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Vascular malformations (VMs) are clinically diverse with regard to the vessel type, anatomical location, tissue involvement and size. Consequently, symptoms and disease impact differ significantly. Diverse causative mutations in more and more genes are discovered and play a major role in the development of VMs. However, the relationship between the underlying causative mutations and the highly variable phenotype of VMs is not yet fully understood. In this systematic review, we aimed to provide an overview of known causative mutations in genes in VMs and discuss associations between the causative mutations and clinical phenotypes. PubMed and EMBASE libraries were systematically searched on November 9th, 2022 for randomized controlled trials and observational studies reporting causative mutations in at least five patients with peripheral venous, lymphatic, arteriovenous and combined malformations. Study quality was assessed with the Newcastle‐Ottawa Scale. Data were extracted on patient and VM characteristics, molecular sequencing method and results of molecular analysis. In total, 5667 articles were found of which 69 studies were included, reporting molecular analysis in a total of 4261 patients and 1686 (40%) patients with peripheral VMs a causative mutation was detected. In conclusion, this systematic review provides a comprehensive overview of causative germline and somatic mutations in various genes and associated phenotypes in peripheral VMs. With these findings, we attempt to better understand how the underlying causative mutations in various genes contribute to the highly variable clinical characteristics of VMs. Our study shows that some causative mutations lead to a uniform phenotype, while other causal variants lead to more varying phenotypes. By contrast, distinct causative mutations may lead to similar phenotypes and result in almost indistinguishable VMs. VMs are currently classified based on clinical and histopathology features, however, the findings of this systematic review suggest a larger role for genotype in current diagnostics and classification. [ABSTRACT FROM AUTHOR]

16q24 deletion involving the ANKRD11 gene, ranging from 137 kb to 2 Mb, have been associated with a microdeletion syndrome characterized by variable cognitive impairment, autism spectrum disorder, facial dysmorphisms with dental anomalies, brain abnormalities essentially affecting the corpus callosum and short stature. On the other hand, patients carrying either deletions encompassing solely ANKRD11 or its loss-of-function variants were reported in association with the KBG syndrome, characterized by a very similar phenotype, including mild-to-moderate intellectual disability, short stature and macrodontia of upper incisors, with inter and intrafamilial variability. To assess whether the haploinsufficiency of ANKRD11-flanking genes, such as ZFPM1, CDH15 and ZNF778, contributed to either the severity of the neurological impairment or was associated with other clinical features, we collected 12 new cases with a 16q24.2q24.3 deletion (de novo in 11 cases), ranging from 343 kb to 2.3 Mb. In 11 of them, the deletion involved the ANKRD11 gene, whereas in 1 case only flanking genes upstream to it were deleted. By comparing the clinical and genetic features of our patients with those previously reported, we show that the severity of the neurological phenotype and the frequency of congenital heart defects characterize the deletions that, besides ANKRD11, contain ZFPM1, CDH15 and ZNF778 as well. Moreover, the presence of thrombocytopenia and astigmatism should be taken into account to distinguish between 16q24 microdeletion syndrome and KBG syndrome. The single patient not deleted for ANKRD11, whose phenotype is characterized by milder psychomotor delay, cardiac congenital malformation, thrombocytopenia and astigmatism, confirms all this data.

Macroglossia is observed in the majority of paediatric patients diagnosed with Beckwith-Wiedemann syndrome and surgical treatment may be indicated. A 20-year retrospective study was performed to evaluate all patients with Beckwith-Wiedemann syndrome who underwent tongue reduction surgery at the authors' institution. A literature review was performed. Surgical treatment was indicated and carried out in 23 patients with a yearly average varying from 0 to 3 subjects. The mean follow-up time was 7 years. Primary indications for surgical treatment of macroglossia included significant tongue protrusion in 30% (n=7), and a combination of clinical problems in 70% (n=16). In all cases, the procedure was performed by the same surgeon using an anterior, V-shaped, wedge resection technique. Two patients had direct postoperative complications. No recurrence of macroglossia was observed in this study. Reported clinical outcome during follow-up demonstrated a satisfactory resting tongue position in all patients. Review of the literature demonstrated variability in surgical indications and techniques, and postoperative outcome. The results of this study indicate that the anterior wedge resection is a simple, effective and safe technique in the surgical treatment of paediatric patients, diagnosed with Beckwith-Wiedemann syndrome, suffering from macroglossia., (Copyright © 2011 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

We report on two families in which the parental origin of duplications of the BWS imprinted regions on chromosome 11p15 influences the phenotype. In family A the transmission of a t(4; 11)(q35; p15.5) translocation results in duplication of BWSIC1 and BWSIC2. If this duplication is transmitted from the father, the extra chromosomal material has the paternal imprint. This results in overexpression of IGF2 and consequently an overgrowth phenotype. If the duplication is transmitted from the mother, the extra chromosomal material has the maternal imprint, resulting in overexpression of CDKN1C and a growth retardation phenotype. In family B an interstitial duplication of BWSIC1 results in an overgrowth phenotype when inherited from the father, similar to family A. However, no change in phenotype is observed if the duplication is transmitted through the mother suggesting that increased dosage of maternally expressed genes in the duplicated region has limited effect on the phenotype.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth malformation syndrome that maps to human chromosome 11p15.5, a region that harbours a number of imprinted genes. We studied the methylation status of H19 and KCNQ1OT1 (LIT1/KvDMR1) in a large series of BWS patients. Different patient groups were identified: group I patients (20%) with uniparental disomy and hence aberrant methylation of H19 and KCNQ1OT1; group II patients (7%) with a BWS imprinting centre 1 (BWSIC1) defect causing aberrant methylation of H19 only; group III patients (55%) with a BWS imprinting centre 2 (BWSIC2) defect causing aberrant methylation of KCNQ1OT1 only; and group IV patients (18%) with normal methylation patterns for both H19 and KCNQ1OT1. BWS patients have an increased risk of developing childhood tumours. In our patient group, out of 31 patients (group III) with KCNQ1OT1 demethylation only, none developed a tumour. However, tumours were found in 33% of patients with H19 hypermethylation (group I and II) and in 20% of patients with no detectable genetic defect (group IV). All four familial cases of BWS showed reduced methylation of KCNQ1OT1, suggesting that in these cases the imprinting switch mechanism is disturbed.

We report a case of Farber disease in a fetus who died in utero at a gestational age of 29 weeks. Macroscopic examination showed moderate postmortem changes in a microcephalic female fetus (46,XX) with mild internal hydrops, two vessels in the umbilical cord, and a moderately enlarged, relatively well-preserved spleen. Microscopic examination showed foamy cells in the spleen. Electron microscopic examination revealed the presence of Farber bodies within these foamy cells. Enzyme studies of the fetus were not possible because all tissues were formalin fixed. Lipids were extracted from formalin-fixed tissues and increased levels of ceramide and the presence of hydroxyceramide in tissue of the spleen, liver, and lung were found. Glucosylceramide was not increased excluding saposin-precursor-deficiency. Because of these findings, both parents were tested for acid ceramidase activity in their leukocytes. They both had markedly reduced enzyme activity consistent with heterozygosity for Farber disease. To the best of our knowledge, this is the first published case of Farber disease in Dutch nonconsanguineous parents.

Hirschsprung disease (HSCR) is a congenital disorder characterised by intestinal obstruction due to an absence of intramural ganglia along variable lengths of the intestine. RET is the major gene involved in HSCR. Mutations in the GDNF gene, and encoding one of the RET ligands, either alone or in combination with RET mutations, can also cause HSCR, as can mutations in four other genes (EDN3, EDNRB, ECE1, and SOX10). The rare mutations in the latter four genes, however, are more or less restricted to HSCR associated with specific phenotypes. We have developed a novel comprehensive mutation detection system to analyse all but three amplicons of the RET and GDNF genes, based on denaturing gradient gel electrophoresis. We make use of two urea-formamide gradients on top of each other, allowing mutation detection over a broad range of melting temperatures. For the three remaining (GC-rich) PCR fragments we use a combination of DGGE and constant denaturing gel electrophoresis (CDGE). These two dual gel systems substantially facilitate mutation scanning of RET and GDNF, and may also serve as a model to develop mutation detection systems for other disease genes. In a screening of 95 HSCR patients, RET mutations were found in nine out of 17 familial cases (53%), all containing long segment HSCR. In 11 of 78 sporadic cases (14%), none had long segment HSCR. Only one GDNF mutation was found, in a sporadic case., (Copyright 2000 Wiley-Liss, Inc.)

We report on a boy with an interstitial deletion of the long arm of chromosome 2 with breakpoints in chromosome bands q23 and q24.3. Main features were low-set and malformed ears, digital anomalies and congenital heart defects, which have also been reported in most of the previously described cases. A comparison of the features of the present patient with those in previously reported cases suggests the deletion 2q23q24 to be a clinically recognizable syndrome.

Hirschsprung's disease (HSCR) is a congenital disorder characterized by intestinal obstruction due to the absence of intramural ganglia along variable lengths of the colon. Occurrence among family members and recurrence risks among siblings are indications for involvement of genetic predispositions. Mutations have been discovered in five different susceptibility genes. One of the most important findings is the detection of specific mutations in the so-called RET gene, which can also be responsible for the multiple endocrine neoplasia type 2A (MEN2A) syndrome. HSCR patients with such specific mutations run an increased risk of developing MEN type 2A related tumours.

When inversion of the combined penile and scrotal skin flaps for vaginoplasty in male-to-female transsexuals has not led to functional results, rectosigmoid colpopoiesis offers an immediate solution to a complicated and difficult problem. However, open colocolpopoiesis involves major surgery, and it may be associated with substantial extended morbidity and hospitalization, short- and long-term unfavorable results, and extensive scarring of the abdomen. To reduce this associated morbidity, we employ a laparoscopically assisted approach and a total laparoscopic rectosigmoid colpopoiesis. This procedure has been performed safely in the series presented herein, with no apparent compromise in the adequacy of the dissections. We conclude that our patients benefited from this procedure, and we advocate considering a total or partial laparoscopic approach whenever secondary rectosigmoid colpopoiesis is indicated in male-to-female transsexuals.

We report on a large family with the ectrodactyly, ectodermal dysplasia, clefting (EEC) syndrome. The clinical manifestations in this family show great variability. Specific genitourinary anomalies were found. The propositus with micturition problems is discussed in detail. A dysplastic bladder epithelium might be the cause of these problems. A remarkable improvement of the complaints was achieved upon treatment with synthetic sulfonated glycosaminoglycans.

Members of different societies, including Paediatrics, Gastroenterology, Clinical Chemistry, Radiology and Pathology, involved in the treatment of children with inflammatory bowel disease (IBD) reached consensus during 12 meetings about definition, clinical and diagnostic work-up as well as initial treatment options in paediatric IBD. On the basis of history and physical examination a distinction is made between colitis-like or Crohn-like appearance. Further laboratory investigations are required in the presence of malnutrition, extraintestinal manifestations or growth retardation. Pathology plays an important part in the final diagnosis. Special attention is given to pubertal staging and height measurements as routine aspects of the treatment of children with IBD.

The lactase-phlorizin hydrolase gene is widely used as a marker of intestinal differentiation. Recent evidence demonstrating that transcription plays a major role in the regulation of this gene suggests that study of the 5'-flanking region will allow an understanding of how the expression of this gene is controlled. However, sequence, restriction, and primer extension analysis of a rat genomic clone has revealed that previously published data are incomplete. In the present study, we used a directed sequencing strategy to carefully analyze this region. Our expanded analysis of the 5'-flanking region of the lactase-phlorizin hydrolase gene should facilitate future studies of its structure and function.

The number of female residents in the Netherlands has steadily increased in recent years. Due to the increased time on waiting lists to enter residency programmes and to the increased duration of training, female residents will be older during their residencies. This will probably result in an increased number of pregnancies during residencies. A questionnaire regarding pregnancy during residency was sent to 191 residents in two university hospitals in the Netherlands. The response rate was 74.3%. Fifty percent of the male and only 19% of the female residents had children. No negative effects of a pregnancy on their training were experienced or anticipated by the residents. However, a negative effect on the functioning of the department was expected. No formal provisions, like replacements were available and many solutions to replace pregnant colleagues depended on the flexibility of the colleagues. The wish to have children was high and equally distributed among male and female residents, 92% and 96%, resp. Given the difficulty to seek a permanent position and to have children after residency, the choice of many female residents will be to have their children during residency. This increase in number of pregnancies requires anticipation of the residency programme directors. They should take the lead in proposing adequate regulations.

We developed a method for detection and analysis of the local atrial evoked response. Eleven patients undergoing permanent dual chamber pacemaker implantations for standard clinical indications were included in the study. Using a pacing system emulator, charge balancing using a variable triphasic stimulus waveform to reduce polarization artifact amplitude was performed first. This could not be completed in one patient because of a poor signal-to-noise ratio. Subsequent analysis of the local atrial evoked response in the remaining ten patients showed the typical signal to be a biphasic waveform with an initial negative deflection followed by a positive deflection nearly equal in amplitude. The mean amplitude of the atrial evoked response was 3.1 +/- 1.4 mV, while the intrinsic P wave amplitude in these same patients averaged 5.6 +/- 3.0 mV. The summed evoked response, a parameter that is directly proportional to the area of the signal, was used to determine atrial pacing threshold. The median atrial pacing threshold determined by the algorithm was 1.00 V. There was no instance of failure to detect loss of capture, nor was loss of capture inaccurately determined when there was still successful atrial pacing. Atrial capture in permanent pacing systems can thus be determined using an algorithm to record and analyze the local atrial evoked response. This method could potentially be useful in the automatic determination of atrial pacing threshold.

Cross correlation is an accurate method for distinguishing normal sinus rhythm (NSR) from ventricular arrhythmias. The computational demands of the method, however, have prohibited development of an implantable device using correlation. In this study, temporal data compression prior to correlation analysis was used to reduce the total number of computations. Unipolar and bipolar intracardiac electrograms of NSR and 23 episodes of ventricular tachycardia (VT) from 23 patients were obtained from a right ventricular apex electrode catheter during routine electrophysiology studies. The data were filtered (1-11 Hz), digitized (250 samples/sec) and temporally compressed to 50 samples/sec. Data compression removed four out of every five samples by only saving the sample with the maximum excursion from the last saved sample. The average squared correlation coefficient (r2) was computed for the NSR and VT episodes using each patient's NSR waveform as a template. In all 23 patients, the r2 values showed large separation between NSR versus VT in both unipolar (0.93 +/- 0.05 vs 0.20 +/- 0.16, P less than 0.005) and bipolar (0.91 +/- 0.07 vs 0.17 +/- 0.11, P less than 0.005) electrode configurations using template lengths of 80% the intrinsic interval (avg +/- SD). Narrow templates (40% intrinsic interval or less) often resulted in multiple r2 peaks during each heart cycle and degraded the r2 separation (n = 10, P less than 0.005). High pass filtering at 3 Hz also degraded the r2 separation (n = 10, P less than 0.05). Standard noncompressed correlations indicated that data compression had negligible effects on the results. Thus, a computationally efficient cross correlation method was found to be a reliable detector of VT.(ABSTRACT TRUNCATED AT 250 WORDS)

The review is structured in such a way as to fall naturally into four main sections. These are as follows: clinical overview of the common mechanisms leading to the generation of tachyarrhythmias; commonly used sensing techniques and algorithms for the detection of tachyarrhythmias; electrical stimulation algorithms used to terminate many of the rhythms; existing implantable devices and a brief look at the future. The clinical overview introduces the reader unfamiliar with tachyarrhythmias to such mechanisms as sinus tachycardia, supraventricular tachycardias (SVTs), ventricular tachycardia, 'torsade de pointes', and ventricular fibrillation. SVT includes paroxysmal SVT, atrial flutter, atrial tachycardia and junctional tachycardia (enhanced automaticity). Also there is a brief introduction to alternative therapies (drugs, surgery etc.) The sensing techniques section covers input signal processing to enable the R wave to be adequately detected; while the tachycardia detection algorithms section discusses such areas as simple rate detect, rate of change of rate detect, stability of rate, the so-called probability density function technique and some other more complex detection algorithms. The section on electrical stimulation algorithms used for tachycardia therapy discusses burst pacing techniques, special cases such as automatically decrementing bursts and automatically incrementing bursts, defibrillation shock therapy (since fibrillation is a form of tachyarrhythmia) and several other more complex algorithms. The review finishes up with a discussion of current implantable antitachy pacemakers and defibrillators. There is also a speculative look at the future to enable the reader to obtain a full picture.