Imaging of Hereditary Hemorrhagic Telangiectasia

This pictorial review is based on our experience of the follow-up of 120 patients at our multidisciplinary center for hereditary hemorrhagic telangiectasia (HHT). Rendu-Osler-Weber disease or HHT is a multiorgan autosomal dominant disorder with high penetrance, characterized by epistaxis, mucocutaneous telangiectasis, and visceral arteriovenous malformations (AVMs). The research on gene mutations is fundamental and family screening by clinical examination, chest X-ray, research of pulmonary shunting, and abdominal color Doppler sonography is absolutely necessary. The angioarchitecture of pulmonary AVMs can be studied by unenhanced multidetector computed tomography; however, all other explorations of liver, digestive bowels, or brain require administration of contrast media. Magnetic resonance angiography is helpful for central nervous system screening, in particular for the spinal cord, but also for pulmonary, hepatic, and pelvic AVMs. Knowledge of the multiorgan involvement of HHT, mechanism of complications, and radiologic findings is fundamental for the correct management of these patients

CT Density Distribution Analysis in Patients with Cystic Fibrosis: Correlation with Pulmonary Function and Radiologic Scores

International audienceRationale and Objectives: The progressive changes in lung morphology observed in cystic fibrosis (CF) can potentially affect the statistical distribution of computed tomography (CT) density values. This study aimed to characterize the lung CT density distributions by quantifying indices of the kurtosis and skewness of the lung density distribution and to compare these indices to radiologic scores and lung function parameters in children and young adults with CF. Materials and Methods: CT scans and lung function of 26 patients with CF were retrospectively examined. The Bhalla radiologic scoring was performed separately, in random order, by two expert radiologists, blinded to the patient's identity, age, clinical status, results of lung function tests, and the other paired observer's score. Results: Positive relations were evidenced between the log indices of lung density distribution kurtosis (iKurtosis) and the overall radiologic scores (RS) of both observers (R = 0.58; P<.001 vs RS1 and R = 0.71; P<.001 vs RS2). A similar relationship was evidenced with the log index of the degree of distribution asymmetry (iSkewness; R = 0.62; P<.001 vs RS1 and R = 0.62; P <.001 vs RS2). Log-iKurtosis and log-iSkewness were related to FEV1 (R = -0.56; P <10(-5) and R = -0.55;P<10(-5)) and to residual volume (R = 0.40; P<.001 and R = 0.45; P<.001, respectively). Both radiologic scores showed significant relation with lung function. The correlation between RS1 and RS2 was excellent (R = 0.93), with a Cohen weighted kappa of 0.43. Conclusions: Characteristic indices of lung CT density distribution are correlated to lung function and radiologic scores in patients with CF and merit further evaluation as part of more comprehensive automated methods for quantifying CF lung CT data

Sequence variations of ACVRL1 play a critical role in hepatic vascular malformations in hereditary hemorrhagic telangiectasia

International audienceBackground: Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by multiple telangiectases and caused by germline disease-causing variants in the ENG (HHT1), ACVRL1 (HHT2) and, to a lesser extent MADH4 and GDF2, which encode proteins involved in the TGF-β/BMP9 signaling pathway. Common visceral complications of HHT are caused by pulmonary, cerebral, or hepatic arteriovenous malformations (HAVMs). There is large intrafamilial variability in the severity of visceral involvement, suggesting a role for modifier genes. The objective of the present study was to investigate the potential role of ENG, ACVRL1, and of other candidate genes belonging to the same biological pathway in the development of HAVMs.Methods: We selected 354 patients from the French HHT patient database who had one disease causing variant in either ENG or ACVRL1 and who underwent hepatic exploration. We first compared the distribution of the different types of variants with the occurrence of HAVMs. Then, we genotyped 51 Tag-SNPs from the Hap Map database located in 8 genes that encode proteins belonging to the TGF-β/BMP9 pathway (ACVRL1, ENG, GDF2, MADH4, SMAD1, SMAD5, TGFB1, TGFBR1), as well as in two additional candidate genes (PTPN14 and ADAM17). We addressed the question of a possible genetic association with the occurrence of HAVMs.Results: The proportion of patients with germline ACVRL1 variants and the proportion of women were significantly higher in HHT patients with HAVMs. In the HHT2 group, HAVMs were more frequent in patients with truncating variants. Six SNPs (3 in ACVRL1, 1 in ENG, 1 in SMAD5, and 1 in ADAM17) were significantly associated with HAVMs. After correction for multiple testing, only one remained significantly associated (rs2277383).Conclusions: In this large association study, we confirmed the strong relationship between ACVRL1 and the development of HAVMs. Common polymorphisms of ACVRL1 may also play a role in the development of HAVMs, as a modifying factor, independently of the disease-causing variants

Diagnostic strategy for patients with suspected pulmonary embolism: a prospective multicentre outcome study.

International audienceBACKGROUND: We designed a prospective multicentre outcome study to evaluate a diagnostic strategy based on clinical probability, spiral CT, and venous compression ultrasonography of the legs in patients with suspected pulmonary embolism (PE). The main aim was to assess the safety of withholding anticoagulant treatment in patients with low or intermediate clinical probability of PE and negative findings on spiral CT and ultrasonography. METHODS: 1041 consecutive inpatients and outpatients with suspected PE were included. Patients with negative spiral CT and ultrasonography and clinically assessed as having a low or intermediate clinical probability were left untreated. Those with high clinical probability underwent lung scanning, pulmonary angiography, or both. All patients were followed up for 3 months. FINDINGS: PE was diagnosed in 360 (34.6%) patients; 55 had positive ultrasonography despite negative spiral CT. Of 601 patients with negative spiral CT and ultrasonography, 76 were clinically assessed as having a high probability of PE; lung scanning or angiography showed PE in four (5.3% [95% CI 1.5-13.1]). The remaining 525 patients were assessed as having low or intermediate clinical probability, and 507 of them were not treated. Of these patients, nine experienced venous thromboembolism during follow-up (1.8% [0.8-3.3]). The diagnostic strategy proved inconclusive in 95 (9.1%) patients, and pulmonary angiography was done in 74 (7.1%). INTERPRETATION: Withholding of anticoagulant therapy is safe when the clinical probability of PE is assessed as low or intermediate and spiral CT and ultrasonography are negative

Sequence variations of ACVRL1 play a critical role in hepatic vascular malformations in hereditary hemorrhagic telangiectasia

International audienceAbstract Background Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by multiple telangiectases and caused by germline disease-causing variants in the ENG (HHT1) , ACVRL1 (HHT2) and, to a lesser extent MADH4 and GDF2 , which encode proteins involved in the TGF-β/BMP9 signaling pathway. Common visceral complications of HHT are caused by pulmonary, cerebral, or hepatic arteriovenous malformations (HAVMs). There is large intrafamilial variability in the severity of visceral involvement, suggesting a role for modifier genes. The objective of the present study was to investigate the potential role of ENG , ACVRL1 , and of other candidate genes belonging to the same biological pathway in the development of HAVMs. Methods We selected 354 patients from the French HHT patient database who had one disease causing variant in either ENG or ACVRL1 and who underwent hepatic exploration. We first compared the distribution of the different types of variants with the occurrence of HAVMs. Then, we genotyped 51 Tag-SNPs from the Hap Map database located in 8 genes that encode proteins belonging to the TGF-β/BMP9 pathway ( ACVRL1, ENG, GDF2, MADH4, SMAD1, SMAD5, TGFB1, TGFBR1 ), as well as in two additional candidate genes ( PTPN14 and ADAM17 ). We addressed the question of a possible genetic association with the occurrence of HAVMs. Results The proportion of patients with germline ACVRL1 variants and the proportion of women were significantly higher in HHT patients with HAVMs. In the HHT2 group, HAVMs were more frequent in patients with truncating variants. Six SNPs (3 in ACVRL1 , 1 in ENG , 1 in SMAD5 , and 1 in ADAM17 ) were significantly associated with HAVMs. After correction for multiple testing, only one remained significantly associated (rs2277383). Conclusions In this large association study, we confirmed the strong relationship between ACVRL1 and the development of HAVMs. Common polymorphisms of ACVRL1 may also play a role in the development of HAVMs, as a modifying factor, independently of the disease-causing variants

Sequence variations of ACVRL1 play a critical role in hepatic vascular malformations in hereditary hemorrhagic telangiectasia

International audienceAbstract Background Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by multiple telangiectases and caused by germline disease-causing variants in the ENG (HHT1) , ACVRL1 (HHT2) and, to a lesser extent MADH4 and GDF2 , which encode proteins involved in the TGF-β/BMP9 signaling pathway. Common visceral complications of HHT are caused by pulmonary, cerebral, or hepatic arteriovenous malformations (HAVMs). There is large intrafamilial variability in the severity of visceral involvement, suggesting a role for modifier genes. The objective of the present study was to investigate the potential role of ENG , ACVRL1 , and of other candidate genes belonging to the same biological pathway in the development of HAVMs. Methods We selected 354 patients from the French HHT patient database who had one disease causing variant in either ENG or ACVRL1 and who underwent hepatic exploration. We first compared the distribution of the different types of variants with the occurrence of HAVMs. Then, we genotyped 51 Tag-SNPs from the Hap Map database located in 8 genes that encode proteins belonging to the TGF-β/BMP9 pathway ( ACVRL1, ENG, GDF2, MADH4, SMAD1, SMAD5, TGFB1, TGFBR1 ), as well as in two additional candidate genes ( PTPN14 and ADAM17 ). We addressed the question of a possible genetic association with the occurrence of HAVMs. Results The proportion of patients with germline ACVRL1 variants and the proportion of women were significantly higher in HHT patients with HAVMs. In the HHT2 group, HAVMs were more frequent in patients with truncating variants. Six SNPs (3 in ACVRL1 , 1 in ENG , 1 in SMAD5 , and 1 in ADAM17 ) were significantly associated with HAVMs. After correction for multiple testing, only one remained significantly associated (rs2277383). Conclusions In this large association study, we confirmed the strong relationship between ACVRL1 and the development of HAVMs. Common polymorphisms of ACVRL1 may also play a role in the development of HAVMs, as a modifying factor, independently of the disease-causing variants

CT Imaging Assessment of Response to Treatment in Chronic Pulmonary Aspergillosis.

Long-term antifungal therapy is usually the only treatment option for chronic pulmonary aspergillosis. However, response rates are difficult to compare because the reported clinical, mycologic, or radiologic criteria are not standardized. Objective parameters are therefore needed. To define the most relevant CT imaging variables in assessment of response to treatment, we investigated changes over time in CT imaging variables. Changes in CT imaging variables were assessed by systematic analysis of the CT scan findings of 36 patients at diagnosis and 6 months after initiation of treatment. The relevant radiologic variables were determined by selecting those showing significant changes over time. Two experienced thoracic radiologists, blinded for clinical and serologic response, independently performed CT scan analyses. Interreader agreement and concordance between radiologic and clinical response were evaluated. Of the 36 patients, seven experienced clinical deterioration while undergoing therapy. Significantly evolving radiologic variables included cavity and pleural wall thickening (P &lt; .05), which were associated with clinical improvement. There was a strong association between fungus ball disappearance and cavity/pleural wall thickening reduction and clinical improvement (P = .04). There was poor agreement between size changes of cavities or nodules, and clinical evolution (Cohen's κ, -0.13 to -0.24). Variations in cavity and pleural wall thickness may be the most relevant CT imaging variables for assessing response to treatment. Loss of fungus ball is strongly associated with clinical and radiologic improvement, but cavity size changes are unrelated to chronic pulmonary aspergillosis evolution. All these CT imaging variables may be applied in future clinical trials to assess treatment outcome

Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France

International audienceHereditary hemmorrhagic telangiectasia (HHT, or Osler-Rendu-Weber syndrome) is an autosomal dominant disease characterized by arteriovenous malformations, affecting 1 out of 10,000 individuals in France. The disease is caused by mutations of two genes: ENG and ALK1 (ACVRL1). We screened the coding sequence of ENG and ALK1 in 160 unrelated French index cases. A germline mutation was identified in 100 individuals (62.5%). A total of 36 mutations were found in ENG, including three nonsense mutations, 19 small insertions/deletions leading to a frameshift, two inframe deletions, seven missense mutations, and five intronic or splice-site mutations. Of the 36 mutations, 33 were novel mutations. A total of 64 mutations were found in ALK1, including six nonsense mutations, 28 small insertions/deletions leading to a frameshift, one inframe deletion, 27 missense mutations, and two intronic or splice-site mutations. Of the 64 mutations, 27 were novel mutations. Mutations were found in most parts of the coding sequence for both genes, except ALK1 exon 5 and ENG exons 12 to 14. Missense mutations in ALK1 were more frequent in exons 7, 8, and 10. ENG cDNA was sequenced for three intronic mutations: c.689+2T>C produced an abnormal transcript excluding exon 5, c.1103+3-1103+8del activated a cryptic splice site 22 bp upstream, and c. 1428G>A produced two abnormal transcripts, one including intron 11 and the other excluding exon 10. Although most of the mutations were private, some recurrent mutations in ALK1 were of particular interest. Mutation c.1112-1113dupG (p.Gly371fsX391) was found in 17 unrelated individuals sharing a common haplotype, strongly suggesting a founder effect related to the concentration of patients previously reported in a specific French region (Rhone-Alpes). Three missense mutations involved the same codon: c.1231C>T (p.Arg411Trp), c.1232G>C (p.Arg411Pro), and c.1232G>A (p.Arg411Gln) were found in seven, two, and one patients, respectively. Haplotype analysis was in favor of both a founder effect and a mutation hot-spot