Genotype–phenotype correlation in hereditary hemorrhagic telangiectasia: Mutations and manifestations*

Bayrak-Toydemir, Pınar; McDonald, Jamie; Markewitz, Boaz A.; Lewin, Susan O.; Miller, Franklin J.; Chou, Lan Szu; Gedge, Friederike; Tang, Wei; Coon, Hilary; Mao, Rong

doi:10.1002/ajmg.a.31101

Cited by 207 publications

(271 citation statements)

References 29 publications

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“…Pulmonary AVMs are more common in HHT1 than HHT2, 22-27 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. In one series, positive contrast echocardiography reflecting intrapulmonary shunting was found in 85% of HHT1 patients, and 35% of HHT2 patients 52 compared to 7% of a control normal population.…”

Section: 2b) Genotype Phenotype Correlationsmentioning

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%

“…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%

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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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Section: 2b) Genotype Phenotype Correlationsmentioning

confidence: 99%

Section: Overview Of Hhtmentioning

confidence: 99%

Section: 2a) Geneticsmentioning

confidence: 99%

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Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

2010

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“…Based on several studies, 9% to 16% of hereditary hemorrhagic telangiectasia patients had an AVM, 27% of whom had a history of ICH. [44][45][46][47] Homozygous loss of these genes leads to death in utero. 48 ENG and ALK1 are expressed on ECs and bind TGF-β, modulating EC proliferation, migration, adhesion, and apoptosis.…”

Section: Endoglin and Its Role In Inflammation And Vascular Remodelingmentioning

confidence: 99%

Biology of Cerebral Arteriovenous Malformations with a Focus on Inflammation

Mouchtouris

Jabbour

Starke

et al. 2014

J Cereb Blood Flow Metab

128

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Cerebral arteriovenous malformations (AVMs) entail a significant risk of intracerebral hemorrhage owing to the direct shunting of arterial blood into the venous vasculature without the dissipation of the arterial blood pressure. The mechanisms involved in the growth, progression and rupture of AVMs are not clearly understood, but a number of studies point to inflammation as a major contributor to their pathogenesis. The upregulation of proinflammatory cytokines induces the overexpression of cell adhesion molecules in AVM endothelial cells, resulting in enhanced recruitment of leukocytes. The increased leukocyte-derived release of metalloproteinase-9 is known to damage AVM walls and lead to rupture. Inflammation is also involved in altering the AVM angioarchitecture via the upregulation of angiogenic factors that affect endothelial cell proliferation, migration and apoptosis. The effects of inflammation on AVM pathogenesis are potentiated by certain single-nucleotide polymorphisms in the genes of proinflammatory cytokines, increasing their protein levels in the AVM tissue. Furthermore, studies on metalloproteinase-9 inhibitors and on the involvement of Notch signaling in AVMs provide promising data for a potential basis for pharmacological treatment of AVMs. Potential therapeutic targets and areas requiring further investigation are highlighted.

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“…[46] As a class, the inherited AVMs in HHT have some distinguishing morphological features, but are generally similar to the sporadic lesions and cannot be distinguished individually on the basis of their angioarchitecture [37,40]. Brain AVMs are approximately ten times more common in HHT1/ENG (~20%) than HHT2/ALK-1 (~2%) patients [6,36,50]. Compared to sporadic lesions, presence of an ENG or ALK-1 mutation results in approximately a 1,000 and 100 fold increased risk, respectively, of developing a brain AVM.…”

Section: Mendelian Diseasementioning

confidence: 99%

Genetic considerations relevant to intracranial hemorrhage and brain arteriovenous malformations

Kim

Marchuk

Pawlikowska

et al.

Acta Neurochirurgica Supplementum

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SUMMARYBrain arteriovenous malformations (AVM) cause intracranial hemorrhage (ICH), especially in young adults. Molecular characterization of lesional tissue provides evidence for involvement of both angiogenic and inflammatory pathways, but the pathogenesis remain obscure and medical therapy is lacking. Abnormal expression patterns have been observed for proteins related to angiogenesis (e.g., VEGF, Angiopoietin-2, MMP-9), and inflammation (e.g., IL-6 and MPO). Macrophage and neutrophil invasion has also been observed in the absence of prior ICH. Candidate gene association studies have identified a number of germline variants associated with clinical ICH course and AVM susceptibility. A single nucleotide polymorphism (SNP) in ALK-1 is associated with AVM susceptibility, and SNPs in IL-6, TNF-α and APOE are associated with AVM rupture. These observations suggest that even without a complete understanding of the determinants of AVM development, the recent discoveries of downstream derangements in vascular function and integrity may offer potential targets for therapy development. Further, biomarkers can now be established for assessing ICH risk. Finally, these data will generate hypotheses that can be tested mechanistically in model systems, including surrogate phenotypes, such as vascular dysplasia and/or models recapitulating the clinical syndrome of recurrent spontaneous ICH. Keywords angiogenesis; inflammation; vascular malformationsBrain arteriovenous malformations (AVM) represent a relatively infrequent but important source of neurological morbidity in relatively young adults [4]. Brain AVMs have a population prevalence of 10-18 per 100,000 adults [3,7], and a new detection rate of ~1.3 per 100,000 person-years [58]. The basic morphology is of a vascular mass, called the nidus, that directly shunts blood between the arterial and venous circulations without a true capillary bed. There is usually high flow through the feeding arteries, nidus and draining veins. The nidus is a

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Genotype–phenotype correlation in hereditary hemorrhagic telangiectasia: Mutations and manifestations*

Cited by 207 publications

References 29 publications

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

Biology of Cerebral Arteriovenous Malformations with a Focus on Inflammation

Genetic considerations relevant to intracranial hemorrhage and brain arteriovenous malformations

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