Clinical symptoms according to genotype amongst patients with hereditary haemorrhagic telangiectasia

Kjeldsen, Anette Drøhse; Möller, Thomas; Brusgaard, Klaus; Vase, P.; Andersen, Poul Erik

doi:10.1111/j.1365-2796.2005.01555.x

Cited by 96 publications

(93 citation statements)

References 22 publications

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“…5,23,24 Several recent studies, published almost simultaneously, confirmed the higher prevalence of PAVMs and CAVMs in HHT1 and suggested a major prevalence of HAVMs in HHT2. [25][26][27][28][29] In these studies, the frequency of clinical symptomatic manifestations was not distinguishable from the frequency of AVMs found during systematic screening in mutation carriers. Up to now, phenotype-genotype correlation studies included a relatively small number of patients, except for the study of Letteboer et al 27 However, in this latter case DNA analysis was not performed on all members of the families that were included in the study.…”

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confidence: 80%

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Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: Data from the French-Italian HHT network

Lesca

Olivieri

Burnichon³

et al. 2007

Genetics in Medicine

201

187

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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.

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confidence: 80%

“…The difference was highly significant, even in studies including a relatively small number of patients. [25][26][27]29 The higher prevalence of PAVMs in HHT1 was already obvious in HHT pedigrees at the time of the identification of ENG. 22 In addition to their earlier age of onset, PAVMs have more severe consequences in HHT1 patients.…”

Section: Discussionmentioning

confidence: 99%

Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: Data from the French-Italian HHT network

Lesca

Olivieri

Burnichon³

et al. 2007

Genetics in Medicine

201

187

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“…Pulmonary AVMs are more common in HHT1 than HHT2, [22][23][24][25][26][27] though in the relatively small number of SMAD4 patients described, the prevalence of PAVMs may be higher still. 127 HHT1 patients are also more commonly affected by cerebral AVMs, [23][24][25][26] and by microscopic intrapulmonary shunting.…”

Section: 2b) Genotype Phenotype Correlationsmentioning

confidence: 97%

“…122 Individual series describe ENG or ACVRL1 predominance. [22][23][24][25][26][27] It is not known whether these reflect genuine geographical variation, or the clinical referral practice of the relevant HHT centres, since there are differences in patterns of HHT between families with HHT1, HHT2, and JPHT (see below). Blood Reviews _ HHT 2010_ Shovlin 10 …”

Section: 2a) Geneticsmentioning

confidence: 99%

“…Many hundreds of different mutations have been described in HHT families, with no common mutation identified ( 21 , summarised in 3 ). The mutated gene has some Blood Reviews _ HHT 2010_ Shovlin 4 influence on the resultant HHT phenotype, [22][23][24][25][26][27] although more profound variation in disease expression is seen between members of the same family.…”

Section: Overview Of Hhtmentioning

confidence: 99%

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Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

2010

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Hereditary haemorrhagic telangiectasia, inherited as an autosomal dominant trait, affects approximately 1 in 5,000 people. The abnormal vascular structures in HHT result from mutations in genes (most commonly endoglin or ACVRL1) whose protein products influence TGF-ß superfamily signalling in vascular endothelial cells. The cellular mechanisms underlying the generation of HHT telangiectasia and arteriovenous malformations are being unravelled, with recent data focussing on a defective response to angiogenic stimuli in particular settings. For affected individuals, there is often substantial morbidity due to sustained and repeated haemorrhages from telangiectasia in the nose and gut. Particular haematological clinical challenges include the management of severe iron deficiency anaemia; handling the intricate balance of antiplatelet or anticoagulants for HHT patients in whom there are often compelling clinical reasons to use such agents; and evaluation of apparently attractive experimental therapies promoted in high profile publications when guidelines and reviews are quickly superseded. There is also a need for sound screening programmes for silent arteriovenous malformations. These occur commonly in the pulmonary, cerebral, and hepatic circulations, may haemorrhage, but predominantly result in more complex pathophysiology due to consequences of defective endothelium, or shunts that bypass specific capillary beds. This review will focus on the new evidence and concepts in this complex and fascinating condition, placing these in context for both clinicians and scientists, with a particular emphasis on haematological settings. Blood Reviews _ HHT 2010_ Shovlin 3 Overview of HHTHHT, also known as Osler Weber Rendu syndrome [1][2][3] , is one of the most common disorders to be inherited as an autosomal dominant trait. Careful epidemiological studies reveal that it affects approximately 1 in 5,000 individuals, 4,5 with regional differences, 6 and isolated communities displaying higher prevalences due to founder effects. 7 8 HHT was first described as a familial disease characterised by severe recurrent nasal and gastrointestinal bleeding with associated anaemia, and visible dilated blood vessels (telangiectasia) on the lips and finger tips. The majority of HHT patients are also affected by larger arteriovenous malformations (AVMs) in the pulmonary, hepatic, cerebral, pancreatic, spinal and other circulations. 1,2,9 These features, presented in more detail within Table 1, are used as criteria to diagnose HHT. 2 The spectrum of disease within the HHT umbrella has extended beyond the telangiectatic/AVM HHT pathology delineated by the Curaçao criteria. 2 More recently recognised features include pulmonary arterial hypertension 10 ; juvenile polyposis 11 ; pulmonary hypertension in the context of high output cardiac failure secondary to hepatic AVMs, when PH may be reversible after hepatic AVM treatment [12][13][14][15][16] ; a prothrombotic state associated with elevated plasma levels of factor VIII 17 , and poten...

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Oral Manifestation of Gastrointestinal Diseases

Ramappa

Mahida

2015

Yamada' S Textbook of Gastroenterology

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Clinical symptoms according to genotype amongst patients with hereditary haemorrhagic telangiectasia

Cited by 96 publications

References 22 publications

Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: Data from the French-Italian HHT network

Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: Data from the French-Italian HHT network

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

Oral Manifestation of Gastrointestinal Diseases

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