Hirschsprung-associated inflammatory bowel disease: A multicenter study from the APSA Hirschsprung disease interest group

Background/PurposeA small number of Hirschsprung disease (HD) patients develop inflammatory bowel disease (IBD)-like symptoms after pullthrough surgery. The etiology and pathophysiology of Hirschsprung-associated IBD (HD-IBD) remains unknown. This study aims to further characterize HD-IBD, to identify potential risk factors and to evaluate response to treatment in a large group of patients.MethodsRetrospective study of patients diagnosed with IBD after pullthrough surgery between 2000 and 2021 at 17 institutions. Data regarding clinical presentation and course of HD and IBD were reviewed. Effectiveness of medical therapy for IBD was recorded using a Likert scale.ResultsThere were 55 patients (78% male). 50% (n = 28) had long segment disease. Hirschsprung-associated enterocolitis (HAEC) was reported in 68% (n = 36). Ten patients (18%) had Trisomy 21. IBD was diagnosed after age 5 in 63% (n = 34). IBD presentation consisted of colonic or small bowel inflammation resembling IBD in 69% (n = 38), unexplained or persistent fistula in 18% (n = 10) and unexplained HAEC >5 years old or unresponsive to standard treatment in 13% (n = 7). Biological agents were the most effective (80%) medications. A third of patients required a surgical procedure for IBD.ConclusionMore than half of the patients were diagnosed with HD-IBD after 5 years old. Long segment disease, HAEC after pull through operation and trisomy 21 may represent risk factors for this condition. Investigation for possible IBD should be considered in children with unexplained fistulae, HAEC beyond the age of 5 or unresponsive to standard therapy, and symptoms suggestive of IBD. Biological agents were the most effective medical treatment.Level of EvidenceLevel 4     

Is the skin microbiota a modifiable risk factor for breast disease?: A systematic review

PurposeHigh prevalence, unreliable risk discrimination and poor clinical outcomes are observed in malignant and benign breast diseases (BD). The involvement of microbial communities in the development of BD has become topical, and distal influences of microbial dysregulation in the breast have been well established. Despite advances, the role of the breast skin microbiota in BD remains unclear. Interactions between the skin microbiota and the underlying mucosal immune system are complex. In homeostasis, the skin offers a physical barrier protecting underlying breast tissue from skin commensals and noxious environmental triggers. Our review aims to illuminate the role of the skin microbiota in the development of BD.MethodsAdhering to the PRISMA protocol, a systematic review was conducted utilising the Medline and Embase search engines.ResultsThrough a comprehensive search of the last ten years, twenty-two studies satisfied the inclusion criteria. Proteobacteria, Firmicutes, Actinobacteria and Bacteroidetes were identified as the most prevalent phyla of both breast tissue and skin in healthy controls and BD. High abundance of skin commensals, specifically some species of Staphylococcus, have been linked in breast cancer and metastases. Similarly, dysregulated microbial abundance is also seen in inflammatory and implant-associated BD. These findings raise the hypothesis that the skin microbiota plays a role in tissue homeostasis and may contribute to a range of breast pathologies. Several mechanisms of microbial transfer to underlying tissue have been proposed, including retrograde transfer through ductal systems, breakdown of the skin barrier, and migration through nipple-aspirate fluid.ConclusionOur review provides preliminary insights into the skin microbiota as a modifiable risk factor for BD. This raises opportunities for future studies in antimicrobials/probiotics as an adjunct to, or replacement of surgery; a diagnostic and/or prognostic tool for BD; and the possibility of conditioning the microbiota to manage BD.     

The emerging role of ultrasound in detecting interstitial lung disease in patients with rheumatoid arthritis

ObjectiveTo investigate the potential role of US in the detection of ILD in a cohort of patients with RA.MethodsPatients with diagnosis of RA were consecutively enrolled. All patients underwent pulmonary examination, laboratory data, DLCO measure, chest HRCT and radiographs, and US examination. A healthy group was included as control group. US was performed according the 14-intercostal space scanning protocol using the following semiquantitative scale [0 = normal (≤ 5 B-lines); 1 = slight (≥ 6 and ≤ 15 B-lines); 2 = moderate, (≤ 16 and ≥ 30 B-lines); 3 = severe (≥ 30 B-lines)].ResultsA total of 74 RA patients and 74 healthy controls were included. Thirty of 74 patients (40.5%) showed US signs of ILD with respect to the healthy controls (3 subjects, 4.1%) (P < 0.001); whereas HRCT showed ILD in 27 (36.4%) of 74 patients. Among the 30 patients that showed US findings of ILD, 17 (56.6%) were asymptomatic from respiratory view-point. The sensitivity and specificity of US were 92% and 89% respectively. A positive correlation between US and HRCT findings were found (P < 0.001) whereas no correlation was found with chest radiographs and DLCO findings. Positive association between US findings and DAS28-ESR, anti-CCP and RF (P < 0.01 for each respectively) was found. Feasibility, represented by the mean time spent to perform the pulmonary US assessment was 7.8 minutes (± SD 1.2, range 6 to 10 minutes).ConclusionsOur results support the potential of US in detect accurately ILD in patients with RA and provide a rationale to consider it as a friendly screening tool to be implemented in early phases of the disease.     

Pre-transplantation vitamin E levels and acute graft-versus-host disease after non-myeloablative allogeneic hematopoietic cell transplantation

BackgroundLow pre-transplantation plasma vitamin E levels have been associated with increased risk of acute graft-versus-host disease (GvHD) after myeloablative allogeneic hematopoietic cell transplantation (allo-HCT). We aimed to investigate the association between pre-transplantation plasma vitamin E levels and acute GvHD in patients undergoing allo-HCT with non-myeloablative conditioning.MethodsIn a cohort of 194 adults who underwent non-myeloablative allo-HCT at Rigshospitalet between July 2015 and December 2019, we measured pre-transplantation plasma vitamin E levels by high-performance liquid chromatography in stored plasma samples. Univariable ordinary least squares linear models were used to investigate associations between vitamin E levels and patient characteristics. A multivariable logistic regression model was used to estimate the association between vitamin E levels and grade II–IV acute GvHD, adjusted for recipient age, donor age, female-male donor-recipient pairing, and donor type.ResultsThe median (Q1, Q3) pre-transplantation plasma vitamin E level was 32.3 (26.4, 40.4) μmol/L. No patients had a vitamin E level below the normal reference range. Vitamin E levels were higher in females (mean difference: 8.0 μmol/L, 95% confidence interval [CI]: 4.9, 11.1 μmol/L) and in patients transplanted for acute leukemia (mean difference: 6.2 μmol/L, CI: 3.0, 9.4 μmol/L). Grade II–IV acute GvHD developed in 33 (17%) patients. Patients who developed acute GvHD had similar pre-transplantation vitamin E levels compared with patients who did not develop grade II–IV acute GvHD (mean difference: 0.7 μmol/L, bootstrap CI: −3.3, 4.7 μmol/L). In the adjusted logistic regression model, an increase in the pre-transplantation vitamin E level from 26.4 (Q1) to 40.4 (Q3) μmol/L was associated with an odds ratio of grade II–IV acute GvHD of 1.17 (CI: 0.64, 2.12).ConclusionsContrary to the previously reported association between pre-transplantation vitamin E levels and acute GvHD after myeloablative allo-HCT, we did not find support for an association in patients who received non-myeloablative conditioning. The potential protective effects of vitamin E may not be efficacious in the reduced inflammatory response following non-myeloablative conditioning.     

Postoperative spino-pelvic stereoradiography to predict adjacent segment disease

PurposeThe purpose of this study was to identify sagittal spinopelvic parameters predictive of adjacent segment disease (ASD) on postoperative whole spine weight-bearing stereoradiography.Materials and methodsA total of 84 patients with previous spinal fusion surgery and documented radiological follow-up with early weight-bearing postoperative whole spine stereoradiography (EOS® Imaging System) were retrospectively included. A pathological group of 42 patients (9 men, 33 women; mean age, 63.1 ± 11.5 [SD] years) who developed documented ASD (mean follow-up, 76.75 months; range: 31.5–158.5 months) was compared with a control group of 42 asymptomatic patients (7 men, 35 women; mean age, 60.9 ± 11.8 [SD] years) (mean follow-up, 115 months; range: 60–197 months) based on sagittal balance evaluation and routinely used spino-pelvic parameters. Comparisons were made using uni- and multivariate analyses.ResultsAt univariate analysis, patients with ASD had an anteriorly displaced sagittal vertical axis (CAM plumb line) and an inadequate lumbar lordosis (LL) in reference to pelvic incidence (PI) compared to controls. They also had higher C7 slope and C2-C7 offset. At multivariate analysis, C2-C7 offset (OR = 1.152; 95% CI: 1.056–1.256; P = 0.001) and a lack of LL (OR = 5.063; 95% CI: 1.139–22.498; P = 0.033) were significantly associated with ASD.ConclusionAnterior cervical imbalance, reflected by an increase in C2-C7 offset and insufficient restoration of LL are postoperative predictive factors of ASD on stereoradiography.     

Disappearance of hemichorea as the initial presentation of moyamoya disease after revascularization surgery regardless of residual hypoperfusion evaluated by quantitative N-isopropyl-p-123I-iodoamphetamine SPECT

Background and importanceAlthough hypoperfusion of the basal ganglia or the frontal subcortical matter is suspected, the pathology of chorea in moyamoya disease remains unclarified. Herein, we report a case of moyamoya disease presenting with hemichorea and evaluate pre- and postoperative perfusion using single photon emission computed tomography with N-isopropyl-p-¹²³I-iodoamphetamine (¹²³I-IMP SPECT).Clinical presentationAn 18-year-old woman presented with choreic movement of her left limbs. Magnetic resonance imaging revealed an ivy sign, and ¹²³I-IMP SPECT demonstrated decreased cerebral blood flow (CBF) and cerebral vascular reserve (CVR) values in the right hemisphere. The patient underwent direct and indirect revascularization surgery to improve cerebral hemodynamic impairment. The choreic movements entirely resolved immediately after surgery. Although CBF and CVR values in the ipsilateral hemisphere demonstrated by quantitative SPECT increased, these did not reach the normal values threshold.ConclusionChoreic movement in moyamoya disease may be related to cerebral hemodynamic impairment. Further studies are required to elucidate its pathophysiological mechanisms.     

Results of staged repair of aortic disease in patients with Marfan syndrome

ObjectiveWe present our open surgical strategies for staged replacement of the thoracic and thoracoabdominal aorta in patients with Marfan syndrome.MethodsBetween October 1999 and December 2017, 82 patients with Marfan syndrome underwent 118 aortic repairs. We divided the aorta into 4 segments for categorization: (1) the aortic root, (2) aortic arch, (3) descending thoracic, and (4) abdominal aorta. Procedures were categorized according to the types of surgery. Staged repair was defined as a subsequent operation on a different segment of the aorta after initial repair (n = 111, 94.1%), and reoperation was defined as an operation on the same segment (n = 7, 5.9%).ResultsThe mean age at initial operation was 41.7 ± 14.9 years. Staged repairs included aortic root replacement (n = 42, 36%), total arch replacement (n = 11, 9.3%), combined aortic root and total arch replacement (n = 13, 11%), descending aorta replacement (n = 4, 3.4%), thoracoabdominal aortic repair (n = 36, 31%), and extensive arch-descending or thoracoabdominal repair (n = 5, 4.2%). Four patients received 3 staged repairs. Operative mortality was 0.8% (1/118). Stroke occurred in 1.7% (2/118), and spinal cord injury occurred in 1.7% (2/117). Overall survival was 95.8 ± 2.4% at 10-years. Twenty-four patients underwent replacement of the whole aorta after 2.5 ± 3.8 years following initial repair.ConclusionsOur strategies for staged replacement of the thoracic and thoracoabdominal aorta in patients with Marfan syndrome resulted in excellent early- and long-term outcomes.     

Diagnosis of postoperative recurrence of Crohn disease with MR-enterography: Value of diffusion-weighted imaging

PurposeTo compare the diagnostic capabilities of MR enterography (MRE) using contrast-enhanced (CE) sequences with those of MRE using diffusion-weighted (DW) imaging for the diagnosis of postoperative recurrence at the neo-terminal ileum and/or anastomosis after ileocolonic resection in patients with Crohn disease (CD), and to clarify the role of additional DW imaging to CE-MRE in this context.Material and methodsForty patients who underwent ileal resection for CD, and both endoscopy and MRE within the first year after surgery were included. There were 21 men and 19 women, with a mean age of 38 years ± 12 (SD) years (range: 18–67 years). MRE examinations were blindly analyzed independently by one senior (R1) and one junior (R2) radiologist for the presence of small bowel postoperative recurrence at the anastomotic site. During a first reading session, T2-, steady-state- and DW-MRE were reviewed (DW-MRE or set 1). During a separate distant session, T2-, steady-state- and CE-MRE were reviewed (CE-MRE or set 2). Lastly, all sequences were analyzed altogether (set 3). Performances of each reader for the diagnosis of postoperative recurrence were evaluated using endoscopic findings as the standard of reference (Rutgeerts score ≥ i2b).ResultsFifteen patients out of 40 (37.5%) had endoscopic postoperative recurrence at the anastomotic site. Sensitivity for the diagnosis of postoperative recurrence was 73% (95% CI: 51–96%) for R1 and 67% (95% CI: 43–91%) for R2 using set 1, and 80% (95% CI: 60–100%) for both readers using set 2. There was no significant differences in sensitivity between reading set 1 and reading set 2, for either R1 or R2 (R1, P  > 0.99; R2, P = 0.48). Specificity was 96% (95% CI: 88–100%) for both readers using set 1 or using set 2. Reading set 3 yielded an area under the ROC curve (AUC) of 0.93 (95% CI: 0.84–1) versus 0.89 (95% CI: 0.75–1) with set 1 (P = 0.18) and versus 0.89 (95% CI: 0.78–1) with set 2 (P = 0.21). No significant differences in AUC were found between set 1 or 2 and set 3 (P = 0.18), nor between set 1 and 2 (P = 0.76). Accuracies were 88% (95% CI: 74–95%) and 85% (95% CI: 71–93%) for DW-MRE for R1 and R2, respectively; 90% (95% CI: 77–96%) for CE-MRE for both readers; and 93% (95% CI: 80–97%) and 88% (95% CI: 74–95%) for R1 and R2 with set 3, respectively.ConclusionDW-MRE has diagnostic capabilities similar to those of CE-MRE for the diagnosis of postoperative recurrence of CD at the anastomotic site.     

Patient-related risk factors and lifestyle factors for lumbar degenerative disc disease: a systematic review

ObjectiveBack pain is a very widespread disease pattern and is one of the most frequent causes for consultation of a physician in general. In most cases, discogenic changes are the pathomorphological correlate of back pain. Numerous risk factors have been identified for these degenerative changes, but the influence and significance of the risk factors remain unclear, which was the aim of this systematic review.MethodsA systematic literature search of the commonly used Pubmed database was performed using specific MESH terms. Further selection of the included studies was performed according to the PRISMA scheme, taking into account scientific merit as well as the relation to the research question.ResultsA total of 111 studies out of 1035 found were finally included in the literature search. 134 risk factors for disc degeneration and disc herniation were identified. These were divided into (1) patient-specific risk factors (n░=░34), (2) radiological risk factors (n░=░31), (3) lifestyle risk factors (n░=░6), (4) workplace-related risk factors (n░=░12), (5) genetic risk factors (n░=░50), and (6) other risk factors (n░=░1). Non-adjustable risk factors were age >50 years (OR 1.7/year), female gender (OR 1.41), family disposition (OR 4.0), comorbidities like atherosclerosis (OR 2.24), arthritic changes in other joints (OR 3.1) and history of injuries of the back (OR 3.1). Adjustable factors were elevated BMI (OR 2.77), comorbidities like hypertension (OR 1.25), dyslipidemia (OR 1.26) and diabetes mellitus (OR 6.8), as well as lifestyle habits like smoking (OR 3.8).DiscussionIn summary, intervertebral disc degenerations and herniations represent multifactorial events whose risk factors can be partly influenced and partly not influenced. This systematic review highlights the current state of knowledge as a basis for creating patient-specific algorithms to calculate risk for the development or progression of degenerative disc changes and disc herniations.     

Timing of reintervention influences survival and resource utilization following first-stage palliation of single ventricle heart disease

ObjectiveOutcomes after first-stage palliation of single-ventricle heart disease are influenced by many factors, including the presence of residual lesions requiring reintervention. However, there is a dearth of information regarding the optimal timing of reintervention. We assessed if earlier reintervention would be favorably associated with in-hospital outcomes among patients requiring unplanned reinterventions after the Norwood operation.MethodsThis was a single-center, retrospective review of all patients who underwent the Norwood procedure from January 1997 to November 2017 and required a predischarge unplanned surgical or transcatheter reintervention on 1 or more subcomponent areas repaired at the index operation. Outcomes of interest included in-hospital mortality or transplant, postoperative hospital length of stay, and inpatient cost. Associations between timing of reintervention and outcomes were assessed using logistic regression (mortality or transplant) or generalized linear models (postoperative hospital length of stay and cost), adjusting for baseline patient-related and procedural factors.ResultsOf 500 patients who underwent the Norwood operation, 92 (18.4%) required an unplanned reintervention. Median time to reintervention was 12 days (interquartile range, 5-35 days). There were 31 (33.7%) deaths or transplants, median postoperative hospital length of stay was 49 days (interquartile range, 32-87 days), and median cost was $328,000 (interquartile range, $204,000-$464,000). On multivariable analysis, each 5-day increase in time to reintervention increased the odds of mortality or transplant by 20% (odds ratio, 1.2; 95% confidence interval, 1.1-1.3; P = .004). Longer time to reintervention was also significantly associated with greater postoperative hospital length of stay (P < .001) and higher cost (P < .001).ConclusionsFor patients requiring predischarge unplanned reinterventions after the Norwood operation, earlier reintervention is associated with improved in-hospital transplant-free survival and resource use.     

Nationwide outcomes of newborns with rectosigmoid versus long-segment Hirschsprung disease

PurposeHirschsprung Disease (HD) is a common congenital intestinal disorder. While aganglionosis most commonly affects the rectosigmoid colon (rectosigmoid HD), outcomes for patients in which aganglionosis extends to more proximal segments (long-segment HD) remain understudied. This study sought to compare postoperative outcomes among newborns with rectosigmoid and long-segment HD.MethodsThe Nationwide Readmission Database was queried from 2016 to 2018 for newborns with HD. Newborns were stratified into those with rectosigmoid or long-segment HD. Those who received no rectal biopsy or pull-through procedure during their newborn hospitalization were excluded. A propensity score-matched analysis (PSMA) of newborns with either type of HD was constructed utilizing 17 covariates including demographics, comorbidities, and congenital-perinatal conditions.ResultsThere were 1280 newborns identified with HD (82% rectosigmoid HD, 18% long-segment HD). Patients with rectosigmoid HD had higher rates of laparoscopic resections (35% vs. 12%) and less frequently received a concomitant ostomy (14% vs. 84%), both p < 0.001. Patients with long-segment HD were more likely to have a delayed diagnosis (12% vs. 5%) and require multiple bowel operations (19% vs. 4%), both p < 0.001. They experienced higher rates of complications, including small bowel obstructions (10% vs. 1%), infections (45% vs. 20%), and Hirschsprung-associated enterocolitis (11% vs. 5%), all p < 0.001. After PSMA, newborns with long-segment HD were found to have a longer length of stay and higher hospitalization costs.ConclusionNewborns with long-segment HD experience significant delays in diagnosis, surgery, and complications compared to those with rectosigmoid HD. This information should be utilized to improve healthcare delivery for this patient population.Type of StudyRetrospective comparative study.Level of EvidenceIII.     

COVID-19: A qualitative chest CT model to identify severe form of the disease

PurposeThe purpose of this study was to identify clinical and chest computed tomography (CT) features associated with a severe form of coronavirus disease 2019 (COVID-19) and to propose a quick and easy to use model to identify patients at risk of a severe form.Materials and methodsA total of 158 patients with biologically confirmed COVID-19 who underwent a chest CT after the onset of the symptoms were included. There were 84 men and 74 women with a mean age of 68 ± 14 (SD) years (range: 24–96 years). There were 100 non-severe and 58 severe cases. Their clinical data were recorded and the first chest CT examination was reviewed using a computerized standardized report. Univariate and multivariate analyses were performed in order to identify the risk factors associated with disease severity. Two models were built: one was based only on qualitative CT features and the other one included a semi-quantitative total CT score to replace the variable representing the extent of the disease. Areas under the ROC curves (AUC) of the two models were compared with DeLong's method.ResultsCentral involvement of lung parenchyma (P < 0.001), area of consolidation (P < 0.008), air bronchogram sign (P < 0.001), bronchiectasis (P < 0.001), traction bronchiectasis (P < 0.011), pleural effusion (P < 0.026), large involvement of either one of the upper lobes or of the middle lobe (P < 0.001) and total CT score ≥ 15 (P < 0.001) were more often observed in the severe group than in the non-severe group. No significant differences were found between the qualitative model (large involvement of either upper lobes or middle lobe [odd ratio (OR) = 2.473], central involvement [OR = 2.760], pleural effusion [OR = 2.699]) and the semi-quantitative model (total CT score ≥ 15 [OR = 3.342], central involvement [OR = 2.344], pleural effusion [OR = 2.754]) with AUC of 0.722 (95% CI: 0.638–0.806) vs. 0.739 (95% CI: 0.656–0.823), respectively (P = 0.209).ConclusionWe have developed a new qualitative chest CT-based multivariate model that provides independent risk factors associated with severe form of COVID-19.     

Impact of Operative Management on Recurrence of Adhesive Small Bowel Obstruction: A Longitudinal Analysis of a Statewide Database

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Evolution of Pulmonary Valve Management During Repair of Tetralogy of Fallot: A 14-year Experience

BackgroundThe optimal repair strategy for tetralogy of Fallot remains controversial. This report presents a 14-year evolution of management of the pulmonary valve (PV) from transannular patch to valve-sparing repair to neovalve creation using living right atrial appendage tissue.MethodsA retrospective review of 172 consecutive patients undergoing complete repair for TOF between January 2007 and June 2021 was performed. Clinical and follow-up data were analyzed by repair group. Neopulmonary valve (NPV) creation using right atrial appendage tissue was introduced in 2019. Failure of valve-sparing repair was defined as needing reintervention for recurrent right ventricular outflow tract obstruction (RVOTO).ResultsMedian age and weight at repair were 4.9 months and 6 kg, respectively. Median preoperative PV size and z-score were 6.4 mm (5.2-8.3 mm) and ?3.2 (?4.1 to ?2.1), respectively. Patients who underwent valve-sparing repair had larger PV size and z-score compared with patients who underwent transannular patch procedures (8 mm vs 5.6 mm; ?2.1 vs ?3.2; both P < .001). There were no hospital mortalities. Overall follow-up was 44 months. At last follow-up, 10% of patients who underwent valve-sparing repair had repeat intervention for recurrent RVOTO. Patients who had failed valve-sparing repair had significantly lower PV z-scores (?2.6 vs ?1.9; P = .01). An NPV was used in 8 patients with a median PV z-score of ?4 (?4.7 to ?3.9). At 6 months, 6 patients (75%) had mild or trivial pulmonary insufficiency after NPV placement.ConclusionsRepair of tetralogy of Fallot is a safe operation with excellent outcomes. Valve-sparing repair avoids right ventricular dilation but may fail for RVOTO at a PV z-score <?2. NPV creation offers an alternative option in patients with a small PV.     

Exome sequencing identifies novel genes and variants in patients with Hirschsprung disease

BackgroundHirschsprung disease (HSCR) is a complex genetic disease characterized by the absence of ganglion cells in the intestines, leading to a functional obstruction in infants. At least 24 genes have been identified for the pathogenesis of HSCR. They contributed to approximately 72% of HSCR cases. We aimed to elucidate further the genetic basis of HSCR in Indonesia using the whole-exome sequencing (WES) approach.MethodsWES was performed in 39 sporadic non-syndromic HSCR patients and 16 non-HSCR subjects as controls. Variants presented in controls were excluded, followed by in silico prediction tools and population allele frequency databases to select rare variants. We determined the minor allele frequency (MAF) using gnomAD (MAF <0.1%).ResultsWe involved 24 (61.5%) males and 15 (38.5%) females. Most patients (62%) had short-segment aganglionosis and underwent the Duhamel procedure (41%). We identified several candidate novel variants in HSCR-related genes, including UBR4, GDNF, and ECE1. Moreover, we also identified some novel candidate genes, including a possible compound heterozygous variant in the MUTYH gene: the first variant, a known protein-truncating variant associated with colorectal cancer (CRC), p.Glu452Ter and the second variant is novel, p.Ala39Val. Moreover, the type of variants was not associated with the aganglionosis type.ConclusionsWe identified several novel genes and variants, including the variant associated with CRC, that might contribute to the pathogenesis of HSCR. No genotype–phenotype associations were noted. Our study further confirms the complex network involved in enteric nervous system development and HSCR pathogenesis.Level of evidenceLevel III.