Functional characterization of variants found in Japanese patients with hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant form of vascular dysplasia. Genetic diagnosis is made by identifying loss-of-function variants in genes, such as ENG and ACVRL1. However, the causal mechanisms of various variants of unknown significance remains unclear. In this study, we analyzed 12 Japanese patients from 11 families who were clinically diagnosed with HHT. Sequencing analysis identified 11 distinct variants in ACVRL1 and ENG. Three of the 11 were truncating variants, leading to a definitive diagnosis, whereas the remaining eight were splice-site and missense variants that required functional analyses. In silico splicing analyses demonstrated that three variants, c.526-3C > G and c.598C > G in ACVRL1, and c.690-1G > A in ENG, caused aberrant splicing, as confirmed by a minigene assay. The five remaining missense variants were p.Arg67Gln, p.Ile256Asn, p.Leu285Pro, and p.Pro424Leu in ACVRL and p.Pro165His in ENG. Nanoluciferase-based bioluminescence analyses demonstrated that these ACVRL1 variants impaired cell membrane trafficking, resulting in the loss of bone morphogenetic protein 9 (BMP9) signal transduction. In contrast, the ENG mutation impaired BMP9 signaling despite normal cell membrane expression. The updated functional analysis methods performed in this study will facilitate effective genetic testing and appropriate medical care for patients with HHT.

Radial MRI during free breathing in contrast-enhanced hepatobiliary phase imaging.

BACKGROUND: Use of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) for diagnosis of hepatic tumors has been previously reported. Fat-saturated 3D T1-weighted gradient echo sequence (TIGRE) imaging using a breath-hold technique is usually used for dynamic studies and hepatobiliary phase Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI). In cases where the patient has difficulty holding their breath, this scanning method can be difficult. PURPOSE: To investigate the usefulness of a fat-saturated T1-weighted spin-echo (SE) sequence using a radial read-out (radial acquisition regime-SE, RADAR-SE) during free breathing for hepatobiliary phase Gd-EOB-DTPA-enhanced MRI. MATERIAL AND METHODS: Images were acquired at 1.5 T. First, a phantom with diluted Gd-EOB-DTPA was scanned using the TIGRE sequence and the RADAR-SE sequence. Contrast ratios of the sequences were compared. Next, the hepatobiliary phase was imaged in 62 patients using the TIGRE sequence with breath-hold and the RADAR-SE during free breathing. Qualitative and quantitative evaluations were compared. RESULTS: In the phantom study, RADAR-SE had a higher contrast ratio than TIGRE. In the clinical study, artifacts were more conspicuous in RADAR-SE compared to TIGRE images in the qualitative evaluation. However, RADAR-SE images were equal to or better than TIGRE images in patients who had difficulty holding their breath. The signal intensity ratio of the liver was statistically higher using RADAR-SE than TIGRE. CONCLUSION: RADAR-SE can be useful for hepatobiliary phase Gd-EOB-DTPA-enhanced MRI in patients who have difficulty holding their breath.

Wandering spleen with gastric volvulus and intestinal non-rotation in an adult male patient.

We report an extremely rare case of wandering spleen (WS) complicated with gastric volvulus and intestinal non-rotation in a male adult. A 22-year-old man who had been previously treated for Wilson disease was admitted with severe abdominal pain. Radiological findings showed WS in the midline of the pelvic area. The stomach was mesenteroaxially twisted and intestinal non-rotation was observed. Radiology results did not show any evidence of splenic or gastrointestinal (GI) infarction. Elective emergency laparoscopy confirmed WS and intestinal non-rotation; however, gastric volvulus was not observed. It was suspected that the stomach had untwisted when gastric and laparoscopic tubes were inserted. Surgery is strongly recommended for WS because of the high risk of serious complications; however, some asymptomatic adult patients are still treated conservatively, such as the patient in this study. The present case is reported with reference to the literature.

ACVRL1 gene variant in a patient with vein of Galen aneurysmal malformation.

Although mutations in the RASA1 gene in vein of Galen aneurysmal malformation (VGAM) and an endoglin gene mutation in a VGAM patient with a family history of hereditary hemorrhagic telangiectasia (HHT) have been identified, most VGAM cases have no mutation in these genes. We sought to detect mutations in other genes related to HHT. We screened for mutations in RASA1 and three genes (endoglin, activin receptor-like kinase 1 (ACVRL1), encoding ALK1, and SMAD4) related to HHT in four VGAM patients. One variant (c.652 C>T p.R218W) in ACVRL1 was identified. Immunoblotting revealed that the ALK1-R218W protein could not promote SMAD1/5/8 phosphorylation by BMP9 stimulation. On the other hand, wild-type ALK1 could enhance the phosphorylation as expected. Furthermore, the transcriptional activation of ALK1-R218W was less efficient than that of wild-type ALK1. We identified 1 variant in ACVRL1 in a VGAM patient. These findings suggest that the ACVRL1 variant-R218W may be associated with the pathogenesis of VGAM.

Vein of Galen aneurysmal malformation associated with an endoglin gene mutation.

A child with vein of Galen aneurysmal malformation (VGAM) presented with cardiac failure in the neonatal period. The family history revealed his mother to have hereditary hemorrhagic telangiectasia. The child underwent an endoglin genetic analysis after the newborn period, which eventually demonstrated an endoglin mutation. The pathogenesis of VGAM is currently unknown. The findings of this case suggest that an endoglin mutation might be linked with VGAM.

Pediatric high-flow, cervical spinal, macro-arteriovenous fistula, treated with the endovascular cotton candy glue injection technique.

CASE REPORT: A 3-year-old boy presented to our hospital with progressive neurological deficits. Spinal magnetic resonance imaging (MRI) revealed a perimedullary macro-arteriovenous fistula (PMAVF) resulting in a large venous pouch within the parenchyma of the lower cervical spinal cord. Transarterial varix embolization of the fistula from the venous side was performed using N-butyl cyanoacrylate with tantalum powder. Postembolization angiography confirmed obliteration of the fistula, and MRI revealed thrombosis and reduction in size of the venous component. The patient's clinical symptoms were reduced dramatically following the intervention, and no neurological complications occurred due to the treatment. The prognosis of spinal PMAVF depends primarily on the presence of medullar signs and symptoms and on time to treatment. The volume of the venous pouch after the intervention was markedly reduced, and complete clinical recovery was obtained. Urgent endovascular intervention, as seen in this case, is considered first-line therapy and aims to decrease the risk of neurological sequela.

Endovascular remodeling technique for vein of Galen aneurysmal malformations--angiographic confirmation of a connection between the median prosencephalic vein and the deep venous system.

It is commonly believed that in vein of Galen aneurysmal malformations (VGAMs) venous structures normally constituting the deep or Galenic venous system, such as the internal cerebral vein (ICV) and the basal vein of Rosenthal, are not connected to the vein of Galen. In this report, the authors describe 2 cases of successfully treated VGAM in which drainage of an ICV into the vein of Galen was confirmed by follow-up angiography. Two mural types of VGAM were treated using transarterial glue embolization when 1 child was 5 months and the other was 6 months old. The postoperative outcomes for these babies were complete cures. Follow-up digital subtraction angiography obtained after 12 months (Case 1) and 6 months (Case 2) confirmed that the shrunken median prosencephalic vein connects with the deep venous system. The possibility of normal deep Galenic venous drainage must be considered in endovascular management of VGAM. The goal of endovascular intervention is to close only the ventral component of the dilated median prosencephalic vein.

High-flow Paraspinal Osseous Epidural Arteriovenous Fistula. A Case Report.

We report the clinical and neuroradiological imaging findings of a 26-year-old man who presented with lumbago related to high flow paraspinal osseous epidural arteriovenous fistulas in the thoracic spine. This case was of particular interest because of his exclusive epidural and paraspinal venous drainage and the presence of a prominent dilated venous pouch in the spinal canal. Angiography demonstrated multiple high flow arteriovenous fistulas with an osseous nidus. Transarterial glue embolization was performed by multistage sessions. Clinical symptoms improved dramatically. The unusual features of this case have important implications for therapeutic management.

Congenital fibromuscular dysplasia involving multivessels in an infant with fatal outcome.

UNLABELLED: We report the unusual case of a 2-month-old boy with systemic fibromuscular dysplasia (FMD). He presented with congenital renovascular hypertension due to stenosis of the right renal artery, and later developed renal infarction on the contralateral side resulting in renal failure. The boy subsequently died of intracranial haemorrhage at the age of 14 months. During the course, hemiconvulsion caused by a Moyamoya disease-like vascular lesion was noted. Stenotic lesions of both the abdominal aorta and its branches were also revealed by angiography. Post-mortem examination confirmed that the coronary, splenic and mesenteric arteries were also affected and their histological findings were compatible with FMD. To our knowledge, this is the first congenital case of FMD demonstrating a rapidly progressive course resulting in a fatal outcome. In this case, multivessels in both intracranial and extracranial arteries were involved. CONCLUSION: Our case suggests that the nature of fibromuscular dysplasia is congenital in origin and its aetiology, at least in some cases, is a systemic abnormality of vascular development.