Loshan Kangesu

Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects

Mutations in the angiopoietin receptor TIE2/TEK have been identified as the cause for autosomal dominantly inherited cutaneomucosal venous malformation (VMCM). Thus far, two specific germline substitutions (R849W and Y897S), located in the kinase domain of TIE2, have been reported in five families. The mutations result in a fourfold increase in ligand-independent phosphorylation of the receptor. Here, we report 12 new families with TEK mutations. Although the phenotype is primarily characterized by small multifocal cutaneous vascular malformations, many affected members also have mucosal lesions. In addition, cardiac malformations are observed in some families. Six of the identified mutations are new, with three located in the tyrosine kinase domain, two in the kinase insert domain, and another in the carboxy terminal tail. The remaining six are R849W substitutions. Overexpression of the new mutants resulted in ligand-independent hyperphosphorylation of the receptor, suggesting this is a general feature of VMCM-causative TIE2 mutations. Moreover, variation in the level of activation demonstrates, to the best of our knowledge for the first time, that widely differing levels of chronic TIE2 hyperphosphorylation are tolerated in the heterozygous state, and are compatible with normal endothelial cell function except in the context of highly localized areas of lesion pathogenesis.

Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations.

Blue rubber bleb nevus syndrome (Bean syndrome) is a rare, severe disorder of unknown cause, characterized by numerous cutaneous and internal venous malformations; gastrointestinal lesions are pathognomonic. We discovered somatic mutations in TEK, the gene encoding TIE2, in 15 of 17 individuals with blue rubber bleb nevus syndrome. Somatic mutations were also identified in five of six individuals with sporadically occurring multifocal venous malformations. In contrast to common unifocal venous malformation, which is most often caused by the somatic L914F TIE2 mutation, multifocal forms are predominantly caused by double (cis) mutations, that is, two somatic mutations on the same allele of the gene. Mutations are identical in all lesions from a given individual. T1105N-T1106P is recurrent in blue rubber bleb nevus, whereas Y897C-R915C is recurrent in sporadically occurring multifocal venous malformation: both cause ligand-independent activation of TIE2, and increase survival, invasion, and colony formation when expressed in human umbilical vein endothelial cells.

Increasing accuracy of antenatal ultrasound diagnosis of cleft lip with or without cleft palate, in cases referred to the North Thames London Region

To determine the accuracy of antenatal ultrasound diagnosis of cleft lip with or without cleft palate (CL ± P) and isolated cleft palate (CP).

Genotypes and Phenotypes of 162 Families with a Glomulin Mutation

A decade ago, we identified a novel gene, glomulin (GLMN) in which mutations cause glomuvenous malformations (GVMs). GVMs are bluish-purple cutaneous vascular lesions with characteristic glomus cells in the walls of distended venous channels. The discovery of the genetic basis for GVMs allowed the definition of clinical features to distinguish GVMs from other venous anomalies. The variation in phenotype was also highlighted: from a single punctate blue dot to a large plaque-like lesion. In this study, we screened GLMN in a large cohort of patients to broaden the spectrum of mutations, define their frequency and search for possible genotype-phenotype correlations. Taking into account 6 families published by others, a mutation in GLMN has been found in 162 families. This represents 40 different mutations; the most frequent one being present in almost 45% of them. Expressivity varies largely, without a genotype/phenotype relationship. Among 381 individuals with a mutation, we discovered 37 unaffected carriers, implying a penetrance of 90%. As nonpenetrant individuals may transmit the disease to their descendants, knowledge on the mutational status is needed for appropriate genetic counseling.

Palate Lengthening by Buccinator Myomucosal Flaps for Velopharyngeal Insufficiency

Objective To assess the outcome of palate lengthening by myomucosal buccinator flaps for velopharyngeal insufficiency both in terms of speech and changes in palate length. Design Thirty-two consecutive patients who underwent the buccinator flap procedure were reviewed retrospectively. Palate length and the presence or absence of a velopharyngeal gap were assessed on pre- and postoperative videofluoroscopic recordings using a calibrated image analysis system. Hypernasality, nasal emission, nasal turbulence, and passive cleft type articulation errors were evaluated blindly by a speech-language pathologist external to the team using pre- and postoperative speech recordings. Setting Multidisciplinary cleft team based in a tertiary referral center. Results In 81% of patients, speech outcome was such that no further velopharyngeal surgery was considered necessary at the time of follow-up. The buccinator flap procedure resulted in a mean palate lengthening of 7.5 mm (±5.5 SD). After the operation, there was a complete elimination of the velopharyngeal gap on lateral videofluoroscopy in 77% of patients. There were significant decreases in hypernasality ratings and passive cleft type articulation errors postoperatively. Conclusion Palatal lengthening with myomucosal buccinator flaps in patients with velopharyngeal insufficiency is effective and safe. It has become one of our routinely practiced procedures for velopharyngeal insufficiency.

Histopathological features of Proteus syndrome.

Background.  Proteus syndrome is a rare, sporadic overgrowth disorder for which the underlying genetic defect remains unknown. Although the clinical course is well‐described there is no systematic histopathological description of the lesional pathology.

Two siblings with an unusual nasal malformation: further instances of craniorhiny?

We report a brother and sister born to consanguineous parents. The siblings have hypertelorism, bifid nose, upturned nares, histologically proven intranasal dermoid, and soft‐tissue swellings of the philtrum. One sibling also has a midline cleft lip and the other has narrowing of the posterior choanae. We suggest that they have craniorhiny, despite the absence of an abnormal skull shape. The differential diagnosis is discussed.

Venous malformation associated nerve profiles and pain: An immunohistochemical study

INTRODUCTION More than 90% of venous malformations (VM) are associated with pain, which is presumed related to phlebolith formation and subsequent nociceptive mediator release. Increasing evidence supports a link between angiogenesis and nerve patterning. Since vascular malformations are aberrations of angiogenesis, it was hypothesised VM pain may be due to differences in nerve profiles associated with these lesions. METHODS Immunohistochemical staining was performed on retrospective archival paraffin embedded samples of arteriovenous (AVM; n = 9), capillary (CM; n = 4), lymphatic (LM; n = 29) and VM (n = 14). Antibodies to three nerve markers, neurofilament, S100 and protein gene product 9.5 were employed. Light microscopy was used to assess the density of interstitial nerves and nervi vasorum, and assessments were validated by a second investigator. Significance testing was performed using Mann-Whitney U and Fishers exact tests. RESULTS There was no significant difference in nerve profile between VM and AVM or CM. LM and normal control skin each exhibited a lower nerve density compared to VM (p < 0.0075). The presence of nervi vasorum was found to be lower in VM than normal cutaneous controls when immunostained with S100 antibody (p = 0.044). CONCLUSION VM-associated pain is unlikely to be due to simple anatomical differences in nerve structure in this condition. As the nerve profile between VM and normal cutaneous control appears to be distinct, further work may elucidate common neurogenic/angiogenic mediators in the pathogenesis of vascular malformations which could prove targets in treating these conditions. In the meantime, current regimes of compression and non-steroidal anti-inflammatory drugs should be continued.

Does nasogastric feeding reduce distress after cleft palate repair in infants

AIMS To determine the effect of nasogastric (NG) feeding compared with oral feeding on morphine requirements after primary cleft palate repair, and secondarily on enteral intake. METHODS This was a pilot study involving 50 infants, aged five to ten months, who were randomised to receive NG or oral feeding after palate repair. All infants received the same anaesthetic and analgesic management. Post-operatively, paracetamol and ibuprofen were administered regularly and intravenous (IV) morphine was given on demand using a nurse-controlled analgesia device. The primary outcome measure was the total morphine consumption in the first 24 hours. Secondary outcome measures included the numbers of painful episodes and the volumes of IV fluid and enteral feed administered. RESULTS Of the 50 infants enrolled, 18 and 23 received either NG or oral feeding, respectively, and completed the study. Numbers of painful episodes and morphine consumption in the first 24 hours were similar in each group. Volumes of feed administered in the first 24 hours were significantly different: the NG group received approximately three times more than the oral group. Nine of the oral group required IV fluids in the 24 hours compared with none in the NG group. CONCLUSION NG feeding was more effective than oral feeding in the first 24 hours after surgery, but numbers of painful episodes recorded were similar. Further research is required.

Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy

BACKGROUND. Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM). METHODS. To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency. RESULTS. We discovered multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germline RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterization and 2 transgenic zebrafish AVM models that recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inhibitor vemurafinib restored blood flow in AVM. CONCLUSION. Our findings uncover a major cause of sporadic VMs of different clinical types and thereby offer the potential of personalized medical treatment by repurposing existing licensed cancer therapies. FUNDING. This work was funded or supported by grants from the AVM Butterfly Charity, the Wellcome Trust (UK), the Medical Research Council (UK), the UK National Institute for Health Research, the L’Oreal-Melanoma Research Alliance, the European Research Council, and the National Human Genome Research Institute (US).