| Hereditary Hemorrhagic Telangiectasia | |
|---|---|
 | |
| Characteristic lip telangiectases. | |
| Specialty | Medical genetics,Gastroenterology |
| Symptoms | Nosebleeds,Gastrointestinal bleeding |
Hereditary hemorrhagic telangiectasia (HHT), also known asOsler–Weber–Rendu disease andOsler–Weber–Rendu syndrome, is a rare autosomal dominantgenetic disorder that leads to abnormal blood vessel formation in theskin,mucous membranes, and often in organs such as thelungs,liver, andbrain.[1][2]
It may lead tonosebleeds,acute and chronic digestive tract bleeding, and various problems due to the involvement of other organs. Treatment focuses on reducing bleeding from telangiectasias, and sometimessurgery or other targeted interventions to removearteriovenous malformations in organs. Chronic bleeding often requiresiron supplements, iron infusions and sometimesblood transfusions. HHT is transmitted in anautosomal dominant fashion, and occurs in one in 5,000–8,000 people in North America.[1][2]
The disease carries the names of SirWilliam Osler,Henri Jules Louis Marie Rendu, andFrederick Parkes Weber, who described it in the late 19th and early 20th centuries.[3]
Telangiectasia (small vascular malformations) may occur in the skin and mucosal linings of the nose and gastrointestinal tract. The most common problem isnosebleeds (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%.[1][2] The skin lesions characteristically occur on thelips, thenose and thefingers, and on the skin of the face in sun-exposed areas. They appear suddenly, with the number increasing over time.[2]
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 ofbloody vomiting orblack stool), but can eventually lead to depletion ofiron in the body, resulting iniron-deficiency anemia.[1][2]
Arteriovenous malformations (AVMs, larger vascular malformations) occur in larger organs, predominantly the lungs (pulmonary AVMs) (50%), liver (30–70%) and thebrain (cerebral AVMs, 10%), with a very small proportion (<1%) of AVMs in thespinal cord.[1][2]
Vascular malformations in the lungs may cause a number of problems. The lungs normally "filter out"bacteria andblood clots from the bloodstream; AVMs bypass the capillary network of the lungs and allow these tomigrate to the brain, where bacteria may cause abrain abscess and blood clots may lead tostroke.[1] HHT is the most common cause of lung AVMs: out of all people found to have lung AVMs, 70–80% are due to HHT.[4][5] Bleeding from lung AVMs is relatively unusual, but may causehemoptysis (coughing up blood) orhemothorax (blood accumulating in the chest cavity).[1][2][4] Large vascular malformations in the lung allow oxygen-depleted blood from theright ventricle to bypass thealveoli, meaning that this blood does not have an opportunity to absorb fresh oxygen. This may lead tobreathlessness.[4][5] Large AVMs may lead toplatypnea, difficulty in breathing that is more marked when sitting up compared to lying down; this probably reflects changes in blood flow associated with positioning.[4] Very large AVMs cause a marked inability to absorb oxygen, which may be noted bycyanosis (bluish discoloration of the lips and skin),clubbing of the fingernails (often encountered in chronically low oxygen levels), and ahumming noise over the affected part of the lung detectable bystethoscope.[4][5]
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 betweenarteries andveins, a large amount of blood bypasses the body's organs, for which the heart compensates by increasing thecardiac output. Eventuallycongestive cardiac failure develops ("high-output cardiac failure"), with breathlessness and leg swelling among other problems.[1][6] If the AVM creates a connection between theportal vein and the blood vessels of the liver, the result may beportal hypertension (increased portal vein pressure), in which collateral blood vessels form in theesophagus (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 tohepatic encephalopathy (confusion due to portal waste products irritating the brain). Rarely, the bile ducts are deprived of blood, leading to severecholangitis (inflammation of the bile ducts).[1][6] Liver AVMs are detectable in over 70% of people with HHT, but only 10% experience problems as a result.[2]
In the brain, AVMs occasionally exert pressure, leading toheadaches. They may also increase the risk ofseizures, as would any abnormal tissue in the brain. Finally, hemorrhage from an AVM may lead tointracerebral 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 thesubarachnoid space (subarachnoid hemorrhage), there is usually asevere, sudden headache and decreased level of consciousness and often weakness in part of the body.[1][2]
Pulmonary hypertension is a rare (<5%), recognized but heterogeneous complication of HHT.Pulmonary hypertension associated with HHT can result from distinct, and sometimes overlapping, pathophysiological mechanisms, including pre-capillary pulmonary hypertension (usually consistent withpulmonary arterial hypertension), post-capillary pulmonary hypertension due toleft heart failure, and high cardiac output resulting from AVMs. Primary symptoms include exertional dyspnea,peripheral edema (swelling of the legs),chest pain, fatigue and syncope.
A very small proportion (those affected bySMAD4 (MADH4) mutations, see below) havemultiple benign polyps in thelarge intestine, which may bleed or transform intocolorectal cancer. It has been observed that the risk ofthrombosis (particularlyvenous thrombosis, in the form ofdeep vein thrombosis orpulmonary embolism) may be increased. There is a suspicion that those with HHT may have a mildimmunodeficiency and are therefore at a slightly increased risk from infections.[1]
HHT is agenetic disorder with anautosomal dominant inheritance pattern. Those with HHT symptoms that have no relatives with the disease may have a new mutation.[7] Homozygosity appears to be fatal in utero.[1]
Five genetic types of HHT are recognized. Of these, three have beenlinked to particulargenes, while the two remaining have currently only been associated with a particularlocus. More than 80% of all cases of HHT are due to mutations in eitherENG orACVRL1.[8] 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 fromMADH4, it is not clear whether mutations inENG andACVRL1 lead to particular symptoms,[1] although some reports suggest thatENG mutations are more likely to cause lung problems whileACVRL1 mutations may cause more liver problems,[2][5] and pulmonary hypertension may be a particular problem in people withACVRL1 mutations.[8] 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.[2][8]
| Name | OMIM | Gene | Locus | Description |
|---|---|---|---|---|
| HHT1 | 187300 | ENG | 9q34.1 | ENG codes for endoglin, areceptor ofTGF-β1 (transforming growth factor beta 1) andTGF-β3; the genetic linkage was identified in 1994.[9] A high proportion offrameshift mutations has been observed.[1] Practically all mutations occur in the extracellular part of the protein (the part that sits on thesurface of the cell).[8] |
| 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.[10] |
| HHT3 | 601101 | Unknown | 5q31 | Function unknown, linkage identified in 2005.[11] |
| HHT4 | 610655 | Unknown | 7p14. | Function unknown, linkage identified in 2006.[12] |
| 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.[13] Mutations mostly in exons 8–11, oftende novo (newly acquired, not inherited).[1] |
Telangiectasias and arteriovenous malformations in HHT are thought to arise because of changes inangiogenesis, 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, chieflyendothelium,smooth muscle andpericytes. 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 unusuallyfriable, which explains the tendency of these lesions to bleed.[1]
All genes known so far to be linked to HHT code for proteins in theTGF-β signaling pathway. This is a group of proteins that participates insignal transduction of hormones of thetransforming growth factor beta superfamily (thetransforming growth factor beta,bone morphogenetic protein andgrowth differentiation factor classes), specificallyBMP9/GDF2 andBMP10. 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).[1] For the hormone signal to be adequately transduced, a combination of proteins is needed: two each of two types ofserine/threonine-specific kinase typemembrane receptors and endoglin. When bound to the hormone, the type II receptor proteinsphosphorylate (transferphosphate) onto type I receptor proteins (of which Alk-1 is one), which in turn phosphorylate a complex ofSMAD proteins (chieflySMAD1,SMAD5 andSMAD8). These bind to SMAD4 and migrate to thecell nucleus where they act astranscription factors and participate in thetranscription of particular genes. In addition to the SMAD pathway, the membrane receptors also act on theMAPK pathway, which has additional actions on the behavior of cells.[2] Both Alk-1 and endoglin areexpressed predominantly in endothelium, perhaps explaining why HHT-causing mutations in these proteins lead predominantly to blood vessel problems.[2][8] BothENG andACVRL1 mutations lead predominantly to underproduction of the related proteins, rather than misfunctioning of the proteins.[8]
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.[7]
The skin and oral cavity telangiectasias are visually identifiable onphysical examination, and similarly the lesions in the nose may be seen onendoscopy of thenasopharynx or onlaryngoscopy. 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.[2]
Digestive tract telangiectasias may be identified onesophagogastroduodenoscopy (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 withcapsule 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.[2]
Identification of AVMs requires detailedmedical 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.[1]
Lung AVMs may be suspected because of the abnormal appearance of the lungs on achest X-ray, orhypoxia (low oxygen levels) onpulse oximetry orarterial blood gas determination.Bubble contrast echocardiography (bubble echo) may be used as a screening tool to identify abnormal connections between thelung arteries andveins. This involves the injection of agitatedsaline into a vein, followed by ultrasound-based imaging of the heart. Normally, the lungs remove small air bubbles from the circulation, and they are therefore only seen in theright atrium and theright ventricle. If an AVM is present, bubbles appear in theleft atrium andleft ventricle, usually 3–10cardiac cycles after the right side; this is slower than inheart defects, in which there are direct connections between the right and left side of the heart. A larger number of bubbles is more likely to indicate the presence of an AVM. Bubble echo is not a perfect screening tool as it can miss smaller AVMs and does not identify the site of AVMs. Oftencontrast-enhancedcomputed tomography (CT angiography) is used to identify lung lesions; this modality has asensitivity of over 90%.[1][2] It may be possible to omit contrast administration on modern CT scanners.[5] Echocardiography is also used if there is a suspicion of pulmonary hypertension or high-output cardiac failure due to large liver lesions, sometimes followed bycardiac catheterization to measure the pressures inside the various chambers of the heart.[1]
Liver AVMs may be suspected because of abnormalliver function tests in the blood, because the symptoms of heart failure develop, or because ofjaundice or other symptoms of liver dysfunction. The most reliable initial screening test isDoppler ultrasonography of the liver; this has a very high sensitivity for identifying vascular lesions in the liver. If necessary, contrast-enhanced CT may be used to further characterize AVMs.[1][2][6] It is extremely common to find incidental nodules on liver scans, most commonly due tofocal nodular hyperplasia (FNH), as these are a hundredfold times more common in HHT compared to the general population. FNH is regarded as harmless. Generally,tumor markers and additional imaging modalities are used to differentiate between FNH and malignant tumors of the liver.Liver biopsy is discouraged in people with HHT as the risk of hemorrhage from liver AVMs may be significant.[6][7] Liver scans may be useful if someone is suspected of HHT, but does not meet the criteria (see below) unless liver lesions can be demonstrated.[7]
Brain AVMs may be detected oncomputed tomography angiography (CTA or CT angio) ormagnetic resonance angiography (MRA); CTA is better in showing the vessels themselves, and MRA provides more detail about the relationship between an AVM and surrounding brain tissue.[14] In general, MRI is recommended.[2][7] Various types of vascular malformations may be encountered: AVMs, micro-AVMs, telangiectasias and arteriovenousfistulas.[7] If surgery, embolization, or other treatment is contemplated (see below),cerebral angiography may be required to get sufficient detail of the vessels. This procedure carries a small risk of stroke (0.5%) and is therefore limited to specific circumstances.[7][14] Recent professional guidelines recommend that all children with suspected or definite HHT undergo a brain MRI early in life to identify AVMs that can cause major complications.[7] Others suggest that screening for cerebral AVMs is probably unnecessary in those who are not experiencing any neurological symptoms, because most lesions discovered on screening scans would not require treatment, creating undesirable conundrums.[1]
Genetic tests are available for theENG,ACVRL1 andMADH4 mutations. Testing is not always needed for diagnosis, because the symptoms are sufficient to distinguish the disease from other diagnoses. There are situations in which testing can be particularly useful. Firstly, children and young adults with a parent with definite HHT may have limited symptoms, yet be at risk from some of the complications mentioned above; if the mutation is known in the affected parent, absence of this mutation in the child would prevent the need for screening tests. Furthermore,genetic testing may confirm the diagnosis in those with limited symptoms who otherwise would have been labeled "possible HHT" (see below).[7]
Genetic diagnosis in HHT is difficult, as mutations occur in numerous different locations in the linked genes, without particular mutations being highly frequent (as opposed to, for instance, theΔF508 mutation incystic fibrosis).Sequence analysis of the involved genes is therefore the most useful approach (sensitivity 75%), followed by additional testing to detect large deletions and duplications (additional 10%). Not all mutations in these genes have been linked with disease.[7]
Mutations in theMADH4 gene is usually associated with juvenile polyposis, and detection of such a mutation would indicate a need to screen the patient and affected relatives for polyps and tumors of the large intestine.[7]
The diagnosis can be made depending on the presence of four criteria, known as the "Curaçao criteria".[15] If three or four are met, a patient has "definite HHT", while two gives "possible HHT":
Despite the designation "possible", someone with a visceral AVM and a family history but no nosebleeds or telangiectasias is still extremely likely to have HHT, because these AVMs are very uncommon in the general population. At the same time, the same cannot be said of nosebleeds and sparse telangiectasias, both of which occur in people without HHT, in the absence of AVMs. Someone's diagnostic status may change in the course of life, as young children may not yet exhibit all the symptoms; at age 16, thirteen percent are still indeterminate, while at age 60 the vast majority (99%) have a definite diagnostic classification. The children of established HHT patients may therefore be labeled as "possible HHT", as 50% may turn out to have HHT in the course of their life.[1]
Treatment of HHT issymptomatic (it deals with the symptoms rather than the disease itself), as there is no therapy that stops the development of telangiectasias and AVMs directly. Furthermore, some treatments are applied to prevent the development of common complications.[7] Chronic nosebleeds and digestive tract bleeding can both lead to anemia; if the bleeding itself cannot be completely stopped, the anemia requires treatment withiron supplements. Those who cannot tolerate iron tablets or solutions may require administration ofintravenous iron, andblood transfusion if the anemia is causing severe symptoms that warrant rapid improvement of the blood count.[2][7]
Most treatments used in HHT have been described in adults, and the experience in treating children is more limited.[7] Women with HHT who getpregnant are at an increased risk of complications, and are observed closely, although the absolute risk is still low (1%).[1]
An acute nosebleed may be managed with a variety of measures, such as packing of the nasal cavity with absorbent swabs or gels. Removal of the packs after the bleeding may lead to reopening of the fragile vessels, and therefore lubricated or atraumatic packing is recommended.[7] Some patients may wish to learn packing themselves to deal with nosebleeds without having to resort to medical help.[16]
Frequent nosebleeds can be prevented in part by keeping the nostrils moist, and by applyingsaline solution,estrogen-containing creams ortranexamic acid; these have few side effects and may have a small degree of benefit.[7] A number of additional modalities has been used to prevent recurrent bleeding if simple measures are unsuccessful. Medical therapies include oral tranexamic acid and estrogen; theevidence for these is relatively limited, and estrogen is poorly tolerated by men and possibly carries risks of cancer and heart disease in women past the menopause.[2][7] Nasal coagulation andcauterization may reduce the bleeding from telangiectasias, and is recommended before surgery is considered. However, it is highly recommended to use the least heat and time to prevent septal perforations and excessive trauma to the nasal mucosa that are already susceptible to bleeding.[citation needed] Sclerotherapy is another option to manage the bleeding. This process involves injecting a small amount of an aerated irritant (detergent such as sodium tetradecyl sulfate) directly into the telangiectasias. The detergent causes the vessel to collapse and harden, resulting in scar tissue residue. This is the same procedure used to treat varicose veins and similar disorders.[citation needed]
It may be possible toembolize vascular lesions throughinterventional radiology; this requires passing a catheter through a large artery and locating themaxillary artery underX-ray guidance, followed by the injection into the vessel of particles that occlude the blood vessels. The benefit from the procedure tends to be short-lived,[7] and it may be most appropriate in episodes of severe bleeding.[16]
To more effectively minimize recurrence and severity of epistaxis, other options may be used in conjunction with therapies listed above. Intravenously administered anti-VEGF substances such as bevacizumab (brand name Avastin), pazopanib, and thalidomide or its derivatives (lenalidomide, pomalidomide) interfere with the production of new blood vessels that are weak and therefore prone to bleeding. Because thalidomide is a teratogen, thalidomide is considered by many to be a last resort therapy, and additionally can cause neuropathy, which can be mitigated by titrating dosages or prescribing thalidomide derivatives such as lenolidomide and pomalidomide. Pomalidomide causes a significant, clinically relevant reduction in epistaxis severity and improvement in quality of life.[17] Nevertheless, many doctors prefer alternative VEGF inhibitors; eg bevacizumab nasal spray also significantly reduces epistaxis severity without side effects.[18]
If other interventions have failed, several operations have been reported to provide benefit. One is septal dermoplasty or Saunders' procedure,[19] in which skin is transplanted into the nostrils, and the other is Young's procedure,[20] in which the nostrils are sealed off completely.[7][16]
The skin lesions of HHT can be disfiguring, and may respond to treatment with long-pulsedNd:YAG laser.[2] Skin lesions in the fingertips may sometimes bleed and cause pain.Skin grafting is occasionally needed to treat this problem.[2]
With regards to digestive tract lesions, mild bleeding and mild resultant anemia is treated with iron supplementation, and no specific treatment is administered. There is limited data on hormone treatment and tranexamic acid to reduce bleeding and anemia. Severe anemia or episodes of severe bleeding are treated with endoscopicargon plasma coagulation (APC) or laser treatment of any lesions identified; this may reduce the need for supportive treatment. The expected benefits are not such that repeated attempts at treating lesions are advocated.[7] Sudden, very severe bleeding is unusual—if encountered, alternative causes (such as apeptic ulcer) need to be considered[7]—but embolization may be used in such instances.[1]
Lung lesions, once identified, are usually treated to prevent episodes of bleeding and more importantly embolism to the brain. This is particularly done in lesions with a feeding blood vessel of 3 mm or larger, as these are the most likely to cause long-term complications unless treated. The most effective current therapy is embolization with detachable metal coils or plugs.[21] The procedure involves puncture of a large vein (usually under ageneral anesthetic), followed byadvancing of a catheter through the right ventricle and into thepulmonary artery, after whichradiocontrast is injected to visualize the AVMs (pulmonary angiography). Once the lesion has been identified, coils are deployed that obstruct the blood flow and allow the lesion to regress. In experienced hands, the procedure tends to be very effective and with limited side effects, but lesions may recur and further attempts may be required. CTA scans are repeated to monitor for recurrence.[2][4][5][7] Surgical excision has now essentially been abandoned due to the success of embolotherapy.[5][7]
Those with either definite pulmonary AVMs or an abnormal contrast echocardiogram with no clearly visible lesions are deemed to be at risk from brain emboli. They are therefore counselled to avoidscuba diving, during which small air bubbles may form in the bloodstream that may migrate to the brain and cause stroke. Similarly,antimicrobial prophylaxis is advised during procedures in which bacteria may enter the bloodstream, such asdental work, and avoidance of air bubbles duringintravenous therapy.[2][5][7]
Given that liver AVMs generally cause high-output cardiac failure, the emphasis is on treating this withdiuretics to reduce the circulating blood volume, restriction of salt and fluid intake, andantiarrhythmic agents in case ofirregular heart beat. This may be sufficient in treating the symptoms of swelling and breathlessness. If this treatment is not effective or leads to side effects or complications, the only remaining option isliver transplantation. This is reserved for those with severe symptoms, as it carries amortality of about 10%, but leads to good results if successful.[6][7] The exact point at which liver transplantion is to be offered is not yet completely established.[6] Embolization treatment has been attempted, but leads to severe complications in a proportion of patients and is discouraged.[5][6][7]
Other liver-related complications (portal hypertension, esophageal varices, ascites, hepatic encephalopathy) are treated with the same modalities as used incirrhosis, although the use oftransjugular intrahepatic portosystemic shunt treatment is discouraged due to the lack of documented benefit.[6]
The decision to treat brainarteriovenous malformations depends on the symptoms that they cause (such as seizures or headaches). The bleeding risk is predicted by previous episodes of hemorrhage, and whether on theCTA orMRA scan the AVM appears to be deep-seated or have deep venous drainage. Size of the AVM and the presence ofaneurysms appears to matter less.[14] In HHT, some lesions (high-flow arteriovenous fistulae) tend to cause more problems, and treatment is warranted. Other AVMs may regress over time without intervention.[7] Various modalities are available, depending on the location of the AVM and its size: surgery, radiation-based treatment and embolization. Sometimes, multiple modalities are used on the same lesion.[2][14]
Surgery (bycraniotomy, open brain surgery) may be offered based on the risks of treatment as determined by the Spetzler–Martin scale (grade I-V); this score is higher in larger lesions that are close to important brain structures and have deep venous drainage. High grade lesions (IV and V) have an unacceptably high risk and surgery is not typically offered in those cases.Radiosurgery (using targetedradiation therapy such as by agamma knife) may be used if the lesion is small but close to vital structures. Finally, embolization may be used on small lesions that have only a single feeding vessel.[14]
Several anti-angiogenesis drugs approved for other conditions, such as cancer, have been investigated in small clinical trials.[22] The anti-VEGF antibodybevacizumab, for instance, has been usedoff-label in several studies. In a large clinical trial, bevacizumab infusion was associated with a decrease in cardiac output and reduced duration and number of episodes of epistaxis in treated HHT patients.[23]Thalidomide, another anti-angiogenesis drug, was also reported to have beneficial effects in HHT patients.[24] Thalidomide treatment was found to induce vessel maturation in an experimental mouse model of HHT and to reduce the severity and frequency of nosebleeds in the majority of a small group of HHT patients. The blood hemoglobin levels of these treated patients rose as a result of reduced hemorrhage and enhanced blood vessel stabilization.[25]
Population studies from numerous areas in the world have shown that HHT occurs at roughly the same rate in almost all populations: somewhere around 1 in 5000. In some areas, it is much more common; for instance, in theFrench region ofHaut Jura the rate is 1:2351 - twice as common as in other populations. This has been attributed to afounder effect, in which a population descending from a small number of ancestors has a high rate of a particular genetic trait because one of these ancestors harbored this trait.[8] In Haut Jura, this has been shown to be the result of a particularACVRL1 mutation (named c.1112dupG or c.1112_1113insG).[2] The highest rate of HHT is 1:1331, reported inBonaire andCuraçao, two islands in theCaribbean belonging to theNetherlands Antilles.[8]
Most people with HHT have a normal lifespan.[1] The skin lesions and nosebleeds tend to develop during childhood. AVMs are probably present from birth, but don't necessarily cause any symptoms. Frequent nosebleeds are the most common symptom and can significantly affectquality of life.[7]
Several 19th century English physicians, starting withHenry Gawen Sutton (1836–1891)[26] and followed byBenjamin Guy Babington (1794–1866)[27] andJohn Wickham Legg (1843–1921),[28] described the most common features of HHT, particularly the recurrent nosebleeds and the hereditary nature of the disease. The French physician Henri Jules Louis Marie Rendu (1844–1902) observed the skin and mucosal lesions, and distinguished the condition fromhemophilia.[29] The Canadian-bornSir William Osler (1849–1919), then atJohns Hopkins Hospital and later atOxford University, made further contributions with a 1901 report in which he described characteristic lesions in thedigestive tract.[30] The English physician Frederick Parkes Weber (1863–1962) reported further on the condition in 1907 with a series of cases.[31] The term "hereditary hemorrhagic telangiectasia" was first used by the American physician Frederic M. Hanes (1883–1946) in a 1909 article on the condition.[3][32]
The diagnosis of HHT remained a clinical one until the genetic defects that cause HHT were identified by a research group atDuke University Medical Center, in 1994 and 1996 respectively.[9][10] In 2000, the international scientific advisory committee of cureHHT formerly called the HHT Foundation International published the now widely used Curaçao criteria.[7][15] In 2006, a group of international experts met inCanada and formulated anevidence-basedguideline, sponsored by cureHHT.[7] This guideline has since been updated in 2020 and can be foundhere.