Quality of life

After undergoing appropriate pull-through surgery for rectosigmoid HSCR, most patients experience favourable bowel functional outcomes in the long-term. However, symptoms of impaired bowel function are common during the first few years after surgery183,184. These symptoms include difficulties with faecal control, impaired rectal sensation, an elevated stooling frequency, episodically obstructive defaecation and enterocolitis. By adulthood, most patients report bowel function similar to that in peers from the general population, but ~10% continue to experience problematic faecal soiling, which can impact their quality of life138.

Although no substantial differences exist in outcomes between Yancey–Soave (endorectal) pull-through and Duhamel (retrorectal) pull-through, an elevated bowel frequency and overall incidence of enterocolitis episodes may be more frequent after Yancey–Soave pull-through than after the Duhamel procedure, whereas constipation and defects in faecal control may be slightly more prevalent after the Duhamel operation than after Yancey–Soave pull-through185. Long-segment and total colonic aganglionosis have more guarded outcomes, with more disease-specific complications, including a greater incidence of HAEC and an increased requirement for attention to growth and nutritional needs linked to a loss of a greater segment of bowel, including small intestine186.

In the presence of a HSCR-associated chromosomal disorder such as Down syndrome, Mowat–Wilson syndrome or cartilage–hair hypoplasia, bowel functional outcomes and quality of life outcomes are generally less favourable and more difficult to predict in individual patients than in patients without an associated disorder. When neurocognitive­ issues are present, the functional outlook is markedly affected, with rates of faecal soiling and urinary incontinence reaching 50%, and the requirement for a permanent stoma to manage these issues is high, reaching 22%187. In cartilage–hair hypoplasia, cellular immunodeficiency has a major impact on clinical outcome, with an increased risk of infections, lung diseases and malignancy188,189. Multiple inter-dependent factors, including deficits in bowel function, sexual or urinary function or related neuropsychological effects can

impair quality of life in patients190–192. Clustering of these issues may occur in certain individuals and lead to poor outcomes187.

During infancy and early childhood, issues with bowel function are frequent and are often related to functional obstruction and HAEC. In early childhood, the priorities are securing age-appropriate faecal continence and the management of bowel functional symptoms to enable participation in normal activities and social interactions19. Patients who have suboptimal outcomes during this phase should receive close follow-up and aftercare to minimize pain and stress from surgical interventions, encourage parental involvement in the care processandaddressparentalstressrelatedtothechild’scondition138,193.

Preserving intestinal homeostasis, including age-specific development of normal intestinal microbiota, is important in optimizing functional outcomes and health-related quality of life in patients with HSCR194. A multidisciplinary specialized approach to care, including surgical and medical factors, is required to address potential urological complications involved with low pelvic surgery195, gynaecological complications such as female infertility191, and increased risk of familial medullary thyroid cancer and inflammatory bowel disease during adulthood196–199 (Fig. 7).

Transition of care to adult practice should be commenced after puberty in patients who continue to have impaired bowel function or other complications. Follow-up arrangements should be clear for patients and families to support the development of adequate health literacy among patients and positivestrategies for coping with residual symptoms,whichmaybepermanent.Patientsupportorganizationsare available in many parts of the world for peer support and information on personal past experiences with HSCR.

Outlook

Although considerable advances have been made in the diagnosis and treatment of HSCR since its original description in 1886, several outstanding research questions remain to be addressed. There is tremendous potential for emerging technologies, promising new areas of research, and advances from related fields to influence the trajectory of HSCR research in several ways.

Genetics and genomics

Despite evidence indicating a crucial role for genetics in the development of HSCR, the exact genetic interactions and pathways involved are still not fully understood. Further research is warranted to unravel the different signalling pathways, which could lead to improved diagnosis and treatment. Researchers will continue to identify new genes associated with HSCR and investigate how different genetic mutations impact the severity of the disease. Furthermore, advances in genomics, proteomics, metabolomics and transcriptomics, and new gene editing technologies, could help researchers better understand the genetic basis of HSCR and potentially develop novel therapies targeting specific genetic mutations.

Diagnosis

Although several diagnostic tests are available for HSCR, they are not alwaysaccurate.Hence,moreresearchisneededtodeveloplessinvasive, more accurate and reliable diagnostic tests for HSCR and its complications,suchasHAEC.Newimagingtechniques,suchasMRIandCTscans, to detect abnormalities in the colon or rectum, including the potential forprenataldetectionofthedisease,mustbeexplored.Machinelearning andartificialintelligencetechnologiesmayhavethepotentialtoimprove the accuracy of diagnostic tests for HSCR. For example, artificial intelligence algorithms are being developed to analyse histological images and identify subtle abnormalities in the colon or rectum that might be missed by human observers200. Moreover, the use of artificial intelligencemaybeparticularlyusefulinsettingswherepathologyexpertise islacking201.Accuratelydeterminingtheextentofaganglionosisduring surgeryiscrucialtoavoidresidualaganglionosisafterpull-throughand thecurrentapproachreliesonintraoperativefrozenbiopsies,whichcan betime-consumingandrequiretheavailabilityofanexperthistopatholo- gist.ConfocallaserendomicroscopyhasbeenusedtovisualizetheENS invitroandinvivo,andmaybecomeausefulreal-timetooltodetermine the length of aganglionosis during pull-through202,203.

Treatment

To date, no consensus exists to suggest the best surgical technique and no evidence is available to suggest that one approach is superior to all others. Further research is needed to determine the most effective surgical technique or subsets of patients who might benefit more from one technique than from another. In parallel, new treatments including robot-assisted approaches and non-surgical approaches are being explored. Multiple groups worldwide have ongoing research programmes employing the use of stem cell therapy to regenerate the missing ganglion cells in the aganglionic bowel or transition zone, or to develop bioengineered intestinal segments, which could potentially restore normal bowel function. Indeed, enteric NCCs transplanted in vitro into the aganglionic gut of a mouse model of HSCR have been shown to migrate, proliferate and differentiate, resulting in successful colonic contractile responses204,205. Moreover, the development of ENS progenitors from human pluripotent stem cells is a promising tool to identify potential cellular targets and develop drug-based strategies for HSCR treatment206. However, safety and quality control, patient selection and timing of interventions have been an enormous challenges in the past few decades.

Patient-centred research

Further research is needed to understand the long-term outcomes of HSCR and to develop strategies to prevent or manage these complications207. Efforts to understand the psychological and social

effects of the condition and to develop interventions to improve the quality of life of affected individuals and their families are warranted. Over the past decade, patient-centred research and family-centred care and research, involving patients and families in the design and implementation of research studies have gained attention. This shift will help ensure that research efforts are prioritized on the needs of patients and families. This approach will enable ‘value-based care’, shifting from improving patient health to improving patient-relevant outcomes208. Advances in patient-centred technologies, such as mobile apps and wearable devices, could be used to monitor bowel function, track symptoms and provide personalized support and advice to patients and their families. These methods have the potential to enable earlier interventions to improve the quality of life of patients with HSCR, which is the ultimate end-goal of treatment.

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