Caracterização clínica e molecular de pacientes com Telangiectasia Hemorrágica Hereditária da Região de Campinas (SP) e Manaus (AM)

Abstract

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disease characterized by the presence of diffuse vascular malformations, affecting the dermis, mucous membranes and solid organs. The estimated prevalence of HHT worldwide is 1: 10,000 individuals, it is possible that these data represent an underestimation of reality. As for Brazil, there is no data on the actual estimated prevalence of HHT. The diagnosis of THH is essentially clinical and established according to the "Criteria of Curaçao". Currently, about 80% of the cases have mutations in two genes encoding endoglin (ENG) and the Activase Receptor Kinase-1 (ACVRL1). Our objective was to characterize the clinical and molecular aspects of a population of HHT individuals from two different Brazilian regions. Thus, demographic, clinical and laboratory data were collected through medical records and patient interviews. The DNA was extracted from leukocytes. Automated sequencer was used for sequencing the ENG and ACVRL1 gene exons. A total of 40 patients were included in the study, seven (07) from Manaus (age ± SD = 67.10±25.24) and 33 from Campinas (Age ± SD = 51.25±22.25). Respectively, epistaxis and mucosal telangiectasia were observed at the most frequent clinics, with 85.7% / 57.1% in patients Manaus and 75.7% / 87.8% in Campinas. Comorbidities such as Diabetes, hypertension and heart disease were more frequent in Campinas (45.4%) than Manaus (28.5%). Gene sequencing was performed in just 16 patients, being seven (07) from Manaus and nine (09) from Campinas. In ENG we identified 20 different variants, 7 in exons (3 unpublished) and 13 in introns (13 unpublished). In ACVRL-1 we identified 26 different variants, 16 in exons (6 unpublished) and 10 in introns (9 unpublished). Just one patient from São Paulo didn’t presented mutations in the genes studied. Fifteen patients presenting mutation rate to 93,75% (n=15/16) and the higher numbers of intronic mutations and three large deletions 5ÙTR regions and the predominance of ACVRL1 over ENG mutations. We believe that an identical and unique mutation of these genes in different countries is unlikely. Different and random variations between series can not be excluded, since this has already been demonstrated in countries like France, Holland and England. In our study, we found that the ENG and ACVRL-1 genes showed mutations associated with a more serious phenotype, including early onset of epistaxis and increased occurrence of pulmonary arteriovenous malformations. Our results may open the way to be studied or may indicate limitations in the care of these patients, who need a multidisciplinary attention to prevent and treat complications of this condition.