thumb|Lesions lips, patient with hemorrhagic hereditary 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. 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. Bleeding from lung AVMs is relatively unusual, but may cause hemoptysis (coughing up blood) or hemothorax (blood accumulating in the chest cavity). 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). Homozygosity appears to be fatal in utero. 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, A high proportion of frameshift mutations has been observed.
|-
| HHT3
|
| Unknown
| 5q31
| Function unknown, linkage identified in 2005.
|-
| HHT4
|
| Unknown
| 7p14.
| Function unknown, linkage identified in 2006.
|-
| JPHT
|
| 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). In general, MRI is recommended.
If three or four are met, a patient has HHT:
- Epistaxis: spontaneous and recurrent nosebleeds
- Telangiectases: multiple telangiectases at characteristic sites, including the lips, oral cavity, fingers, and nose
- Visceral lesions: including pulmonary, hepatic, cerebral, or spinal arteriovenous malformations (AVMs), or gastrointestinal telangiectasia
- Family history: a first-degree relative previously diagnosed with HHT according to these criteria
The original diagnostic classification was determined by the number of criteria present:
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.
Frequent nosebleeds can be prevented in part by keeping the nostrils moist, and by applying saline solution, estrogen-containing creams or tranexamic acid; these have few side effects and may have a small degree of benefit. Nevertheless, many doctors prefer alternative VEGF inhibitors; eg bevacizumab nasal spray also significantly reduces epistaxis severity without side effects.
If other interventions have failed, several operations have been reported to provide benefit. One is septal dermoplasty or Saunders' procedure, in which skin is transplanted into the nostrils, and the other is Young's procedure, in which the nostrils are sealed off completely. The procedure involves puncture of a large vein (usually under a general anesthetic), followed by advancing of a catheter through the right ventricle and into the pulmonary artery, after which radiocontrast 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. The anti-VEGF antibody bevacizumab, for instance, has been used off-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. Thalidomide, another anti-angiogenesis drug, was also reported to have beneficial effects in HHT patients. 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.
Epidemiology
right|thumb|The [[Netherlands Antilles, where HHT is more common than anywhere in the world, located off the coast of Venezuela.]]
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 the French region of Haut Jura the rate is 1:2351 - twice as common as in other populations. This has been attributed to a founder 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. and followed by Benjamin Guy Babington (1794–1866) and John Wickham Legg (1843–1921), 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 from hemophilia. The Canadian-born Sir William Osler (1849–1919), then at Johns Hopkins Hospital and later at Oxford University, made further contributions with a 1901 report in which he described characteristic lesions in the digestive tract. The English physician Frederick Parkes Weber (1863–1962) reported further on the condition in 1907 with a series of cases. The term "hereditary hemorrhagic telangiectasia" was first used by the American physician Frederic M. Hanes (1883–1946) in a 1909 article on the condition.
Genetic and diagnostic developments
The diagnosis of HHT remained a clinical one until the genetic defects that cause HHT were identified by a research group at Duke University Medical Center, in 1994 and 1996 respectively.