Rectosigmoid Hirschsprung’s Disease - ERNICA guidelines

P O S I T I O N S T A T E M E N T Open Access ERNICA guidelines for the management of rectosigmoid Hirschsprung ’s disease Kristiina Kyrklund 1*, Cornelius E. J. Sloots 2, Ivo de Blaauw 3, Kristin Bjørnland 4, Udo Rolle 5, Duccio Cavalieri 6, Paola Francalanci 7, Fabio Fusaro 8, Annette Lemli 9, Nicole Schwarzer 9, Francesco Fascetti-Leon 10, Nikhil Thapar 11, Lars Søndergaard Johansen 12, Dominique Berrebi 13, Jean-Pierre Hugot 14, Célia Crétolle 15, Alice S. Brooks 16, Robert M. Hofstra 16, Tomas Wester 17 and Mikko P. Pakarinen 1 Abstract Background: Hirschsprung’s disease (HSCR) is a serious congenital bowel disorder with a prevalence of 1/5000. Currently, there is a lack of systematically developed guidelines to assist clinical decision-making regarding diagnostics and management. Aims: This guideline aims to cover the diagnostics and management of rectosigmoid HSCR up to adulthood. It aims to describe the preferred approach of ERNICA, the European Reference Network for rare inherited and congenital digestive disorders. Methods: Recommendations within key topics covering the care pathway for rectosigmoid HSCR were developed by an international workgroup of experts from 8 European countries within ERNICA European Reference Network from the disciplines of surgery, medicine, histopathology, microbiology, genetics, and patient organization representatives. Recommendation statements were based on a comprehensivereview of the available literature and expert consensus. AGREE II and GRADE approaches were used during development. Evidence levels and levels of agreement are noted. Results: Thirty-three statements within 9 key areas were generated. Most recommendations were based on expert opinion. Conclusion:In rare or low-prevalence diseases such as HSCR, there remains limited availability of high-quality clinical evidence. Consensus-based guidelines for care are presented. Keywords: Rectosigmoid Hirschsprung’s disease, HSCR, Diagnosis, Management, Follow-up Background Hirschprung’s disease (HSCR) is a congenital intestinal mo- tility disorder with an incidence of 1:5000, with a male to female predominance of 4:1. It is characterized by an ab- sence of enteric ganglion cells from the distal intestine, causing chronic functional bowel obstruction [1]. Although HSCR can affect any length of bowel from the anus prox- imally, 80 –85% of cases are limited to the rectosigmoid colon [2]. Operative management involves resection of the abnormally innervated bowel. Despite surgical treatment, postoperative defects in bowel function are common, and highly specialist long-term aftercare that includes transition to adult care providers is required. Currently, there is a lack of systematically developed g uidelines to assist clinical decision-making in HSCR, although standardization of diagnostics, treatments and care pathways would clearly benefit patients. Addressing healthcare inequalities and ensuring deliv- ery of high-quality care for patients with rare or low- prevalence, complex diseases has been identified as an © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. * Correspondence: kristiina.kyrklund@hus.fi 1Department of Pediatric Surgery, Children ’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Full list of author information is available at the end of the article Kyrklund et al. Orphanet Journal of Rare Diseases (2020) 15:164 https://doi.org/10.1186/s13023-020-01362-3 important target at the level of the European Union (EU) [3]. To address the geographical scattering of expert healthcare providers and patients, European Reference Networks (ERNs) for were founded. These currently com- prise 24 ERNs from over 900 highly specialized healthcare units and 313 hospitals [ 3]. ERNICA is the ERN for rare inherited and congenital digestive disorders, including Hirschsprung’s disease. This document aims to describe the preferred approach of ERNICA for the diagnostics and management of rectosigmoid HSCR up to adulthood. A core aim of ERNICA is to improve the quality of care that patients receive, and to reduce the long-term impact of HSCR for patients [3]. Results Recommendations for the diagnosis of HSCR (Table 1) Around 90% of patients with HSCR present during the neonatal period [ 4]. In rectosigmoid HSCR, there is a male predominance of 4:1 [ 5]. The classic clinical symp- toms include abdominal distension (> 90%), vomiting (> 85%), which may be bilious, and failure to pass meco- nium during the first 24 h of life (> 60%) [ 4]. Digital rec- tal examination or passage of a rectal tube typically results in the evacuation of gas and faeces, which may be explosive and/or foul-smelling. Plain abdominal x-ray findings include dilated gas-filled loops of bowel suggest- ive of a distal obstruction. Some patients may have symptoms of enterocolitis at presentation. A family his- tory of HSCR or presence of a syndrome associated with HSCR lowers the threshold for investigation. According to a recent systematic review, only 5% of 4127 infants di- agnosed with HSCR between 1964 and 2013 were pre- mature (< 37 weeks ’s gestation), but this proportion was higher (14%) amongst patients born during recent years [6]. Contemporary studies suggest that late presentation beyond 3 years of age is unusual [ 4, 7]. Representative rectal histology is required for the diag- nosis of HSCR. Rectal biopsies may be taken as suction or open surgical biopsies, opting for the least invasive, feasible method. Biopsies should be taken a minimum of 2 cm above the dentate line to avoid the physiologic aganglionic/hypoganglionic zone of the distal rectum [ 8]. The International Working Group of the 2009 World Congress of Gastroenterology advocates that a biopsy specimen should be at least 3 mm diameter, and a mini- mum of one-third of the sample should comprise sub- mucosa [ 9, 10]. Hematoxylin-eosin (H&E) staining and Acetylcholine-Esterase (AChE) histochemistry are widely used. The presence of any number of ganglion cells on H&E staining excludes HSCR. However, H&E has Table 1 Recommendations for the diagnosis of HSCR The diagnosis of HSCR should be based on representative rectal histology, and should be confirmed before pull-through surgery.  Rectal suction biopsy (RSB) and open biopsy are equally accurate if they provide enough submucosal tissue. The least invasive, feasible method should be chosen.  Biopsies should be taken from the posterior and/or lateral rectal wall at least 2 cm proximal to the dentate line or 3 cm from the anal orifice, and must contain a representative amount of submucosa.  A minimum of 1 histologically representative tissue sample is required. One open biopsy usually provides sufficient tissue but with RSB it is advisable to take 2 –3 biopsies. Level of evidence III Strength of recommendation: Strong, for Level of agreement: 100% Rectal biopsy is indicated if the clinical history and physical signs are suggestive of HSCR.  The classic triad of symptoms is delayed passage of meconium (> 24 h in a term infant), abdominal distension and bilious vomiting.  The majority of patients present during the neonatal period or early infancy .  The threshold for biopsy is lowered by the presence of a syndrome associated with HSCR or family history of HSCR Level of evidence III Strength of recommendation: Strong, for Level of agreement: 100% Rectal biopsy should also be considered for the exclusion of HSCR in:  Early-onset constipation associated with failure to thrive  Older children with persistent constipation or symptoms of more generalized intestinal motility disorders  Patients with an absent recto-anal inhibitory reflex (RAIR) on anorectal manometry Level of evidence III Strength of recommendation: Conditional, for Level of agreement: 100% Biopsies should be evaluated by an experienced consultant histopathologist, seeking external consultation if necessary  The presence of any number of ganglion cells on hematoxylin and eosin (H&E) staining excludes HSCR.  If ganglion cells are not seen, additional histologic evaluation should be considered before setting a diagnosis of HSCR.  Calretinin and/or peripherin should be used to look for ganglion cells, particularly in premature infants where these are small and not well visualised on H&E.  In HSCR, acetylcholinesterase activity is increased, and calretinin immunohistochemistry is negative. (Within Europe, external consultation can be requested from an ERNICA centre. A Clinical Patient Management System e-platform is under development) Level of evidence III Strength of recommendation: Strong, for Level of agreement: 100% Kyrklund et al. Orphanet Journal of Rare Diseases (2020) 15:164 Page 2 of 16 limitations for the visualisation of ganglion cells, particu- larly in neonates and premature babies, where these may be small and immature. If ganglion cells are not seen, add- itional staining with calretinin and/or peripherin immuno- histochemistry is advisable before setting the diagnosis of HSCR [ 11, 12]. Increased AChE expression is associated with the hypertrophied extrinsic nerve fibres of the agan- glionic segment in most patients with HSCR [ 13]. With AChE, false negatives are primarily related to age, and ab- sence of an AChE reaction does not reliably exclude HSCR in very young neonates [13, 14]. The sensitivity and specifi- city of other methods, including anorectal manometry and contrast enema are inferior to those of an adequate rectal biopsy, particularly in young infants [ 15, 16]. The histo- pathologic assessment of HSCR is demanding, as it remains centered around demonstrating an absence of ganglion cells [ 8] .C a r e f u le v a l u a t i o nb ya ne x p e r i - enced consultant histopathologist is necessary, using a combination of staining techniques whenever possible. External consultation is recommended in unclear cases. Recommendations for who should operate on patients with HSCR (Table 2) The ERNICA recommendations for centres performing pull-through surgery for HSCR are in accordance with re- cent European recommendations concerning the manage- ment of patients with rare diseases [ 17]. There is reliable evidence that performing the definitive surgical manage- ment of rare pediatric neonatal surgical conditions in specialist units improves treatment outcomes and safety for several reasons [18–20]. The concentration of care in cases with an otherwise low preval ence permits care based on sufficient cumulative experience of the indications for sur- gery, surgical procedures, perioperative management and post-operative follow-up [21]. The presence of allied med- ical specialists, including neonatal intensivists, nurses, and out-of-hours emergency services with experience in the condition also improves the “rescue phenomenon,” which refers to the ability to preven t minor postoperative events from escalating into severe c omplications and mortality [21, 22]. At index centers, the need for re-do pull-through operations is low, with mostly good to normal long-term continence outcomes in rectosigmoid HSCR [ 2, 23, 24]. From economic and policy-planning standpoints, the pre- vention of severe complications is also the most important determinant of the cost-effectiveness of care [25]. On a national level, favouring the feasibility of orga- nized care networks for HSCR is the finding that pa- tients are willing to travel long distances in order to even marginally reduce th eir risk of complications and death, and for better access to multidisciplinary services [ 21, 26]. Registries of care volumes, out- comes, cost of care and service infrastructure are ne- cessary to enable patients, healthcare professionals and policy-makers to make informed decisions regard- ing the choice of care provider. Having at least two pediatric colorectal surgeons within units assists to ensure the availability of a year-round surgical service for HSCR, and the option of two-consultant operating in complex cases. Commitment to training surgeons Table 2 Recommendations for who should operate on patients with HSCR Patients with HSCR should undergo pull-through surgery in centres with at least two pediatric colorectal surgeons and pathological, radiological and anesthetic expertise, including pediatric and neonatal intensive care and specialized nursing 24/7.  Concentration of interdisciplinary experience is associated with better outcomes in complex or rare pediatric surgical conditions.  Accurate primary assessment of the disease phenotype in HSCR permits appropriate surgical management  The need for re-do surgery is low in centres that regularly manage HSCR and complications are appropriately identified and managed Level of evidence III Strength of recommendation: Strong, for Level of agreement: 100% Centres performing pull-through surgery for HSCR should have the capabilities to manage the entire care pathway  This includes management of surgical complications and primary surgical management of all forms of HSCR, provision of multidisciplinary care until adulthood, and specialist nursing  Ability to deliver comprehensive follow-up until adulthood, including provision of transition of care Level of evidence III Strength of recommendation: Strong, for Level of agreement: 100% Centres that operate on HSCR patients should demonstrate active involvement in quality control and improvement  Maintaining prospective registries permits assessment and monitoring case volumes and outcomes  Commitment to training surgeons, pathologists and nurse practitioners in diagnostics and management of HSCR ensures continuity of local expertise  Up-to-date care practices and understanding of the disease process through networking and participation in continued medical and surgical education  Information should be given about the availability of patient support organizations as early as possible, and patients should be informed about the availability of current guidelines Level of evidence III Strength of recommendation: Strong, for Level of agreement: 100% Kyrklund et al. Orphanet Journal of Rare Diseases (2020) 15:164 Page 3 of 16 and other allied specialists ensures long-term service continuity. Centres performing pull-through surgery for HSCR should have the capacity to manage all levels of HSCR, as aganglionosis extending proximal to the rectosigmoid af- fects 15 –20% of patients [ 23]. Despite an optimal pull- through, impairment of bowel function and enterocolitis are common during the first few years after surgery, and between 4 and 30% of patients have an associated develop- mental disorder or syndrome [ 23, 27, 28]. Competence in the management of HSCR is therefore not only defined by an ability to perform complex surgery or hospital volumes alone, but also on capacity to manage the disease process as a whole and to provide individualized long-term follow- up into adulthood [ 21]. For this, a properly functioning multidisciplinary approach is essential [ 21]. Evidence of quality should be based on outcome registries, alongside regular participation in internal and external assessment of benchmarks. Involvement in research is beneficial for generating knowledge regarding the effects of current and competitive therapies, which are needed to develop prac- tices towards new standards. Recommendations for preoperative care (Table 3) Whilst awaiting the results of the rectal biopsy, saline rectal irrigations should be commenced to overcome the functional bowel obstruction and to enable enteral feed- ing. Parents can be trained to continue them at home on a daily basis until the pull-through operation. Rectal irri- gations with physiological saline are performed with a soft rectal tube one to three times a day. Rectal irriga- tions provide effective bowel decompression in approximately 75% of HSCR patients. Patients in whom rectal irrigations fail often turn out to have long- or ex- tended segment aganglianosis [ 2]. In these cases or if there is enterocolitis unresponsive to non-operative treatment, or intestinal perforation, a diverting enteros- tomy is indicated [ 29]. The safest empiric level is the dis- tal ileum, based on the likelihood that aganglionosis will be confined distally to the colon. Whenever possible, frozen section biopsies at the planned stoma site should be obtained to confirm the presence of ganglion cells. A circumferential full thickness ‘doughnut’ biopsy from the site of bowel transection is most informative regarding the ganglion status at that level [ 29]. Additional full- thickness or seromuscular mapping biopsies may be ob- tained during the same operation to define the exact level of the histologic transition zone for planning the definitive pull-through surgery [ 30]. In a recent European survey, 96% of responders per- formed a pre-operative contrast enema to guide on the likely level of aganglionosis [ 31]. Although a contrast enema is not considered sufficient on its own for the diagnosis of HSCR, a distinct calibre change from prox- imally dilated to distal constantly narrow colon suggests a transition zone at this level. The most demonstrative images are often obtained just after evacuation of the contrast material. If a contrast enema examination fails to suggest a clear transition zone in the recto-sigmoid colon, the possibility of long-segment aganglionosis and additional mapping biopsies should be considered [ 30]. In adult colorectal surgery, administration of a single preoperative dose of antibiotics has been shown to re- duce postoperative wound infections by 75% [ 32]. A Table 3 Recommendations for preoperative care in HSCR Patients should receive saline rectal irrigations 1 –3 times per day to decompress the bowel until the definitive pull-through operation  An additional colonic wash-out may be given for pre-operative bowel preparation  See below, if there is an inadequate response to rectal irrigations Level of evidence III Strength of recommendation: Strong, for Level of agreement: 100% A stoma is indicated if rectal irrigations do not sufficiently decompress the bowel, or there are complications such as enterocolitis unresponsive to non-operative treatment, or bowel perforation.  The safest empiric level is an ileostomy  In pneumoperitoneum, also an ileostomy provided it is proximal to the site of perforation  A representative circumferential ‘doughnut’ biopsy taken from the site of stoma formation is informative regarding the ganglionic status of the bowel at that level Level of evidence III Strength of recommendation: Strong, for Level of agreement: 100% When possible, a pre-operative contrast enema is recommended to guide on the likely level of aganglianosis  A colonic caliber change suggests a histological transition zone at this level.  Proximal to the rectosigmoid junction, colonic caliber changes are less accurate in predicting the disease level, and the possibility of long-segment HSCR should be considered  Contrast studies are complementary tools during the pre-operative workup. They do not replace the need for histological assessment to confirm the diagnosis. Level of evidence III Strength of recommendation: Conditional, for Level of agreement: 100% At pull-through surgery, one dose of broad-spectrum intravenous antibiotics should be given preoperatively.  The choice of antibiotics is determined by local regimens and regional resistance profiles, but should include coverage of both aerobic and anaerobic bacteria  No additional benefit has been shown for giving more than one pre-operative dose, but antibiotics may be continued for 24 –48 h post-operatively Level of evidence II-III Strength of recommendation: Strong, for Level of agreement: 100% Kyrklund et al. Orphanet Journal of Rare Diseases (2020) 15:164 Page 4 of 16 combination of aerobic and anaerobic bacteria coverage with a single agent or combination therapy is most ef- fective, the choice depending on local resistance patterns. Administration of prolonged antibiotic prophylaxis has not been proven to be more effective in preventing surgi- cal wound infections [ 33]. It is unknown to what extent this reduces sequelae from anastomotic leakage, deep sur- gical infections, urinary tract or respiratory infections [ 32]. Studies of antibiotic prophylaxis in the pediatric surgical population are scarce and do not include the latest tech- niques for HSCR surgery using minimally invasive or transanal approaches [33]. Recommendations for operative management of rectosigmoid HSCR (Table 4) Endorectal pull-through (ERP) and Duhamel pull-through are the most common definitive operations for HSCR [ 31, 34]. Both ERP and Duhamel can be performed laparoscopy- or laparotomy assisted, although ERP can also be per- formed entirely transanally in rectosigmoid HSCR [35–38]. Currently, there is no evidence to favor superiority of one technique over another in term s of surgical complications or long-term bowel functional outcomes [ 39–43]. Pull- through surgery is usually performed electively within 2–3 months after diagnosis and when the infant is stable, grow- ing well and the bowel has been decompressed. No specific advantages have been identi fied for performing pull- through surgery during the immediate neonatal period. However, there remains insuffi cient data for establishing the optimal timing of pull-through surgery. Based on case series, it remains debated whether lapar- oscopy- or laparotomy assisted ERP results in less stretching of the anal sphincters than a totally transan- ally performed ERP [ 28, 44, 45]. In Duhamel operation, no difference in bowel functional outcomes between lap- aroscopic and open approaches has been shown [ 38, 46]. There are also no data regarding the optimal length of the Duhamel pouch, and if modifications of the retro- rectal anastomosis reduce the need for spur divisions [38]. Although the Duhamel operation leaves a distal segment of aganglionic bowel anteriorly, it causes very little anal stretching and affords good visibility during surgery. A totally transanal ERP, on the other hand, con- fers excellent cosmesis [ 46]. The original transanal ERP described a long muscular rectal cuff that was split [ 47– 50]. Later reports showed equally good results with a short muscle cuff without splitting, and no cuff with full-thickness plane dissection [ 44, 48, 51–53]. Based on current understanding, long seromuscular cuffs should be avoided as they are associated with obstruction, con- stipation, and enterocolitis [ 46]. Preserving the integrity of the anal canal is a key goal during the operative man- agement of all forms of HSCR. The mucosa above the dentate line contains the nerve endings responsible for the reflex arc in sensation and fecal continence, includ- ing the sampling reflex. In ERP, transanal dissection is commenced 0.5 –2 cm proximal to the dentate line and in the Duhamel operation the posterior incision is per- formed 0,5-1 cm above it [ 47, 49, 51, 54]. No definite pull-through surgery should be performed without first establishing that normal ganglion cells are present in the bowel brought down to the anal canal for anastomosis. During surgery, frozen sections are a valid means for determining the presence of ganglion cells. Table 4 Recommendations for operative management of rectosigmoid HSCR Centres should perform the type of pull-through in which they have the most experience, including management of post-operative complications and follow-up  Transanal endorectal pull-through (ERP), including laparoscopy-assisted ERP, and Duhamel pull-through represent the most commonly performed operations. Currently, there is no evidence for overall superiority of one method over another in terms of surgical complications or long-term bowel function. Level of evidence III Strength of recommendation: Conditional, for Level of agreement: 100% The pull-through operation should be performed when the patient is stable and growing well, and the bowel has been sufficiently decompressed  Elective pull-through within 2 –3 months after diagnosis is usual  No specific advantages have been identified for performing pull-through surgery during the neonatal period  Anaesthetic considerations, clinical and nutritional status of the patient, parental concerns and surgical risks/technical feasibility influence the timing of pull-through surgery Level of evidence III Strength of recommendation: Conditional, for Level of agreement: 100% The anal canal should be preserved during pull-through surgery  The transitional mucosa above the dentate line contains the nerve endings responsible for the reflex arc in sensation and fecal continence, including the sampling reflex.  Transanal dissection should be commenced 0.5 –2 cm proximal to the dentate line  In endorectal pull-through, either no muscle cuff (Swenson) or a short muscle cuff (< 2-3 cm) have comparable outcomes, but long seromuscular cuffs should be avoided Level of evidence II-III Strength of recommendation: Strong, for Level of agreement: 100% The colon should be transected at least 5 to 10 cm proximal to the first normal biopsy minimize the risk of a transition zone pull-through.  If the level of disease remains intraoperatively uncertain, ‘mapping’ biopsies should be obtained from different colonic levels.  Intraoperatively, fresh frozen sections are a valid means for determining the presence of normal ganglionated bowel but single samples may miss asymmetrical histologic extension of the transition zone.  A circular ‘doughnut’ biopsy from the level of transection permits circumferential (4-quadrant) optimal histologic assessment  If feasible, any abnormally dilated colon proximally should be resected to avoid a transition zone pull-through.  At the end of the operation, the resected specimen should be sent in full (marked oral to anal) to the pathologist. Level of evidence III Strength of recommendation: Strong, for Level of agreement: 100% Kyrklund et al. Orphanet Journal of Rare Diseases (2020) 15:164 Page 5 of 16 Full-thickness biopsies permit examination of both the myenteric and submucosal plexuses and thereby minimize the chance of anastomosing abnormally innervated bowel to the anal canal. Seromuscular biopsies have a lower risk of fecal spillage and postoperative perforations, but may be more prone to sampling errors if the transition zone is irregular due to a lack of full submucosal assessment [ 46]. As the length of the transition zone may be variable, the proximal transection margin should be a minimum of 5 – 10 cm orally to where normal ganglion cells are found, un- less a “doughnut” biopsy, showing ganglion cells circum- ferentially in both the submucosal and myenteric plexus is available intraoperatively [55]. Recommendations for early postoperative management after pull-through surgery (Table 5) Enhanced recovery after surgery (ERAS) protocols, which have improved outcomes in adult surgical populations were recently adapted for children undergoing elective colorectal surgery [56]. ERAS aims to optimize care in major surgical procedures through maintenance of physiologic homeosta- sis and by minimizing the effects of surgical stress. In chil- dren undergoing colorectal surgery, the median the time to regular diet, requirement for narcotic analgesia requirement and length of hospital stay were significantly reduced [ 56]. General tenets of ERAS include avoidance of prolonged fasting, use of minimally inva sive surgical techniques, opioid-sparing analgesia, earlyreinstitution of enteral nutri- tion and judicious use of drains and catheters [ 56]. A crit- ical feature involves engagement of the patient and carers at all phases of care. This is conducted by creating clear goals, establishing management plans for pain and nutri- tion, and defining the criteria for discharge to facilitate an o p t i m a ls u r g i c a le x p e r i e n c e[57]. Perianal rash or skin excoriation is common after pull- through surgery, particularly among children who have had a stoma before the pull-through, long segment co- lonic or total colonic aganglionosis, and patients who have undergone surgery as neonates [ 58]. Preventive strategies involve active perineal nursing and the use of barrier ointments such as petroleum jelly, zinc-ointment, or other protective non-irritant creams. Topical antimi- crobials may be also required if bacterial or fungal infec- tion occurs. Anastomotic strictures are a potential complication in colorectal surgery when there is a low circular anasto- mosis, as in ERP. Risk factors include ischemia, anasto- motic leakage, and anastomotic tension. Anastomotic strictures may be less frequent after Duhamel procedure than ERP, where the reported occurrence is up to 10.6% (range: 0–18.9%) [59]. Calibration of the coloanal anasto- mosis at least once is advisable at around 2 –3 weeks after pull-through surgery; Hegar size 12 is appropriate for in- fants from term up to 6 months of age. Some surgeons within ERNICA performed calibration checks infrequently during follow-up, whereas others felt that a single calibra- tion was sufficient. There is no evidence to suggest that routine anal dilatation programs after pull-through surgery prevent strictures or enterocolitis [ 60, 61]. For an anasto- motic stricture, a course of gentle once or twice daily anal dilatations may be attempted, however maintaining a low threshold for examination and dilatation under anesthesia. Recommendations for long-term follow-up (Table 6) Structured follow-up to adulthood, including transition of care is indicated in HSCR [ 62–66]. As bowel dysfunc- tion is most common during the first few years after sur- gery [ 23], patients should be monitored more closely for the early detection of problems, including defective Table 5 Recommendations for early postoperative management after pull-through surgery Patients should receive specialist pediatric and nursing care during the early post-operative period, and anaesthetic consultation should be available on request  Use of Enhanced Recovery After Surgery (ERAS) [ 56] principles may reduce length of stay, requirement for narcotic analgesia and time to full enteral feeds  Parental counselling is important to ensure understanding and engagement with the care plan  Once bowel movements begin, perianal rash/skin excoriation is initially common and requires pre-emptive nursing Level of evidence III Strength of recommendation: Conditional, for Level of agreement: 100% Enteral feeding can be started gradually when the patient has recovered from anaesthesia and is clinically stable  Within 24 –48 h in most cases  Advance feeds as tolerated to normal diet  There is no evidence to suggest prolonged nil by mouth periods or prevent anastomotic complications Level of evidence III Strength of recommendation: Conditional, for Level of agreement: 100% The urinary catheter should be removed as soon as normal micturition is expected after pelvic floor surgery  Epidural anaesthesia post-operatively is an indication for keeping a urinary catheter  Urinary retention after removal can occur following anaesthesia or post-operative tissue swelling in the pelvic floor, and adequacy of urine output should initially be monitored. Level of evidence III Strength of recommendation: Conditional, for Level of agreement: 100% The coloanal anastomosis should be calibrated around 2 –3 weeks after pull-through surgery  Hegar size 12 is appropriate for infants from term up to 6 months of age  Routine serial dilatations have not been shown to reduce the prevalence of enterocolitis or late anastomotic strictures.  If an anastomotic stricture is found, a course of gentle serial dilatations may be attempted, however with a low threshold for examination and dilatation under anaesthesia Level of evidence III Strength of recommendation: Conditional, for Level of agreement: 100% Kyrklund et al. Orphanet Journal of Rare Diseases (2020) 15:164 Page 6 of 16 continence, enterocolitis and late complications. Clinical follow-up should be maintained even if patients are doing well. Among patients with HSCR and a syndrome associ- ated with cognitive impairment, reaching continence is often significantly delayed. In patients with poor func- tional outcomes, adequate follow-up permits the institu- tion of interventions before school age. This is important to prevent social discrimination, and to allow participation in normal childhood activities with minimal limitations from the condition [ 62]. As HSCR is a rare disorder in general practice, patients should also be managed by spe- cialized medical personnel familiar with the disease [ 67], and receive instructions on whom to contact and where to seek medical attention in both elective and emergency cir- cumstances. The availability of specialist nurses improves communication and access to care, and may reduce hospi- talizations/admissions and health care costs [68]. In patients with HSCR, life events that necessitate follow-up include puberty and sexual development, pro- creation and heritability, and transition to adulthood and adult care [ 64, 69, 70]. Psychological factors to be ad- dressed include self-efficacy, social functioning and cop- ing skills for residual symptoms [ 71, 72]. As the parents of chronically ill children also experience considerable stress, strategies to reduce psychological morbidity that also involve the parents are likely to be beneficial [ 62]. Achieving optimal outcomes requires collaboration be- tween medical specialists, nurses and auxiliary resources, including psychologists and sexual therapists, physical and nutritional therapists. In addition to pediatric sur- geons and gastroenterologists, urologic, gynecologic and genetic consultation should be sought as appropriate. Active involvement of the patient/family at all stages of follow-up is important to enable understanding the care plan, and to establish mutually agreed priorities for care [73]. For peer support on lived experience of the disease, patient support organizations encourage contact from patients and their families for advice and networking. During the care pathway, as capacity for understanding increases, patients should be encouraged to acquire health literacy skills and gradually assume responsibility for their own care. Adequate information provision is important in this regard, so that including issues relating to sexual health during adulthood can be addressed [ 62]. Planning transition of care should commence sufficiently early, around 13 –14 years of age to allow sufficient time for adjustment and should have sufficient flexibility to allow overlap and contact between the existing and fu- ture practitioners until patients are satisfactorily estab- lished in adult care [ 74]. Recommendations for Hirschsprung ’s-associated enterocolitis (HAEC; Table 7) HAEC is the most frequent serious complication after pull-through surgery for Hirschsprung disease. Predis- posing factors include family history of HSCR, long seg- ment disease, Down syndrome (trisomy 21) and previous episodes of HAEC [ 75]. Approximately 30% of HSCR patients have at least one episode of postoperative HAEC. Although the definition remains imprecise, using the Pastor et al. HAEC score items (Table 8)[ 76], with a cut-off of > 4 points to identify suspected HAEC is more sensitive and may have better clinical applicability [ 75] than Pastor and co-workers' original cut-off of >1 0 points. HAEC should be suspected in the presence of diarrhea with explosive, foul-smelling or bloody stool, Table 6 Recommendations for long-term follow-up Children with HSCR should receive regular follow-up to adulthood within the context of an interdisciplinary care team, led by a pediatric surgeon  Follow-up should be more frequent during 1st year of life, but regular contact should be maintained 1–2 yearly thereafter  Opportunities to engage multidisciplinary resources, including gastroenterologists, nutritional therapists, psychologists, physiotherapists, specialist nurses and social workers should be available  Attention to development of wider areas of social functioning, including self-efficacy, coping skills and sexual functioning should be addressed  Growth, nutrition and development should be followed Level of evidence III Strength of recommendation: Strong, for Level of agreement: 100% Access to care and specialist consultation should be available  Patients should have a named surgeon in charge of their care and clear information about where and how they should attend follow-up, including in adulthood  Instructions for where to seek emergency care should also be clearly defined  Patient support organizations networks are active in many countries for information and peer support on lived experience of the disease Level of evidence III Strength of recommendation: Strong, for Level of agreement: 100% The introduction to adult medical disciplines should be prepared well before transition  Discussions concerning long-term follow-up should be initiated around adolescence/puberty, and individualized care plans involving the appropriate disciplines should be formulated  Maintaining continuity and consistency of the health care into adulthood is very important to patients  Patients should be given sufficient information and increasingly engaged in decision-making regarding their healthcare with age  The future care provider should be clearly identified, with an opportunity for staged transition and liaison with paediatric services during the transition phase. Level of evidence III Strength of recommendation: Strong, for Level of agreement: 100% Kyrklund et al. Orphanet Journal of Rare Diseases (2020) 15:164 Page 7 of 16 and/or fever. Patients with explosive diarrhea and de- creased peripheral perfusion, lethargy, and/or, dilated loops of bowel on abdominal radiographs have severe HAEC and should be admitted [ 75]. Management with rectal irrigations and close obser- vation at home with a low threshold for oral metro- nidazole may be an option for carefully selected, clinically well patients with mild symptoms and nor- mal fluid balance. Differentiation from simple viral gastroenteritis may be difficult. Patients with severe HAEC should receive rectal washouts, intravenous fluid resuscitation and int ravenous broad-spectrum antibiotics in hospital. Consultation of a specialist paediatric colorectal surgeon on admission, and follow-up after admission is strongly recommended. Antibiotics may be changed to oral metronidazole when sufficient clinical improvement occurs, and rectal washouts 2 –3 times per day should be performed until the child is well enough for discharge. Rectal washouts should be continued at home in cases of recurrent HAEC [77]. In recurrent or persistent HAEC accompanied by symptoms of outlet obstruction (defecation difficulties, re- quiring assistance with e.g. a rectal tube to pass motions), mechanical obstruction or residual aganglionosis should be ruled out [ 78]. Contrast enemas should not be per- formed during an acute episode owing to the risk of per- foration [79]. Intrasphincteric botulinum toxin injections [ 80–82]r e - duce the incidence of HAEC or symptoms of outlet obstruction in 62 –89% of HSCR patients after the first Table 7 Recommendations for Hirschsprung ’s-associated enterocolitis (HAEC) HAEC should be clinically suspected in the presence of diarrhoea with explosive, foul-smelling stool, and/or > 4 points from the Pastor et al. HAEC score items (Table 8)[ 76]  The definition of HAEC remains imprecise even based on current understanding  A cut-off of > 10 points has a reported sensitivity of 42% and specificity of 100% for HAEC [ 75]  A cut-off of > 4 points has a reported sensitivity of 84% and specificity of 98% for HAEC [ 75] Level of evidence III Strength of recommendation: Strong, for Level of agreement: 100% In suspected HAEC, there should be a low threshold for hospital admission  In mild symptoms with no fluid or electrolyte balance disturbance and normal inflammatory markers, outpatient treatment with oral hydration +/ − oral metronidazole and rectal irrigations may be appropriate, but prompt admission is indicated if symptoms do not improve. Recovery should be followed up.  Admit all other cases for in-patient monitoring and treatment  Young age (< 1 year) lowers the threshold for admission Level of evidence III Strength of recommendation: Strong, for Level of agreement: 100% Following admission to hospital, patients with HAEC should be treated with intravenous fluid resuscitation, intravenous broad-spectrum antibiotics and rectal washouts.  Saline rectal washouts to decompress the bowel should be performed 2 –3 times per day until the patient is well enough for discharge  Antibiotics may be changed to oral metronidazole once sufficient clinical improvement occurs  Vital functions, fluid and electrolyte balance, including urine output, should be closely monitored.  Abdominal plain film x-ray should be considered  Consulting the colorectal surgical team responsible for the patient ’s care is recommended  Consult intensive care unit as appropriate Level of evidence III Strength of recommendation: Strong, for Level of agreement: 100% Intersphincteric botulinum toxin injections are recommended for patients with recurrent or persistent symptoms of outlet obstruction and/or HAEC  In reports, 62 –89% of HSCR patients with HAEC and/or outlet obstruction improved after the first botulinum toxin injection [ 82–86]  Injections may need to be repeated 3 –6 monthly  The tendency to HAEC reduces over time; most episodes usually occur within the first few years after pull through Principles of botulinum toxin administration  Botox should be injected under a short general anaesthesia  The patient is positioned in lateral decubitus or lithotomy position  Injections are given in the four quadrants at the level of the dentate line into the anal sphincter musculature  Exposure of the dentate line with retractors, and/or ultrasound guidance can facilitate correct localization of the injections Level of evidence III Strength of recommendation: Conditional,for Level of agreement: 100% Prophylactic antibiotics may be considered for patients with frequently recurring or persistent HAEC  Antibiotics may be effective treatment of HAEC in individual patients, but it has not been shown that prophylactic antibiotics prevent recurrent HAEC.  Recurrent courses of antibiotics interfere with the long-term composition of the gut microbiota, and therefore rationalized use based on severity of symptoms is indicated Level of evidence III Strength of recommendation: Conditional,for Level of agreement: 100% At present, there is insufficient evidence to support recommending the routine use of probiotics for the prevention of HAEC  Although intestinal dysbiosis has been shown to be of importance in the aetiology of HAEC, there are only two randomized controlled studies of probiotics and HAEC in the literature, showing conflicting results. Level of evidence I-III Strength of recommendation: Conditional, against Level of agreement: 100% In children with recurrent HAEC, consultation with a gastroenterologist and endoscopy should be considered  Patients with HSCR have an increased risk of developing inflammatory bowel disease  Fecal calprotectin is a non-invasive measure of intestinal inflammation in acute and chronic enterocolitis Level of evidence III Strength of recommendation: Conditional,for Level of agreement: 100% Kyrklund et al. Orphanet Journal of Rare Diseases (2020) 15:164 Page 8 of 16 injection [81, 83–86]. The number of hospitalizations for obstructive symptoms, particularly enterocolitis, are re- duced by botulinum in jection treatment [ 84]. Botulinum toxin injections may need to be repeated after 3 –6m o n t h s , as the effects decrease over time. In rectosigmoid HSCR, the tendency to HAEC reduces over time, and most epi- sodes occur during the first few years after pull- through surgery [ 23]. Although the etiology of HAEC is not fully known, in- testinal dysbiosis may be an important factor [ 87]. The gut microbiota composition of patients with HSCR may be significantly altered compared to healthy controls. Dys- biosis in HSCR has been characterized by a lack of micro- bial richness, and pathologic expansions of certain taxa, particularly Enterobacteria and Bacilli [ 87–90], and an al- tered Candida community [87]. Although antibiotics may be effective for treating HAEC in individual patients, it has not been shown that prophylactic antibiotics reduce the incidence of recurrent HAEC. This is likely to relate to the multifactorial etiology of HAEC in HSCR, which often includes concurrent obstruction. As recurrent courses of antibiotics may also interfere with the long-term compos- ition of the gut microbiota [ 90], rationalized use based on the severity of symptoms is indicated. It has been hypothesized that the prophylactic adminis- tration of probiotics after pull-through might decrease the incidence of HAEC. However, the only two randomized controlled trials to date have shown conflicting results. In one, no risk reduction was suggested [ 91], but the second suggested that probiotics significantly decreased the inci- dence of HAEC [ 92]. A recent systematic review and meta-analysis included three additional studies that could not show that probiotics prevent HAEC [ 93]. On this basis, there is currently insufficient evidence to recom- mend the routine use of probiotics for the prevention of HAEC. Recent studies have showed that patients with HSCR have an approximately 5-fold increased risk of de- veloping inflammatory bowel disease compared to the general population [ 94]. Endoscopic surveillance should be considered if inflammatory bowel disease is suspected, particularly if faecal calprotectin is continuously elevated. Management of patients with poor outcomes (Table 9) Although surgery is effective in most cases and tech- niques have improved over recent years, a small propor- tion of patients still experience poor functional outcomes [ 28, 95, 96]. These can be grossly divided into faecal incontinence and obstructive symptoms, including severe constipation. In children with normal intellectual development, In children with normal intellectual devel- opment, if adequate social continence for stool has not been achieved by the age of 4 after properly conducted surgery, further evaluation is advisable [ 97, 98]. Manage- ment protocols should not only aim for functional im- provement, but also regard the prevention of the psycho-social consequences of fecal incontinence as an important goal [ 72]. The initial evaluation comprises a full survey of the stool- ing pattern, dietary history, growth and development. Examination of the integrity oft h ed e n t a t el i n ea n ds p h i n c - ter muscles should be performed, preferably under general anaesthesia. This may be complemented by anorectal manometry or endorectal ultrasound [ 44, 99]. In fae- cal incontinence, contrast enemas are helpful in dif- ferentiating between hypo- and hypermotile colon. Both hypomotility and outl et obstruction may lead to overflow incontinence and colonic dilatation, and should be differentiated from hypermotility disorders because their treatment is different. In patients with an intact dentate line and good sphincter function without outlet obstruction but colonic hypomotility , first line management comprises oral laxatives, sup- plemented with a short course of enemas if required. These aim to ensure complete colonic emptying to prevent faecal incontinence and soiling due to over- flow. Patients with an intact dentate line and good sphincters but colonic hypermotility ,m o s tc o m m o n l y due to loss of rectal reservoir, need interventions to Table 8 Pastor et al. (2009) HAEC score items [ 76] History Diarrhea with explosive stool 2 Diarrhea with foul-smelling stool 2 Diarrhea with bloody stool 1 Previous history of enterocolitis 1 Physical examination Explosive discharge of gas and stool on rectal examination 2 Distended abdomen 2 Decreased peripheral perfusion 1 Lethargy 1 Fever 1 Radiologic examination Multiple air fluid levels 1 Dilated loops of bowel 1 Sawtooth appearance with irregular mucosal lining 1 Cut off sign in rectosigmoid region with absence of distal air 1 Pneumatosis 1 Laboratory Leukocytosis 1 Shift to left 1 Note: Using a cut-off of > 4 points to identify suspected HAEC is more sensitive and may have better clinical applicability than Pastor and co-workers' original cut-off of > 10 points [ 75] Kyrklund et al. Orphanet Journal of Rare Diseases (2020) 15:164 Page 9 of 16 slow down colonic transit. These include a constipat- ing diet, loperamide and bulking agents (e.g. pectin, psyllium). If the dentate line and/or sphincter muscu- lature are significantly damaged, bowel management to empty the colon by artificial means will be neces- sary to achieve social continence (see below) [ 100]. If both medical management and bowel management fail, a permanent stoma may be the last resort. Several mechanical factors can lead to postoperative obstructive symptoms. These include an anastomotic stricture, Duhamel spur, obstructed Soave muscular cuff, twisted pull-through or retained aganglionotic or transition zone pull-through. Obstructive symptoms can occur with or without HAEC. Following a thorough clin- ical, dietary and stooling history as for fecal incontin- ence, rectal examination and contrast enema should be performed [ 101–105]. Histology should be reviewed, particularly with regard to the adequacy of the proximal resection margins of the pull-through [ 55, 101]. Repeat- ing transanal colonic biopsies should be considered to confirm normal innervation of the pulled through colon. For anastomotic strictures, a gentle course of anal dilata- tions may be attempted, with a low threshold for general anaesthesia if poorly tolerated. If no mechanical cause is Table 9 Recommendations for management of patients with poor functional outcomes Children with normal intellectual development who are not continent of stool by 4 years of age should be considered for further evaluation. This should include:  A stooling history and stooling pattern to evaluate for tendency to constipation or diarrhoea (for treatment, see below), and involuntary passage of flatus.  Dietary history and growth  Examination under anaesthesia +/ − anorectal manometry to assess the integrity of the anal canal, sphincter complex and dentate line, and for the presence of rolled muscle cuff, stricture or rectal spur  Contrast enema to evaluate whether there is colonic dilatation, rectal spur, constipation or a twisted pull-through  +/− Endorectal ultrasound to assess for sphincter defects Level of evidence III Strength of recommendation: Strong, for Level of agreement: 100% The management of fecal incontinence should aim for age-appropriate continence in children with normal intellectual development  Primary prevention of the social consequences of fecal incontinence is a key goal of treatment  Enabling normal social integration, school attendance and ability to participate in recreational activities from the outset is important for self-esteem, friendships and long-term quality of life  Deficient fecal continence in a child is also a source of stress for caregivers and psychological support should be available for patients and families  Cognitive impairment is associated with delays in achieving voluntary bowel control Level of evidence III Strength of recommendation: Strong, for Level of agreement: 100% Patients with an intact anal canal and appropriate pull-through but fecal incontinence should receive medical management as the first-line treatment  For patients with a dilated colon and constipation (hypomotility), oral laxatives +/ − a short course of enemas to ensure regular and complete colonic emptying  For patients without colonic dilatation and a tendency to loose stools (hypermotility), a constipating diet +/− loperamide +/− bulking agents (pectin, psyllium)  Measure fecal calprotectin, consider ileo-colonoscopy and repeat rectal biopsy  Proceed to bowel management if there is failure to respond, despite adequate dosing and compliance Level of evidence III Strength of recommendation: Conditional,for Level of agreement: 100% Patients with fecal incontinence and damaged anal canal should receive bowel management  Maintaining an intact anal canal is a central goal in all standard operations for HSCR, and an indication for performing pull-through surgery in specialist units  An enterostomy is an option if bowel management fails to control symptoms Level of evidence III Strength of recommendation: Conditional,for Level of agreement: 100% Children with persistent obstructive symptoms following pull-through surgery should undergo further evaluation and treatment:  Rectal examination and contrast enema to rule out a mechanical cause and to assess for colonic dilatation  If no mechanical cause is found, a trial of intersphincteric botulinum toxin injections  Review the histology of the proximal margins of the originally resected bowel  Repeat rectal biopsies to ensure normal innervation of the pulled-through bowel  If repeated botulinum toxin injections are ineffective, histology is normal and there is no mechanical cause, bowel management can be offered  Consider re-do surgery in patients with a recalcitrant stricture, twisted pull-through, rolled muscle cuff (Soave), rectal spur (Duhamel) or transition zone pull-through Level of evidence III Strength of recommendation: Strong, for Level of agreement: 100% Bowel management programme should comprise individualized care based on the symptom profile, local recommendations and values/preferences of the patient/carer(s)  The goal of bowel management is to achieve regular and complete colonic emptying at predictable intervals  Options include regular retrograde enemas or antegrade colonic irrigation via an antegrade continence enema appendicostomy (ACE) or cecostomy +/ − dietary modifications +/ − laxatives  Psychological support can assist patients and families in coping with symptoms  An enterostomy may be required in isolated cases for intractable symptoms Level of evidence III Strength of recommendation: Conditional,for Level of agreement: 100% Kyrklund et al. Orphanet Journal of Rare Diseases (2020) 15:164 Page 10 of 16 found, first-line treatment is intersphincteric botulinum toxin injections to relieve internal sphincter achalasia. If symptoms fail to improve after repeated (> 3) botulinum toxin injections, bowel management is the second-line choice of treatment. Bowel management comprises individualized man- agement based on the patient ’s preferences. Options include regular retrograde enemas, or antegrade co- lonic irrigation via an antegrade continence enema appendicostomy (ACE) or cecostomy (CHAIT, button) in conjunction with oral laxatives and dietary modifi- cations. Re-do surgery should be considered in symp- tomatic patients with a recalcitrant stricture, twisted pull-through, rolled muscle cuff (Soave), rectal spur (Duhamel), or aganglionic/transition zone pull- through. The full evaluation and re-do surgical pro- cedure should be performed in a centre with experi- ence of complex pathology in HSCR and re-do procedures. Although redo- surgery is appropriate in selected cases resolves obstructing symptoms, it may be associated with relatively high rates of fecal incon- tinence and thus, careful patient selection is import- ant [ 103, 105]. Recommendations for genetic screening (Table 10) Most cases of HSCR that occur without an associ- ated genetic syndrome or chromosomal anomaly are sporadic. The main gene in non-syndromic HSCR is the proto-oncogene RET. Coding mutations, which usually cause a loss of function in RET are present in approximately 15 –35% of sporadic cases [ 106– 114]. In patients with a family history of HSCR, the occurrence of RET coding mutations is much higher, up to 50% [ 108, 109, 111]. The second most com- monly mutated gene in non-syndromic HSCR is EDNRB (endothelin receptor-beta) which is affected in ~ 5% of cases [ 112]. Besides RET and EDNRB, many other genes have been implicated in HSCR, but the chances of detecting a mutation in these genes are very low. Although most HSCR is found in isolation it also is seen in the context of several syndromes, including Down syndrome (Trisomy 21), which is the most common, Shah-Waardenburg syn- drome, Congenital Central H ypoventilation syndrome (CCHS), Mowat-Wilson s yndrome, and Goldberg- Shprintzen syndrome. Although most mutations in RET are inactivating, activating RET mutations are present in approximately 2–3% of all sporadic HSCR cases [ 113]. These muta- tions can cause multiple endocrine neoplasia type 2A (MEN2A), a cancer syndrome characterized by medul- lary thyroid carcinoma, phaeochromocytoma of the adrenal glands, and hyperplasia of the parathyroid glands [ 114, 115]. In non-syndromic HSCR, referral for genetic testing of RET to exclude the rare possibil- ity of a MEN 2A associated RET mutation that is also associated with an elevated risk for MTC should therefore be considered [ 113]. Molecular testing out- comes may also give a more accurate estimation for the parents of a HSCR patient of the risk of recurrence in future pregnancies. As many RET mutations prove to be sporadic and have not been inherited from the parents, screening is preferably performed in a TRIO setting that involves testing the father, mother and child. In suspected syndromic HSCR, patients should be screened for the gene that is associated with that specific phenotype. Evidence gaps and targets for further research There remain many caveats in the knowledge of Hirschsprung ’s disease. There are currently no prac- tical capabilities for the prenatal diagnosis of HSCR, as abnormal sonographic findings are absent in the majority of fetuses with HSCR [ 116]. The definitions, causes and predisposing factors for HAEC and bowel dysmotility in the remaining ganglionic bowel remain incompletely understood. The composition intestinal microbiota and gut mucosal immunity in the pathogenesis of HAEC is a topic of current research interest. With re- gard to operative management, more comparative studies of the predominant pull-through techniques (Duhamel Table 10 Recommendations for genetic screening of patients with HSCR In non-syndromic HSCR, genetic testing of RET should be considered  RET remains the major gene in HSCR  Molecular testing allows a more accurate estimation of the risk of recurrence  Genetic testing of RET allows exclusion of the rare possibility of MEN 2A- associated RET mutation that is associated with an increased risk of medullary thyroid cancer  Parents or patients who wish to have genetic screening should be offered referral for genetic consultation  Genetic consultation is also recommended for patients with a family history of HSCR, where the incidence of RET mutations is even higher Level of evidence II-III Strength of recommendation: Conditional, for Level of agreement: 100% In syndromic HSCR, patients should be offered referral for genetic consultation and screening for the specific gene associated with the syndromic phenotype Level of evidence III Strength of recommendation: Conditional, for Level of agreement: 100% Kyrklund et al. Orphanet Journal of Rare Diseases (2020) 15:164 Page 11 of 16 and ERP) are needed to gather higher quality evidence of the long-term outcomes, and whether laparoscopy- assisted techniques confer advantages. Little is also known about the sexual function and fertility after pull-through surgery, although physical sexual functions appear to be preserved in the majority [ 117]. However, it has been shown that technically comparable low pelvic surgery for other pediatric bowel problems, impacts on later fertility, especially in females [ 118]. Further prospective research and multicenter studies are needed to obtain a full under- standing of the long-term implications of HSCR on pa- tients’ health. Conclusions In rare or low-prevalence diseases such as HSCR, there is limited availability of high-quality clinical evi- dence. However, patients born with these conditions continue to require highly specialized care from in- fancy up to adulthood. In this document, consensus- based guidelines that describe the preferred approach of ERNICA, an international panel of experts from 10 major European centres to the management of recto- sigmoid HSCR are presented. ERNICA remains com- mitted to upholding and improving care standards for patients with HSCR. Materials and methods Membership of the guideline workgroup The workgroup comprised an international panel of experts in HSCR from specialist centres in 8 European countries (Denmark, France, Germany, Finland, Italy, Netherlands, Norway, Sweden and the United Kingdom). These included pediatric surgeons, histopathologists, gas- troenterologists, microbiologists and geneticists from 10 ERNICA (ERN) member centres and 3 associated experts selected by ERNICA. Patient representatives from SoMA, the German patient support organisation for anorectal malformations and HSCR and A.Mor.Hi, the Italian Soci- ety for HSCR, participated throughout the process. Accreditation as an ERN centre requires demonstration and approval of specific specialist competencies and compli- ance with a comprehensive set of operational criteria [119]. These include demonstration of quality in organizational in- frastructure, patient-centered management, clinical govern- ance, sufficient care volumes, ability to report outcomes and commitment to upholding expertise through research, train- ing and education. Recognition of competencies and mem- bership is based on regular internal and external assessment. Background preparation A literature search was conducted using PubMed of arti- cles published on HSCR from 1990 to 2018, and their ref- erences to identify articles that had not been brought up by the original search. Where studies of HSCR or pediatric populations were scarce or unavailable, data was derived from relevant studies from adult populations. Within groups, expert clinicians selected those publications they considered most relevant and highest quality for the refer- ence pool of the guideline. Patient representatives contrib- uted publications that best reflected their values to the workgroup. All authors had access to the reference pool during development. Articles were assigned an evidence level of I-III based on the Canadian Task Force on the Periodic Health Examinatio n classification system (1979) summarized in Table 11 [120], with the expectation that in rare or low prevalence diseases most would fall into cat- egory III (descriptive studies, expert opinion). Determination of the core recommendation statements The working group met on three occasions: 1) to discuss t h ec o n t e n to ft h eg u i d e l i n e ,2 )t od e c i d eo nt h ec o r e recommendations and supporting statements, and 3) to finalize the content, including voting on levels of agree- ment. After drafting recommendations, the supporting text and summary of the evidence was prepared. The AGREE II framework was used to assess the scope and rigour of the methodology [121]. The GRADE approach was used to rate the strength of the recommendations [ 122, 123]. Updating of the recommendations at 5-year intervals by ERNICA was planned. Assigning strength of the recommendations Recommendations were classed as strong (for or against), if the workgroup felt highly confident of the balance be- tween desirable and undesirable consequences [ 122, 123]. Recommendations were classed as conditional (for or against), if the appropriate course of action was con- sidered subject to patient values and preferences, avail- ability of resources and/or setting of the intervention [122, 123]. Voting on levels of agreement Voting on levels of agreement was conducted at the final meeting. Recommendations r eceiving < 100% agreement were further discussed, rev ised and voted on again at the meeting until consensus was reached; > 75% agreement was considered necessary to finalize recommendations [124]. Table 11 Grading of levels of Evidence [ 120] Level of Evidence  I Evidence from at least one randomized controlled trial  II1 Evidence from well-designed case-control or cohort studies, preferably from more than one research group or centre  II2 Comparisons between times and places with or without the intervention, or dramatic results of uncontrolled experiments  III Opinions of respected authorities, based on clinical experience, descriptive studies or reports of expert committees. Kyrklund et al. Orphanet Journal of Rare Diseases (2020) 15:164 Page 12 of 16 Abbreviations ACE: Antegrade continence enema; AChE: Acetylcholine esterase; EDNRB: Endotheln receptor beta; ERN: European Reference Network; ERNICA: The European Reference Network for for rare inherited and congenital digestive disorders; ERAS: Enhanced recovery after surgery; ERP: Endorectal pull-through; EU: European Union; HSCR: Hirschsprung ’s disease; H&E: Haematoxylin and eosin; MEN: Multiple endocrine neoplasia; MTC: Medullary thyroid cancer; RET: Rearranged during transfection proto- oncogene Acknowledgments We would like to thank Prof. Dr. René Wijnen, Renée de Ruiter and Olivia Spivack from ERNICA for organising the Network ’s meetings, that also enabled completion of this project. Authors’ contributions All authors of the work have made substantial contributions to the conception and design of the work and to the literature search and its analysis. All authors have been involved in drafting the work and revising it critically for important intellectual content, and all authors read and approved the final manuscript. Funding Workgroup meetings and article-processing charges for open access publication in Orphanet Journal of Rare Diseases were supported by ERNICA European Reference Network. The authors have no other sources of funding to disclose. Availability of data and materials Not applicable to article type. Ethics approval and consent to participate Not applicable to article type. Consent for publication Not applicable to article type. Competing interests The authors declare that they have no competing interests Author details 1Department of Pediatric Surgery, Children ’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 2Department of Pediatric Surgery, Erasmus MC – Sophia Children ’s Hospital, Rotterdam, The Netherlands. 3Department of Surgery, Division of Pediatric Surgery, Radboudumc-Amalia Children ’s Hospital, Nijmegen, The Netherlands. 4Department of Pediatric Surgery, Oslo University Hospital and University of Oslo, Oslo, Norway. 5Department of Pediatric Surgery and Pediatric Urology, University Hospital Frankfurt, Frankfurt/M, Germany. 6Department of Biology, University of Florence, A.Mor.Hi, The Italian Association for Hirschsprung ’s disease, Florence, Italy. 7Pathology Unit, Bambino Gesù Children ’s Hospital, IRCSS, Rome, Italy. 8Neonatal Surgery Unit – Department of Medical and Surgical Neonatology, Bambino Gesù Children ’s Hospital, IRCSS, Rome, Italy. 9SoMA, The German patient support organization for anorectal malformations and Hirschsprung Disease, Munich, Germany. 10Pediatric Surgery, Department of Women ’s and Children ’s Health, University Hospital of Padua, Padua, Italy. 11UCL Great Ormond Street Institute of Child Health; Department of Pediatric Gastroenterology, Great Ormond Street Hospital for Children, London, UK. 12Department of Surgery and Transplantation, Abdominal Centre, Rigshospitalet, Copenhagen, Denmark. 13Department of Pediatric Pathology, Hôpital Universitaire Robert Debré, Paris Diderot University, Paris, France. 14Department of Pediatric Gastroenterology, Hôpital Universitaire Robert Debré, Assistance Publique Hôpitaux de Paris, Université de Paris, Paris, France. 15Department of Pediatric Surgery, University Hospital Necker-Enfants Malades, APHP centre, Paris University, Paris, France. 16Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands. 17Department of Pediatric Surgery, Karolinska University Hospital, Stockholm, Sweden. 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