Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia leading to telangiectases and arteriovenous malformations of skin, mucosa, and viscera. Epistaxis and gastrointestinal bleeding are frequent complications of mucosal involvement. Visceral involvement includes that of the lung, ... Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia leading to telangiectases and arteriovenous malformations of skin, mucosa, and viscera. Epistaxis and gastrointestinal bleeding are frequent complications of mucosal involvement. Visceral involvement includes that of the lung, liver, and brain. The most frequent form of hereditary hemorrhagic telangiectasia maps to the long arm of chromosome 9. - Genetic Heterogeneity of Hereditary Hemorrhagic Telangiectasia See also HHT2 (600376), which is caused by mutations in the ALK1 gene (ACVRL1; 601284) on chromosome 12q. HHT3 (601101) has been mapped to chromosome 5q31 and HHT4 (610655) to chromosome 7p14. See also juvenile polyposis/HHT syndrome (175050), caused by mutation in the SMAD4 gene (600993).
HHT is highly penetrant; Plauchu et al. (1989) in a series of 384 patients found at least 1 manifestation in 97%, while Porteous et al. (1992) found complete penetrance by 40 years of age in a series of ... HHT is highly penetrant; Plauchu et al. (1989) in a series of 384 patients found at least 1 manifestation in 97%, while Porteous et al. (1992) found complete penetrance by 40 years of age in a series of 35 British families with 98 affected members. Sixty-two percent of these were clinically affected by age 16, with epistaxes being the presenting feature in 90% of cases. Aassar et al. (1991) found that the mean age of onset of epistaxis in HHT was 12 years with more than 90% becoming manifest before 21 years. Blood loss from the nasal mucosa may become severe. Telangiectases also occur on the mucosal surface of the tongue (where bleeding may prove difficult to control), lips, face, conjunctiva, ears and fingers. Plauchu et al. (1989) noted facial involvement in 33% and lesions on the hands or wrists of 41% of their patients Porteous et al. (1992) found significant gastrointestinal hemorrhage in 16% of patients with half of these requiring transfusion. The preponderance of upper GI involvement may have reflected the reliance on upper GI endoscopy. By angiographic methods, various types of visceral angiodysplasias have been demonstrated (Halpern et al., 1968). These include arterial aneurysm, arteriovenous communication including discrete arteriovenous fistula, conglomerate masses of angiectasia, phlebectasia, and angioma. Pulmonary arteriovenous malformations (PAVMs) are a significant cause of morbidity. Some are sufficiently large to cause heart failure leading to polycythaemia and clubbing. Paradoxical emboli may cause infarction or abscess formation in the brain and elsewhere. Vase et al. (1985) reported PAVMs in 20% of their series. Plauchu et al. (1989) found PAVMs in 4.6% with an age range of 1 to 78 years. In the study of Porteous et al. (1992) 13 (23%) of those who had undergone chest radiography had a visible PAVM; 4 suffered embolic complications, 3 cerebral abscesses, and one a stroke. In one 17-year-old, 50% of the circulating volume was passing through a single PAVM. Reyes-Mujica et al. (1988) described HHT in a 23-month-old girl who died of massive pulmonary hemorrhage. There were no skin lesions but vascular anomalies of varying severity were found in the tongue, esophagus, liver, kidney, central nervous system, ovaries, spleen, and lymph nodes. Before death, the child had 15 episodes of hemoptysis and 2 of epistaxis. The parents, by contrast, had no evidence of the disease but 1 grandfather had died after bleeding from the mouth following physical exertion. Dines et al. (1974) reviewed 63 cases of pulmonary arteriovenous fistula seen at the Mayo Clinic; HHT was recognized in 38 (60%). Cirrhosis of the liver may occur; Plauchu et al. (1989) found liver involvement in 27 patients (8%); 17 of these had cirrhosis, which was the cause of death in 5. Michaeli et al. (1968) described a 47-year-old woman with HHT disease and hepatic portacaval shunts of sufficient magnitude to cause repeated episodes of encephalopathy. The liver was not scarred. Nikolopoulos et al. (1988) raised the question of familial tendency to hepatic involvement in HHT. They described 2 brothers with intrahepatic arteriovenous shunts of sufficient size to cause hyperdynamic circulation, leading to cirrhosis; the mother and 3 maternal uncles died of cirrhosis with rupture of esophageal varices. Members of the previous generation also had a history of hyperdynamic circulation. Selmaier et al. (1993) described the case of a 50-year-old woman with heart failure resulting from calcified hemangiomatosis of the liver with a high shunt volume. Saxena et al. (1998) reported the case of a 43-year-old woman who received a transplant for end-stage liver disease due to HHT and fibropolycystic liver disease. The liver showed extensive vascular malformations of arteries and veins, as well as telangiectasia and fibrosis. In addition, there were cystically dilated ducts containing inspissated bile and extensive von Meyenburg complexes. The case raised the question of a possible relationship between polycystic liver disease (174050) and HHT. (A von Meyenburg complex consists of clusters of small bile ducts occurring in polycystic livers, separate from the portal areas.) In the liver, the vascular abnormalities of HHT are associated with marked fibrosis and/or cirrhosis. Weik and Greiner (1999) found hepatic manifestations of HHT in 4 women and 1 man (51 to 63 years of age) presenting initially with slight disturbances of liver function. In 3 patients, progressive liver insufficiency developed. Garcia-Tsao et al. (2000) described the clinical findings and results of hemodynamic, angiographic, and imaging studies in 19 patients with HHT and symptomatic liver involvement. Ages ranged from 34 to 74 years in the 14 women and 5 men. All but 1 had a hyperdynamic circulation (cardiac index, 4.2 to 7.3 liters per minute per square meter of body-surface area). In 8 patients, the clinical findings were consistent with the presence of high-output heart failure. Manifestations of portal hypertension such as ascites or variceal bleeding were present in 6 patients. Manifestations of biliary disease, such as an elevated alkaline phosphatase level and abnormalities on bile duct imaging, were present in 5 patients. One of these patients died after an unsuccessful attempt at liver transplantation. Cooke (1986) described renal arteriovenous malformations in a patient with episodic hematuria and renal colic due to clots. Telangiectases may occur in the bladder though Plauchu et al. (1989) found only 2 symptomatic patients among their 324 cases. Kurnik and Heymann (1989) described 3-vessel coronary artery ectasia without evidence of atherosclerosis in a 51-year-old man with classic HHT disease. This manifestation had not previously been described although ectasia of other vessels such as intraabdominal ones is well known. In a study of 20 patients with HHT, Brant et al. (1989) found conjunctival telangiectases in 7 and retinal vascular malformations in 2. Visual loss from the intraocular lesions is a rare complication. Bloody tears sometimes occur in patients with conjunctival telangiectases and bleeding from the eyes may also result from the backing up of blood in the lacrimal duct during epistaxis with packing of the nostrils. Most of the neurologic morbidity is related to emboli but vascular malformations may occur; Guillen et al. (1991) found 1 individual, in a Mexican family with 15 affected members, who needed surgical treatment for a cerebral lesion, while 3 of the patients seen by Porteous et al. (1992) had symptomatic cerebral lesions. In the latter report, 46.3% of patients with no known CNS pathology described visual symptoms suggestive of migrainous aura in the absence of headache and nausea compared to 5.7% of controls. Steele et al. (1993) investigated migraine prevalence in 58 British adult HHT gene carriers without known neurologic deficits; 40 carriers of the gene for familial adenomatous polyposis (FAP; 175100) were used as controls. They found that 50% of the HHT carriers fulfill diagnostic criteria for migraine with aura, 4 times the disease control group and 10 times the estimated population prevalence. White had observed this symptom separately and noted that headaches improved in patients who had undergone balloon occlusion of PAVMs (White et al., 1988). This raises the possibility of vasoactive substances which would normally be removed in the pulmonary vascular bed reaching the central nervous system, though if this is the explanation it would suggest that almost half of gene carriers have pulmonary involvement. Another factor may be occult intracranial AVMs; 6 to 8% of HHT patients with PAVMs also have intracranial lesions (Romain et al., 1978). Fulbright et al. (1998) reviewed brain magnetic resonance imaging (MRI) of 184 consecutive patients with HHT. Catheter angiography was performed in 17 patients in whom cerebrovascular malformations (CVMs) were detected on MRIs. They found 63 CVMs in 42 patients. Classic arteriovenous malformations (n = 10) had a conspicuous network of vessels with flow voids and enlarged adjacent pial vessels. Apparent venous malformations (n = 5) were best seen after administration of contrast material as a prominent vessel coursing through normal brain parenchyma. Indeterminate vascular malformations (n = 48) had a spectrum of appearances characterized by variable combinations of heterogeneous signal intensity, enhancement, or hemosiderin. Angiography in 17 patients revealed 47 CVMs. Forty-six were arteriovenous malformations (AVMs), including 25 CVMs not seen with MRI and 21 CVMs that by MR criteria included 8 AVMs and 13 indeterminate vascular malformations. Angiography confirmed 1 venous malformation seen with MRI but failed to detect 3 indeterminate lesions revealed by MRI. Thus, MRI revealed a CVM prevalence of 23% (42 of 184). Most CVMs (48 of 63) had an atypical appearance for vascular malformations on MR images. Angiographic correlation suggests that MRI underestimates the prevalence of CVMs and that the majority of indeterminate CVMs, despite their variable MRI appearance, are AVMs. Kopel and Lage (1998) described a 37-year-old woman with HHT who developed a large pericardial effusion with cardiac tamponade. Pericardiocentesis yielded a large amount of hemorrhagic pericardial fluid. Because of recurrent cardiac tamponade, the patient underwent partial surgical pericardial excision. Histologic examination of the pericardium showed vascular dysplasia with signs of hemorrhage and inflammation. - Reviews Guttmacher et al. (1995) reviewed all aspects of HHT. They emphasized that it is important for those affected to be aware of their diagnosis and its implications and to inform health care providers of their codition. Guttmacher et al. (1995) announced that educational materials for patients and providers are available from the HHT Foundation International, Inc. Haitjema et al. (1996) provided a review. Marchuk et al. (1998) reported on a 1997 workshop on hereditary hemorrhagic telangiectasia. Govani and Shovlin (2009) reviewed the molecular and genetic basis of hereditary hemorrhagic telangiectasia and discussed approaches for diagnosis and clinical management.
Berg et al. (2003) performed a questionnaire-based study to delineate phenotypic differences between HHT1 and HHT2, which are caused by mutation in the ENG gene and ALK1 (601284) gene, respectively. The questionnaires were completed by 83 patients with ... Berg et al. (2003) performed a questionnaire-based study to delineate phenotypic differences between HHT1 and HHT2, which are caused by mutation in the ENG gene and ALK1 (601284) gene, respectively. The questionnaires were completed by 83 patients with known mutations (49 had HHT1 and 34 had HHT2). Patients with HHT1 reported an earlier onset of epistaxis and telangiectasis than those with HHT2. Pulmonary arteriovenous malformations were reported only in the group of HHT1 patients. Among 14 kindreds with HHT1 and 12 with HHT2 confirmed by genetic analysis, Bayrak-Toydemir et al. (2006) found that HHT2 was associated with later onset and more hepatic involvement than HHT1. Letteboer et al. (2006) analyzed phenotype in relation to sex in 584 Dutch probands and affected family members with HHT1 and HHT2 confirmed by genetic analysis. For the HHT1 group, they found a significantly higher prevalence of PAVM and hepatic AVM in women than in men. In a study of 268 Dutch patients with HHT1 and 130 Dutch patients with HHT2, Letteboer et al. (2008) found that oral and nasal mucosal telangiectases were present earlier in life in patients with HHT1 compared to patients with HHT2, whereas dermal lesions were more frequent and appeared earlier in life in patients with HHT2. In both groups, telangiectases of the nasal mucosa were present at a higher prevalence and started to appear earlier in life than those of the oral mucosa or dermal sites. The number of sites affected increased with age in both groups. In patients with HHT1, more women than men had skin telangiectases, particularly on the face. These results confirmed that the frequency of AVMs differ between patients with HHT1 and HHT2, and that these differences can be detected on physical examination.
McAllister et al. (1994) examined endoglin (ENG; 131195), a transforming growth factor-beta (TGF-beta) binding protein, as a candidate gene for HHT because of its chromosomal location, expression pattern, and function. They identified mutations in the ENG gene in ... McAllister et al. (1994) examined endoglin (ENG; 131195), a transforming growth factor-beta (TGF-beta) binding protein, as a candidate gene for HHT because of its chromosomal location, expression pattern, and function. They identified mutations in the ENG gene in 3 affected individuals from different families. This was the first human disease defined as due to a mutation in a member of the TGF-beta receptor complex. Primary pulmonary hypertension (PPH1; 178600) is another autosomal dominant inherited vascular disorder that is caused by a defect in BMPR2 (600799), which is a member of the TGF-beta signaling pathway. In 160 unrelated cases of HHT, Lesca et al. (2004) screened the coding sequences of the ENG and ALK1 genes. Germline mutations were identified in 100 patients (62.5%): 36 of the mutations were in ENG and 64 were in ALK1. Wehner et al. (2006) identified mutations in 32 (62.7%) of 51 unrelated German patients with HHT. Thirteen mutations were in the ENG gene, consistent with HHT1, and 17 mutations were in the ACVRL1 gene, consistent with HHT2. Analysis of genotype/phenotype correlations was consistent with a more common frequency of PAVMs in patients with HHT1. Bossler et al. (2006) described the results of mutation analysis on a consecutive series of 200 individuals undergoing clinical genetic testing for HHT. A total of 127 probands were found, with sequence changes consisting of 103 unique alterations, 68 of which were novel. In addition 8 intragenic rearrangements in the ENG gene (131195), and 2 in ACVRL1 gene (601284) were identified. Surprisingly, almost 50% of the individuals with a single symptom were found to have a significant sequence alteration; 3 of these reported only nosebleeds. In a German woman with clinical features of HHT and negative direct sequencing results, Shoukier et al. (2008) identified a deletion of exon 4 of the ENG gene using quantitative real-time polymerase chain reaction (QRT-PCR) and confirmed by multiplex ligation-dependent probe amplification (MLPA). - Exclusion Studies Greenspan et al. (1995) excluded the COL5A1 gene as a candidate for HHT mapping to chromosome 9q.
In a study of 18 families, Tuente (1964) estimated the frequency of the condition to be 1 or 2 in 100,000. The mutation rate was estimated to be 2 x 10(-6) to 3 x 10(-6).
Porteous ... In a study of 18 families, Tuente (1964) estimated the frequency of the condition to be 1 or 2 in 100,000. The mutation rate was estimated to be 2 x 10(-6) to 3 x 10(-6). Porteous et al. (1992) asked all clinicians in the northern region of England for information regarding their patients with HHT; 79 patients were identified in a population of 3.1 million, giving a minimum point prevalence of 1 in 39,216. Given the variable expression, the true incidence is likely to be much higher than this figure. Plauchu et al. (1980) found a concentration of HHT patients in Haut-Jura in eastern France; 120 affected individuals from 42 families lived in a 300-km square area. Bideau et al. (1992) reported that only 17.8% of the genes of inhabitants of the Valserine valley of the French Jura could be traced to the 'original population,' although persons affected with HHT disease belonged to a subset of the population that had lived in the villages for more than 10 generations. All patients in 85 sibships were related. The smallest number of originator couples who lived at the beginning of the 18th century amounted to 16; the unique originator may, therefore, have lived approximately 4 generations earlier. Guttmacher et al. (1994) suggested that the prevalence of HHT has been underestimated at the level of 1 in 50,000 to 100,000 and that the disorder has not received the attention it deserves from the medical genetics community. He urged clinical geneticists and genetic counselors to play an active role in making the diagnosis, coordinating care, and providing genetic counseling. They estimated the minimal prevalence rate of HHT in Vermont to be 1:16,500 and suggested that this frequency is not atypical of rates elsewhere. Dakeishi et al. (2002) estimated the population prevalence of HHT in the Akita prefecture of northern Japan to be 1:5,000 to 1:8,000, roughly comparable with those reported in European and U.S. populations, which is contradictory to the traditional view that HHT is rare among Asians. Westermann et al. (2003) studied HHT in the Afro-Caribbean population of the Netherlands Antilles and found a point prevalence of 1 in 1,331 inhabitants older than 12 years, the highest known in the world.