Medical Mystery of the Week

      Because of the COVID19 pandemic, you are practicing telemedicine. You interview a 65-year-old man who is being evaluated for chronic low grade gastrointestinal bleeding detected by intermittently positive hemoccult tests.
   The patient (pictured below) denies having dysphagia, odonophagia, abdominal pain, early satiety, gastroesophageal reflux, fatty food intolerance, flatulence, icterus, diarrhea, constipation, or obstipation. He does not use aspirin or nonsteroidal inflammatory drugs and has no history of a bleeding diathesis. Gastroesophageal endoscopies and colonoscopies have failed to reveal the source of bleeding.
   The patient notes that since early childhood he has had frequent nosebleeds often requiring nasal packing to stem the hemorrhage. 
      What is your diagnosis, what lab test(s) would you order to confirm you suspicions, and what treatment, if any, do you recommend? 

DIAGNOSIS: Hereditary hemorrhagic telangiectasia (HHT). HHT is an autosomal dominant  disorder affecting up to 1 in 5000 persons in which patients develop large arterial-venous malformations (AVMs) in the lungs, liver and/or brain, and smaller AVMs (telangiectases) in the skin and mucosal lining of the nose, mouth and gastrointestinal tract. The smaller AVMs are particularly prone to hemorrhage, whereas the larger AVMs may cause high output congestive heart failure.
   HHT is due to loss of function mutations in endoglin (ENG) (HHT1) or ACVRL1 (HHT2) whose transmembrane receptors are expressed on endothelial cells (EC) and bind bone morphogenic protein (BMP)-9 and BMP-10 and activate the SMAD1/5/8 signaling pathway. A minority of cases are due to mutations in SMAD4 or BMP-9. HHT mutations lead to abnormal EC responses to angiogenic and hemodynamic cues.
   Patients that meet at least three of the following features are considered to have a definitive diagnosis of HHT: 1. multiple mucocutaneous telangiectases; 2. recurrent nosebleeds; 3. viseral organ AVMs; and 4. a first degree relative with HHT. Whenever possible, the diagnosis should be confirmed by genetic testing. 
   The presented case has multiple mucocutaneous telangiectases, a history of frequent nosebleeds, and chronic blood loss due to intestinal telangiectases which are often detected only by visualizing the mucosa of the small bowel. He should be assessed for the possibility of having CNS, pulmonary or hepatic AVMs by appropriate radiographic studies.




   There is increasing evidence that vascular endothelial growth factor (VEGF) inhibitors such as bevacizumab may benefit patients with HHT.