Of these, three have been linked to particular genes, while the two remaining have currently only been associated with a particular locus. More than 80% of all cases of HHT are due to mutations in either ENG or ACVRL1. 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, although some reports suggest that ENG mutations are more likely to cause lung problems while ACVRL1 mutations may cause more liver problems, and pulmonary hypertension may be a particular problem in people with ACVRL1 mutations. 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. Pathophysiology
Telangiectasias and arteriovenous malformations in HHT are thought to arise because of changes in angiogenesis, 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, chiefly endothelium, smooth muscle and pericytes. 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.
Pseudostrabismus is the false appearance of crossed eyes. When the eyes are actually crossed or not completely aligned with one another, it is called strabismus. Pseudostrabismus is more likely to be observed in East Asian or Native American infants, due to the presence of epicanthic folds obscuring the medial aspect of each eye. Pseudostrabismus generally occurs in infants and toddlers, whose facial features are not fully developed. The bridge of their nose is wide and flat, creating telecanthus (increased distance between medial canthus of both eyes). With age, the bridge will narrow, and the epicanthic folds in the corner of the eyes will go away. This will cause the eyes to appear wider and thus not have the appearance of strabismus. To detect the difference between strabismus and pseudostrabismus, clinicians use a flashlight to shine into the childs eyes. When the child is looking at the light, a reflection can be seen on the front surface of the pupil. If the eyes are aligned with one another, the reflection from the light will be in the same spot of each eye. If strabismus is present, the reflection from the light will not be in the same spot of each eye. Rakels Textbook of Family Medicine states, "A common misconception is that children with crossed eyes outgrow the condition, but this is generally not the case. This belief stems from the confusion between true strabismus and pseudostrabismus.