Введение
Медицинское состояние (генетическое расстройство)
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 "definite HHT", while two gives "possible HHT":
Spontaneous recurrent epistaxis
Multiple telangiectasias in typical locations (see above)
Proven visceral AVM (lung, liver, brain, spine)
First degree family member with 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. 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. 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.
Наследственная геморрагическая телеангиэктазия (НГТ), также известная как болезнь Ослера-Вебера-Ренду и синдром Ослера-Вебера-Ренду, является редким аутосомно-доминантным генетическим расстройством, приводящим к аномальному образованию кровеносных сосудов в коже, слизистых оболочках и часто в органах, таких как легкие, печень и мозг. Кожные проявления обычно возникают на губах, носу и пальцах, а также на коже лица в областях, подверженных воздействию солнечных лучей. Они появляются внезапно, и их количество увеличивается со временем. Кровотечение из легочных артериовенозных мальформаций (АВМ) относительно нечасто, но может вызывать гемоптиз (кашель с кровью) или гемоторакс (накопление крови в плевральной полости). Если АВМ создает соединение между портальной веной и кровеносными сосудами печени, результатом может быть портальная гипертензия (повышенное давление в портальной вене), при которой в пищеводе формируются коллатеральные сосуды (варикозное расширение вен пищевода), склонные к сильному кровотечению; кроме того, повышенное давление может привести к накоплению жидкости в брюшной полости (асцит). Если кровоток в АВМ направлен в противоположную сторону, венозная кровь из портальной вены поступает непосредственно в вены, минуя печень; это может привести к печеночной энцефалопатии (спутанность сознания, вызванная токсинами, раздражающими мозг). Редко желчные протоки оказываются лишенными кровоснабжения, что приводит к тяжелому холангиту (воспалению желчных протоков). Гомозиготность, по-видимому, приводит к летальному исходу внутриутробно. Известно более 600 различных мутаций. Вероятно, в определенных популяциях преобладает один из типов, но данные противоречивы. Мутации в гене MADH4, вызывающие полипоз толстой кишки в дополнение к НГТ, составляют около 2% мутаций, вызывающих заболевание. Помимо MADH4, неясно, приводят ли мутации в генах ENG и ACVRL1 к определенным симптомам. Наблюдается высокая доля мутаций со сдвигом рамки считывания.
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 "definite HHT", while two gives "possible HHT":
Spontaneous recurrent epistaxis
Multiple telangiectasias in typical locations (see above)
Proven visceral AVM (lung, liver, brain, spine)
First degree family member with 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. 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. 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.
| HHT3 |
| Неизвестна | 5q31 | Неизвестна, связь идентифицирована в 2005 году. |
| HHT4 |
| Неизвестна | 7p14 | Неизвестна, связь идентифицирована в 2006 году. |
| JPHT |
| MADH4 | 18q21.1 | MADH4 кодирует SMAD4, внутриклеточный сигнальный белок для рецепторов семейства TGF. Мутации в этом гене вызывают НГТ и ювенильный полипоз. Связь идентифицирована в 2004 году. Мутации в основном в экзонах 8–11, часто de novo (новоприобретенные, не унаследованные). В общем, рекомендуется МРТ. Если выполняются три или четыре критерия, у пациента диагностируется "определенная НГТ", а два критерия соответствуют "возможной НГТ":
Спонтанный рецидивирующий носовой кровотечение
Множественные телеангиэктазии в типичных локализациях (см. выше)
Подтвержденная висцеральная АВМ (легкие, печень, мозг, спинной мозг)
Член семьи первой степени родства с НГТ
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 "definite HHT", while two gives "possible HHT":
Spontaneous recurrent epistaxis
Multiple telangiectasias in typical locations (see above)
Proven visceral AVM (lung, liver, brain, spine)
First degree family member with 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. 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. 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.
Несмотря на обозначение "возможная", человек с висцеральной АВМ и семейным анамнезом, но без носовых кровотечений или телеангиэктазий, все равно имеет очень высокую вероятность наличия НГТ, поскольку эти АВМ очень редки в общей популяции. В то же время, то же самое нельзя сказать о носовых кровотечениях и скудных телеангиэктазиях, которые встречаются у людей без НГТ в отсутствие АВМ. Диагностический статус человека может меняться в течение жизни, поскольку у маленьких детей могут еще не проявляться все симптомы; в 16 лет у тринадцати процентов все еще неопределенный диагноз, в то время как в 60 лет подавляющее большинство (99%) имеют четкую диагностическую классификацию. Поэтому дети пациентов с установленной НГТ могут быть классифицированы как "возможная НГТ", поскольку у 50% из них в течение жизни может развиться НГТ. Частые носовые кровотечения можно частично предотвратить, поддерживая влажность в ноздрях и применяя солевой раствор, кремы, содержащие эстроген, или транексамовую кислоту; они имеют мало побочных эффектов и могут оказать небольшое положительное влияние. Существуют два хирургических метода: один заключается в пересадке кожи в ноздри, а другой – процедура Янга, при которой ноздри полностью закрываются. Процедура включает в себя пункцию крупной вены (обычно под общим наркозом), затем продвижение катетера через правый желудочек и в легочную артерию, после чего вводится рентгеноконтрастное вещество для визуализации АВМ (легочная ангиография). После выявления поражения разворачиваются спирали, которые блокируют кровоток и позволяют поражению регрессировать. В опытных руках процедура, как правило, очень эффективна и имеет ограниченные побочные эффекты, но поражения могут рецидивировать и могут потребоваться дальнейшие попытки. Компьютерная томографическая ангиография (КТА) повторяется для контроля рецидива. Например, анти-VEGF-антитело бевацизумаб использовалось вне инструкции в нескольких исследованиях. В крупном клиническом исследовании инфузия бевацизумаба была связана со снижением сердечного выброса и уменьшением продолжительности и количества эпизодов носовых кровотечений у пациентов с НГТ, получавших лечение. Талидомид, другой антиангиогенный препарат, также показал положительные эффекты у пациентов с НГТ. Лечение талидомидом, как было обнаружено, индуцирует созревание сосудов в экспериментальной мышиной модели НГТ и снижает тяжесть и частоту носовых кровотечений у большинства небольшой группы пациентов с НГТ. Уровень гемоглобина в крови у этих пациентов, получавших лечение, повысился в результате уменьшения кровотечений и усиления стабилизации сосудов.
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 "definite HHT", while two gives "possible HHT":
Spontaneous recurrent epistaxis
Multiple telangiectasias in typical locations (see above)
Proven visceral AVM (lung, liver, brain, spine)
First degree family member with 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. 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. 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.
Эпидемиология
Исследования популяций из различных регионов мира показали, что HHT встречается с примерно одинаковой частотой в большинстве популяций: примерно в 1 случае на 5000. В некоторых областях заболеваемость значительно выше; например, во французском регионе О-Жюра она составляет 1:2351, то есть в два раза выше, чем в других популяциях. Это связывают с эффектом основателя, когда популяция, происходящая от небольшого числа предков, имеет высокую частоту определенного генетического признака, поскольку один из этих предков был носителем этого признака. За описанием наиболее распространенных признаков HHT, в частности, рецидивирующих носовых кровотечений и наследственного характера заболевания, последовали работы Бенджамина Гая Бэбингтона (1794–1866) и Джона Уикхема Легга (1843–1921). Французский врач Анри Жюль Луи Мари Ренду (1844–1902) наблюдал поражения кожи и слизистых оболочек и отделил это состояние от гемофилии. Канадский врач сэр Уильям Ослер (1849–1919), работавший в больнице Джона Хопкинса, а затем в Оксфордском университете, внес дальнейший вклад, опубликовав в 1901 году доклад, в котором описал характерные поражения желудочно-кишечного тракта. Английский врач Фредерик Паркс Вебер (1863–1962) представил дополнительные данные о заболевании в 1907 году, опубликовав серию случаев. Термин «наследственная геморрагическая телеангиэктазия» впервые был использован американским врачом Фредериком М. Хейнсом (1883–1946) в статье 1909 года, посвященной этому состоянию. Диагноз HHT оставался клиническим до тех пор, пока генетические дефекты, вызывающие HHT, не были идентифицированы исследовательской группой Медицинского центра Университета Дьюка в 1994 и 1996 годах соответственно. В 2000 году международный научный консультативный комитет cureHHT, ранее известный как Международный фонд HHT, опубликовал широко используемые в настоящее время критерии Кюрасао. В 2006 году группа международных экспертов встретилась в Канаде и разработала руководство, основанное на доказательствах, при поддержке cureHHT. Это руководство было обновлено в 2020 году и доступно здесь.