Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu Syndrome) with Transfusion Requirement. Effect of Danazol in 18 Patients with Long Follow-Up.

Hereditary hemorrhagic telangiectasia (HHT) is a relatively uncommon, autosomal dominant disorder characterized by telangiectases that develop in the skin, mucous membranes, and visceral organs. Mucous localization may seldom bleed profusely, especially epistaxis and upper gastrointestinal (GI) tract. Effective drug treatment is not well established, and multiple blood transfusions and endoscopic or surgical procedures may be the ultimate solution to the frequently bleeding HHT patient. Danazol (DZ) is a mild androgen that has been used in small series of HHT pts with ambiguous results. Its toxicity profile in long standing administration is now well known. Eighteen patients with HHT with transfusion requirements (TR) were treated with DZ at 400–600 mg/daily for the initial three months and 200–400 mg/daily thereafter as a maintenance treatment. At the time of initiation of DZ therapy, median age was 54 yr-old (32–73), nine were female and 9 male, and the median previous TR was 16 RBC units/yr. (2–46). All patients had epistaxis and oral cavity bleeding, with 2 additional upper gastrointestinal tract active bleeding that were detected in ten patients in which an upper GI endoscopy was performed. One patient had a cerebral angioma, surgically treated. None had pulmonary fistula. All patients had some kind of iron treatment. DZ was the first drug treatment intended to reduce the HHT bleeding in 10/18 pts. Median follow-up was 7 years (1.2–14) and two pts were lost to follow-up at 4 and 11 years respectively. At three months of DZ therapy, 12/18 pts (66.6%) showed a remarkable reduction of bleeding, and in 6 patients that showed no response, DZ treatment was stopped. In 7 pts (39%) TR dropped to none and in 5 pts median RT dropped from 22 RBC units/yr. to 10 units/yr. Two of responders had a relapse with upper GI tract bleeding and 1 pts with epistaxis within the first 2 years of DZ treatment. Attempts to reduce the maintenance dose below 200 mg/daily were related to new bleeding or worsening of the active sites. None of the long standing DZ therapy had any significant toxicity. DZ treatment have shown efficacy and safety in this cohort of HHT patients. Mecanism of action may involve the increase of synthesis or expression of ALK-1 dependent proteins and less likely of endoglin. We propose DZ as a first line treatment for the transfusion dependent HHT patients.