nueva página del texto (beta)
Inglés (pdf)
Artículo en XML
Referencias del artículo
Traducción automática
Enviar artículo por email
Citado por SciELO 
Similares en
SciELO 
Permalink
Introduction
Hirschsprung's disease (HSCR) is characterized by the congenital absence of enteric ganglion cells, at the Meissner's plexus (submucosa) and Auerbach's plexus (muscularis) of the terminal rectum that extends in a variable distance proximally1-3, with the rectosigmoid segment being the most frequent. The estimated incidence rate is 1 in 4,417 live births, and approximately 5% of the cases show syndromic associations such as Mowat-Wilson syndrome (MWS)3.
The MWS is an autosomal dominant genetic disease with an incidence of 1:50,000-1:70,000, resulting from a variant in the ZEB2 gene (ZFHX1B), OMIM #235730, located on 2q22-q23 chromosome. ZFHX1B is a transcription factor with a critical role in the migration and maturation of the vagal crest cells during the embryonic period4 and involves severe clinical manifestations such as ocular hypertelorism, intellectual disability, congenital heart defects, epilepsy, and HSCR. More than 300 individuals with MWS have been reported in the literature, with approximately 280 variants in the gene ZEB2 (ZFHX1B), OMIM #2357302,5.
One of the most classical components in the constellation of features found in children with MWS is the association with HSCR. This clinical association is present in 45-50% of patients1,4,6,7 and is considered a severe condition. The phenotype also includes stereotypical movements and various congenital malformations, heart defects, corpus callosum agenesis, genitourinary system anomalies, and eye abnormalities8. The only genotype-phenotype correlation is based on differences in the clinical course of disease in patients with a point mutation in the ZEB2. Post-operative outcomes for patients with HSCR and MWS are unpredictable, and many issues regarding motility disorders have been reported. This study aims to analyze the management and outcome of patients with HSCR and MWS association.
Methods
We conducted a descriptive study of a series of cases. We included all patients with MWS who were treated at our institution between January 2011 and January 2024. We reviewed the patient's medical records to collect demographic, molecular, and clinical data.
We categorized the population into two groups: patients with MWS and HSCR and those without MWS and HSCR. Finally, we divided the patients into two subgroups: those who underwent surgical correction and those who received medical treatment. A detailed analysis was performed to determine postoperative complications (anastomosis leak or stenosis, small bowel obstruction, and the need for a reoperation) and long-term outcomes (recurrent enterocolitis, soiling, chronic motility disorder, and the need for a stoma diversion).
In our institution, the surgical technique used for HSCR is the transanal pull-through Swenson (TPTS) procedure. The protocol for recurrent enterocolitis after the pull-through procedure involves initiating rectal irrigations as the first step. In addition, a digital rectal exam is performed to exclude stenosis of the anastomosis, a contrast enema is performed to rule out twisting of the neorectum, and a histopathological review of the proximal margin of the resected colon is performed to exclude a histological transition zone. In the scenario where all the mentioned studies are negative, we proceed to inject botulinum toxin into the anal sphincter, and we keep the patient on rectal irrigations and metronidazole for 3 months.
Results
Four patients diagnosed with MWS were included in the study. All had a pathogenic variant of the ZEB2 gene (ZFHX1B), OMIM #235730. Three (75%) exhibited HSCR; two identical twins were among the four analyzed patients. The distribution included two males (50%) and two females (50%). Two males were full-term neonates, whereas the two females were premature. Furthermore, the two females were identical twins (Table 1).
Table 1 Demographic data, molecular variant, and Mowat-Wilson syndrome characteristics
| Patient | Gender | Age (years) | Gene mutation | Zygosity | OMIM | Variant in ZEB2 gene | MWS characteristics | Rectal biopsy | HSCR type |
|---|---|---|---|---|---|---|---|---|---|
| 1 | Female | 6 | ZEB2 | Heterozygous | 16053902 | c.2761C>T (P.Arg921) | Cardiac defect: ASD + PDA Brain defect: ID + DD + microcephaly Others: facial dysmorphic features, asplenia |
Positive for HSCR | Rectosigmoid |
| 2 | Female | 6 | ZEB2 | Heterozygous | 16053902 | c.2761C>T (P.Arg921) | Cardiac defect: PDA + ASD + PLVC. Brain defect: ID + DD + microcephaly Others: myopia, facial dysmorphic features. |
Positive for HSCR | Short (according to contrast enema) |
| 3 | Male | 12 | ZEB2 | Heterozygous | 16053902 | c.425C>G (p.Ser142) | Cardiac defect: Dextrocardia. Brain defect: ID + DD + ACC, Epilepsy Others: hypospadias, pyloric stenosis, facial dysmorphic features |
Positive for HSCR | Rectosigmoid |
| 4 | Male | 6 | ZEB2 | Heterozygous | 235730 | c.808-2A>G (p.?) | Cardiac defect: PDA + AS Brain defect: ID + DD + microcephaly, Epilepsy Genito-urinary: hypospadias, cryptorchidism Others: facial dysmorphic features, hypopigmentation of the skin, asplenia |
No | No |
ACC: agenesis of the corpus callosum; AS: aortic stenosis; ASD: atrial septal defect; DD: developmental delay; HSCR: Hirschsprung's disease; ID: intellectual disability; PDA: patent ductus arteriosus; PLVC: persistent left vena cava.
MWS characteristics
All patients exhibited typical clinical manifestations, including facial dysmorphism (square-shaped face, large eyes), cardiac defects, moderate intellectual disability, and brain abnormalities. Further characteristics are detailed in table 1.
HSCR characteristics and surgical outcomes
Of the three patients with HSCR, two experienced the onset of symptoms during the neonatal period, marked by neonatal enterocolitis. The remaining patient exhibited constipation at the age of 5 years, and the diagnosis was suspected due to the presence of the association in his identical twin, along with the pathogenic variant of the ZEB2 gene (ZFHX1B), OMIM #235730.
The rectal biopsy confirmed the diagnosis in all three patients. During the TPTS, the histopathological study identified a rectosigmoid variant in two cases (66%) that underwent surgical correction. The remaining patient has not had surgery, so the affected segment of the colon was estimated based on the contrast enema, which showed a short-segment variant.
The clinical details for each patient are outlined table 2.
Table 2 Hirschsprung's disease and surgical outcomes
| Patient | Onset of symptoms | HSCR type | TPTS | Age at TPTS | Surgical complication | Number of enterocolitis events after TPTS | Second rectal biopsy | Redo TPTP | Surgical complication after redo TPTP | Others colorectal surgical procedures | Current managment |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 1 month (neonatal enterocolitis) | Rectosigmoid | Yes | 2 months | No | 13 | Transition zone | 2-year after TPTS | Anastomosis leak | 4 botulism toxin application | Metronidazole + rectal irrigations |
| 2 | 1 month (neonatal enterocolitis) | Short-segment | No | No | - | - | No | - | - | No | Senna (senosidos) |
| 3 | 6 months (chronic constipation) | Rectosigmoid | Yes | 2 months | Small bowel obstruction. Stoma creation | 9 | Transition zone | 2-year after TPTS | No | Colostomy closure with anastomosis leak. Permanent stoma |
Permanent colostomy |
HSCR: Hirschsprung's disease; TPTS: transanal pull-through Swenson.
PATIENT ONE
At 2 weeks of age, an episode of neonatal enterocolitis was recorded. A rectal biopsy confirmed HSCR. A TPTS was performed at 2 months of age, and multiple episodes of enterocolitis and repeated hospitalizations were documented. Two years later, a second rectal biopsy showed a transition zone. The patient underwent a redo pull-through TPTS, complicated by an anastomosis leak that was treated with conservative management, but the episodes of enterocolitis persisted. She has received four injections of botulinum toxin and is undergoing rectal irrigations every 12 h, along with metronidazole.
PATIENT TWO
Started constipation at 6 months, and at 5 years of age, was seen for the 1st time in our institution due to fecal impaction. At the physical examination, the clinical findings of MWS were documented. This is due to family history (identical twin with the association), including the pathogenic ZEB2 gene (ZFHX1B) variant, OMIM #235730. We decided to take a rectal biopsy to confirm an HSCR. A contrast enema was performed, which suggests a short-segment variant; however, the patient has never experienced an enterocolitis event and is doing well with the senna. The sister (patient one) had a poor outcome after the surgical correction, so we discussed the scenario with the family, and the decision for conservative management was made.
PATIENT THREE
At 1 week of age, the patient experienced a neonatal enterocolitis event, and a rectal biopsy was performed, confirming HSCR. At 2 months of age, the patient underwent a pull-through surgery (TPTS). Four days later, the first post-procedure enterocolitis event occurred, necessitating management in the neonatal intensive care unit and treatment with broad-spectrum antibiotics. Recurrent episodes of enterocolitis continued. Two months later, the patient developed a small bowel obstruction, leading to an exploratory laparotomy and colostomy creation. A second rectal biopsy was conducted, which indicated a transition zone pull-through. Two years later, a redo pull-through was performed. One year afterward, the patient was taken to the operating room for colostomy closure; however, 6 days later, an anastomosis leak was noted. After discussing the case with the family, they opted for a permanent colostomy. The patient is currently doing well.
Discussion
MWS is a rare genetic syndrome characterized by various symptoms, some of which are specific, including seizures and congenital heart defects8. We present a case series of patients with MWS and their association with HSCR. Our study included identical twins, both of whom had a heterozygous variant with the same genetic alteration, clinically manifesting across the broad spectrum of the disease. It is well known that the outcome of HSCR in patients with MWS is unpredictable, presenting numerous challenges1,4,6,7. Bonnard et al. reported on five patients with this association, and only one achieved a satisfactory outcome7.
To the best of our knowledge, this is the first report from Mexico regarding patients with HSCR and MWS. In this study, 75% of patients with MWS presented with an associated HSCR, a higher rate than reported in the literature, which indicates a 45-50% association. Regarding the type of HSCR, 66% of our patients had a rectosigmoid variant, while 33% had a short-segment variant. This differs from Dagorno et al., who reported that 50% of their patients had the long variant, 30% had the total variant, and 20% had the rectosigmoid variant.
A retrospective study conducted by Dagorno et al.4 found that over 15 years, 43% of patients had the association. HSCR was suspected in the neonatal period in 80% of cases, while it was identified later in life as chronic constipation in 20% of cases. All patients underwent surgical correction, and 80% required a second surgery due to complications (28% of patients underwent a redo pull-through). The complications included: 10% with abdominal wall necrotizing cellulitis, 10% with intestinal perforation, 10% with anal margin abscess, 10% with intra-abdominal abscess secondary to rectal stump leakage after the Duhamel procedure, 10% with anastomotic stenosis, 10% with intra-abdominal bleeding, 10% with septic shock and cardiac failure due to septic shock from enterocolitis, 10% with adhesive small bowel obstruction, 10% with sphincter hypertonia, and 10% with rectovaginal fistula. In addition, 50% of patients experienced symptoms of sub-occlusion, and one patient died from enterocolitis 1 month after the pull-through.
About 50% of the patients had a long variant, 30% patients had a total variant, and 20% had a rectosigmoid variant of HSCR. In our study, all patients required a second surgery due to an anastomotic leak (colorectal anastomosis from TPTS and colo-colonic anastomosis from colostomy closure). It is essential to note that both patients in the present study were in the Transitional zone, which could be a factor in the failure of the first procedure. However, Torre et al.9 suggested that receiving a final report indicating a transitional zone creates a dilemma. In his retrospective study, he does not recommend performing a reoperation in the transitional zone; instead, he suggests a wait-and-see approach regarding the patient's progress before considering a new pull-through. A biopsy of the neorectum is applicable only to diagnose or confirm a ganglionic rectum.
The literature frequently reports this complication in patients with this association, leading us to speculate, as Dagorno4 suggested, that the musculoskeletal anomalies associated with MWS may be connected to soft-tissue anomalies and impaired healing. However, further studies and molecular analyses are needed to support this conclusion.
Similarly, Coyle et al.1 reported that 46% of patients with the association had a long-term colostomy or ileostomy. In this study, 33% of the cases required a permanent colostomy due to recurrent enterocolitis and surgical complications. In some cases, patients may also experience a severe chronic motility disorder, which could lead to the need for a stoma diversion1,7,8.
Bonnard et al.7 analyzed their retrospective study of five patients and concluded that this association (MWS and HSCR) is a serious condition leading to a poor quality of life, mainly due to prolonged parenteral nutrition and stoma diversion. Therefore, parents should be aware of this potential progression, and the surgical team should be fully involved in managing HSCR and related disorders, which require high levels of expertise in pathological examination and specific management.
Patients with MWS exhibit various clinical features with differing phenotypic penetrance10. As Birkhoff described, there is a haploinsufficiency in ZEB2 that causes this new and rare, well-defined, monogenic syndrome10. In this study, we observed identical twins with the same heterozygous mutation and pathogenic variant in the ZEB2 gene (ZFHX1B), OMIM #235730. However, they displayed different clinical manifestations of the disease. One of the twins (patient one) was diagnosed with HSCR in the neonatal period. In contrast, the other twin was diagnosed later due to a high suspicion index and current episodes of constipation (patient two). Further studies are necessary to understand the manifestations of the syndrome and the correlations between phenotype and genotype.
The ZEB2 gene comprises ten exons of varying lengths and encodes six protein domains of different sizes and functions, as described by St Peter et al.11. They found that exon 8 encodes at least three of the six protein domains of the ZEB2 gene and accounts for 66% (198/298) of the variants identified. One of the most common variants, c.2083C>T, OMIM #235730, in exon 8, contrary to two of our female patients, presents a ZEB2 gene variant at exon 8, c.2761C>T, OMIM #16053902. In contrast to the two males identified in our study, patient three had a variant located in exon 5, which is not present in population databases. Finally, patient four had an unknown inheritance of a variant located in exon 7, c.808-2A>G, OMIM #235730. In this case, a segregation analysis was recommended.
The prevailing notion in clinical and surgical fields is that HSCR has a polygenic or multifactorial etiology. Consequently, genetic evaluation is not routinely pursued when a patient is diagnosed with this condition. However, this is not true for all patients, as various monogenic disorders, such as megacystis microcolon intestinal hypoperistalsis syndrome, can present a ganglionic colon as one of their features8. This requires physicians caring for patients with chronic constipation to consider rare diseases whenever they encounter one of these children, as specific treatments or protocols may need to be implemented.
As massive parallel sequencing technologies become more available, even in low- and middle-income countries, the only genotype-phenotype correlation is based on differences in clinical courses of disease in patients with point mutations in the ZEB2 gene and patients with ZFHX1B deletions, OMIM #235730. However, still, not all mutations tend to develop aganglionosis affecting longer segments12, which is expressed in most human tissues and is essential for the development and migration of neural crest cells5.
The active pursuit of genetic diagnosis in every patient with HSCR should be considered, as improved care could be achieved with knowledge of the genetic etiology. MWS is a rare genetic syndrome characterized by various symptoms, and a distinctive facial appearance in patients with developmental delays or intellectual disabilities should prompt consideration of this syndrome5,8,13.
The association between HSCR and MWS is a severe condition with unpredictable outcomes after surgery. Numerous studies, including this one, report a high rate of surgical complications and poor long-term outcomes following the pull-through procedure1,7,8. Currently, there are no established guidelines for performing rectal biopsies on these patients. However, considering the literature and the results presented in this study regarding long-term outcomes and surgical complications experienced by these patients, we recommend conducting a rectal biopsy for every patient with MWS. Patients without clinical complications, such as severe episodes of abdominal distention, recurrent enterocolitis, or failure to thrive, must be assessed to determine if they are suitable candidates for conservative management. Conversely, consulting with an interdisciplinary and specialized colorectal team is crucial for patients who require surgery. Effectively communicating potential outcomes to the family is vital.
Conclusions
The association between MWS and HSCR is a serious condition with high morbidity. The outcome following the pull-through procedure is unpredictable. Based on the existing literature and our findings, we recommend that these patients be assessed through a multidisciplinary consensus. Those without recurrent enterocolitis or chronic motility disorders are suitable candidates for conservative management. Further studies are needed to determine surgical and long-term outcomes and to identify the most effective approach to treating and managing these patients.
