Anorectal malformations (ARM) are rare abnormalities that occur in approximately 1 in 3000 live births with around 40% of patients presenting with isolated forms. Multiple familial cases reported, ...suggest underlying genetic factors that remain largely unknown. The recurrence in relatives is considered rare, however transmission rates of ARM by affected parents have never been determined before. The inheritance pattern of ARM was investigated in our database of patients with isolated ARM.
Within our cohort of 327 patients with isolated ARM we identified eight adult patients from eight families who had in total 16 children with their healthy spouse. Of these ten had ARM, resulting in a recurrence risk of approximately one in two live births (10 of 16; 62%). From 226 families with 459 siblings we found two affected siblings in five families. Hence, the recurrence risk of ARM among siblings is approximately one in 92 live births (5 of 459; 1.0%).
Comparing the observed recurrence risk in our cohort with the prevalence in the general population, we see a 1500-fold increase in recurrence risk for offspring and a 32-fold increase if a sibling is affected. The recurrence risk of approximately 62% indicates an autosomal dominant mode of inheritance. Reliable figures on recurrence of ARM are becoming increasingly important since improved surgical techniques are able to maintain sexual function resulting in more offspring of patients with ARM. These data allow more precise counseling of families with ARM and support the need for genetic studies.
The bladder exstrophy-epispadias complex (BEEC) is a spectrum of congenital abnormalities that involves the abdominal wall, the bony pelvis, the urinary tract, the external genitalia, and, in severe ...cases, the gastrointestinal tract as well.
Herein, we performed an exome analysis of case-parent trios with cloacal exstrophy (CE), the most severe form of the BEEC. Furthermore, we surveyed the exome of a sib-pair presenting with classic bladder exstrophy (CBE) and epispadias (E) only. Moreover, we performed large-scale re-sequencing of CBE individuals for novel candidate genes that were derived from the current exome analysis, as well as for previously reported candidate genes within the CBE phenocritical region, 22q11.2.
The exome survey in the CE case-parent trios identified two candidate genes harboring de novo variants (
,
), four candidate genes with autosomal-recessive biallelic variants (
,
,
,
) and one candidate gene with suggestive uniparental disomy (
). However, re-sequencing did not identify any additional variant carriers in these candidate genes. Analysis of the affected sib-pair revealed no candidate gene. Re-sequencing of the genes within the 22q11.2 CBE phenocritical region identified two highly conserved frameshift variants that led to early termination in two independent CBE males, in
(c.978_985del, p.Ser327fster6) and in
(c.1087delC, p.Arg363fster68).
According to previous studies, our study further implicates
in CBE formation. Exome analysis-derived candidate genes from CE individuals may not represent a frequent indicator for other BEEC phenotypes and warrant molecular analysis before their involvement in disease formation can be assumed.
In the past, an anteriorly located anus was often misdiagnosed and treated as an anorectal malformation (ARM) with a perineal fistula (PF). The paper aims to define the criteria for a normal anus, an ...anterior anus (AA) as an anatomic variant, and milder types of ARM such as congenital anal stenosis (CAS) and PF. An extensive literature search was performed by a working group of the ARM-Net Consortium concerning the subject “Normal Anus, AA, and mild ARM”. A consensus on definitions, clinical characteristics, diagnostic management, and treatment modalities was established, and a diagnostic algorithm was proposed. The algorithm enables pediatricians, midwives, gynecologists, and surgeons to make a timely correct diagnosis of any abnormally looking anus and initiate further management if needed. Thus, the routine physical inspection of a newborn should include the inspection of the anus and define its position, relation to the external sphincter, and caliber. A correct diagnosis and use of the presented terminology will avoid misclassifications and allow the initiation of correct management. This will provide a reliable comparison of different therapeutic management and outcomes of these patient cohorts in the future.
The use of assisted reproductive techniques (ART) for treatment of infertility is increasing rapidly worldwide. However, various health effects have been reported including a higher risk of ...congenital malformations. Therefore, we assessed the risk of anorectal malformations (ARM) after in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI).
Data of the German Network for Congenital Uro-REctal malformations (CURE-Net) were compared to nationwide data of the German IVF register and the Federal Statistical Office (DESTATIS). Odds ratios (95% confidence intervals) were determined to quantify associations using multivariable logistic regression accounting for potential confounding or interaction by plurality of births.
In total, 295 ARM patients born between 1997 and 2011 in Germany, who were recruited through participating pediatric surgeries from all over Germany and the German self-help organisation SoMA, were included. Controls were all German live-births (n = 10,069,986) born between 1997 and 2010. Overall, 30 cases (10%) and 129,982 controls (1%) were born after IVF or ICSI, which translates to an odds ratio (95% confidence interval) of 8.7 (5.9-12.6) between ART and ARM in bivariate analyses. Separate analyses showed a significantly increased risk for ARM after IVF (OR, 10.9; 95% CI, 6.2-19.0; P < 0.0001) as well as after ICSI (OR, 7.5; 95% CI, 4.6-12.2; P < 0.0001). Furthermore, separate analyses of patients with isolated ARM, ARM with associated anomalies and those with a VATER/VACTERL association showed strong associations with ART (ORs 4.9, 11.9 and 7.9, respectively). After stratification for plurality of birth, the corresponding odds ratios (95% confidence intervals) were 7.7 (4.6-12.7) for singletons and 4.9 (2.4-10.1) for multiple births.
There is a strongly increased risk for ARM among children born after ART. Elevations of risk were seen after both IVF and ICSI. Further, separate analyses of patients with isolated ARM, ARM with associated anomalies and those with a VATER/VACTERL association showed increased risks in each group. An increased risk of ARM was also seen among both singletons and multiple births.
Background:
The VATER/VACTERL association (VACTERL) is defined as the non-random occurrence of the following congenital anomalies: Vertebral, Anal, Cardiac, Tracheal-Esophageal, Renal, and Limb ...anomalies. As no unequivocal candidate gene has been identified yet, patients are diagnosed phenotypically. The aims of this study were to identify patients with monogenic disorders using a genetics-first approach, and to study whether variants in candidate genes are involved in the etiology of VACTERL or the individual features of VACTERL: Anorectal malformation (ARM) or esophageal atresia with or without trachea-esophageal fistula (EA/TEF).
Methods:
Using molecular inversion probes, a candidate gene panel of 56 genes was sequenced in three patient groups: VACTERL (
n
= 211), ARM (
n
= 204), and EA/TEF (
n
= 95). Loss-of-function (LoF) and additional likely pathogenic missense variants, were prioritized and validated using Sanger sequencing. Validated variants were tested for segregation and patients were clinically re-evaluated.
Results:
In 7 out of the 510 patients (1.4%), pathogenic or likely pathogenic variants were identified in
SALL1, SALL4
, and
MID1
, genes that are associated with Townes-Brocks, Duane-radial-ray, and Opitz-G/BBB syndrome. These syndromes always include ARM or EA/TEF, in combination with at least two other VACTERL features. We did not identify LoF variants in the remaining candidate genes.
Conclusions:
None of the other candidate genes were identified as novel unequivocal disease genes for VACTERL. However, a genetics-first approach allowed refinement of the clinical diagnosis in seven patients, in whom an alternative molecular-based diagnosis was found with important implications for the counseling of the families.
Introduction:
To evaluate the impact of reconstructive strategies and post-operative management on short- and long-term surgical outcome and complications of classical bladder exstrophy (CBE) ...patients' comprehensive data of the multicenter German-wide Network for Congenital Uro-Rectal malformations (CURE-Net) were analyzed.
Methods:
Descriptive analyses were performed between 34 prospectively collected CBE patients born since 2009, median 3 months old interquartile range (IQR), 2–4 months, and 113 cross-sectional patients, median 12 years old (IQR, 6–21 years).
Results:
The majority of included individuals were males (67%). Sixty-eight percent of the prospectively observed and 53% of the cross-sectional patients were reconstructed using a staged approach (
p
= 0.17). Although prospectively observed patients were operated on at a younger age, the post-operative management did not significantly change in the years before and after 2009. Solely, in prospectively observed patients, peridural catheters were used significantly more often (
p
= 0.017). Blood transfusions were significantly more frequent in males (
p
= 0.002). Only half of all CBE individuals underwent inguinal hernia repair. Cross-sectional patients after single-stage reconstructions showed more direct post-operative complications such as upper urinary tract dilatations (
p
= 0.0021) or urinary tract infections (
p
= 0.023), but not more frequent renal function impairment compared to patients after the staged approach (
p
= 0.42). Continence outcomes were not significantly different between the concepts (
p
= 0.51). Self-reported continence data showed that the majority of the included CBE patients was intermittent or continuous incontinent. Furthermore, subsequent consecutive augmentations and catheterizable stomata did not significantly differ between the two operative approaches. Urinary diversions were only reported after the staged concept.
Conclusions:
In this German multicenter study, a trend toward the staged concept was observed. While single-stage approaches tended to have initially more complications such as renal dilatation or urinary tract infections, additional surgery such as augmentations and stomata appeared to be similar after staged and single-stage reconstructions in the long term.
Purpose
The recently established International Consortium on Anorectal Malformations aims to identify genetic and environmental risk factors in the etiology of syndromic and nonsyndromic anorectal ...malformations (ARM) by promoting collaboration through data sharing and combined research activities.
Methods
The consortium attempts to recruit at least 1,000 ARM cases. DNA samples are collected from case–parent triads to identify genetic factors involved in ARM. Several genetic techniques will be applied, including SNP arrays, gene and whole exome sequencing, and a genome-wide association study. Questionnaires inquiring about circumstances before and during pregnancy will be used to obtain environmental risk factor data.
Results
Currently, 701 ARM cases have been recruited throughout Europe. Clinical data are available from all cases, and DNA samples and questionnaire data mainly from the Dutch and German cases. Preliminary analyses on environmental risk factors in the Dutch and German cohort found associations between ARM and family history of ARM, fever during first trimester of pregnancy and maternal job exposure to cleaning agents and solvents.
Conclusion
First results show that both genetic and environmental factors may contribute to the multifactorial etiology of ARM. The International Consortium on Anorectal Malformations will provide possibilities to study and detect important genes and environmental risk factors for ARM, ultimately resulting in better genetic counseling, improved therapies, and primary prevention.
Zusammenfassung
Für Patienten mit seltenen Erkrankungen ist es deutlich schwerer, erfahrene Behandler, rechtzeitige Diagnosestellung und korrekte Therapie zu finden. Die EU hat deswegen 2017 ...24 Europäische Referenznetzwerke (ERN) gegründet.
Die wissenschaftliche Begründung dieser Zentralisierung, die Fallzahl-Ergebnis-Beziehung und ihre Umsetzung in verschiedenen Ländern werden dargestellt.
Die Qualitätsanforderungen der ERN sind hoch:
Maßgebliche Rolle der Patientenorganisationen; multidisziplinäre Teams; geregelte Stellvertretung; lebenslange Betreuung der Patienten, Offenlegung von finanziellen und nichtfinanziellen Interessenkonflikten, wissenschaftlich fundierte minimale Patienten- und Operationszahlen; Veröffentlichung der Patientenzahlen, Komplikationsraten und Therapieergebnisse im Internet; Aus- und Weiterbildung; Forschung.
Um das bahnbrechende ERN-Projekt weiter zu realisieren, ist die Bildung lokaler Netzwerke von ERN- und Nicht-ERN-Kliniken ein wichtiger nächster Schritt.
Das erforderliche Umdenken von Konkurrenz zu Kooperation wird eine bleibende Herausforderung darstellen, bei der weitere Initiativen der Patientenorganisationen und politische Rahmenvorgaben unverzichtbar sind.
Early post-twinning mutational events can account for discordant phenotypes in monozygotic (MZ) twin pairs. Such mutational events may comprise genomic alterations of different sizes, ranging from ...single nucleotides to large copy-number variations (CNVs). Anorectal malformations (ARM) and the bladder exstrophy-epispadias complex (BEEC) represent the most severe end of the urorectal malformation spectrum. Recently, CNV studies in patients with sporadic ARM and the BEEC have identified de novo events that occur in specific chromosomal regions. We hypothesized that early arising, post-twinning CNVs might contribute to discordance in MZ twin pairs with ARM or the BEEC; knowledge of such CNVs might help to identify additional chromosomal regions involved in the development of these malformations. We investigated four discordant MZ twin pairs (three ARM and one BEEC) using molecular karyotyping arrays comprising 1,140,419 markers with a median marker spacing of 1.5 kb. Filtering the coding regions for possible disease-causing post-twinning de novo CNVs present only in the affected twin, but not in the unaffected twin or the parents, identified a total of 136 CNVs. These 136 CNVs were then filtered against publicly available databases and finally re-evaluated visually. No potentially causative CNV remained after applying these filter criteria. Our results suggest that post-twinning CNV events that affect coding regions of the genome did not contribute to the discordant phenotypes in MZ twin pairs that we investigated. Possible causes for the discordant phenotypes include changes in regulatory elements or smaller genetic changes within coding regions which may be detectable by whole-exome sequencing.
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