Common pathogenesis for sirenomelia, OEIS complex, limb-body wall defect, and other malformations of caudal structures.

Decades of clinical, pathological, and epidemiological study and the recent application of advanced microarray and gene sequencing technologies have led to an understanding of the causes and pathogenesis of most recognized patterns of malformation. Still, there remain a number of patterns of malformation whose pathogenesis has not been established. Six such patterns of malformation are sirenomelia, VACTERL association, OEIS complex, limb-body wall defect (LBWD), urorectal septum malformation (URSM) sequence, and MURCS association, all of which predominantly affect caudal structures. On the basis of the overlap of the component malformations, the co-occurrence in individual fetuses, and the findings on fetal examination, a common pathogenesis is proposed for these patterns of malformation. The presence of a single artery in the umbilical cord provides a visible clue to the pathogenesis of all cases of sirenomelia and 30%-50% of cases of VACTERL association, OEIS complex, URSM sequence, and LBWD. The single artery is formed by a coalescence of arteries that supply the yolk sac, arises from the descending aorta high in the abdominal cavity, and redirects blood flow from the developing caudal structures of the embryo to the placenta. This phenomenon during embryogenesis is termed vitelline vascular steal.

Turbulent Cerebrospinal Fluid Flow in Enlarging Terminal Myelocystocele.

Terminal myelocystocele is a rare type of neural tube malformation, consisting of a skin-covered lumbosacral mass, highly associated with other complex abdominal malformations within the OIES complex (omphalocele, imperforate anus, exstrophy of the cloaca and spinal defects). We present a case of a premature female with an extensive lumbosacral mass at birth, as well as an omphalocele, cloacal exstrophy, renal abnormalities, and sacral agenesis. Lumbar magnetic resonance imaging revealed a meningocele sac herniating through the bone defects and containing a syringocele sac. Advanced imaging techniques showed turbulent cerebrospinal fluid flow. At control, 4 weeks later, the defect doubled in size. The myelocystocele sac was evacuated and closed, and the patient persisted with paraparesis. The role of cerebrospinal fluid flow analysis is well established in Chiari-type malformations, in which turbulent flow within the syrinx is related to a better outcome after surgery. It is possible that the same principle could be applied to other spinal malformations, as shown in this case of terminal myelocystocele.

Helicase-inactivating BRIP1 mutation yields Fanconi anemia with microcephaly and other congenital abnormalities.

Fanconi anemia is a genetically and phenotypically heterogeneous disorder characterized by congenital anomalies, bone marrow failure, cancer, and sensitivity of chromosomes to DNA cross-linking agents. One of the 22 genes responsible for Fanconi anemia is BRIP1, in which biallelic truncating mutations lead to Fanconi anemia group J and monoallelic truncating mutations predispose to certain cancers. However, of the more than 1000 reported missense mutations in BRIP1, very few have been functionally characterized. We evaluated the functional consequence of BRIP1 p.R848H (c.2543G > A), which was homozygous in two cousins with low birth weight, microcephaly, upper limb abnormalities, and imperforate anus and for whom chromosome breakage analysis of patient cells revealed increased mitomycin C sensitivity. BRIP1 p.R848H alters a highly conserved residue in the catalytic DNA helicase domain. We show that BRIP1 p.R848H leads to a defect in helicase activity. Heterozygosity at this missense has been reported in multiple cancer patients but, in the absence of functional studies, classified as of unknown significance. Our results support that this mutation is pathogenic for Fanconi anemia in homozygotes and for increased cancer susceptibility in heterozygous carriers.

Long-term follow-up for anorectal function after anorectoplasty in patients with high/intermediate imperforate anus: a single center experience.

PURPOSE: The aim of this study was to evaluate the clinical outcomes and postoperative anorectal function in the patients with high/intermediate imperforate anus (HIA/IIA) treated in our institution. In addition, we report our novel procedure, laparoscopically assisted anorectoplasty with anterior perineal incision (LAARP-API), which allows direct approach to the anterior edge of the puborectal sling and muscle complex, and is useful for the creation of a pulling-through route for the rectal pouch. METHODS: From 1976 to 2016, 22 patients with HIA and 43 patients with IIA underwent sacroperineal/sacroabdominoperineal pull-through anorectoplasty (SP/SAP), Potts procedure (Potts), SP with API (SP-API) or LAARP-API. Clinical data and anorectal function of those patients were retrospectively evaluated using the Japanese clinical score. RESULTS: Of the 22 cases of HIA, 15 were treated by SAP, 2 were SP and 5 were LAARP-API. Of the 43 cases of IIA, one was treated by SAP, 31 were SP, two were Potts and nine were SP-API. The mean score of anorectal function of HIA/IIA both increased with age. In IIA, the score after SP-API was significantly higher than the score after SP. CONCLUSION: Long-term outcomes of our anorectoplasty for HIA/IIA are good with excellent anorectal function score.

MED12 missense mutation in a three-generation family. Clinical characterization of MED12-related disorders and literature review.

Mutations in MED12 gene have been described in association with syndromic and non-syndromic X-linked intellectual disability (XLID). Up to date at least three distinct XLID syndromes have been described: FG syndrome, Lujan-Fryns syndrome (LS) and Ohdo syndrome (OSMKB). In the last years, thanks to the massive use of next generation sequencing techniques (NGS) it has been possible to discover at least 16 others MED12 mutations and to expand the phenotype of MED12-related disorders. Here we report three subjects from a large non-consanguineous family presenting with a mild to severe ID, important speech delay, behavior problems, dysmorphic facial features and hearing loss. NGS allows us to detect the MED12 missense variant c.3883C > T (p.(Arg1295Cys)) carried by the three patients. This variant has been reported in 2016 by Hu et al. in one family from a big cohort of XLID families. This clinical report contributes to expanding the phenotype associated with MED12-mutations.

Clinical and risk factor analysis of cloacal defects in the National Birth Defects Prevention Study.

Cloacal exstrophy (CE) and persistent cloaca (PC) (alternatively termed urorectal septum malformation sequence [URSMS]), represent two major cloacal defects (CDs). Clinical characteristics and risk factors often are studied for both defects combined, rather than exploring if these defects have different etiologies. We enumerated clinical features for 47 CE and 54 PC (inclusive of URSMS) cases from the National Birth Defects Prevention Study. Thirty-three CE cases were classified as isolated and 14 as multiple (presence of unassociated major defects); respective totals for PC cases were 26 and 28. We compared selected child and maternal characteristics between 11,829 non-malformed controls and CE and PC cases using chi-square or Fisher's exact tests. Compared to controls, CE and PC cases were statistically more likely (p < 0.05) to be preterm; CE cases were more likely to be multiple births. We conducted logistic regression analysis to estimate odds ratios and 95% confidence intervals for any CD, CE, and PC with selected self-reported maternal prepregnancy and periconceptional (one month prior to 3 months following conception) exposures. In crude and adjusted analyses, we observed significant positive associations for any CD, CE, and PC with use of any fertility medication or assisted reproductive technology procedure. Significant positive associations observed only in crude analyses were any CD with maternal obesity or use of progesterone, any CD and CE with any x-ray, and any CD and PC with use of folate antagonist medications. Our findings provide some of the first insights into potential differing etiologies for CE and PC.

A novel variant in MED12 gene: Further delineation of phenotype.

MED12 is a multiprotein mediator complex, which has a role in cell growth and differentiation and has been implicated in three distinct X-linked intellectual disability syndromes with distinctive clinical features. These include Opitz-Kaveggia syndrome (FG syndrome), Lujan syndrome, and X-linked Ohdo syndrome. Recently MED12 variants have been implicated in isolated X-linked intellectual disability. We describe a 5-year-old male patient with intellectual disability and facial dysmorphism and a novel variant in MED12 gene identified by Whole Exome Sequencing. His dysmorphic facial features are distinct from the previously described phenotypes. With a strong genotype-phenotype correlation that is already known for MED12, this could be a new phenotype linked to MED12, thus expanding the phenotypic spectrum of MED12-related disorders.

Is 1p36 deletion associated with anterior body wall defects?

Epispadias and exstrophy of the cloaca, also known as OEIS complex (omphalocele, exstrophy, imperforate anus, spinal defects), respectively constitute the most benign and severe ends of the bladder exstrophy-epispadias complex (BEEC) spectrum. In 2009, El-Hattab et al. reported the first patient with OEIS complex associated with a chromosome 1p36 deletion. Here we report a second patient with 1p36 deletion who also has classic bladder exstrophy, supporting the possible role of genes in this region in the development of BEEC. The absence of omphalocele and imperforate anus in our patient places him toward classic bladder exstrophy while presence of spina bifida and the absence of coccyx suggest an overlap with OEIS complex. An additional differential diagnosis is the pentalogy of Cantrell in our patient as he also has a diaphragmatic hernia and an incomplete sternum. This is the second observation of a ventral midline birth defect in association with 1p36 deletion syndrome, following El-Hattab et al.'s report [2009]. The three genes (NOCL2, DVL1, and MMP23B) discussed as possible candidates are also among the deleted ones in our patient, supporting the possible role of these genes in BEEC spectrum. © 2016 Wiley Periodicals, Inc.

Can we expect a favorable outcome after surgical treatment for an anorectal malformation?

BACKGROUND: The aim of this study was to retrospectively review the classification, surgical experience, and the functional outcome of anorectal malformations (ARMs) according the type of ARM. METHODS: A total of 311 children (M:F=200:111) who underwent surgical treatment for ARM between 1990 and 2011 were reviewed. Functional outcomes were evaluated using the Krickenbeck classification. The mean follow-up period was 112.2 ± 76.7months (range: 36.8-414.9months). RESULTS: In the male patients, 90 (45%) had perineal fistulas, 60 (30%) had urethral fistulas, and 7 (3.5%) had rectovesical fistulas. There were 17 cases of ARM without a fistula (8.5%), and we could not determine the type of fistula in 26 boys (13%) because of follow-up losses and death. In the female patients, 34 (30.6%) had perineal fistulas, 71 (64%) had rectovestibular fistulas, and 2 (1.8%) had rectovaginal fistulas. Four patients did not have a fistula (3.6%). For 264 patients, we did anoplasty (121 cases), fistula transposition (14 cases), and posterior sagittal anorectoplasty (PSARP, 129 cases). We found that 224 (84.8%) patients showed voluntary bowel movements. The overall rate for constipation was 30.7% and for soiling was 6.5%. The continence outcome was good for 82.2% of children, fair for 2.7%, and poor for 15.2%. For rectovestibular fistulas, constipation was higher in the perineal operation group, but the continence outcome was similar. CONCLUSION: Through a review of 20years' experience, an accurate diagnosis based on the Krickenbeck classification and operations following the principles of PSARP are crucial to achieve a good functional outcome in children with an ARM.

Evaluation of postoperative anal functions using endoanal ultrasonography and anorectal manometry in children with congenital anorectal malformations.

PURPOSE: The aim of this study was to assess the postoperative anorectal anatomy and function in children with congenital anorectal malformations (ARM) using endoanal ultrasonography (EUS) and anorectal manometry. METHODS: This study included 47 children who had undergone posterior sagittal anorectoplasty (PSARP) or transperineal anorectoplasty for the repair of an ARM. Children were grouped according to symptoms of defecation disorder, including normal defecation, fecal soiling, fecal incontinence, and constipation. Ten children with no history of anal or rectal diseases served as healthy controls. A well-established scoring system was used for the evaluation of anal function and defecation disorder. RESULTS: EUS showed significant differences in the thickness of the interior sphincter between the ARM patients and the healthy controls (P<0.05). However, no significant difference was found in the thickness of the interior sphincters between the PSARP group and transperineal anorectoplasty group (P>0.05). Anorectal manometry showed that the balloon volumes were significantly different between the surgical group and the control group (P<0.01), and between the low defect group and the intermediate-high defect group (P=0.022). Balloon volume was significantly correlated with anal function scores (r=-0.30, P<0.05). CONCLUSIONS: EUS and anorectal manometry can provide objective assessment of postoperative anorectal anatomy and function in children with ARM.

Early reported rectal sensation predicts continence in anorectal anomalies.

BACKGROUND: Straining at stool is an automatic reflex in babies and implies the presence of rectal sensation. We hypothesised that early reported rectal sensation would predict future continence in children with anorectal anomalies. AIM OF THE STUDY: The aim of this study is to determine if early straining at stool was a useful predictor of future continence in infants born with high anorectal malformations. METHODS: A retrospective case note review of prospectively collected clinical information was performed with institutional review board approval. All patients with intermediate/high anorectal malformation operated on by a single surgeon from 1984 to 2010 were included. After stoma closure, parents were asked: The responses were noted within the first year of stoma closure and then all patients were followed up until they were at least 3 ½years old and continence could be assessed using the Krickenbeck outcome classification. Data were compared using Fisher's exact test and sensitivity, specificity and positive predictive value (PPV) were calculated. MAIN RESULTS: Forty-eight patients were included in the study. Sixteen (33%) were female (12 cloacal malformation, 3 rectovaginal fistula, 1 rectal atresia) and 32 (66%) were male (6 rectovesical fistulae, 22 rectourethral fistulae, 4 no fistula). Median follow-up was 9.7years (range 3.5-17.9). Twenty-one children were noted by their parents to exhibit early straining at stool after stoma closure. Twenty of them achieved long term continence. The sensitivity of early straining as a predictor for long term continence was 77%, specificity 95% and positive predictive value 95%. CONCLUSION: The presence of early rectal sensation reported by parents is a good predictor of long term continence. This allows more informed discussion with families in the early years of life.

Prognostic evaluation of biofeedback response in patients treated for anorectal malformation.

PURPOSE: Functional bowel outcome in patients with anorectal malformation often is poor. For fecal incontinence resulting from sphincter dysfunction, biofeedback (BFB) training appears to be effective. The aim of study was to investigate the bowel function in incontinent children treated for ARM, using a clinical score, a manometric and pelvic magnetic resonance evaluation, in order to establish predictive parameters of response after BFB. METHODS: 25 children (median age of 6.5 years) with true fecal incontinence were evaluated by clinical score, anorectal manometry and magnetic resonance imaging (MRI). According to these evaluations patients were divided in 4 groups: group 1 (favorables manometry and MRI); group 2 (favorable manometry and unfavorable MRI); group 3 (unfavorable manometry and favorable MRI); group 4 (unfavorables manometry and MRI). All groups started a cycle of BFB and six months after end of BFB, were reevaluated by clinical score and manometry. RESULTS: The overall response to BFB was excellent in 44%, discrete in 40% and poor in 16%; a better response was found in groups 1 and 2 than groups 3 and 4. The differences between groups before BFB proportionally correlated with values after BFB; a correlation with genitourinary and spinal anomalies was found. CONCLUSIONS: Our results showed that BFB is an effective for fecal incontinence when the assessment pretreatment (functional and morphologic) is favorable; the manometry can evaluate the potential sphincterial recovery after BFB with a further prognostic benefit if correlated to morphologic evaluation with MRI.

One stage operation through modified posterior sagittal approach preserving the sphincter intact for anal agenesis with rectovestibular fistula.

PURPOSE: To describe the surgical technique and outcomes of an one stage operation through modified posterior sagittal approach (PSAP) preserving the sphincter intact for anal agenesia with rectovestibula fistula. PATIENTS AND METHODS: 57 patients suffering from anal agenesis with rectovestibular fistula were operated by a one-stage operation through a modified PSAP preserving the external sphincter intact from 2002 to 2010. The operation was performed in one-stage through a posterior sagittal approach with three modifications: The external sphincter complex was not opened on the posterior side, the dissection was carried out outside the rectal pouch, the rectal pouch was not tapered and was pulled through the center of the external sphincter identified by muscle stimulator. RESULTS: Patients age varied from 3 days to 30 days (mean: 21±9 days). The mean operative time was 57±8 min (range, 35-90 min). There were no intraoperative complications. There were no intraoperative or postoperative deaths. There were no early postoperative complications. Follow up from 40 months to 140 was obtained in 52 (91.2%) patients. Constipation has seen in 3 patient, 46 patients (88.5%) had 1-2 defecations per day, 2 patients (3.85%) had 3-4 defecations per day, 1 patients (1.9%) had more than 4 defecations, and 3 patients(5.8%) had one defecation every 2-3 days. Rectal mucosal prolapse occurred in 7 patients who required a second operation. CONCLUSION: One stage operation through modified PSAP is feasible, is safe and provides good continence outcomes for anal agenesis with rectovestibular fistula.

Use of congenital pouch colon for augmenting the neurogenic bladder in a child: a 13-year follow-up.

Congenital pouch colon is an anomaly always associated with anorectal malformation, where the colon is replaced by or terminates into a large aperistaltic intestinal pouch. Vertebral anomalies leading to neurogenic bladder are rare associated malformations. The pouch is aperistaltic and thus a poor rectal substitute but this very property makes it ideal for bladder augmentation. We report the first case where the pouch has been used to augment a high-pressure neurogenic bladder.

Posterior sagittal anorectoplasty results in better bowel function and quality of life in adulthood than pull-through procedures.

BACKGROUND/PURPOSE: The short-term outcome of posterior sagittal anorectoplasty (PSARP) procedure has been reported to be better than after abdominoperineal or abdominosacroperineal (AP) procedures. This study aimed to investigate the long-term functional outcome and quality of life after PSARP in adulthood and compare with the outcome after AP procedures. METHODS: Twenty-four patients operated with PSARP at the Department of Pediatric Surgery, Uppsala, Sweden, from 1984 to 1993 were identified. They were compared with 20 patients that underwent AP pull-through procedures from 1974 to 1983. The patients were sent validated bowel function and quality of life (SF-36) questionnaires. Sixteen PSARP (median age 21, five females) patients and fourteen AP patients (seven abdominosacroperineal and seven abdominoperineal pull-throughs, median age 32, seven females) responded and were included in the study. RESULTS: The median Miller incontinence score was 1 (range 0-13) in the PSARP group and 10 (range 3-16) in the pull-through group (P=0.0042). The use of underwear protection and oral loperamide was significantly less frequent in the PSARP group (P=0.0096 and 0.0021 respectively). The SF-36 scores of Vitality, Mental health and Mental Cluster Scale were higher in the PSARP group (P=0.0291, 0.0500, 0.0421 respectively). CONCLUSIONS: PSARP results in superior bowel function and better quality of life in adulthood compared with AP procedures for the repair of anorectal malformations.

Dyssynergic defecation may aggravate constipation: results of mostly pediatric cases with congenital anorectal malformation.

BACKGROUND: Most patients with congenital anorectal malformation suffer from mild chronic constipation. To date, it is unclear why a subgroup of patients develops a persistent form of constipation. Because dyssynergic defecation is a common cause of constipation in the general population, we hypothesized that the severe form of constipation may be caused by dyssynergic defecation. METHODS: Retrospectively, we reviewed the medical records of 29 patients with anorectal malformations who had undergone anorectal function tests because of severe constipation. The study was conducted at the University Medical Center Groningen, The Netherlands. RESULTS: All patients had increased maximum rectal pressure and increased anal sphincter pressure during balloon expulsion and therefore suffered from dyssynergic defecation. CONCLUSIONS: Patients with congenital anorectal malformations may also suffer from dyssynergic defecation. It is important, therefore, to check whether these patients have severe constipation due to dyssynergic defecation because perhaps it may be treated effectively with pelvic physiotherapy.

Bowel function and lower urinary tract symptoms in males with low anorectal malformations: an update of controlled, long-term outcomes.

PURPOSE: This study aimed to define the controlled outcomes into adulthood for bowel function and lower urinary tract symptoms (LUTS) for males treated for low ARMs with individualized, minimally invasive approaches that preserve the native continence mechanisms as far as possible. METHODS: This is a single-institution, cross-sectional study. All males treated for low ARMs with cutback anoplasty, incision of anocutaneous membrane or dilatations based on the exact type of each malformation between 1983 and 2006 were invited to answer a detailed questionnaire on bowel function and LUTS. Each patient was matched to three controls representing the normal population. Ethical approval was obtained. RESULTS: Amongst 46 respondents (67%; median age 12.3 (5-29) years), overall fecal control was comparable to controls (p = NS). All patients had voluntary bowel movements; 98% of patients and 97% of controls were socially continent (p = NS); 67% of patients and 64% of controls were totally continent (p = NS). Constipation amongst patients (33 vs 3% in controls; p < 0.0001) declined significantly with age. Outcomes by bowel function score were good in 85%, satisfactory in 15% and poor in 0%. Prevalence of LUTS and age at completion of toilet training were comparable to controls (p = NS). CONCLUSIONS: Our results support the adequacy and appropriateness of treating males with low ARMs with individualized, minimally invasive perineal procedures. Long-term functional outcomes comparable to controls are achieved in the majority, provided that constipation is effectively addressed.

The passage of meconium alone is not a sign of correctly positioned anus.

OBJECTIVE: The aim of this study is to determine the consequences of delayed presentation of anorectal malformations and emphasize the causes of delayed diagnosis of these malformations. METHODS: We retrospectively reviewed 54 neonatal patients with a diagnosis of anorectal malformations. Group 1 consisted of 35 patients diagnosed within the first 48 h of life and Group 2 included 19 patients diagnosed after 48 h of life. RESULTS: Obstructive symptoms at the time of diagnosis, overall complications and the mean postoperative hospitalization period in Group 2 were markedly higher than that of Group 1. A comprehensive neonatal examination within the first 48 h of life was performed in 32 (91.4%) patients in Group 1 and 5 (26.3%) of the patients in Group 2 (p < 0.001). CONCLUSIONS: The passage of meconium is not the only sign of correctly positioned anus. A careful physical examination and awareness of this anomaly are of great importance in making a timely diagnosis of anorectal malformations.