hereditary hemorrhagic telangiectasia hereditary hemorrhagic telangiectasia hereditary hemorrhagic telangiectasia (hht), also known as osler–weber–rendu disease and osler–weber–rendu syndrome, is a rare autosomal dominant genetic disorder that leads to abnormal blood vessel formation in the skin, mucous membranes, and often in organs such as the lungs, liver, and brain. hereditary hemorrhagic telangiectasiacharacteristic lip telangiectases.specialtymedical genetics, gastroenterologysymptomsnosebleeds, gastrointestinal bleeding it may lead to nosebleeds, acute and chronic digestive tract bleeding, and various problems due to the involvement of other organs. treatment focuses on reducing bleeding from blood vessel lesions, and sometimes surgery or other targeted interventions to remove arteriovenous malformations in organs. chronic bleeding often requires iron supplements and sometimes blood transfusions. hht is transmitted in an autosomal dominant fashion, and occurs in one in 5,000–8,000 people in north america. the disease carries the names of sir william osler, henri jules louis marie rendu, and frederick parkes weber, who described it in the late 19th and early 20th centuries. signs and symptoms telangiectasias tongue telangiectases as seen in a person with hereditary hemorrhagic telangiectasia telangiectasia (small vascular malformations) may occur in the skin and mucosal linings of the nose and gastrointestinal tract. the most common problem is nosebleeds (epistaxis), which happen frequently from childhood and affect about 90–95% of people with hht. lesions on the skin and in the mouth bleed less often but may be considered cosmetically displeasing; they affect about 80%. the skin lesions characteristically occur on the lips, the nose and the fingers, and on the skin of the face in sun-exposed areas. they appear suddenly, with the number increasing over time. about 20% are affected by symptomatic digestive tract lesions, although a higher percentage have lesions that do not cause symptoms. these lesions may bleed intermittently, which is rarely significant enough to be noticed (in the form of bloody vomiting or black stool), but can eventually lead to depletion of iron in the body, resulting in iron-deficiency anemia. arteriovenous malformation a very large arteriovenous malformation in the left hemisphere (on the right in this image) of the brain. arteriovenous malformations (avms, larger vascular malformations) occur in larger organs, predominantly the lungs (pulmonary avms) (50%), liver (30–70%) and the brain (cerebral avms, 10%), with a very small proportion (<1%) of avms in the spinal cord. vascular malformations in the lungs may cause a number of problems. the lungs normally "filter out" bacteria and blood clots from the bloodstream; avms bypass the capillary network of the lungs and allow these to migrate to the brain, where bacteria may cause a brain abscess and blood clots may lead to stroke. hht is the most common cause of lung avms: out of all people found to have lung avms, 70–80% are due to hht. bleeding from lung avms is relatively unusual, but may cause hemoptysis (coughing up blood) or hemothorax (blood accumulating in the chest cavity). large vascular malformations in the lung allow oxygen-depleted blood from the right ventricle to bypass the alveoli, meaning that this blood does not have an opportunity to absorb fresh oxygen. this may lead to breathlessness. large avms may lead to platypnea, difficulty in breathing that is more marked when sitting up compared to lying down; this probably reflects changes in blood flow associated with positioning. very large avms cause a marked inability to absorb oxygen, which may be noted by cyanosis (bluish discoloration of the lips and skin), clubbing of the fingernails (often encountered in chronically low oxygen levels), and a humming noise over the affected part of the lung detectable by stethoscope. the symptoms produced by avms in the liver depend on the type of abnormal connection that they form between blood vessels. if the connection is between arteries and veins, a large amount of blood bypasses the body's organs, for which the heart compensates by increasing the cardiac output. eventually congestive cardiac failure develops ("high-output cardiac failure"), with breathlessness and leg swelling among other problems. if the avm creates a connection between the portal vein and the blood vessels of the liver, the result may be portal hypertension (increased portal vein pressure), in which collateral blood vessels form in the esophagus (esophageal varices), which may bleed violently; furthermore, the increased pressure may give rise to fluid accumulation in the abdominal cavity (ascites). if the flow in the avm is in the other direction, portal venous blood flows directly into the veins rather than running through the liver; this may lead to hepatic encephalopathy (confusion due to portal waste products irritating the brain). rarely, the bile ducts are deprived of blood, leading to severe cholangitis (inflammation of the bile ducts). liver avms are detectable in over 70% of people with hht, but only 10% experience problems as a result. in the brain, avms occasionally exert pressure, leading to headaches. they may also increase the risk of seizures, as would any abnormal tissue in the brain. finally, hemorrhage from an avm may lead to intracerebral hemorrhage (bleeding into the brain), which causes any of the symptoms of stroke such as weakness in part of the body or difficulty speaking. if the bleeding occurs into the subarachnoid space (subarachnoid hemorrhage), there is usually a severe, sudden headache and decreased level of consciousness and often weakness in part of the body. other problems a very small proportion (those affected by smad4 (madh4) mutations, see below) have multiple benign polyps in the large intestine, which may bleed or transform into colorectal cancer. a similarly small proportion experiences pulmonary hypertension, a state in which the pressure in the lung arteries is increased, exerting pressure on the right side of the heart and causing peripheral edema (swelling of the legs), fainting and attacks of chest pain. it has been observed that the risk of thrombosis (particularly venous thrombosis, in the form of deep vein thrombosis or pulmonary embolism) may be increased. there is a suspicion that those with hht may have a mild immunodeficiency and are therefore at a slightly increased risk from infections. genetics hereditary hemorrhagic telangiectasia has an autosomal dominant pattern of inheritance. hht is a genetic disorder with an autosomal dominant inheritance pattern. those with hht symptoms that have no relatives with the disease may have a new mutation. homozygosity appears to be fatal in utero. five genetic types of hht are recognized. of these, three have been linked to particular genes, while the two remaining have currently only been associated with a particular locus. more than 80% of all cases of hht are due to mutations in either eng or acvrl1. a total of over 600 different mutations are known. there is likely to be a predominance of either type in particular populations, but the data are conflicting. madh4 mutations, which cause colonic polyposis in addition to hht, comprise about 2% of disease-causing mutations. apart from madh4, it is not clear whether mutations in eng and acvrl1 lead to particular symptoms, although some reports suggest that eng mutations are more likely to cause lung problems while acvrl1 mutations may cause more liver problems, and pulmonary hypertension may be a particular problem in people with acvrl1 mutations. people with exactly the same mutations may have different nature and severity of symptoms, suggesting that additional genes or other risk factors may determine the rate at which lesions develop; these have not yet been identified. name omim gene locus description hht1 187300 eng 9q34.1 eng codes for endoglin, a receptor of tgf-β1 (transforming growth factor beta 1) and tgf-β3; the genetic linkage was identified in 1994. a high proportion of frameshift mutations has been observed. practically all mutations occur in the extracellular part of the protein (the part that sits on the surface of the cell). hht2 600376 acvrl1 12q11-q14 acvrl1 codes for alk-1 (acvr1, activin receptor-like kinase 1), a tgf-β1 receptor; genetic linkage was identified in 1996. hht3 601101 unknown 5q31 function unknown, linkage identified in 2005. hht4 610655 unknown 7p14. function unknown, linkage identified in 2006. jpht 175050 madh4 18q21.1 madh4 codes for smad4, an intracellular signalling protein for the tgf superfamily receptors. mutations in this gene cause hht and juvenile polyposis. linkage was identified in 2004. mutations mostly in exons 8–11, often de novo (newly acquired, not inherited). pathophysiology a schematic representation of the tgf-β signaling pathway. endoglin (yellow) is needed for signalling. the ligand (blue) binds to the receptor complex; red indicates a type ii receptor protein, which activates a type i receptor protein (turquoise) such as alk-1, which in turn phosphorylates a smad-based nuclear transcription factor (green and purple). telangiectasias and arteriovenous malformations in hht are thought to arise because of changes in angiogenesis, the development of blood vessels out of existing ones. the development of a new blood vessel requires the activation and migration of various types of cells, chiefly endothelium, smooth muscle and pericytes. the exact mechanism by which the hht mutations influence this process is not yet clear, and it is likely that they disrupt a balance between pro- and antiangiogenic signals in blood vessels. the wall of telangiectasias is unusually friable, which explains the tendency of these lesions to bleed. all genes known so far to be linked to hht code for proteins in the tgf-β signaling pathway. this is a group of proteins that participates in signal transduction of hormones of the transforming growth factor beta superfamily (the transforming growth factor beta, bone morphogenetic protein and growth differentiation factor classes), specifically bmp9/gdf2 and bmp10. the hormones do not enter the cell but link to receptors on the cell membrane; these then activate other proteins, eventually influencing cellular behavior in a number of ways such as cellular survival, proliferation (increasing in number) and differentiation (becoming more specialized). for the hormone signal to be adequately transduced, a combination of proteins is needed: two each of two types of serine/threonine-specific kinase type membrane receptors and endoglin. when bound to the hormone, the type ii receptor proteins phosphorylate (transfer phosphate) onto type i receptor proteins (of which alk-1 is one), which in turn phosphorylate a complex of smad proteins (chiefly smad1, smad5 and smad8). these bind to smad4 and migrate to the cell nucleus where they act as transcription factors and participate in the transcription of particular genes. in addition to the smad pathway, the membrane receptors also act on the mapk pathway, which has additional actions on the behavior of cells. both alk-1 and endoglin are expressed predominantly in endothelium, perhaps explaining why hht-causing mutations in these proteins lead predominantly to blood vessel problems. both eng and acvrl1 mutations lead predominantly to underproduction of the related proteins, rather than misfunctioning of the proteins. diagnosis diagnostic tests may be conducted for various reasons. firstly, some tests are needed to confirm or refute the diagnosis. secondly, some are needed to identify any potential complications. telangiectasias a vascular lesion in the digestive tract, being treated with argon plasma coagulation. the skin and oral cavity telangiectasias are visually identifiable on physical examination, and similarly the lesions in the nose may be seen on endoscopy of the nasopharynx or on laryngoscopy. the severity of nosebleeds may be quantified objectively using a grid-like questionnaire in which the number of nosebleed episodes and their duration is recorded. digestive tract telangiectasias may be identified on esophagogastroduodenoscopy (endoscopy of the esophagus, stomach and first part of the small intestine). this procedure will typically only be undertaken if there is anemia that is more marked than expected by the severity of nosebleeds, or if there is evidence of severe bleeding (vomiting blood, black stools). if the number of lesions seen on endoscopy is unexpectedly low, the remainder of the small intestine may be examined with capsule endoscopy, in which the patient swallows a capsule-shaped device containing a miniature camera which transmits images of the digestive tract to a portable digital recorder. arteriovenous malformations identification of avms requires detailed medical imaging of the organs most commonly affected by these lesions. not all avms cause symptoms or are at risk of doing so, and hence there is a degree of variation between specialists as to whether such investigations would be performed, and by which modality; often, decisions on this issue are reached together with the patient. lung avms may be suspected because of the abnormal appearance of the lungs on a chest x-ray, or hypoxia (low oxygen levels) on pulse oximetry or arterial