I.A.L.M. van Rooij

Acknowledgement to the 2000 Reviewers

Adam, O., München, Germany Bauer, C.P., Gaissach, Germany Berdel, D., Wesel, Germany Boeing, H., Bergholz-Rehbrücke, Germany Eder, K., Halle, Germany Elmadfa, I., Wien, Austria Erbersdobler, H., Kiel, Germany Flynn, A., Cork, Ireland Goldenberg, H., Wien, Austria Götz, M., Wien, Austria Grimm, H., Giessen, Germany Hagemeister, H., Rostock, Germany Heymsfield, G., New York, USA Krawinkel, M., Giessen, Germany Krempf, M., Nantes, France Laplace, J.P., Paris, France Lemmens, R., Wien, Austria Linseisen, J., Heidelberg, Germany Martinez, J.A., Pamplona, Spain Metges, C., Bergholz-Rehbrücke, Germany Moser, U., Basel, Switzerland Müller, M.J., Kiel, Germany Pfeuffer, E., Kiel, Germany Pietrzik, K., Bonn, Germany Pils, K., Wien, Austria Roth, H.P., Freising-Weihenstephan, Germany Rust, P., Wien, Austria Saris, W., Mastricht, Netherlands Schrezenmeir, J., Kiel, Germany Schümann, K., München, Germany Schweigert, F.J., Bergholz-Rehbrücke, Germany Seiler, W., Basel, Switzerland Thorsdottir, I., Reykjavik, Iceland Van den Berg, H., AJ Zeist, Netherlands Vasson, M.P., Clermont-Ferrand, France Vermeer, C., Mastricht, Netherlands Wernermann, J., Huddinge, Sweden Zunft, H.J., Bergholz-Rehbrücke, Germany

Anorectal malformations and pregnancy‐related disorders: a registry‐based case–control study in 17 European regions

To identify pregnancy‐related risk factors for different manifestations of congenital anorectal malformations (ARMs).

Novel IRF6 Mutations Detected in Orofacial Cleft Patients by Targeted Massively Parallel Sequencing

Common variants in interferon regulatory factor 6 (IRF6) have been associated with nonsyndromic cleft lip with or without cleft palate (NSCL/P) as well as with tooth agenesis (TA). These variants contribute a small risk towards the 2 congenital conditions and explain only a small percentage of heritability. On the other hand, many IRF6 mutations are known to be a monogenic cause of disease for syndromic orofacial clefting (OFC). We hypothesize that IRF6 mutations in some rare instances could also cause nonsyndromic OFC. To find novel rare variants in IRF6 responsible for nonsyndromic OFC and TA, we performed targeted multiplex sequencing using molecular inversion probes (MIPs) in 1,072 OFC patients, 67 TA patients, and 706 controls. We identified 3 potentially pathogenic de novo mutations in OFC patients. In addition, 3 rare missense variants were identified, for which pathogenicity could not unequivocally be shown, as all variants were either inherited from an unaffected parent or the parental DNA was not available. Retrospective investigation of the patients with these variants revealed the presence of lip pits in one of the patients with a de novo mutation suggesting a Van der Woude syndrome (VWS) phenotype, whereas, in other patients, no lip pits were identified.

Homocysteine-lowering effect of 500 μg folic acid every other day versus 250 μg/day

Background/Aims: Elevated plasma total homocysteine (tHcy) concentrations are a risk factor for neural tube defects and vascular diseases. Supplementation with folic acid decreases tHcy. We investigated whether supplementation with 500 µg folic acid every other day is as effective in lowering tHcy as 250 µg folic acid each day. Methods: In a 4-week intervention study, 22 healthy young women (18–40 years old) took either 500 µg folic acid every other day (500-µg/2d group) or 250 µg folic acid each day (250-µg/d group). Fasting blood was collected on days 0 and 28. Results: Plasma folate concentrations increased by 11.4 nmol/l (6.8–15.9) in the 250-µg/d group and by 9.1 nmol/l (95% Cl 1.9–16.3) in the 500-µg/2d group. These increases were not significantly different from each other. THcy concentrations decreased by 1.52 µmol/l (95% Cl –2.09 to –0.95; p < 0.001) in the 250-µg/d group and by 0.88 µmol/l (–1.53 to –0.23; p < 0.05) in the 500-µg/2d group. The difference in decrease between the 250-µg/d group and the 500-µg/2d group was 0.64 µmol/l (p = 0.11). Conclusion: Although not conclusive, this study suggests that supplying subjects with folic acid each day decreases tHcy more effectively than a double dose every other day.

Towards the perfect ARM center: the European Union’s criteria for centers of expertise and their implementation in the member states. A report from the ARM-Net

BackgroundPediatric surgeons and patient organisations agree that fewer centers for anorectal malformations with larger patient numbers are essential to reach better treatment. The European Union transacts a political process which aims to realize such centers of expertise for a multitude of rare diseases. All the centers on a specific rare disease should constitute an ERN on that disease. ARM-Net members in different countries report on first experiences with the implementation of national directives, identifying opportunities and risks of this process.MethodsRelevant details from the official European legislation were analyzed. A survey among the pediatric surgeons of the multidisciplinary ARM-Net consortium about national implementation was conducted.ResultsEuropean legislation calls for multidisciplinary centers treating children with rare diseases, and proposes a multitude of quality criteria. The member states are called to allocate sufficient funding and to execute robust governance and oversight, applying clear methods for evaluation. Participation of the patient organisations is mandatory. The national implementations all over Europe differ a lot in respect of extent and timeframe.ConclusionsEstablishing Centers of Expertise and a ERN for anorectal malformations offers great opportunities for patient care and research. Pediatric surgeons should be actively engaged in this process.

The Challenges of the European Anorectal Malformations-Net Registry

Anorectal malformations (ARM) have a low prevalence, patients need specialized surgical care, and in many cases, patients born with ARM even need life-long aftercare. Due to its low prevalence most patients are still treated in low-volume pediatric surgical centers without any adequate monitoring of the outcome. Data on prevalence, comparison of different surgical techniques, and prospective outcome measurements are still scarce and difficult to interpret. In 2010, a consortium was founded (ARM-Net consortium) including several European pediatric surgical centers to collaborate more in research and share knowledge on ARM. One of the structures started by the consortium was an ARM-Net registry for the inclusion of all future patients treated in these centers. With this review, we report the structure of the ARM-Net registry, some of the results, and discuss the challenges we faced and still face after its introduction in 2010.