Phenotype of CM-AVM2 caused by variants in EPHB4: how much overlap with hereditary hemorrhagic telangiectasia (HHT)?

PURPOSE: EPHB4 variants were recently reported to cause capillary malformation-arteriovenous malformation 2 (CM-AVM2). CM-AVM2 mimics RASA1-related CM-AVM1 and hereditary hemorrhagic telangiectasia (HHT), as clinical features include capillary malformations (CMs), telangiectasia, and arteriovenous malformations (AVMs). Epistaxis, another clinical feature that overlaps with HHT, was reported in several cases. Based on the clinical overlap of CM-AVM2 and HHT, we hypothesized that patients considered clinically suspicious for HHT with no variant detected in an HHT gene (ENG, ACVRL1, or SMAD4) may have an EPHB4 variant. METHODS: Exome sequencing or a next-generation sequencing panel including EPHB4 was performed on individuals with previously negative molecular genetic testing for the HHT genes and/or RASA1. RESULTS: An EPHB4 variant was identified in ten unrelated cases. Seven cases had a pathogenic EPHB4 variant, including one with mosaicism. Three cases had an EPHB4 variant of uncertain significance. The majority had epistaxis (6/10 cases) and telangiectasia (8/10 cases), as well as CMs. Two of ten cases had a central nervous system AVM. CONCLUSIONS: Our results emphasize the importance of considering CM-AVM2 as part of the clinical differential for HHT and other vascular malformation syndromes. Yet, these cases highlight significant differences in the cutaneous presentations of CM-AVM2 versus HHT.

Characterization of a family mutation in the 5' untranslated region of the endoglin gene causative of hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is a vascular disease characterized by nose and gastrointestinal bleeding, telangiectases in skin and mucosa, and arteriovenous malformations in major internal organs. Most patients carry a mutation in the coding region of the endoglin (ENG) or activin A receptor type II-1 (ACVRL1) gene. Nonetheless, in around 15% of patients, sequencing analysis and duplication/deletion tests fail to pinpoint mutations in the coding regions of these genes. In these cases, it has been shown that sequencing of the 5'-untranslated region (5'UTR) of ENG may be useful to identify novel mutations in the ENG non-coding region. Here we report the genetic characterization and functional analysis of the heterozygous mutation c.-142A>T in the 5'UTR region of ENG found in a family with several members affected by HHT. This variant gives rise to a new initiation codon of the protein that involves the change in its open reading frame. Transfection studies in monkey cells using endoglin expression vectors demonstrated that c-142A>T mutation results in a clear reduction in the levels of the endoglin protein. These results support the inclusion of the 5'UTR of ENG in the standard genetic testing for HHT to increase its sensitivity.

Genome sequencing reveals a deep intronic splicing ACVRL1 mutation hotspot in Hereditary Haemorrhagic Telangiectasia.

INTRODUCTION: Hereditary haemorrhagic telangiectasia (HHT) is a genetically heterogeneous disorder caused by mutations in the genes ENG, ACVRL1, and SMAD4. Yet the genetic cause remains unknown for some families even after exhaustive exome analysis. We hypothesised that non-coding regions of the known HHT genes may harbour variants that disrupt splicing in these cases. METHODS: DNA from 35 individuals with clinical findings of HHT and 2 healthy controls from 13 families underwent whole genome sequencing. Additionally, 87 unrelated cases suspected to have HHT were evaluated using a custom designed next-generation sequencing panel to capture the coding and non-coding regions of ENG, ACVRL1 and SMAD4. Individuals from both groups had tested negative previously for a mutation in the coding region of known HHT genes. Samples were sequenced on a HiSeq2500 instrument and data were analysed to identify novel and rare variants. RESULTS: Eight cases had a novel non-coding ACVRL1 variant that disrupted splicing. One family had an ACVRL1intron 9:chromosome 3 translocation, the first reported case of a translocation causing HHT. The other seven cases had a variant located within a ~300 bp CT-rich 'hotspot' region of ACVRL1intron 9 that disrupted splicing. CONCLUSIONS: Despite the difficulty of interpreting deep intronic variants, our study highlights the importance of non-coding regions in the disease mechanism of HHT, particularly the CT-rich hotspot region of ACVRL1intron 9. The addition of this region to HHT molecular diagnostic testing algorithms will improve clinical sensitivity.

Brachial plexus entrapment of interscalene nerve catheter after uncomplicated ultrasound-guided placement.

We report on the case of an entrapped interscalene nerve catheter in a 46-year-old male undergoing left shoulder arthroscopic lysis of adhesions for a frozen shoulder. The catheter was placed under ultrasound guidance without any apparent complications. The continuous interscalene nerve block was successfully used as the primary anesthetic and for postoperative pain management. Upon attempted catheter removal, the patient experienced severe pain and paresthesias. Fluoroscopy revealed possible brachial plexus involvement, and surgery was performed to extract the catheter, which had become hooked and entrapped around the C5 nerve root and sheath.

Color Doppler ultrasonography of an agitated solution is predictive of accurate catheter placement for a continuous popliteal sciatic nerve block.

BACKGROUND: Continuous peripheral nerve catheters (PNCs) have been shown to provide superior postoperative analgesia, decrease opioid consumption, and improve patient satisfaction compared with single injection techniques. In order to achieve success and reliability, accurate catheter positioning is an essential element of PNC placement. An agitated solution of normal saline, D5W, or a local anesthetic solution can be produced by the introduction of air to the injectate, creating air bubbles that can enhance ultrasonographic visualization and possibly improve block success. METHODS: Eighty-three patients were enrolled. Ultrasound-guided continuous popliteal sciatic nerve blocks were performed by positioning the tip of a Tuohy needle between the tibial and common peroneal branches of the sciatic nerve and threading a catheter. An agitated local anesthetic solution was injected through the catheter, viewed with color Doppler ultrasound and video recorded. A peripheral block score (lower score = greater blockade, range 0-14) was calculated based upon the motor and sensory testing at 10, 20, and 30 min after block completion. The color Doppler agitation coverage pattern for the branches of the sciatic nerve was graded as follows: complete (> 50%), partial (> 0%, ≤ 50%), or none (0%). RESULTS: The degree of nerve blockade at 30 min as judged by median (10th, 90th percentile) peripheral block score was significant for partial or complete color Doppler coverage of the sciatic nerve injectate compared to no coverage [3 (0, 7) vs 8 (4, 14); p < 0.01] and block onset was faster (p = 0.03). The block success was higher in groups with partial or complete coverage of the branches of the sciatic nerve vs no coverage (96% vs 70%; p = 0.02). CONCLUSIONS: Injection of an agitated solution through a popliteal sciatic perineural catheter is predictive of accurate catheter placement when partial or complete coverage of the sciatic nerve branches is visualized with color Doppler ultrasound. TRIAL REGISTRATION: NCT01591603.

The relationship between adverse childhood experience and obsessive-compulsive symptoms and beliefs: the role of anxiety, depression, and experiential avoidance.

Current cognitive-behavioral models of the etiology of obsessive-compulsive disorder (OCD) suggest that maladaptive appraisal of otherwise normal intrusive thoughts have their origins in early learning experiences. The present study investigated the relationship between adverse childhood experience and OCD symptoms and related dysfunctional beliefs in a general population using a structural equation modeling approach. The role of experiential avoidance and anxiety and depression were also explored in the model. Results indicated that adverse childhood experience was strongly associated with OCD symptoms and beliefs, but after controlling for anxiety and depression the relationship with OCD symptoms became non-significant and only a weak relationship with OCD beliefs remained. Experiential avoidance was significantly associated with OCD symptoms and beliefs and remained significant after controlling for anxiety and depression. Implications of these results in the context of a complete model of the development of OCD are discussed.