All you need to know about hereditary hemorrhagic telangiectasia.

As its name suggests, hereditary hemorrhagic telangiectasia is a genetic disease that causes a deregulation of angiogenesis, the process of blood vessel formation. Also known as Weber-Rendu-Osler syndrome, this disease is characterized by the appearance of cutaneous-mucosal telangiectasias, which is a permanent dilation of the capillaries in these areas, sometimes accompanied by arteriovenous malformations, and often by a chronic iron deficiency. The prevalence of hereditary hemorrhagic telangiectasia is estimated between 1/5000 and 1/8000.

The telangiectatic lesions characteristic of this condition have a red to blue color and are predominantly located on the face, lips, nasal or oral mucosa, and at the tips of the fingers and toes. In more severe cases, the lesions are present in the digestive tract, leading to significant risks of gastrointestinal bleeding. Furthermore, some patients exhibit pulmonary arteriovenous malformations, which can cause difficult breathing, extreme fatigue, or even erythrocytosis, a condition characterized by an overproduction of red blood cells. If left untreated, these malformations can eventually lead to a stroke.

The development of hereditary hemorrhagic telangiectasia is due to genetic mutations on autosomal genes, meaning those carried by non-sex chromosomes. This pathology thus affects both men and women. The transmission is said to be autosomal dominant because it is sufficient for the anomaly to affect a single copy of the gene for the disease to develop. Several studies have focused on the etiology of hereditary hemorrhagic telangiectasia and have determined that over 80% of affected patients present mutations in one of the following genes:

• Endoglin Gene (ENG) : This gene encodes for a homodimeric transmembrane protein, which is a major glycoprotein of the vascular endothelium. This protein is a component of the transforming growth factor beta (TGF-β) receptor complex and it binds to TGF-β1 and TGF-β3 with high affinity. It is primarily expressed in endothelial cells, activated monocytes, and tissue macrophages.

• Activin A receptor-like type 1 gene (ACVRL1) : This gene codes for activin receptor-like kinase (ALK1), a cell surface receptor for ligands of the TGF-beta family. It is predominantly expressed in endothelial cells, but also in lung and placental cells.

• Gene SMADH4 (MADH4) : this gene codes for the SMAD4 protein, playing a major role in the TGF beta signaling pathway.

Hereditary hemorrhagic telangiectasia is caused by a disruption in the TGF signaling pathway. This pathway plays a significant role in regulating numerous cellular processes such as proliferation, differentiation, adhesion, and migration. Moreover, the genes affected by mutations are necessary for the development and maintenance of arteriovenous identity, as well as the recruitment and differentiation of smooth muscle cells during the development of the vascular system.

The management of hereditary hemorrhagic telangiectasia depends on the organ affected. The goal is to prevent and stop bleeding. Treatment may include applying pressure, using a topical medication with a vasoconstrictor effect, or a laser beam to destroy the affected blood vessels in the nose or digestive tract. In cases of severe bleeding, surgery may be considered. An oral iron supplement is also typically prescribed.

Certain medications, such as bevacizumab, pazopanib, or pomalidomide, may also be prescribed to reduce the number and density of abnormal blood vessels. Finally, to minimize bleeding and inhibit the breakdown of blood clots, patients may require regular blood transfusions. These transfers are carried out from a healthy individual to a person suffering from hereditary hemorrhagic telangiectasia and must take into account blood group compatibility.

• PYERITZ R. E. & al. Hereditary Hemorrhagic Telangiectasia: An Overview of Diagnosis, Management, and Pathogenesis. Genetics in Medicine (2011).

• ZIZA J. M. & al. Rendu-Osler Disease: An Osteoarticular Infection Risk Factor Not to Be Overlooked. Rheumatism Review (2017).

• STEVENSON D. A. & et al. Hereditary Hemorrhagic Telangiectasia. GeneReviews (2021).