinical features.ResultsMale to female ratio of our series of patients was 3,4:1. Aganglionosis was confined to the rectosigmoid colon (classic forms) in 74,5% of cases. We detected 112 associated anomalies in 61 (57,5%) patients. The percentage did not significantly differ according to gender or length of aganglionosis. Overall, 43,4% of patients complained ophthalmologic issues (mostly refraction anomalies), 9,4% visual impairment, 20,7% congenital anomalies of the kidney and urinary tract, 4,7% congenital heart disease, 4,7% hearing impairment or deafness, 2,3% central nervous system anomalies, 8,5% chromosomal abnormalities or syndromes and 12,3% other associated anomalies.ConclusionsOur study confirmed the underestimation of certain associated anomalies in Hirschsprung patients, such as hearing impairment and congenital anomalies of the kidney and urinary tract. Subsequently, based on our results we strongly suggest performing renal US and audiometry in all patients. Conversely, ophthalmologic assessment and cerebral and heart US can be performed according to guidelines applied to the general population or in case of patients with suspected clinical features or chromosomal abnormalities. This updated diagnostic algorithm aims at improving overall outcome thanks to better prognostic expectations, prevention strategies and early rehabilitation modalities. The investigation of genetic background of patients with associated anomalies might be the next step to explore this intriguing multifactorial congenital disease.

Laparoscopic Proximal Roux-en-Y Gastrojejunal Diversion in Children: Preliminary Experience from a Single Center

BACKGROUNDnNeurologically impaired children (NIC) have a high risk of recurrence of gastroesophageal reflux (GER) following fundoplication. A postpyloric feeding tube may be useful when gastric emptying disorders occur; however, dislocation and difficulty in feeding management often require more aggressive procedures. Total esophagogastric dissociation (Bianchis TEGD) is an alternative to the classic fundoplication procedure, whereas laparoscopic gastric bypass is a frequently performed procedure in morbid obesity, improving gastric outlet.nnnAIMnThe aim of this paper is to present a preliminary experience on the laparoscopic Roux-en-Y gastrojejunal bypass, associated with Nissen fundoplication and gastrostomy, to treat and prevent GER in NIC with gastric emptying disorders.nnnMATERIALS AND METHODSnEight neurologically impaired children underwent surgical treatment because of feeding problems and pulmonary complications. The procedure included: 1) hiatoplasty, 2) Nissen fundoplication, 3) 20-cm Roux-en-Y gastrojejunal anastomosis and jejuno-jejunal anastomosis, and 4) gastrostomy.nnnRESULTSnAll cases were fed on postoperative day 3 without any intraoperative complications. One case developed an obstruction of the distal anastomosis due to adhesion and needed reoperation. Outcome was clinically evaluated with serial upper gastrointestinal contrast studies and endoscopies.nnnCONCLUSIONSnLaparoscopic proximal Roux-en-Y gastrojejunal diversion, without gastric resection, is a safe, feasible procedure that improves gastric emptying and reduces the risk of GER recurrence. Yet, long-term results still have to be evaluated.

Inguinal hernia in neonates and ex-preterm: complications, timing and need for routine contralateral exploration.

Background/purposeAim of this study was to present a series of neonates and ex-preterm babies who underwent inguinal hernia repair focusing on complications and possible indication to perform routine contralateral groin exploration.MethodsThis is a retrospective study of a series of consecutive patients weighing less than 5xa0kg who underwent inguinal hernia repair between January 2007 and December 2012. Only the affected side was treated. Patients have been routinely followed up postoperatively. We resorted to available outpatients’ charts and admission notes to record demographic data, surgical details, complications and the occurrence of metachronous hernias. A questionnaire was administered to all patients’ relatives to confirm the long-term outcome.ResultsOne hundred fifty-four patients were operated for a total of 184 herniotomies (88 right sided, 36 left sided and 30 bilateral). Median length of follow-up was 42xa0months (range 6xa0months–7.5xa0years). Thirteen patients (13/124xa0=xa010.5xa0%) developed metachronous hernia that proved to be significantly more frequent in patients weighing less than 1,500xa0g at birth (pxa0<xa00.05). We observed 10xa0% of complications, including 2.7xa0% testicular atrophy and 4.5xa0% recurrence. Atrophy proved to occur more frequently in patients who experienced preoperative incarceration (pxa0<xa00.05). No other risk factors were identified.ConclusionsThe results of our series demonstrated that, though technically demanding, herniotomy in the neonate and ex-preterm is associated with a relatively low incidence of complications. Based on our results and in accordance with literature data, we do not advocate routine contralateral exploration in case of unilateral hernia but surgery to be performed only on the symptomatic side, as soon as possible after initial diagnosis. Very low birth weight patients should be followed with care in the early postoperative period due to the higher likelihood of developing a metachronous hernia.