Toilet training in individuals with Angelman syndrome: A case series

Objective: To assess if adapted versions of the response restriction toilet training protocol, based on the behavioral phenotype of Angelman syndrome (AS), were successful in fostering urinary continence in seven individuals with AS.

Method: Data were collected in AB-designs during baseline, training, generalization and follow-up. The response restriction protocol was adapted: individuals were trained in their natural environment, were prompted to void and along with improving continence, the interval between voids was prolonged and time-on-toilet decreased.

Results: During generalization five individuals had less than two accidents and one to six correct voids per day; during baseline more accidents and/or less correct voids occurred. In two participants correct voids increased, but several accidents still occurred. Three participants maintained positive results after 3–18 months.

Conclusion: Despite their intellectual and behavioral challenges, urinary continence can be acquired in AS. Several indications of voiding dysfunctions were found; further research is indicated.     

Optimization and regeneration kinetics of lymphatic-specific photodynamic therapy in the mouse dermis

Lymphatic vessels transport fluid, antigens, and immune cells to the lymph nodes to orchestrate adaptive immunity and maintain peripheral tolerance. Lymphangiogenesis has been associated with inflammation, cancer metastasis, autoimmunity, tolerance and transplant rejection, and thus, targeted lymphatic ablation is a potential therapeutic strategy for treating or preventing such events. Here we define conditions that lead to specific and local closure of the lymphatic vasculature using photodynamic therapy (PDT). Lymphatic-specific PDT was performed by irradiation of the photosensitizer verteporfin that effectively accumulates within collecting lymphatic vessels after local intradermal injection. We found that anti-lymphatic PDT induced necrosis of endothelial cells and pericytes, which preceded the functional occlusion of lymphatic collectors. This was specific to lymphatic vessels at low verteporfin dose, while higher doses also affected local blood vessels. In contrast, light dose (fluence) did not affect blood vessel perfusion, but did affect regeneration time of occluded lymphatic vessels. Lymphatic vessels eventually regenerated by recanalization of blocked collectors, with a characteristic hyperplasia of peri-lymphatic smooth muscle cells. The restoration of lymphatic function occurred with minimal remodeling of non-lymphatic tissue. Thus, anti-lymphatic PDT allows control of lymphatic ablation and regeneration by alteration of light fluence and photosensitizer dose.     

Tachykarde Herzrhythmusstörungen bei Kindern ohne angeborene Herzfehler

Based on invasive electrophysiological studies and ablation procedures of tachycardias in children and adolescents, the understanding and knowledge of the different tachycardia substrates have significantly increased in recent years. This article describes the underlying pathophysiological mechanisms together with the expected changes in electrocardiogram (ECG) of the four most common types of supraventricular tachycardia in children and adolescents without congenital heart defects: atrioventricular reentrant tachycardia, atrioventricular nodal reentrant tachycardia, focal atrial tachycardia and permanent junctional reentrant tachycardia. Furthermore, idiopathic ventricular tachycardia is described. The incidence, clinical symptoms, natural course and prognosis of each particular tachycardia will be specified . The pharmacological and interventional treatment will be the focus of other reports in this issue. Finally, the current recommendations for the approach to asymptomatic children and adolescents with preexcitation are discussed according to the current guidelines.     

Genetic basis of neurodevelopmental disorders in 103 Jordanian families

We recruited 103 families from Jordan with neurodevelopmental disorders (NDD) and patterns of inheritance mostly suggestive of autosomal recessive inheritance. In each family, we investigated at least one affected individual using exome sequencing and an in-house diagnostic variant interpretation pipeline including a search for copy number variation. This approach led us to identify the likely molecular defect in established disease genes in 37 families. We could identify 25 pathogenic nonsense and 11 missense variants as well as 3 pathogenic copy number variants and 1 repeat expansion. Notably, 11 of the disease-causal variants occurred de novo. In addition, we prioritized a homozygous frameshift variant in PUS3 in two sisters with intellectual disability. To our knowledge, PUS3 has been postulated only recently as a candidate disease gene for intellectual disability in a single family with three affected siblings. Our findings provide additional evidence to establish loss of PUS3 function as a cause of intellectual disability.     

Obraz kliniczny neurofibromatozy typu 1 na podstawie obserwowanych przypadków

Neurofibromatosis type 1 (NF1) eponymically called von Recklinghausen disease is autosomal dominant disease and remains an example of phakomatose. They are congenital, genetic disorders affecting mainly nervous and integumentary system. The aim of this study is to report six cases of NF1 in which diagnostic management is based on clinical findings in physical examination: observing characteristic dermatological and ophthalmological manifestations such as cafe au lait spots, Crowe sign (axillary and inguinal freckling), neurofibromas or Lish nodules within the eyes. Existence of those characteristic findings frequently precedes important pathologies (neoplasia) in different areas of the body, especially in nervous system. In the paper we emphasize that genetic MLPA test does not always correlate with clinical manifestation, what had been observed in our patients as well.     

Expanding the spectrum of PTH1R mutations in patients with primary failure of tooth eruption

Objectives

Primary failure of tooth eruption (PFE) is a rare autosomal-dominant disease characterized by severe lateral open bite as a consequence of incomplete eruption of posterior teeth. Heterozygous mutations in the parathyroid hormone 1 receptor (PTH1R) gene have been shown to cause PFE likely due to protein haploinsufficiency. To further expand on the mutational spectrum of PFE-associated mutations, we report here on the sequencing results of the PTH1R gene in 70 index PFE cases.

Materials and methods

Sanger sequencing of the PTH1R coding exons and their immediate flanking intronic sequences was performed with DNA samples from 70 index PFE cases.

Results

We identified a total of 30 unique variants, of which 12 were classified as pathogenic based on their deleterious consequences on PTH1R protein while 16 changes were characterized as unclassified variants with as yet unknown effects on disease pathology. The remaining two variants represent common polymorphisms.

Conclusions

Our data significantly increase the number of presently known unique PFE-causing PTH1R mutations and provide a series of variants with unclear pathogenicity which will require further in vitro assaying to determine their effects on protein structure and function.

Clinical relevance

Management of PTH1R-associated PFE is problematic, in particular when teeth are exposed to orthodontic force. Therefore, upon clinical suspicion of PFE, molecular DNA testing is indicated to support decision making for further treatment options.     

Human Cadaver Study Evaluating a New Measurement Technique for Graft Volumes after Sinus Floor Elevation

Purpose: Volumetric data can be used as complementary information to characterize grafting materials. The aim of this cadaveric study was to analyze a noncommercial measurement technique based on the novel concept of an “interactive rigid registration algorithm” (IRRA). Parameters analyzed included the reproducibility of IRRA measurements and their reliability in comparison with the established measurement technique of “region growing segmentation thresholding” (RGST). Materials and Methods: Three human skulls were used to simulate a total of 18 sinus grafts, using three incremental grafting procedures in each sinus (three skulls × two sinuses × three grafting increments). Radiopaque impression material was used for the simulated grafts, whose volumes were recorded by computed tomography from three different tilt angles. The reproducibility of IRRA measurements and the reliability of volumetric results obtained with both the IRRA and RGST techniques were evaluated by appropriate intraclass correlation coefficient (ICC) and Bland–Altman analysis. Results: ICC greater than 0.9 indicated close to perfect agreement of the results obtained with both methods and good reproducibility of the IRRA measurements. Bland–Altman analysis demonstrated good inter‐method and intramethod agreement. Conclusions: The IRRA measurement technique can be recommended as a noninvasive tool to evaluate graft volumes in human maxillary sinuses.