Rare diseases bullet 4: Hereditary haemorrhagic telangiectasia and pulmonary arteriovenous malformations: issues in clinical management and review of pathogenic mechanisms

Abstract

Hereditary haemorrhagic telangiectasia (HHT, Rendu-Osler-Weber syndrome) exemplifies an important group of diseases which have catalysed advances in the understanding of fundamental pathophysiological mechanisms. In this paper areas of clinical management of HHT are discussed and the molecular pathogenesis is reviewed. The first section is aimed at all clinicians and concentrates on the recognition of a disorder in which silent cerebral and pulmonary involvement may be life threatening if left untreated. Recent data concerning the diagnostic and treatment modalities for pulmonary arteriovenous malformations (PAVMs) are also reviewed, and the growing concern that many patients with HHT may have small or residual PAVMs is highlighted. The paucity of good longitudinal data on these patients and others with different forms of HHT highlights the need for further clinical studies. In the second section the results of molecular research which suggests a role for receptors and ligands of the transforming growth factor (TGF)-β superfamily in the pathogenesis of this vascular disease are discussed. The means by which such information may relate to the clinical heterogeneity observed in HHT are specifically addressed, and more fundamental questions such as how reduced cell surface expression of endoglin predisposes a patient to develop PAVMs are also discussed. The classical patient with the vascular disorder hereditary haemorrhagic telangiectasia (HHT) has nose bleeds, dilated blood vessels over the lips and finger tips, and gastrointestinal bleeding in later life. However, this clinical scenario represents only one of the presentation patterns of HHT.1 2 It is now recognised that, in addition to microscopic mucocutaneous telangiectases derived from post capillary venules (fig 1A),3 HHT leads to the development of larger abnormal vascular structures at other sites. Arteriovenous malformations in the pulmonary, cerebral, and hepatic circulations account for some of the most devastating clinical complications of the disease. Figure 1 Hereditary haemorrhagic telangiectasia …