Dermatologic Manifestations of Osler-Weber-Rendu Syndrome 

Osler-Weber-Rendu syndrome, or hereditary hemorrhagic telangiectasia (HHT), is a rare genetically determined disorder that affects blood vessels throughout the body and results in a tendency for bleeding. HHT is an autosomal dominant disorder characterized by vascular dysplasia and hemorrhage. The prognosis for the disease is good as long as bleeding is promptly recognized and adequately controlled.

The pathogenesis regarding the heterogeneity of vascular malformations in patients with Osler-Weber-Rendu syndrome, or hereditary hemorrhagic telangiectasia (HHT), is obscure. A partial explanation of the pathogenesis of HHT has become possible with the identification of 2 distinct genes: the endoglin gene and the activin receptorlike kinase type I (ALK-1) gene. Endoglin and ALK-1 are type III and type I transforming growth factor-beta (TGF-B) receptors, and both are exclusively expressed on vascular endothelial cells. The binding of TGF-B to the type II TGF-B receptor on endothelial cells, which is accelerated in the presence of endoglin, results in the phosphorylation of type I TGF-B receptors, activin receptorlike kinase type 5 (ALK-5), and ALK-1. Phosphorylated ALK-5 and ALK-1 activate the downstream proteins Smad2/3 and Smad1/5, respectively.^[1]

The activated Smad proteins dissociate from the type I TGF-B receptor, bind to Smad4, and enter the nucleus to transmit TGF-B signals by regulating transcription from specific gene promoters involved in angiogenesis. Therefore, a balance between the 2 signaling pathways involving ALK-5 and ALK-1 is important in determining the properties of endothelial cells during angiogenesis.

Mutations of endoglin genes and ALK-1 genes are involved in the genetic pathogenesis of HHT type 1 and HHT type 2, respectively. To date, different mutations in endoglin (at least 29) and ALK-1 (at least 17) have been found; these include missense, nonsense, frameshift, and deletion mutations. The precise mechanisms of by which these mutations elicit the vascular abnormalities in patients with HHT remain uncertain. However, the elucidation of the intracellular signal transduction mechanisms and change in targeted gene expressions by using mutant recombinant endoglin or ALK-1 proteins and knockout mice will enable physicians to understand the genetic and molecular pathogenesis of HHT and to effectively treat patients with HHT.

HHT is a disorder that is inherited in an autosomal dominant fashion,^[2] although 20% of patients are unaware of a positive family history, partly because the lesions may be minimal and because 10% of patients have no episodes of bleeding. The homozygous condition probably is fatal. Histopathologic studies reveal large, irregular, thinly walled blood vessels, but the pathogenesis has not been fully established. One current theory states that systemic nevus vascular damage may not be equally expressed in all individuals with HHT. Individuals with blood group type O are affected more often, whereas males and females are affected equally. Coagulation abnormalities and increased fibrinolytic activity in the lesions may contribute to the tendency for bleeding.

Frequency

United States

Osler-Weber-Rendu syndrome, or hereditary hemorrhagic telangiectasia (HHT), is rare. Prevalence is 1-2 cases per 100,000 population.

International

The onsets, courses of illness, and sex distributions are the same worldwide. The condition is much more common on the Danish island of Fyn, in the Dutch Antilles, and in parts of France.

Mortality/Morbidity

Most patients with Osler-Weber-Rendu syndrome, or hereditary hemorrhagic telangiectasia (HHT), have a favorable prognosis.

• Frequent nosebleeds and melena may result from telangiectasia in the nose and GI tract. Patients with the severe form of HHT have heavy bleeding and resultant iron-deficiency anemia. Recurrent epistaxis is observed in 50-80% of patients. In half the patients, the epistaxis becomes more serious with age, and blood transfusions are required in 10-30% of patients.
• Pulmonary and CNS arteriovenous aneurysms may appear later in life. Patients with pulmonary AVMs and telangiectasis of the GI tract are at risk for life-threatening hemorrhage of the lungs and GI tract.
• Other sites of bleeding may include sites in the GI tract, kidney, spleen, bladder, liver, meninges, and brain. Strokes in patients with Osler-Weber-Rendu syndrome may be either hemorrhagic or ischemic. Of patients who have pulmonary AVMs, 2% per year are estimated to have a stroke and 1% per year are estimated to develop a brain abscess. Retinal arteriovenous aneurysms occur only rarely.

Race

No racial predilection is recognized.

Sex

Males and females are affected equally.

Age

HHT may occur in children, in whom a tendency to bleed may be the first symptom.^[3] However, HHT is far more common during puberty or adulthood. The syndrome most often manifests by the second or third decade of life. Pulmonary AVMs may be congenital and, therefore, diagnosed within the first year of life. The risk of GI tract bleeding increases in patients older than 50 years.