Hereditary Hemorrhagic Telangiectasia

Historical Aspects

Whereas hereditary epistaxis was described by Babington in 1865, Henri Jules Rendu is credited with the initial description of HHT. In his report in 1896, he described the case of a 52 year old sailor with recurrent, spontaneous epistaxis and multiple, small, superficial “angioma” over the face, neck, and chest. The patient's mother and brother also had a history of recurrent epistaxis, suggesting this may be an inherited disorder with an autosomal dominant transmission. In 1901, William Osler described four patients with familial epistaxis and “telangiectasias” over the skin and mucus membranes. He reported that bleeding in these patients only occurred from these mucocutaneous telangiectasias thus distinguishing it from hemophilia. He acknowledged the reports of Drs. Babington and Rendu in his publication. In 1907, Frederick Parkes Weber reported on a cohort of eight families with a propensity for nosebleeds who all had developmental angiomata (telangiectases) of the skin and mucus membranes. In his report, Weber described the appearance and distribution of the telangiectases in detail. The disorder was originally named Osler-Weber-Rendu disease in recognition of those contributors. The term “hereditary hemorrhagic telangiectasia” was coined by Frederic Hanes in 1909, while he was a resident house officer at the Johns Hopkins Hospital. This has become the most commonly used designation for the disorder. Following these initial descriptions, the next significant advance in HHT would not be until the 1980s, when the discovery of endoglin paved the way for our understanding of the pathophysiology of HHT (discussed below).

Epidemiology

HHT is inherited in an autosomal dominant fashion, with an estimated prevalence between 1 in every 5000 to 8000 individuals. The prevalence may be underestimated as HHT is underdiagnosed and it is believed that only 2 of 10 affected individuals carries a diagnosis of HHT. To further compound this, patients with milder disease manifestations may go undiagnosed or be misdiagnosed. The above prevalence estimates are primarily based on a combination of surveys from probands, first-degree, and more distant relatives. It is likely that some variation in prevalence exists based on geographic location of the population sampled. Based on available data, it appears that HHT equally affects men and women. The vast majority of subjects in the published HHT literature are Caucasian, although HHT has been reported in all racial and ethnic groups. Further, in the North American population, the racial distribution of HHT dovetails with the population demographics of the given region. These data suggest that HHT may not have a racial preponderance.

Molecular Biology

HHT is caused by mutations within members of the transforming growth factor beta (TGF-β) signaling pathway, a key regulator of angiogenesis. Three disease-causing genes have been identified, including endoglin (ENG) , activin A receptor ligand type I ( ACVRL1 or ALK1 ), and SMAD family member 4 ( MADH4 or SMAD4 ) ( Table 11.1 ). In 1994, the groups of Marchuk and Shovlin independently discovered that the gene locus for HHT mapped to chromosome 9q3 and their findings were published as accompanying papers in the same issue of Nature Genetics. Shortly beforehand, Michelle Letarte and colleagues had discovered the membrane glycoprotein endoglin and mapped the endoglin gene to chromosome 9q34. By the end of 1994, ENG was established as one of the gene involved in the development of HHT. Following reports of locus heterogeneity in families with HHT, a second locus was mapped to chromosome 12 and subsequently identified as being the ACVRL1 gene (12q13) in 1996. Finally, reports of patients with juvenile polyposis syndrome (JPS) demonstrating features of HHT led to investigations into the genes known to cause JPS and their association with HHT. Interestingly, JPS is the result of mutations in MADH4 or BMPR1A , both of which encode members of the TGF-β pathway. These efforts ultimately resulted in the discovery in 2004 that mutations in SMAD4 (18q21) caused both JPS and HHT, a dual disorder. In patients with JPS/HHT syndrome, clinical characteristics of both diseases are present. Gastrointestinal polyps most commonly manifest in the second decade of life, and close monitoring for oncologic transformation is recommended. SMAD4 -mutated patients seem to have a predilection for pulmonary AVMs, although the full clinical spectrum of HHT associated complications can occur. Of note, all three HHT-associated genes were discovered by Marchuk and colleagues.

Over 750 pathogenic mutations have been identified in ENG and ACVRL1 . Missense mutations are most common ( http://arup.utah.edu/database ), with frameshift mutations more frequently implicated in ENG compared to ACVRL1 . De novo mutations and mosaicism are rare, but have been reported. Homozygous mutations of ENG or ACVRL1 are lethal, and it is the heterozygous mutation that leads to haploinsufficiency and reduced levels of functional protein. The consequence of reduced functional protein is imbalance in regulators of angiogenesis, resulting in the development of vascular malformations characteristic of HHT.

ENG and ACVRL1 mutations account for the majority of HHT cases and appear to occur at an equal proportion overall, while SMAD4 mutations account for roughly 2% to 3% of all HHT. Genetic testing for a causative mutation will identify a mutation in ENG , ACVRL1 , or SMAD4 in over 85% of patients with a clinical diagnosis of HHT. It is likely that yet to be discovered mutations(s) result in disease in the remaining patients. Two additional HHT loci have been identified; one located at 5q31, the other at 7p14. Mutations in these loci may account for HHT in a proportion of those patients without mutations in ENG , ACVRL1 , or SMAD4.

The “HHT-like” syndromes should be borne in mind when considering HHT in any given patient. Mutations in GDF2 (10q11), which encodes bone morphogenic protein 9 (BMP9), and RASA1 have been implicated in the development of “HHT-like” syndromes. BMP9 is a ligand for the ACVRL1 receptor. While mutations in GDF2 and RASA1 produce symptoms that overlap with HHT, each has distinct features separating it from classic HHT. The clinical features of GDF2 mutants are not clearly defined, but case reports describe individuals with nosebleeds, telangiectasias, and a family history of similar symptoms. Telangiectasias tend to be different in appearance and location compared to classical HHT. RASA1 mutations are associated with dermal telangiectasia and cerebral AVMs, in what is known as capillary malformation-AVM syndrome (CM-AVM). Similar to GDF2 mutations, telangiectasias differ from those in HHT, but recurrent nosebleeds are only rarely described.

Pathogenesis

Angiogenesis, the development and maturation of blood vessels, is a complex process. Angiogenesis consists of an activation phase dominated by increased vascular permeability, basement membrane degradation, and reconstruction; and endothelial cell migration and proliferation. The final maturation phase yields a fully formed, functional vascular system through recruitment of pericytes and vascular smooth muscle cells. Disruption of angiogenesis is the driving force behind AVM development in HHT. Angiogenesis is strictly regulated by input from both positive and negative signal transduction pathways. Within endothelial cells, the TGF-β pathway plays a central role in this process through activation of two different type I receptor pathways, ALK1 and ALK5. Binding of TGF-β to the ALK1 receptor induces SMAD1/SMAD5 phosphorylation leading to cell proliferation and migration. Endoglin is a co-receptor for this pathway. The TGF-β pathway is opposed by the ALK5/SMAD2/SMAD3 pathway, which inhibits cell proliferation and migration. SMAD1, 2, 3, and 5 bind to SMAD4, which translocates to the nucleus and modulates transcription ( Fig. 11.1 ). Mutations in ENG , ACVRL1 (ALK1), or SMAD4 are thought to disrupt the intricate balance between the pro- and antiangiogenic signals necessary for normal vascular development.

In addition to the TGF-β pathway, the vascular endothelial growth factor (VEGF) pathway is integral to angiogenesis. The VEGF family includes VEGF-A, -B, -C, -D and placental growth factor. VEGF signaling on endothelial cells is mediated through two receptors, VEGFR-1 and VEGFR-2. Activation of the VEGF pathway induces endothelial cell survival. While VEGF levels have been shown to be abnormally high in the serum of patients with HHT, there appears to be no correlation between plasma VEGF levels and HHT genotype. VEGF is a therapeutic target in HHT, and blockade of VEGF and other mediators of angiogenesis has proven helpful in the management of HHT-related complications.

Vascular malformations in HHT range from dilated microvessels (telangiectasia) to large AVMs, characterized by lack of an intervening capillary bed between the precapillary arterioles and postcapillary venules. These abnormal vessels are prone to hemorrhage as a result of thin, fragile walls and turbulent blood flow. Both ENG and ALK1 are expressed in all vascular endothelial cells. It remains unclear why there is a predilection for certain vascular beds over others in patients with HHT.

Clinical Manifestations

Mucocutaneous telangiectasias, recurrent epistaxis, and visceral organ AVMs are disease-defining characteristics of HHT ( Table 11.2 ). Mucocutaneous telangiectasias occur in characteristic sites including the oral cavity, lips, nasal mucosa, and fingers. Telangiectasia typically appear in the third decade of life ( Fig. 11.2 ). Cutaneous telangiectasias do not typically bleed, but can cause cosmetic concern. Mucosal telangiectasias, on the other hand, can result in bleeding and related complications. Telangiectasias involving the nasal mucosa, gums, tongue, and gastrointestinal (GI) mucosa can all result in bleeding although epistaxis and GI bleeding are the most common among these. Of note, during times of profound anemia, telangiectasia can be nearly invisible, and easy to miss in undiagnosed patients. They become obvious when anemia abates. A number of HHT-related manifestations tend to have an age-dependent presentation, making identification of affected individuals on a clinical basis challenging in childhood.