Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease, characterized by abnormal blood vessel formation. It manifests principally with telangiectatic lesions and arteriovenous malformations and results in bleeding and blood shunting.
Patients most commonly present with telangiectatic formations on their lips, face, oral mucosa and the tips of toes and fingers. These lesions can also be present in the gastrointestinal tract and nasal mucosa, resulting in severe GI bleeding or recurrent nosebleeds. Arteriovenous malformations can also occur in the lungs, leading to the formation of fistulas and right-to-left shunts. Right-sided cardiac stress may subsequently manifest with fatigue, shortness of breath and cyanosis .
HHT can have a sudden and acute neurological presentation. Patients may suffer from transient ischemic attacks, strokes and brain abscesses. Some forms of the disease are characterized by spinal and brain arteriovenous malformations with subsequent subarachnoid hemorrhaging, seizures or paralysis. AVMs can also occur in the liver and lead to high-output failure of the heart .
HHT can be diagnosed with genetic testing, but it is important to note that not all mutations involved in the disease have been identified. Family members of the patient in question should also be tested if the test is positive. On the other hand, a negative genetic test precludes from screening for manifestations and complications of HHT. This can be reassuring for parents, especially since the screening procedures may require anesthesia or the administration of sedatives. Children of parents diagnosed with HHT are considered to have the disease for screening purposes, unless genetic testing is explicitly negative .
Screening for HHT complications is mostly targeted at systemic pulmonary, cardiovascular and neurological manifestations. Contrast transthoracic echocardiography is the most important test used to detect AVMs in the lungs. Children who are too young to undergo the procedure may have their oxygen saturation rate measured with a pulse oximeter. A negative screening result on transthoracic echocardiography necessitates the repetition of the procedures every three to five years to detect any new lesions. MRI, on the other hand, is utilized to screen for the presence of AVMs in the brain. Adults undergo a specific MRI protocol to maximize sensitivity. It involves MRI with and without contrast, in addition to sequences that detect blood products. Children who are diagnosed or suspected to have HHT require a non-contrast MRI in the first 6 months of life. Positive findings necessitate referral to specialized neurovascular centers for possible invasive testing and treatment. Negative test results do not require the repetition of the MRI, although some experts recommend an MRI later in adulthood .
Treatment for HHT is generally supportive, although accessible telangiectatic lesions in the nose or in the gastrointestinal tract may be targeted with laser ablation . Surgical resection or embolization can also be used to remove characteristic arteriovenous fistulas present in the disorder .
Patients require hepatitis B immunization because of frequent blood transfusions. Significant blood loss also necessitates iron supplementation, sometimes parenteral, on top of erythropoietin therapy. Aminocaproic acid and tranexamic acid can also be used to inhibit fibrinolysis.
With aggressive and adequate treatment and screening, the prognosis of HHT is good, with the life expectancy of patients approaching that of the healthy population. On average, however, HHT shortens life expectancy with peaks of mortality occurring at 50 years of age and 60-79 years. The second peak is mostly related to the acute complications of the disease . Prognosis also depends on the extent and severity of the systemic involvement particularly in regards to the pulmonary system, liver and nervous system. Overall, complications of HHT result in the death of only 10% of patients.
Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease transmitted in an autosomal dominant fashion; Cases involving spontaneous mutations have been also described . Around 600 mutations are involved in the 4 genes associated with the disease, although a single family will usually share the same mutation.
Because it an autosomal dominant trait, the risk of transmission from a carrier parent to a child is around 50%, irrespective of the gender of the child. Normally, each individual possesses two copies from every gene, and a single copy of a dominant gene can be sufficient to drive phenotypic expression.
Four genes have been linked to HHT. One gene, called ENG, encodes for a protein called endoglin and is expressed on the membrane of endothelial cells. Scientists have shown that endoglin binds to the transforming growth factor beta (TGF-ß) and is critical to the normal development of blood vessels. Indeed, deficiencies in endoglin result in failure of blood vessel maturation and smooth muscle development .
On the other hand, mutations in the activin receptor-like kinase 1 (ACVRL1) are more strongly associated with liver arteriovenous malformations, as well as increased blood pressure in the pulmonary circulation (pulmonary hypertension) . The latter is also associated with mutations in the BMPR9 gene, which can cause characteristic vascular abnormalities present in HHT too. The fourth mutation that was identified is present in the SMAD4 gene and, in addition to HHT, it is associated with juvenile polyposis, a condition characterized by abnormal polyp growth in the gastrointestinal tract.
All of these genes have been linked to the TGF-ß/BMP (bone morphogenic protein) complex. This group of signaling molecules is associated with cellular growth, differentiation and survival. Abnormalities therein underlie problems in angiogenesis and result in the characteristic features of HHT.
HHT remains a very rare disease in the United States, with its incidence reported to be 1-2 cases per 100,000 individuals and prevalence around 1-2 cases in 10,000 individuals. The disease, however, may be much more common, since many patients have a mild asymptomatic form. For example, overall prevalence of HHT in Vermont is estimated to be 1 case in every 16,400 individuals .
HHT is much more common internationally, particularly in Europe and Japan, where it is estimated to be present in 1 out of 5000 to 8000 individuals . In Denmark, prevalence has increased from 13.8 to 15.6 cases in 100,000 individuals, across a 21-year time range from 1974 to 1995 .
HHT is an autosomal dominant disease with a penetrance of 97%.
Hereditary hemorrhagic telangiectasia is characterized by several abnormalities in vascular structure and function including telangiectasia, arteriovenous malformations and aneurysms. The pathophysiological mechanisms thought to underlie the disease are caused by a dysfunction in the transforming growth factor ß (TGF-ß) signaling complex, resulting in impaired endothelial growth and differentiation. Despite strong genetic links, ultrastructural imaging demonstrates normal vessel architecture in some areas, leading some researchers to propose that lesions are caused by an environmental trigger followed by impaired growth and repair .
Telangiectasias are dilated capillaries and postcapillary venules that are found most commonly in the retina, the gastrointestinal tract, mucous membranes, and conjunctiva. They result from weak perivascular connective tissue as well as disrupted endothelial junctions and degeneration. Arteriovenous malformations (AVMs), on the other hand, are tortuous veins and arteries that can result in left to right shunting and potential high-output heart failure. Aneurysms are caused by a loss of elasticity and muscular layers within the vessels and can be present in the liver, brain and lungs.
Several genes are involved in the pathogenesis of HHT and they generally affect processes related to angiogenesis, cell migration and proliferation, integrity of the cellular skeleton and nitric oxide synthesis . The majority of the genes responsible for telangiectasias and AVM bleeding are related to TGF-ß signaling and interactions. The most common mutations affect the endoglin and ALK-1 genes, which code for TGF-ß Type III and type I receptors respectively.
Endoglin promotes the binding of TGF-ß to type II TGF-ß receptors, ultimately resulting in the phosphorylation of ALK-5 and ALK-1, both type I TGF-ß receptors. These in turn activate Smad 2/3 and Smad 1/5, downstream proteins that dissociate from the TGF-ß receptors and exert their effects by binding to Smad 4. The bound Smad 4 protein can enter the nucleus and regulate the transcription of genes critical to angiogenesis. It is a delicate balance between ALK-5 and ALK-1 signaling pathways that ultimately shapes the characteristics of the endothelium in angiogenesis .
On a histopathological examination, blood vessels are characterized by thin, large and irregular walls but the damage is not equally expressed among individuals with HHT. Patients with O type blood seem to be affected more frequently, and there are no differences between men and women. The exact pathological mechanisms underlying these differences are still not well understood. Bleeding may also be related to coagulopathies and an elevated rate of fibrinolysis.
There are no known preventive measures for HHT.
Hereditary hemorrhagic telangiectasia (HHT) is a rare genetic disease characterized by the formation of telangiectasias and arteriovenous malformations . It is transmitted in an autosomal dominant fashion, although expression is not uniform. HHT is thought to be more common in individuals with an O blood type, but is equally prevalent in men and women.
Mutations in several genes involved in angiogenesis are thought to underlie the disease. They usually affect TGF-ß signaling, a molecule critical for cellular growth and differentiation. Defects in the TGF-ß pathway ultimately result in abnormal gene expression and vessel formation.
HHT most commonly presents with telangiectatic lesions on the face, oral and nasal mucosa, in the lungs, brain and gastrointestinal tract . Patients can suffer from recurrent nosebleeds and gastrointestinal hemorrhage. More severe forms of the disease can present acutely with strokes, transient ischemic attacks or brain abscesses.
Diagnosis is established with testing for genetic mutations, although not all genes responsible for the disease have been identified. Patients with a positive testing result require screening for other systemic manifestations, particularly with an MRI of the brain or a transthoracic echocardiography to detect lesions in the lungs.
Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease that targets the blood vessels and results in their abnormal development, structure and function. It is characterized by vessels with weak walls, as well as an absence of capillaries in some cases, the tiny vessels that are normally present between the arteries and the veins. HHT is transmitted in an autosomal dominant fashion. This entails that having one copy of the abnormal gene is sufficient to develop the disease. A child with an affected parent has a 50% chance of acquiring HHT.
HHT is caused by abnormal development and proliferation of endothelial cells, the cells that line the blood vessels. Several genetic mutations are thought to be involved, although four are most common. They ultimately result in abnormal communication between cells, largely due to defects in the signaling pathway of a molecule called TGF-ß.
Patients with HHT usually present with lesions of their capillaries on their face, in their nose or on the inside of their mouth. In some cases, lesions may also occur in the gastrointestinal tract, lungs and brain. Patients with HHT have an increased tendency to bleed and recurrent nosebleeds or gastrointestinal hemorrhage are not uncommon. More severe forms can also be distinguished. They involve lesions in the lungs, brain and liver and may lead to strokes, liver failure or heart failure.
HHT can be diagnosed with tests that detect abnormal genes. All family members of diagnosed patients need to be tested. Positive tests usually indicate a requirement to perform several screening procedures, to check for the presence of any of the severe systemic manifestations of HHT. These tests can involve sedation or anesthesia, which can be disconcerting for parents. Important screening tests are required to identify any lesions in the lungs and in the brain. In case the results return positive, the patients may need to be transferred to specialized centers for invasive diagnosis and treatment.
Treatment for HHT is mostly supportive although some lesions that are deemed accessible can be removed with laser ablation, embolisation or surgery. Patients may frequently require blood transfusions because of bleeding, so it is important for them to receive hepatitis B immunization. Blood loss can also necessitate supplementation with iron and a hormone called erythropoeitin.
HHT has a good prognosis if the patients are aggressively and adequately treated and screened. Overall, however, patients tend to have a shorter life expectancy. Mortality occurs at two peaks around 50 years of age and 60 - 79 years of age. The latter peak is due to acute complications.
There are no known preventive measures for HHT.