Hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease is an autosomal dominant disorder of localized angiodysplasia. Recent epidemiologic surveys indicate that the disorder is much more frequent than originally thought, possibly due to recent increased awareness of and interest in this disorder. Minimal estimates of the prevalence are 1 in 2,351 individuals in the French department of Ain,[1] approximately 1 in 3,500 on the Danish island of Funen,[2] at least 1 in 16,500 in Vermont,[3] and at least 1 in 39,000 in northern England.[4] Some of these, in turn, may be low estimates, as the disorder is often improperly diagnosed or missed altogether, until a life-threatening episode occurs.[3] Nevertheless, with proper physical examination and recent advances in screening for internal vascular lesions, proper diagnosis can be made in most cases. Penetrance is age-dependent and is nearly complete by age 40 to 45 years.[4,5] HHT occurs with a wide geographic distribution and has been described in all racial and many ethnic groups.
Clinical Features
HHT is characterized by vascular lesions and bleeding in a variety of organs, and diagnosis can often be made by the appearance of telangiectases, recurrent epistaxis, and a family history of the disorder.[6] However, the various organs and tissues that may contain vascular lesions give the disorder a wide range of clinical features, of which the following are characteristic. Telangiectases are red to violet lesions that appear on digits; the facial, nasal, and buccal mucosa; and the GI tract. Epistaxis is present in up to 90% of the individuals[7] and GI tract bleeding is seen in 20 to 40% of patients.[2] Hemorrhage from either site often progresses with age and can result in chronic anemia. Pulmonary arteriovenous malformations (PAVMs), occurring approximately 20% of HHT patients,[8] are often asymptomatic until the third or fourth decade of life and often only are identified when serious complications result. Much of the estimated 10% mortality of HHT is associated with the two serious neurologic sequelae of undetected PAVMs: strokes and brain abscesses.[9] Pregnancy carries a risk for hemorrhage or lesion development in women with PAVMs.[10] Neurologic manifestations from CNS angiodysplasia can also be seen in patients with HHT. Approximately 10% of patients have cerebral arteriovenous malformations (AVMs) and 7% have cerebral aneurysms, which can result in cerebral hemorrhage.[11] Another common neurologic manifestation is migraine headache, appearing in up to 50% of affected individuals. These have been postulated to be the result of undiagnosed cerebral AVMs.[12] Liver involvement due to the presence of multiple AVMs or atypical cirrhosis is a rare but important manifestation of HHT.[13,14] High cardiac output caused by left-to-right shunting within the liver can lead to heart failure.[14]
The diffuse constellation of symptoms has been extensively studied and incidence rates have been calculated in a number of retrospective and prospective studies.[4,5,15,16] Great variability of expression is seen with a wide disparity of clinical features even among members of the same family, indicating that factors other than the inherited germline mutation determine the individual phenotype. However, until recently, it was unclear whether all families present the entire spectrum of clinical features. Any differences might be attributable to either allelic or non-allelic heterogeneity.
Pathophysiology
Ultrastructural analyses of the vascular dysplasia seen in affected individuals have failed to demonstrate a unique pathologic abnormality that might suggest the nature of the primary biochemical defect. Studies indicate that the dilated channels of telangiectases are lined by a single layer of endothelium attached to a continuous basement membrane.[17,18] The earliest event in the formation of telangiectases appears to be dilation of postcapillary venules. Eventually the dilated venules connect to enlarging arterioles through capillary segments that later disappear, creating direct arteriolarvenular connections. This sequence of events is associated with a perivascular mononuclear infiltrate.[19] Various explanations have been put forward to explain the angiodysplasia seen in HHT, including endothelial cell degeneration,[20] defects in endothelial junctions,[18] lack of elastic fibers and incomplete smooth muscle cell coating of the vessels,[17] and weak connective tissue surrounding the vessel.[20] The recurrent hemorrhage must be related to the localized abnormality within the blood vessel since normal hemostasis and platelet function are present.[21-23]
HHT 1 and Endoglin
In the absence of clear candidate genes for this disorder, a positional cloning approach was used to identify the molecular defect. Genetic linkage for some families was recently established to markers on chromosome 9q33-q34,[24,25] The identification of key obligate recombinants in affected individuals allowed refinement of the HHT 1 locus and placed the most likely candidate interval between D9S60 and D9S61 in a 2-centimorgan interval.[24,26,27] Endoglin was considered a strong candidate gene based on its known function, its location on chromosome 9q34,[28] and the suggestion that is was located within the candidate interval on chromosome 9 based on the mouse syntenic map.[29]
Endoglin is a homodimeric integral membrane glyco-protein expressed at high level on human vascular endothelial cells of capillaries, arterioles, and venules.[30] On endothelial cells, endoglin is the most abundant transforming growth factor-beta (TGF-[Beta] binding protein.[31] In the presence of TGF-[Beta] ligand, it can associate with the signaling receptos RI and RII[32] and is thought to initiate response to the growth factor, TGF-[Beta] modulates several processes of endothelial cells, including migration, proliferation, adhesion, and extracellular matrix composition and organization.[33] Perturbations in one or more of these processes may be involved in the angiodysplasia seen in HHT.
TFG-[Beta] signaling is mediated by TGF-[Beta] receptors RI and RII, which form a heteromeric complex upon binding TGF-[Beta].[34] Endoglin binds TFG-[Beta]1 and -[Beta]3, and is structurally related to betaglycan, which binds all three isoforms of TGF-[Beta].[31] Betaglycan in the presence of ligand interacts with the signaling kinase complex of RI and RII and potentiates the response to all three isoforms of the growth factor.[35] Endoglin also interacts with the kinase complex[31] suggesting a potentiating role similar to that of betaglycan. Thus endoglin-deficient endothelial cells, as observed in HHT 1 patients, might lack the regulatory coreceptor capable of controlling the response.
Fifteen distinct mutations have thus far been identified in the endoglin gene in HHT families[36,37] (also C. Gallione, D. Klaus, K. Anthony, E. Yeh, and D.A.M.; unpublished observations; 1997). In only one case has an identical mutation been observed in two apparently unrelated families, indicating that most if not all mutations are unique to each family. Mutation analysis for diagnostic purposes is therefore more difficult, being made even more so by genetic heterogeneity (see below). The following types of mutations have been observed in the endoglin gene: small deletions or insertions of 1 to 4 base pairs (bp); nonsense mutations; a splice-junction mutation; a combination deletion-insertion mutation; and missense mutation in the ATG start codon. Although many mutations would result in a truncated protein if translated, at least some of these mutations result in an unstable messenger RNA for the mutant allele which is either grossly under-represented or entirely absent, with little or no observable truncated protein product (T. Stenzel, MD, PhD, and D.A.M.; unpublished observations; 1997). In addition, the start codon mutation would be predicted to make no functional protein at all, since the next four potential start codons in the gene are not in the correct reading frame. These combined data suggest that the primary nature of most endoglin mutations is to create a null (nonfunctional) allele; however, the effects of any of these mutations on endoglin functions has yet to be examined.
Families that show linkage to endoglin appear to have a higher incidence of pulmonary involvement than other HHT families. It is difficult to gain a completely accurate estimate of the incidence of PAVMs in the families that show this feature, since each family member is not routinely screened for these lesions. Nevertheless, we estimate a 30% risk to develop pulmonary AVM once the mutation is inherited.[38] It is unclear whether this value represents the risk to develop clinically significant lesions, with subclinical lesions being more prevalent.
HHT 2 and ALK1
Locus heterogeneity for HHT was indicated by families that excluded linkage to endoglin.[25-27,39] Families not linked to endoglin show only a 3% risk of developing pulmonary lesions.[38] A second HHT locus (HHT 2) was subsequently identified in the pericentromeric region of chromosome 12.[40,41] Based on haplotype analysis and crossovers in these 12q-linked families, a 4-centimorgan candidate interval was established between D12S347 and D12S359. A potential candidate gene, ALK1 (activin receptor-like kinase), was shown to map within this interval.[42]
ALK1 is a type I cell-surface receptor for the TGF-[Beta] superfamily of ligands. It shares with other type I receptors a high degree of similarity in serine-threonine kinase subdomains, a glycine- and serine-rich region (called the GS domain) preceding the kinase domain, and the short C-terminal tail.[43,44] The ALK1 protein can associate with the TGF-[Beta] or activin type II receptors after cotransfection in COS cells, with the complex binding TGF-[Beta] or activin, respectively.[43,44] However, the ALK1 ligand in vivo remains unknown, due to the promiscuity of ligand binding of type I receptors in cell culture overexpressions systems. The high level of expression of ALK1 in endothelial cells and other highly vascularized tissues (lung and placenta) and lower expression levels in other cells and tissues parallels that of endoglin.[43]
Twelve distinct mutations have been identified in the coding region of the ALK1 gene in HHT 2 patients[42] (also J. Berg, MB, BCh, C. Gallione, and D.A.M.; unpublished observations; 1997). Each mutation appears to be unique to a single family. These include base substitutions resulting in missense and nonsense mutations, as well as small deletions or insertions of 1 to 3 bp. The missense mutations lie within highly conserved residues of protein, either within the kinase domain or in the extracellular ligand binding domain. These mutations suggest a defect in signaling from the kinase domain of the ALK1 receptor, due to reduced kinase activity, reduced ligand binding, or possibly defects in ALK1 association with other members of the heteromeric signaling complex. At least some of the nonsense and frameshift mutations create an unstable messenger RNA from the mutant allele (D. Johnson, Ph.D, and D.A.M.; unpublished observations; 1997), suggesting that the primary nature of the mutation may be to create a null (nonfunctional) allele, again paralleling what is observed with endoglin.
Other Genes
Currently, nearly all of the HHT pedigrees which have been carefully analyzed by genetic linkage analysis and/or mutation analysis fall into the HHT 1 and HHT 2 classes. There is however, a single HHT kindred described which does not show genetic linkage to either the endoglin or ALK1 genes, indicating the existence of a third gene for HHT.[46] This variant of HHT was observed in a large family with hepatic arteriovenous malformations as the major manifestation in most of the affected members. This form may be rare and also may exhibit a distinct clinical phenotype, although additional families must be identified to confirm this. If other genes do exist for HHT, one tempting hypothesis might be that they encode other endothelial cell-specific proteins of the TGF-[Beta] signaling complex, or possibly downstream effectors of the signal.
Conclusions
Although first described 100 years ago, until recently, little was known about the molecular basis of this disorder. To determine this, a positional cloning approach has been taken. Thus far, two genes have been identified that when mutated, give rise to HHT. Endoglin maps to chromosome 9q33-q34 and is mutated in type 1 HHT. HHT 1 families appear to have a higher incidence of pulmonary involvement than other type(s) of HHT families, with an estimate of a 30% risk to develop PAVM once the mutation is inherited. A second gene for HHT maps chromosome 12ql3 and this locus has been termed type 2 HHT. The ALK1 gene, encoding the activin receptor like kinase 1 gene, is mutated in HHT 2. These families exhibit a lower incidence of pulmonary involvement, with an estimate of a 3% risk to develop these lesions once the mutation is inherited.
It appears that HHT may be the result of a defective response of endothelial cells to TGF-[Beta] and/or activin due to receptor mutations. Growth of vascular endothelial cells in culture is inhibited by activin-A and TGF-[Beta] causes an additive inhibitory affect.[47] ALK1 and endoglin may interact at the endothelial cell surface in a common signal transduction pathway involving TGF-[Beta]. Alternatively, ALK1 and endoglin may act in separate pathways (or in ones that converge in the cell) involving different ligands that have similar effects on vascular endothelium.
The vascular lesions in HHT are localized to discrete regions within the affected tissue, with no evidence of abnormal vascular structure or abnormality outside the lesions themselves. This suggests that some genetic, physiologic, or mechanical event initiates the formation of each vascular lesion. The pathobiology of the disease may be related to remodeling of the vascular endothelium following an unknown initiating event. TGF-[Beta] mediates vascular remodeling through effects on extracellular matrix production by endothelial cells, stromal interstitial cells, smooth muscle cells, and pericytes.[48] Perturbations in the TGF-[Beta] signaling pathway in Rendu-Osler-Weber disease may lead to altered repair of vascular endothelium and remodeling of the vascular tissue via changes in expression profiles of extracellular matrix proteins.
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