Purpose: Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder characterized by arteriovenous malformations (AVM), mostly cutaneous and mucous (telangiectases), but also involving the lungs (PAVM), liver (HAVM) and brain (CAVM). We studied the relationship between the phenotype and genotype in patients with a proven mutation in either ENG (HHT1) or ACVRL1 (HHT2). Methods: Clinical features and their age of onset were compared between HHT1 and HHT2. The type of mutation was also analyzed. Clinical manifestations were distinguished from lesions found by screening. Results: Ninety-three HHT1 patients and 250 HHT2 patients were included. Epistaxis occurred later in HHT2, with incomplete penetrance (P Ͻ 0.0001). Symptomatic PAVMs were more frequent in HHT1 (34.4 vs. 5.2%, P Ͻ 0.001), as were cerebral abscesses (7.5 vs. 0.8%, P ϭ 0.002).Gastrointestinal bleeding occurred more frequently in HHT2 (16.4 vs. 6.5%, P ϭ 0.017). Symptomatic hepatic involvement was only seen in HHT2 patients. PAVMs were more frequently detected in asymptomatic HHT1 patients (54 vs. 12.8%, P Ͻ 0.0001). PAVMs and HAVMs were often family clustered in HHT1 and HHT2, respectively. Truncating mutations were associated with a higher frequency of epistaxis and telangiectasis, in HHT2. Conclusion: This study shows major differences between HHT1 and HHT2 phenotypes, which should be taken into account for future clinical studies. Genet Med 2007:9(1):14-22.

BackgroundHereditary hemorrhagic telangiectasia is a genetic disease characterized by teleangiectasias involving virtually every organ. There are limited data in the literature regarding the natural history of liver vascular malformations in hemorrhagic telangiectasia and their associated morbidity and mortality.AimThis prospective cohort study sought to assess the outcome of liver involvement in hereditary hemorrhagic telangiectasia patients.MethodsWe analyzed 16 years of surveillance data from a tertiary hereditary hemorrhagic telangiectasia referral center in Italy. We considered for inclusion in this study 502 consecutive Italian patients at risk of hereditary hemorrhagic telangiectasia who presented at the hereditary hemorrhagic telangiectasia referral center and underwent a multidisciplinary screening protocol for the diagnosis of hereditary hemorrhagic telangiectasia. Of the 502 individuals assessed in the center, 154 had hepatic vascular malformations and were the subject of the study; 198 patients with hereditary hemorrhagic telangiectasia and without hepatic vascular malformations were the controls. Additionally, we report the response to treatment of patients with complicated hepatic vascular malformations.ResultsThe 154 patients were included and followed for a median period of 44 months (range 12–181); of these, eight (5.2%) died from VM-related complications and 39 (25.3%) experienced complications. The average incidence rates of death and complications were 1.1 and 3.6 per 100 person-years, respectively. The median overall survival and event-free survival after diagnosis were 175 and 90 months, respectively. The rate of complete response to therapy was 63%.ConclusionsThis study shows that substantial morbidity and mortality are associated with liver vascular malformations in hereditary hemorrhagic telangiectasia patients.

Paranasal sinus fungus ball is an extramucosal mycosis, usually occurring in immunocompetent people as a monolateral lesion. To review the literature data and to report the Policlinico S. Matteo, University of Pavia experience, 81 patients presenting paranasal fungus ball have been treated (January 1994 to May 2005). Twenty-seven men and 54 women (19-91 years old; mean 49.4 years) were considered. Seventy-three patients had a single sinus affected, but eight presented multiple localisations. Maxillary was the most involved sinus followed by sphenoidal and ethmoidal. Moulds have been isolated in 28/81 cases. Histology showed fungal colonisation but not invasion in all cases. Tomography showed bone erosion in 33.3% of patients. All have been treated only by functional endoscopic sinus surgery. Seventy-seven of 81 patients have been cured. Four of 81 patients needed another surgical treatment. Follow up was between 6 and 132 months (average: 63 months). Fungus ball is a sinusal pathology caused by mycetes like Aspergillus spp. Histology confirms the fungal aethiology excluding tissue invasion. Mycological culture consented to identify the pathogenic mould in 34.5% of cases. Actually functional endoscopic sinus surgery is the gold standard for treatment of this pathology, and antifungal therapy is unnecessary.

On the basis of our proposed grading, hepatic VMs can be easily classified in subjects with HHT by Doppler US. Depending on the degree of hepatic vascular derangement, appropriate programs for follow up and/or therapy can be designed.