Clinical and molecular characterization of patients with hereditary hemorrhagic telangiectasia from two different regions of Brazil
Palavras-chave:
Mutations, Endoglin Gene, ACVRL1 Gene, Hemorrhagic diseasesResumo
Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia characterized hemorrhagic diseases described in consensus clinical diagnostic criteria (Curaçao). We describe the clinical and molecular characteristics of HHT patients from two different geographic regions of Brazil (São Paulo and Manaus). Demographic and clinical data were obtained from the electronic medical records and molecular analysis was performed by Sanger sequencing. We present here the first clinical characterization concomitantly with a molecular study of patients with THH in Brazil. These clinical characterizations may reveal differences in the molecular pathophysiology of HHT in Brazil - that our phenotypic database opens the way to be studied, or indicate limitations in the care of these patients, who need a multidisciplinary attention to prevent and treat the complications of this condition. Our results, combined with our previous data with patients presenting mutation rate to 93,75% (n=15/16) in Brazilians patients with a confirmed clinical diagnosis. Also emphasize the higher numbers of intronic mutations and three large deletions 5ÙTR regions and the predominance of ACVRL1 over ENG mutations.
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ASSIS AM, COSTA FF, ARRUDA VR, et al. Three novel mutations in the activin receptor-like kinase 1 (ALK-1) gene in hereditary hemorrhagic telangiectasia type 2 in Brazilian patients. J Hum Genet. 2007;52(3):237-243.
BERG J, PORTEOUS M, REINHARDT D, et al. Hereditary haemorrhagic telangiectasia: a questionnaire based study to delineate the different phenotypes caused by endoglin and ALK1 mutations. J Med Genet. 2003 Aug;40(8):585-90.
BERG JN, GALLIONE CJ, STENZEL TT, et al. The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2. Am J Hum Genet. 1997 Jul;61(1):60-7.
BERNABEU, CARMELO & BLANCO, FRANCISCO & CARMEN, . (2010). Involvement of the TGF-β superfamily signalling pathway in hereditary haemorrhagic telangiectasia. Journal of Applied Biomedicine. 8. 10.2478/v10136-009-0020-x.
BRUSGAARD K, KJELDSEN AD, POULSEN L, et al. Mutations in endoglin and in activin receptor-like kinase 1 among Danish patients with hereditary haemorrhagic telangiectasia. Clin Genet. 2004 Dec;66(6):556-61.
CAI J, PARDALI E, SÁNCHEZ-DUFFHUES G, TEN DIJKE P. BMP signaling in vascular diseases. FEBS Lett. 2012 Jul 4;586(14):1993-2002.
CHERIF H, KARLSSON T. Combination treatment with an erythropoiesis-stimulating agent and intravenous iron alleviates anaemia in patients with hereditary haemorrhagic telangiectasia. Ups J Med Sci. 2014 Nov;119(4):350-3
DONALDSON JW, MCKEEVER TM, HALL IP, et al. Complications and mortality in hereditary hemorrhagic telangiectasia: A population-based study. Neurology. 2015 May 5;84(18):1886-93.
DUARTE CW, MURRAY K, LUCAS FL, et al. Improved survival outcomes in cancer patients with hereditary hemorrhagic telangiectasia. Cancer Epidemiol Biomarkers Prev. 2014 Jan;23(1):117-125. doi: 10.1158/1055-9965.EPI-13-0665. Epub 2013 Nov 5. Erratum in: Cancer Epidemiol Biomarkers Prev. 2015 May;24(5):880.
FERNANDEZ-L A, SANZ-RODRIGUEZ F, ZARRABEITIA R, et al. Mutation study of Spanish patients with hereditary hemorrhagic telangiectasia and expression analysis of Endoglin and ALK1. Hum Mutat. 2006 Mar;27(3):295.
FLEAGLE JM, BOBBA RK, KARDINAL CG, FRETER CE. Iron deficiency anemia related to hereditary hemorrhagic telangiectasia: response to treatment with bevacizumab. Am J Med Sci. 2012 Mar;343(3):249-51.
GIORDANO P, LENATO GM, PIERUCCI P, et al. Effects of VEGF on phenotypic severity in children with hereditary hemorrhagic telangiectasia. J Pediatr Hematol Oncol. 2009 Aug;31(8):577-82.
GU Y, JIN P, ZHANG L, et al. Functional analysis of mutations in the kinase domain of the TGF-beta receptor ALK1 reveals different mechanisms for induction of hereditary hemorrhagic telangiectasia. Blood. 2006 Mar 1;107(5):1951-4.
HOSMAN AE, SHOVLIN CL. Cancer and hereditary haemorrhagic telangiectasia. J Cancer Res Clin Oncol. 2017 Feb;143(2):369-370.
LATINO GA, KIM H, NELSON J, et al. Brain Vascular Malformation Consortium HHT Investigator Group. Severity score for hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis. 2014 Dec 29;9:188.
LETTEBOER TG, ZEWALD RA, KAMPING EJ, et al. Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients. Hum Genet. 2005 Jan;116(1-2):8-16.
MCDONALD J, WOODERCHAK-DONAHUE W, et al. Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era. Front Genet. 2015 Jan 26;6:1.
OJEDA-FERNANDEZ L, BARRIOS L, RODRIGUEZ-BARBERO A, et al. Reduced plasma levels of Ang-2 and sEng as novel biomarkers in hereditary hemorrhagic telangiectasia (HHT). Clin Chim Acta. 2010 Apr 2;411(7-8):494-9.
PIERUCCI P, LENATO GM, SUPPRESSA P, et al. A long diagnostic delay in patients with Hereditary Haemorrhagic Telangiectasia: a questionnaire-based retrospective study. Orphanet J Rare Dis. 2012 Jun 7;7:33.
PLAUCHU H, DE CHADARÉVIAN JP, BIDEAU A, ROBERT JM. Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population. Am J Med Genet. 1989 Mar;32(3):291-7.
PORTEOUS ME, BURN J, PROCTOR SJ. Hereditary haemorrhagic telangiectasia: a clinical analysis. J Med Genet. 1992 Aug;29(8):527-30.
RAMAKRISHNAN Y, IQBAL IZ, PUVANENDRAN M, et al. A postal survey of hereditary hemorrhagic telangectasia in the northeast of England. Allergy Rhinol (Providence). 2015 Jan;6(1):20-7
RUIZ-LLORENTE L, GALLARDO-VARA E, ROSSI E, et al. Endoglin and alk1 as therapeutic targets for hereditary hemorrhagic telangiectasia. Expert Opin Ther Targets. 2017 Oct;21(10):933-947
SHOVLIN CL, GUTTMACHER AE, BUSCARINI E, et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet. 2000 Mar 6;91(1):66-7.
SILVA BM, HOSMAN AE, DEVLIN HL, SHOVLIN CL. Lifestyle and dietary influences on nosebleed severity in hereditary hemorrhagic telangiectasia. Laryngoscope. 2013 May;123(5):1092-9.
TØRRING PM, LARSEN MJ, KJELDSEN AD, et al. Global gene expression profiling of telangiectasial tissue from patients with hereditary hemorrhagic telangiectasia. Microvasc Res. 2015 May;99:118-26.
VIKKULA M, BOON LM, MULLIKEN JB. Molecular genetics of vascular malformations. Matrix Biol. 2001 Sep;20(5-6):327-35.
WESTERMANN CJ, ROSINA AF, DE VRIES V, DE COTEAU PA. The prevalence and manifestations of hereditary hemorrhagic telangiectasia in the Afro-Caribbean population of the Netherlands Antilles: a family screening. Am J Med Genet A. 2003 Feb 1;116A(4):324-8.
