International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia.

BACKGROUND: HHT is an autosomal dominant disease with an estimated prevalence of at least 1/5000 which can frequently be complicated by the presence of clinically significant arteriovenous malformations in the brain, lung, gastrointestinal tract and liver. HHT is under-diagnosed and families may be unaware of the available screening and treatment, leading to unnecessary stroke and life-threatening hemorrhage in children and adults. OBJECTIVE: The goal of this international HHT guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT and the prevention of HHT-related complications and treatment of symptomatic disease. METHODS: The overall guidelines process was developed using the AGREE framework, using a systematic search strategy and literature retrieval with incorporation of expert evidence in a structured consensus process where published literature was lacking. The Guidelines Working Group included experts (clinical and genetic) from eleven countries, in all aspects of HHT, guidelines methodologists, health care workers, health care administrators, HHT clinic staff, medical trainees, patient advocacy representatives and patients with HHT. The Working Group determined clinically relevant questions during the pre-conference process. The literature search was conducted using the OVID MEDLINE database, from 1966 to October 2006. The Working Group subsequently convened at the Guidelines Conference to partake in a structured consensus process using the evidence tables generated from the systematic searches. RESULTS: The outcome of the conference was the generation of 33 recommendations for the diagnosis and management of HHT, with at least 80% agreement amongst the expert panel for 30 of the 33 recommendations.

Randomized, double-blind, placebo-controlled, crossover trial of oral doxycycline for epistaxis in hereditary hemorrhagic telangiectasia.

BACKGROUND: Vascular malformations in hereditary hemorrhagic telangiectasia (HHT) lead to chronic recurrent bleeding, hemorrhage, stroke, heart failure, and liver disease. There is great interest in identifying novel therapies for epistaxis in HHT given its associated morbidity and impact on quality of life. We aimed to measure the effectiveness of oral doxycycline for the treatment of epistaxis and explore mechanisms of action on angiogenic, inflammatory and pathway markers in HHT using a randomized controlled trial. METHODS: 13 HHT patients with epistaxis were recruited from the Toronto HHT Center at St. Michael's Hospital. Recruitment was stopped early due to COVID-19-related limitations. The study duration was 24 months. Patients were randomly assigned to the treatment-first or placebo-first study arm. We compared the change in weekly epistaxis duration and frequency, biomarkers, blood measurements, and intravenous iron infusion and blood transfusion requirements between treatment and placebo. RESULTS: There was no significant difference in the change in weekly epistaxis duration (p = 0.136) or frequency (p = 0.261) between treatment and placebo. There was no significant difference in the levels of MMP-9, VEGF, ANG-2, IL-6 or ENG with treatment. Hemoglobin levels were significantly higher (p = 0.0499) during treatment. Ferritin levels were not significantly different between treatment and placebo. There was no significant difference in RBC transfusions between treatment periods (p = 0.299). CONCLUSION: Overall, our study did not demonstrate effectiveness of doxycycline as a treatment for epistaxis in patients with HHT, though the study was underpowered. Secondary analyses provided new observations which may help guide future trials in HHT. Trial Registration ClinicalTrials.gov, NCT03397004. Registered 11 January 2018 - Prospectively registered, https://clinicaltrials.gov/ct2/show/NCT03397004.

Idiopathic pulmonary arteriovenous malformations: clinical and imaging characteristics.

Pulmonary arteriovenous malformations (PAVMs) can cause stroke, brain abscess or life-threatening haemorrhage. Most PAVMs are associated with hereditary haemorrhagic telangiectasia (HHT). The aim of the present study was to describe the clinical presentation and treatment outcomes of those with idiopathic PAVMs, which has not previously been described in the literature. Patients with idiopathic PAVMs were identified at our HHT centre. Retrospective review of charts and imaging were performed. 20 patients were identified with idiopathic PAVMs. The most common symptoms reported were dyspnoea and migraines (50 and 30% of patients, respectively). Previous complications of PAVMs included haemoptysis (20%), stroke (20%) and brain abscess (5%). A total of 28 focal PAVMs were identified. Most patients (80%) had a solitary PAVM. 13 out of 28 PAVMs (46%) were located in the lower lobes. Most were simple and fistulous rather than complex and plexiform. Transcatheter embolotherapy was performed in 17 patients and was successful in improving oxygenation in all cases. The clinical manifestations and complications of idiopathic PAVMs are similar to those associated with HHT. Idiopathic PAVMs are anatomically similar to HHT-related PAVMs except for a greater number of solitary PAVMs and a lack of lower lobe predominance. Transcatheter embolotherapy is a safe and effective method for treating idiopathic PAVMs.

Utility of modified Rankin Scale for brain vascular malformations in hereditary hemorrhagic telangiectasia.

BACKGROUND: Approximately 10% of hereditary hemorrhagic telangiectasia (HHT) patients harbour brain vascular malformations (VMs). Intracranial hemorrhage (ICH) from brain VMs can lead to death or morbidity, while treatment options for brain VMs also have associated morbidity. The modified Rankin Scale (mRS) may provide an approach to identifying HHT-brain VM patients with poor outcomes, and their predictors. We aimed to measure the relationship between mRS score and brain VM, brain VM number, as well as other aspects of HHT, at enrollment and during prospective follow-up. METHODS: 1637 HHT patients (342 with brain VMs) were recruited from 14 HHT centres of the Brain Vascular Malformation Consortium since 2010 and followed prospectively (mean = 3.4 years). We tested whether the presence of brain VM, other HHT organ involvement, and HHT mutation genotype were associated with worse mRS scores at baseline and during follow-up, using linear mixed models, adjusting for age, sex, and year of visit. RESULTS: Presence of brain VMs was not associated with worse mRS score at baseline and there was no significant worsening of mRS with prospective follow-up in these patients; 92% had baseline mRS of 0-2. HHT-related gastrointestinal (GI) bleeding was associated with worse mRS scores at baseline (0.37, 95% CI 0.26-0.47, p < 0.001), as were history of anemia (0.35, 95% CI 0.27-0.43, p < 0.001) and liver VMs (0.19, 95% CI 0.09-0.30, p < 0.001). Presence of pulmonary arteriovenous malformations (AVMs) was not associated with worse mRS scores at baseline. mRS score was not associated with either HHT genotype (Endoglin vs ACVRL1). Only GI bleeding was associated with a significantly worsening mRS during prospective follow-up (0.64, 95% CI 0.21-1.08, p = 0.004). CONCLUSION: Most HHT-brain VM patients had good functional capacity (mRS scores 0-2) at baseline that did not change significantly over 3.4 mean years of follow-up, suggesting that mRS may not be useful for predicting or measuring outcomes in these patients. However, HHT patients with GI bleeding, anemia history or liver VMs had worse mRS scores, suggesting significant impact of these manifestations on functional capacity. Our study demonstrates the insensitivity of the mRS as an outcomes measure in HHT brain VM patients and reinforces the continued need to develop outcomes measures, and their predictors, in this group.

Improved survival after liver transplantation in patients with hepatopulmonary syndrome.

Hepatopulmonary syndrome (HPS) is present in 10-32% of chronic liver disease patients, carries a poor prognosis and is treatable by liver transplantation (LT). Previous reports have shown high LT mortality in HPS and severe HPS (arterial oxygen (PaO(2)) < or =50 mmHg). We reviewed outcomes in HPS patients who received LT between 2002 and 2008 at two transplant centers supported by a dedicated HPS clinic. We assessed mortality, complications and gas exchange in 21 HPS patients (mean age 51 years, MELD score 14), including 11/21 (52%) with severe HPS and 5/21 (24%) with living donor LT (median follow-up 20.2 months after LT). Overall mortality was 1/21 (5%); mortality in severe HPS was 1/11 (9%). Peritransplant hypoxemic respiratory failure occurred in 5/21 (24%), biliary complications in 8/21 (38%) and bleeding or vascular complications in 6/21 (29%). Oxygenation improved in all 19 patients in whom PaO(2) or SaO(2) were recorded. PaO(2) increased from 52.2 +/- 13.2 to 90.3 +/- 11.5 mmHg (room air) (p < 0.0001) (12 patients); a higher baseline macroaggregated albumin shunt fraction predicted a lower rate of postoperative improvement (p = 0.045) (7 patients). Liver transplant survival in HPS and severe HPS was higher than previously demonstrated. Severity of HPS should not be the basis for transplant refusal.

The pulmonary vascular complications of hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT) is a rare autosomal dominant disorder, characterised by the presence of vascular malformations. The pulmonary vascular complications of HHT include pulmonary arteriovenous malformations, pulmonary hypertension associated with high-output heart failure and liver vascular malformations and, finally, pulmonary arterial hypertension secondary to HHT. In the present review, the authors describe the clinical presentation, diagnosis and management of all three pulmonary vascular presentations of HHT, as well as the underlying genetics and pathophysiology.

Screening for pulmonary and cerebral arteriovenous malformations in children with hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterised by vascular dysplasia complicated by visceral arteriovenous malformations (AVMs). To date, the diagnostic yield of screening procedures for pulmonary and cerebral AVMs in children with definite or potential HHT is not well defined. The aim of the present study was to prospectively evaluate the diagnostic yield of a screening protocol for pulmonary and cerebral AVMs in children with either a definite or potential HHT diagnosis. All children referred for evaluation for HHT between 1996 and 2008 were included in the present analysis. Screening tests for AVMs included chest computed tomography and brain magnetic resonance imaging. 61 children with a definite clinical and/or genetic diagnosis of HHT were asymptomatic for visceral AVMs at their first baseline assessment (mean+/-SD age 8.7+/-4.7 yrs; range 0-17.0 yrs). Of these, 15 (25%) had pulmonary and/or cerebral AVMs diagnosed on initial screening tests. Pulmonary AVMs predominated in paediatric HHT patients (14 out of 15 patients) and were found in eight children aged <10 yrs. 55 children had a potential HHT diagnosis as they fulfilled only one or two HHT clinical diagnostic criteria and did not have a confirmatory genetic diagnosis (age 10.9+/-4.8 yrs; range 0-17.9 yrs). None of these children had pulmonary or cerebral AVMs on initial screening tests. The present data suggest that children with a definite HHT diagnosis have a high frequency of pulmonary AVMs even when clinically asymptomatic. In contrast, no AVMs were observed in children not fulfilling HHT diagnostic criteria. Genetic testing appears to be useful in defining an at-risk group for pulmonary AVMs in childhood.

SMAD4 gene mutation increases the risk of aortic dilation in patients with hereditary haemorrhagic telangiectasia.

BACKGROUND: Mutations in the genes ENG, ACVRL1 and SMAD4 that are part of the transforming growth factor-beta signalling pathway cause hereditary haemorrhagic telangiectasia (HHT). Mutations in non-HHT genes within this same pathway have been found to associate with aortic dilation. Therefore, we investigated the presence of aortic dilation in a large cohort of HHT patients as compared to non-HHT controls. METHODS: Chest computed tomography of consecutive HHT patients (ENG, ACVRL1 and SMAD4 mutation carriers) and non-HHT controls were reviewed. Aortic root dilation was defined as a z-score>1.96. Ascending and descending aorta dimensions were corrected for age, gender and body surface area. RESULTS: In total 178 subjects (57.3% female, mean age 43.9±14.9years) were included (32 SMAD4, 47 ENG, 50 ACVRL1 mutation carriers and 49 non-HHT controls). Aortopathy was present in a total of 42 subjects (24% of total). Aortic root dilatation was found in 31% of SMAD4, 2% of ENG, 6% of ACVRL1 mutation carriers, and 4% in non-HHT controls (p<0.001). The aortic root diameter was 36.3±5.2mm in SMAD4 versus 32.7±3.9mm in the non-SMAD4 group (p=0.001). SMAD4 was an independent predictor for increased aortic root (ß-coefficient 3.5, p<0.001) and ascending aorta diameter (ß-coefficient 1.6, p=0.04). CONCLUSIONS: SMAD4 gene mutation in HHT patients is independently associated with a higher risk of aortic root and ascending aortic dilation as compared to other HHT patients and non-HHT controls.

Life expextancy of parents with Hereditary Haemorrhagic Telangiectasia.

BACKGROUND: Hereditary Haemorrhagic Telangiectasia (HHT) is an autosomal dominant disease associated with epistaxis, arteriovenous malformations and telangiectasias. Disease complications may result in premature death. METHOD: We investigated life-expectancies of parents of HHT patients compared with their non-HHT partners using self- or telephone-administered questionnaires sent to their children. Patients were extracted from the databases of 2 participating HHT Centres: the Toronto HHT Database (Toronto, Canada) and the St. Antonius Hospital HHT Database (Nieuwegein, The Netherlands). RESULTS: Two hundred twenty five/407 (55%) of respondents were included creating HHT- (n = 225) and control groups (n = 225) of equal size. Two hundred thirteen/225 (95%) of the HHT group had not been screened for organ involvement of the disease prior to death. The life expectancy in parents with HHT was slightly lower compared to parents without (median age at death 73.3 years in patients versus 76.6 years in controls, p0.018). Parents with ACVRL 1 mutations had normal life expectancies, whereas parents with Endoglin mutations died 7.1 years earlier than controls (p = 0.024). Women with Endoglin mutations lived a median of 9.3 years shorter than those without (p = 0.04). Seven/123 (5%) of deaths were HHT related with a median age at death of 61.5 years (IQ range 54.4-67.7 years). CONCLUSION: Our study showed that the life expectancy of largely unscreened HHT patients was lower than people without HHT. Female patients with Endoglin mutations were most strikingly at risk of premature death from complications. These results emphasize the importance of referring patients with HHT for screening of organ involvement and timely intervention to prevent complications.

Visceral manifestations in hereditary haemorrhagic telangiectasia type 2.

Hereditary haemorrhagic telangiectasia (HHT) is a genetic vascular disorder characterised by epistaxis, telangiectases, and visceral manifestations. The two known disease types, HHT1 and HHT2, are caused by mutations in the endoglin (ENG) and ALK-1 genes, respectively. A higher frequency of pulmonary arteriovenous malformations (AVMs) has been reported for HHT1 while HHT2 is thought to be associated with a lower penetrance and milder disease manifestations. In this study, we present 10 families with an ALK-1 genotype. Visceral manifestations were detected in 24 (26%) of the 93 HHT2 patients from nine of the families and included gastrointestinal bleeding (14%), intrahepatic shunts (6%), and AVMs in the lung (4%) and brain (3%). Gastrointestinal bleeding, the most frequent visceral manifestation, was reported in six of the 10 families, mostly in patients over the age of 50. These patients also had frequent epistaxis and suffered from anaemia, often requiring blood transfusions. The identification of ALK-1 mutations in subjects with a suspected diagnosis and without clinical signs of HHT argue in favour of a molecular diagnosis. We also analysed the data published on 44 families with HHT2 and conclude that visceral manifestations occur in 26 of these families and affect 30% of HHT2 patients. This is considered an underestimate given incomplete and variable screening for lung, brain, and/or liver involvement in different clinical centres. These findings, however, stress the need for an early diagnosis of HHT that can be useful for the early control of associated visceral involvement.

Endoglin-deficient mice, a unique model to study hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is a genetic vascular disorder characterized by dilated vessels and arteriovenous malformations. Phenotypic heterogeneity, such as age of onset, severity of disease and organ involvement, is explained in part by two genes being mutated, endoglin (HHT1) and ALK-1 (HHT2). Haploinsufficiency is the mechanism responsible for HHT. This implies that position and type of mutations cannot explain heterogeneity, because mutant proteins are not expressed at the cell surface and consequently cannot interfere with normal function. Based on this model, we generated mice expressing only one allele of endoglin, but in two different inbred strains, 129/Ola and C57BL/6. Phenotypic heterogeneity was also observed among the HHT mice and was very dependent on the genetic background. Our data strongly suggest that additional genes, contributed by the 129/Ola strain, are responsible for the vascular anomalies associated with HHT. The murine model is faithful to the human disease and should allow us to identify the modifier genes of HHT as well as to test potential therapeutic interventions.

Neurovascular manifestations in hereditary hemorrhagic telangiectasia: imaging features and genotype-phenotype correlations.

BACKGROUND AND PURPOSE: Hereditary hemorrhagic telangiectasia is an autosomal dominant disease that presents in 10%-20% of patients with various brain vascular malformations. We aimed to report the radiologic features (phenotype) and the genotype-phenotype correlations of brain vascular malformations in hereditary hemorrhagic telangiectasia. MATERIALS AND METHODS: Demographic, clinical, genotypic, and imaging information of 75 patients with hereditary hemorrhagic telangiectasia with brain arteriovenous malformations enrolled in the Brain Vascular Malformation Consortium from 2010 to 2012 were reviewed. RESULTS: Nonshunting, small, superficially located conglomerates of enhancing vessels without enlarged feeding arteries or draining veins called "capillary vascular malformations" were the most commonly observed lesion (46 of 75 patients; 61%), followed by shunting "nidus-type" brain AVMs that were typically located superficially with a low Spetzler-Martin Grade and a small size (32 of 75 patients; 43%). Direct high-flow fistulous arteriovenous shunts were present in 9 patients (12%). Other types of vascular malformations (dural AVF and developmental venous anomalies) were present in 1 patient each. Multiplicity of vascular malformations was seen in 33 cases (44%). No statistically significant correlation was observed between hereditary hemorrhagic telangiectasia gene mutation and lesion type or lesion multiplicity. CONCLUSIONS: Depending on their imaging features, brain vascular malformations in hereditary hemorrhagic telangiectasia can be subdivided into brain AVF, nidus-type AVM, and capillary vascular malformations, with the latter being the most common phenotype in hereditary hemorrhagic telangiectasia. No genotype-phenotype correlation was observed among patients with this condition.

Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome).

Hereditary Hemorrhagic Telangiectasia (HHT) is easily recognized in individuals displaying the classical triad of epistaxis, telangiectasia, and a suitable family history, but the disease is more difficult to diagnosis in many patients. Serious consequences may result if visceral arteriovenous malformations, particularly in the pulmonary circulation, are unrecognized and left untreated. In spite of the identification of two of the disease-causing genes (endoglin and ALK-1), only a clinical diagnosis of HHT can be provided for the majority of individuals. On behalf of the Scientific Advisory Board of the HHT Foundation International, Inc., we present consensus clinical diagnostic criteria. The four criteria (epistaxes, telangiectasia, visceral lesions and an appropriate family history) are carefully delineated. The HHT diagnosis is definite if three criteria are present. A diagnosis of HHT cannot be established in patients with only two criteria, but should be recorded as possible or suspected to maintain a high index of clinical suspicion. If fewer than two criteria are present, HHT is unlikely, although children of affected individuals should be considered at risk in view of age-related penetration in this disorder. These criteria may be refined as molecular diagnostic tests become available in the next few years.

Diffuse pulmonary arteriovenous malformations: characteristics and prognosis.

OBJECTIVE: To study the clinical characteristics and prognosis of patients with diffuse pulmonary arteriovenous malformations (AVMs). DESIGN: Retrospective chart review of all patients (n = 16) with diffuse pulmonary AVMs seen at Yale New Haven Hospital, Johns Hopkins Hospital, and St. Michael's Hospital. Up-to-date follow-up information was obtained in all living patients. RESULTS: All patients were severely hypoxic. Neurologic complications (stroke or brain abscess) had occurred in 70% of patients by the time of diagnosis. During the follow-up period (mean, 6 years), three patients died and two others developed new neurologic complications. One of the deaths occurred perioperatively during lung transplantation. All patients underwent transcatheter embolotherapy of any large pulmonary AVMs. A selected group underwent pulmonary flow redistribution, a novel technique. Oxygenation did not improve significantly with embolotherapy of the larger AVMs, but there was a small significant improvement in those patients who underwent pulmonary flow redistribution. The majority (85%) of the living patients are currently working or studying full-time. CONCLUSIONS: Patients with diffuse pulmonary AVMs are at increased risk of neurologic complications. Transcatheter embolotherapy does not significantly improve the profound hypoxia, but it may reduce the risk of neurologic complications. Antibiotic prophylaxis is recommended for bacteremic procedures to prevent brain abscess. These patients can live for many years and lead productive lives. We do not recommend lung transplantation because survival with disease is difficult to predict and we have observed a perioperative transplant death.

Transcatheter embolotherapy of maternal pulmonary arteriovenous malformations during pregnancy.

STUDY OBJECTIVES: To determine if transcatheter embolotherapy is safe and effective for the treatment of pulmonary arteriovenous malformations during pregnancy. DESIGN: Prospective study. SETTING: Specialized hereditary hemorrhagic telangiectasia centers at Yale University School of Medicine and St. Michael's Hospital, University of Toronto. PATIENTS: Seven pregnant women (age range, 24 to 34 years; gestational age range, 16 to 36 weeks) undergoing transcatheter embolotherapy. INTERVENTIONS: Transcatheter embolotherapy in all patients. MEASUREMENTS AND RESULTS: Thirteen pulmonary arteriovenous malformations in seven patients were embolized with detachable silicone balloons and/or stainless steel coils without incident. The estimated fetal radiation dose ranged from < 50 to 220 mrad. No complications of pulmonary arteriovenous malformations occurred in any of the patients after transcatheter embolotherapy. The mothers went on to deliver healthy babies in all cases. CONCLUSIONS: Transcatheter embolotherapy of maternal pulmonary arteriovenous malformations performed by an experienced radiologist appears to be safe and effective after 16 weeks of gestational age.

Angiographic and clinical characteristics of patients with cerebral arteriovenous malformations associated with hereditary hemorrhagic telangiectasia.

BACKGROUND AND PURPOSE: Cerebral arteriovenous malformations (AVMs) are occasionally associated with hereditary hemorrhagic telangiectasia (HHT), which is characterized by the presence of multiple mucocutaneous telangiectasia, epistaxis, and familial inheritance. We analyzed the angiographic and clinical characteristics of patients with cerebral AVMs related to HHT. METHODS: Among 638 patients with cerebral AVMs, we identified 14 patients with HHT. The AVMs were classified as those with nidi of 1 cm or less (micro AVMs), those with nidi between 1 and 3 cm (small AVMs), and those of the fistulous type (arteriovenous fistulas [AVFs]). RESULTS: A total of 28 AVMs were found; seven of 14 patients had multiple AVMs. The 28 AVMs were categorized as 12 micro AVMs, eight small AVMs, and eight AVFs. All except one micro AVM were asymptomatic, whereas all small AVMs were symptomatic. Three of eight AVFs were asymptomatic. All 28 AVMs were located on the cortex. All micro AVMs and AVFs had single feeders and single draining veins, whereas the small AVMs had multiple feeders in all lesions and single draining veins in six of eight lesions. CONCLUSION: Multiple, cortical, micro AVMs or AVFs harboring single feeding arteries and single draining veins should raise clinical suspicion of HHT-related AVMs.

Prognostic relevance of dynamic hyperinflation during cardiopulmonary exercise testing in adult patients with cystic fibrosis.

BACKGROUND: Dynamic hyperinflation during cardiopulmonary exercise testing (CPET) in cystic fibrosis (CF) has not been well characterized, and little is known regarding its prevalence, risk factors and clinical associations. METHODS: CPET data from 109 adult patients with mild-to-moderate CF was used, in this retrospective study, to characterize and determine the prevalence of dynamic hyperinflation, and evaluate its relationship with lung function and exercise tolerance, clinical symptoms, and prognosis over a two-year period. RESULTS: 58% of patients responded to CPET with dynamic hyperinflation. These patients had significantly lower lung function (FEV1 66±19 versus 79±18%pred., p<0.01) and exercise tolerance (peak oxygen uptake 28.7±8.1 versus 32.9±6.1 mL·kg(-1)·min(-1), p=0.02), and experienced greater shortness of breath at peak exercise (7±3 versus 5±2 Modified Borg scale, p=0.04) compared to patients who responded without dynamic hyperinflation. Significant relationships between FEV1, FVC, FEV1/FVC, FEF(25-75) and dynamic hyperinflation were shown (p<0.01; p=0.02; p<0.01; p<0.01, respectively). Dynamic hyperinflation was also significantly correlated with oxygen uptake, tidal volume, work-rate and shortness of breath at peak exercise (p=0.03; p<0.01; p<0.01; p=0.04, respectively). Responding to CPET with or without dynamic hyperinflation did not significantly predict FEV1 at 2 years beyond the FEV1 at baseline (p=0.06), or increase the likelihood of experiencing a pulmonary exacerbation over a two-year period (p=0.24). CONCLUSION: The prevalence of dynamic hyperinflation during CPET in adult patients with mild-to-moderate CF is high, and is associated with reduced lung function and exercise tolerance, and increased exertional dyspnea. However, identifying dynamic hyperinflation during CPET had limited prognostic value for lung function and pulmonary exacerbation.

Spinal cord arteriovenous malformations in two patients with hereditary hemorrhagic telangiectasia.

We report two cases, in first cousins, of spinal arteriovenous malformations (AVMs) of the perimedullary fistula type and hereditary hemorrhagic telangiectasia (HHT). Spinal AVMs are a rare clinical presentation of HHT, but can be the first manifestation in a child with this disorder. The importance of considering a coexisting disorder of vascular dysplasia, such as HHT, when a child presents with a spinal AVM is discussed.

Potential role of modifier genes influencing transforming growth factor-beta1 levels in the development of vascular defects in endoglin heterozygous mice with hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder because of mutations in the genes coding for endoglin (HHT1) or ALK-1 (HHT2). The disease is associated with haploinsufficiency and a murine model was obtained by engineering mice that express a single Endoglin allele. Of a total of 171 mice that were observed for 1 year, 50 developed clinical signs of HHT. Disease prevalence was high in 129/Ola strain (72%), intermediate in the intercrosses (36%), and low in C57BL/6 backcrosses (7%). Most mice first presented with an ear telangiectasia and/or recurrent external hemorrhage. One-third of mice with HHT showed severe vascular abnormalities such as dilated vessels, hemorrhages, liver and lung congestion, and/or brain and heart ischemia. Disease sequelae included stroke, hydrocephalus, fatal hemorrhage, and congestive heart failure. Thus the murine model reproduces the multiorgan manifestations of the human disease. Levels of circulating latent transforming growth factor (TGF)-beta1 were significantly lower in the 129/Ola than in the C57BL/6 strain. Intercrosses and 129/Ola mice expressing reduced endoglin also showed lower plasma TGF-beta1 levels than control. These data suggest that modifier genes involved in the regulation of TGF-beta1 expression act in combination with a single functional copy of endoglin in the development of HHT.