Medicine (RMH) - Theses
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ItemHereditary Haemorrhagic Telangiectasia: Genotype, phenotype and clinical practice( 2019)Hereditary Haemorrhagic Telangiectasia (HHT) is caused by pathogenic mutations in one of several genes, most commonly ENG, ACVRL1 or SMAD4. Characterised by dysregulated angiogenesis in multiple organs, it typically presents as bleeding from nasal telangiectasia and gastrointestinal arteriovenous malformations (AVMs). Lung, brain and liver AVMs are also common. As the genes causing HHT are integral to many fundamental cellular pathways additional to angiogenesis, it is likely that occult phenotypic features exist, but are incompletely explored. The studies described in this thesis aimed to document, explore and extend the phenotype of HHT in the Royal Melbourne Hospital HHT patient cohort, utilising basic disease pathophysiology to hypothesise the presence of additional occult phenotypic features, and to explore novel options for therapy. As Vascular Endothelial Growth Factor (VEGF) is known to be mechanistically involved in the abnormal angiogenesis of HHT, monoclonal antibody against VEGF has been used to treat epistaxis. Adverse reactions to systemic use have stimulated interest in topical intranasal administration, although results of previous studies have been mixed. We hypothesised that efficacy may be masked by nasal crusting, preventing the drug from reaching its target receptors. In a pilot open-label study (Chapter 2), topical Bevacizumab, when administered after standardised washout, reduced epistaxis severity. Given access to best care, HHT patients have normal longevity, but Quality of Life (QoL) may be overestimated. Using standardised tools, QoL assessment (Chapter 3) indicates significant disease impact, particularly on pain and discomfort. The propensity to develop AVMs in internal organs in HHT reportedly varies between the two commonest causative genes, ENG and ACVRL1. Lung AVMs are reported more commonly in ENG mutations, and central nervous system AVMs in ACVRL1 mutations. Disturbed angiogenesis may extend to aortic abnormalities. Analysis of aortic dimensions in HHT patients (Chapter 4), across the three most common HHT genes, revealed a limited association between SMAD4 mutation and proximal aortic enlargement. All HHT mutations result in perturbed TGF-Beta physiology, and TGF-Beta is integral to multiple immune system functions. While major immune disturbance is unlikely, decreased natural killer (NK) cell function could compromise normal immune surveillance capacity without being overtly obvious. NK cell function in HHT is explored in Chapter 5. Chapter 6 explores potential renal involvement in HHT, with no phenotype found. As the physiological link between BMP9 and ALK1 could predict disturbed calcification in HHT, circulating calciprotein particles were assayed. Beyond the sequencing of individual genes, Chapter 7 describes utilisation of massively parallel sequencing to attempt to define genotype in patients with classic phenotype but negative routine four-gene testing. Undertaking clinical research in rare diseases requires an understanding of patients’ perspective. Time constraints limit researcher-patient dialogue in the clinic, especially when multiple organ systems demand attention. The “family day” of Chapter 8 was designed to facilitate trilateral communication between patients, researchers and clinicians, and to evaluate its effectiveness.