Consider for a moment that your life is dominated by spontaneous nosebleeds, chronic stomach hemorrhaging, persistent anemia and a complex constellation of other manifestations, some potentially life-threatening.
These symptoms characterize a rare genetic condition known as hereditary hemorrhagic telangiectasia, or HHT.
The disorder disrupts the normal formation of blood vessels and is marked by yet another serious complication: the emergence of abnormal entanglements of blood vessels called arteriovenous malformations (AVMs). These vascular obstructions, like Gordian knots, block normal blood flow and deprive the body’s tissues of oxygen.
In New York, scientists at the Feinstein Institute for Medical Research have embarked on an ambitious study enabling them to examine the molecular mechanisms that drive HHT.
They additionally found that two “off the shelf” medications can fully block or reverse some of the disorder’s most devastating complications.
The discoveries involved strains of specially bred test mice.
Retinal AVMs, retinal bleeding and anemia were prevented in some groups of test animals; gastrointestinal bleeding was significantly reduced in others.
The discovery of major symptom reversal or reduction lays the groundwork for human clinical trials, the medical investigators say.
“HHT is indeed a genetic disorder,” Dr. Philippe Marambaud, lead scientist of the HHT research told Medical Xpress. His institute, which is located in Manhasset on Long Island, has garnered an international reputation for tackling complex medical conditions and researching innovative treatments to address them.
Marambaud defines HHT’s primary features as vascular dysplasia, the abnormal development of cells in blood vessel walls, which are capable of impairing vascular function. Another characteristic of the disorder, hemorrhagic lesions, are common in a variety of organs and tissues, such as the liver, lungs and mucosa.
“The main manifestations of the disease are epistaxis—nosebleeds—internal bleedings, and anemia.
It is an autosomal dominant genetic disease, meaning that inheritance of one of the mutated genes from the mother or father is sufficient to cause the disease.
An estimated 1.4 million people are affected by HHT worldwide, and about 85 percent of patients diagnosed with the condition “carry mutations in one of two genes: ALK1 or endoglin. Mutations are causing factors, not susceptibility factors,” Marambaud said.
He conducted the HHT investigation with colleagues, Drs. Santiago Ruiz and Fabien Campagne, both researchers at the Feinstein Institute.
In a scientific paper newly published in the Journal of Clinical Investigation, Marambaud and his team reported that two well-known drugs already given a green light by the U.S. Food and Drug Administration reversed or reduced disease-related pathology. The drugs acted on key signaling pathways to inhibit complications of the disorder, the scientists discovered.
“We found that a combination of two FDA-approved drugs correct the molecular defects and associated AVMs in HHT mouse models,” Marambaud said.
“Previous work had proposed that the pathways, mTOR and VEGFR2, were abnormally over-activated in HHT models and HHT patients.
We confirmed these observations and found treatments with a combination of two drugs that target mTOR and VEGFR2 significantly blocked the vascular pathology in HHT mice.
“These two drugs are sirolimus, an mTOR inhibitor and nintedanib, a VEGFR2 inhibitor. Our data suggest that repurposing of sirolimus plus nintedanib might provide therapeutic benefit in HHT patients,” Marambaud said.
Sirolimus, one of the drugs studied at the Feinstein Institute, is an old school medication, originally developed in 1972 as an antibiotic.
It is also known as rapamycin and belongs to the class of drugs called macrolides. Scientists have long been aware of the impact that sirolimus has on vascular cells.
Coronary stents, which prop open clogged arteries, are coated with sirolimus. Release of the medication from the mesh-like devices inhibits the proliferation of smooth muscle cells, which can play a role in a vessel becoming reclogged. The coated implants are known as drug-eluting stents.
Sirolimus also has powerful immunosuppressant capabilities and is used in organ transplantation to prevent rejection.
It does so by inhibiting T cell and B cell activation. Blocking these two major fighting forces of the immune system occurs because sirolimus reduces their sensitivity to interleukin-2 via mTOR inhibition. This signaling pathway—mTOR—is also important in HHT, Marambaud and his colleagues found.
Nintedanib, a receptor kinase inhibitor, is the other medication under study by Marambaud and his team. It is conventionally used in the treatment of idiopathic pulmonary fibrosis, a disease marked by stiffening and scarring of lung tissue, impairing the ability to breathe.
The synergistic impact between sirolimus and nintedanib, at least in animal models, suggests a possible role in human HHT.
Currently, doctors have treatments to control HHT’s myriad symptoms, but those interventions are not cures. In the United States, it is strongly recommended that patients seek care in “centers of excellence” where physicians specialize in the treatment of the rare hereditary disorder.
Marambaud, meanwhile, hesitates to call the drug combination a potential cure. “A cure is an ambitious claim,” Marambaud said. “Clinical trials would have to be initiated to determine the therapeutic potential in humans. I would say this is a very promising mechanism-based and disease-modifying approach to treat the AVMs in HHT.”
Hereditary hemorrhagic telangiectasia (HHT), a rare genetic vascular disorder, has been rarely reported in South Korea. We investigated the current prevalence and presenting patterns of genetically confirmed HHT in South Korea.
Materials and Methods
We defined HHT patients as those with proven mutations on known HHT-related genes (ENG, ACVRL1, SMAD4, and GDF2) or those fulfilling 3 or 4 of the Curaçao criteria. A computerized systematic search was performed in PubMed and KoreaMed using the following search term: (“hereditary hemorrhagic telangiectasia” AND “Korea”) OR (“Osler-Weber-Rendu” AND “Korea”). We also collected government health insurance data. HHT genetic testing results were collected from three tertiary hospitals in which the genetic tests were performed. We integrated patient data by analyzing each case to obtain the prevalence and presenting pattern of HHT in South Korea.
We extracted 90 cases from 52 relevant articles from PubMed and KoreaMed. An additional 22 cases were identified from the three Korean tertiary hospitals after excluding seven cases that overlapped with those in the published articles. Finally, 112 HHT patients were identified (41 males and 71 females, aged 4–82 years [mean±standard deviation, 45.3±20.6 years]). The prevalence of HHT in South Korea is about 1 in 500,000, with an almost equal prevalence among men and women. Forty-nine patients underwent genetic testing, of whom 28 had HHT1 (ENG mutation) and 19 had HHT2 (ACVRL1 mutation); the other two patients were negative for ENG, ACVRL1, and SMAD4 mutations.
The prevalence of HHT is underestimated in Korea. The rate of phenotypic presentation seems to be similar to that found worldwide. Korean health insurance coverage is limited to representative genetic analysis to detect ENG and ACVRL1 mutations. Further genetic analyses to detect HHT3, HHT4, and other forms of HHT should be implemented.
Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is a rare genetic vascular disorder affecting about 1 or 2 in 10,000 individuals worldwide . It is a systemic disease characterized by recurrent epistaxis, multiple mucocutaneous telangiectasias, and arteriovenous (AV) shunts in various organs. The diagnosis of HHT is based on the Curaçao criteria: 1) spontaneous and recurrent epistaxis; 2) multiple mucocutaneous telangiectasia at characteristic sites, including the lips, oral cavity, fingers, and nose; 3) visceral involvement, such as gastrointestinal (GI) telangiectasis, pulmonary, cerebral, or hepatic AV shunts; and 4) a first-degree relative with HHT . The diagnosis of HHT is definite when three criteria are met, possible when two criteria are met, and unlikely when less than two criteria are met.
HHT is inherited via an autosomal dominant pattern. To date, six genes and four related protein molecules have been discovered for HHT and HHT-like diseases (Table 1). The majority of HHT cases are HHT1 ([Online] Mendelian Inheritance in Man, [MIM] #187300) or HHT2 (MIM #600376), with roughly equal proportions of each . More than 1,000 different mutations have been identified as associated with HHT1 and HHT2 [4,5]. Other rare subtypes include Juvenile polyposis-HHT overlap syndrome (JPHT, MIM #175050), HHT5 (MIM #615506), HHT3 (MIM %601101), and HHT4 (MIM %610655). HHT1 is caused by mutations in the ENG gene (chromosomal locus, 9q34.11) and HHT2 is caused by mutations in the activin receptor-like kinase 1 (ACVRL1) gene (chromosomal locus, 12q13.13). JPHT is caused by mutations in the SMAD4 gene.
Types of HHT
|Phenotype||Phenotype MIM number||Gene/locus||Gene location||Gene/locus MIM number||Protein|
HHT, hereditary hemorrhagic telangiectasia; MIM, (Online) Mendelian Inheritance in Man; ALK, activin receptor-like kinase; GDF, growth differentiation factor; JPHT, juvenile polyposis-HHT overlap syndrome.
To our knowledge, there has been no nationwide study focusing on HHT in the South Korean population. This study aimed to review HHT cases in South Korea and compare epidemiologic patterns with global patterns.
Clinical manifestation of HHT
Recurrent epistaxis is usually the earliest clinical sign of HHT. The mean age of onset of epistaxis is 12 years, and it occurs in more than 90% of HHT patients . The degree, interval, and duration of epistaxis vary by patient.
The main source of epistaxis is telangiectasis of the nasal mucosa. Recurrent GI bleeding is observed in 20% to 30% of patients with HHT. The main source of GI bleeding is telangiectasis of the GI mucosa. Upper GI telangiectasias are more common than lower GI telangiectasias .
Both epistaxis and GI bleeding can result in iron deficiency anemia and may require blood transfusion in severe cases . Mucocutaneous telangiectasis involving the skin and oral mucosa occurs in more than half of HHT patients, usually in later life .
The fingertips are the most common location of cutaneous telangiectasis.
Dilatation and malformation of larger visceral vessels can occur in HHT and can manifest as AV shunts. Pulmonary AVM is the most common type of AV shunt, occurring in almost half of HHT patients.
AVMs are clinically important in that they are anatomical right-to-left shunts, and they may cause hypoxemia, paradoxical embolic cerebral infarctions, or cerebral abscesses . Hepatic AV shunts are identified in 30% to 60% of HHT patients.
Complications of hepatic AV shunts include hepatic encephalopathy due to portovenous shunts; portal hypertension, heart failure, and pulmonary hypertension due to large left-to-right shunts and high cardiac output; and pseudocirrhosis or cirrhosis of the liver .
Pulmonary AVMs and CNS AV shunts are more common in HHT1 than HHT2, whereas hepatic AV shunts are more common in HHT2 .
Our case analysis showed overall lower incidence of clinical manifestations, compared with worldwide incidence. This may be due to considerable missing data due to the nature of this study, and thus is the limitation of our study. However, the ratios of incidences of clinical manifestations between HHT1 and HHT2 were similar to that of worldwide.
The rate of epistaxis was similar in HHT1 and HHT2. There was no case of GI bleeding in HHT1 and rate of hepatic AV shunt was lower than that of HHT2. On the other hands, there was no case of cerebral AV shunt in HHT2 and the rate of pulmonary AVM was lower than that of HHT1.
Neurological manifestations of HHT
The neurologic manifestations of HHT include embolic stroke, abscess formation, migraine, hemorrhagic stroke, and seizures . The most frequent complications are stroke and cerebral abscess, mainly caused by paradoxical embolism .
Pulmonary AVMs—which are reported in 20% to 30% of HHT patients—are the most frequent manifestations of the disease and are responsible for a right-to-left shunting leading to paradoxical embolism, causing stroke or cerebral abscess formation.
CNS AV shunting is noted in 10% of HHT patients. Unlike pulmonary AVMs, CNS AV shunts also occur in infants and young adults with a tendency toward multiplicity, small size, and cortical location. CNS AV shunts include cerebral AVMs, cerebral micro-AVMs, high-flow arteriovenous fistulas (AVFs), and telangiectasias .
They are usually silent but can present with seizures, ischemia, or hemorrhage. These complications are associated with a higher risk of subsequent hemorrhage, as is the case among patients with sporadic brain AVMs . High-flow AVFs are most commonly found in children.
Developmental venous anomalies and cerebral aneurysms can also be found in HHT patients . Malformations of cortical developments (MCDs), mostly polymicrogyria, are sometimes observed in association with HHT .
The exact pathogenetic mechanism for MCDs is not well established; however, it is postulated that decreased expression of ENG may result in focal hypersprouting angiogenesis during corticogenesis, leading to MCD .
All cases reported to date have been associated with HHT1, and the lesions are characteristically unilateral, focal, and correlate with arterial regions exposed to the lowest fluid shear stress in utero .
Genetic biology in HHT
HHT is characterized by sporadic diameter deviations in smaller and larger vessels, and thus frequent AVMs. AVMs lead to the formation of direct connections between feeding arterioles and the draining veins that shunt blood flow and effectively bypass the capillary network. Between 85% and 90% of HHT genetic drivers are linked to impaired activity of the bone morphogenetic protein (BMP) pathway, and these include heterozygous loss-of-function mutations in endoglin (ENG/CD105), in activin A receptor-like kinase 1 (ACVRL1/ALK1), and in cytosolic sterile alpha motif domain-containing 4A (SMAD4) .
A candidate gene approach identified mutations in the transforming growth factor (TGF)-β coreceptor gene ENG in patients with HHT type 1, whereas mutations in the TGF-β type I receptor ALK1 (ACVRL1) cause HHT type 2 .
Both genes are predominantly expressed in endothelial cells and have been shown to be regulated by hemodynamic forces in mice and zebrafish. Mutations in ENG, which encodes an auxiliary receptor in the TGF-β superfamily signaling pathway, are responsible for HHT type 1, characterized in part by blood vessel enlargement.
Mutations in components of the TGF-β superfamily of signaling molecules disrupt this pattern of hierarchically ordered blood vessel trees and cause AVMs. ENG is a TGF-β coreceptor that enhances signaling through the type I receptor ALK1.
In contrast to what was reported in early studies, endothelial cell proliferation is regarded as a secondary event, driving further enlargement but not the initiation of AVM. A recent report highlighted clonal endothelial proliferation as a major effect of deficient BMP signaling downstream of ALK1-ENG signaling .
BMPs 9 and 10 have been known as the primary ligands for ALK1/ENG. Importantly, ENG potentiates ALK1 pathway activation downstream of hemodynamic forces .
Inducible homozygous endothelial-specific deletion of ALK1 or ENG during development consistently drives AVMs; however, additional triggers in the adult—such as inflammation, wounding, or VEGF overexpression—are required for AVMs to develop .
A full understanding of the mechanisms of vessel diameter control and AVM formation will require insights into quantitative relationships between cell numbers, their movement, their relative shape changes and mutual dependencies on flow, and the gene dose and signaling dose responses in this adaptive system .
Screening of family members with HHT
The life expectancy of unscreened and untreated HHT patients is lower than that of people without HHT with an earlier median age of death ranging from 3 to 7 years [13,24]. HHT guidelines recommend screening children with suspected or diagnosed HHT for pulmonary AVMs and cerebral AVMs. The choice of screening tests for pulmonary AVMs should be decided on a case-by-case basis.
The neurologic complications of HHT attributed to these AVMs include embolic stroke, cerebral abscess formation, migraine, hemorrhagic stroke, and seizures . Screening for cerebral AVMs in children is recommended by HHT guidelines, and it is performed in North American HHT centers; however, in some other countries, screening for cerebral AVMs is postponed until adulthood [24,25].
Unenhanced magnetic resonance imaging is recommended to detect cerebral AVMs as early as possible or at the time of diagnosis, preferably in the first 6 months of life .
If no cerebral AVMs are detected by this scan in adulthood, no further screening for cerebral AVMs is recommended.
Screening for the presence of HHT and of pulmonary and cerebral AVMs, combined with treatment if indicated, will prevent severe complications and will result in a similar life expectancy compared to that of the general population .
Limitations of this study
There were several limitations in this study. First, as mentioned above, there might be some missing data in collecting patients with HHT. However, the methodology to find out specific presenting patterns according to the subtype of HHT is limited due to rarity of the disease and diversity of the symptoms.
Second, genetic studies were not performed in more than half of the cases.
Therefore, analysis of the subtype of HHT may be incomplete for those who did not undergo a genetic study. Third, although we eliminated the overlaps of cases, there is still a possibility of duplicated cases. A large-scale nationwide registry or cross-sectional study is warranted in the future.
More information: Santiago Ruiz et al. Correcting Smad1/5/8, mTOR, and VEGFR2 treats pathology in hereditary hemorrhagic telangiectasia models, Journal of Clinical Investigation (2019). DOI: 10.1172/JCI127425
Journal information:Journal of Clinical Investigation