E1553. Clinical Manifestation of Hereditary Hemorrhagic Telangiectasia Due to GDF2 Mutations and Related Vascular Anomalies
  1. Frank Yuan; Johns Hopkins University School of Medicine
  2. Muhammad Latif; Johns Hopkins University School of Medicine
  3. Prateek Gowda; Johns Hopkins University School of Medicine
  4. Omid Shafaat; Johns Hopkins University School of Medicine
  5. Clifford Weiss; Johns Hopkins University School of Medicine
  6. Ahmed Farhan; Johns Hopkins University School of Medicine
Hereditary hemorrhagic telangiectasia (HHT) is a vascular syndrome with life-threatening complications. Pathogenic mutations of genes associated with the transforming growth factor-beta (TGF-B) superfamily have been implicated. One of these genes is GDF2, which encodes a receptor-ligand (BMP9) for the TGF-B pathway. We derived a series of 4 patients with HHT-like presentations identified with variants of the GDF2 gene. Genetics and clinical manifestation are described. Also, patients were compared to an individual diagnosed with capillary malformation-arteriovenous malformation syndrome (CM-AVM) secondary to a RASA1 mutation to highlight overlapping features of the two disorders.

Materials and Methods:
With IRB exemption and HIPAA compliance, we reviewed our institutional electronic medical records (EMR) from all patients presenting with symptoms resembling HHT-like vascular anomalies (n=776) and whom genetic testing was performed (n=162). We derived 5 patients with HHT-like presentations found to have a novel (GDF2,n=4) or related (RASA1,n=1) mutation.

5 patients were included in the study with mean age 17± 16.8 SD, (range <1 to 37 years) with 40% (2/5) male and 60% (3/5) female. 4 patients had a mutation in the GDF2 gene and of those patients, 2 had missense mutations that were classified as variants of unknown significance. 2 patients had an interstitial deletion of chromosome 10 resulting in multiple genes deleted, including the GDF2 gene. One patient was found to have a nonsense mutation in the RASA1 gene and was diagnosed with CM-AVM. All patients with GDF2 mutation/deletion reported childhood nosebleeds but only 1 of the 4 patients continues to experience epistaxis by adulthood. 2 of the 4 patients reported self-limited nosebleeds that resolved by early adulthood. Mucocutaneous telangiectasia was observed in one patient who developed telangiectasias on her forehead, which is atypical for HHT. Unlike other HHT genetic variants (ENG, ACVRL1, SMAD4), AVM and telangiectasia were not observed in the pulmonary or the hepatic vasculatures of the patients with GDF2 mutations. One patient with a missense GDF2 mutation was found to have focal nodular hyperplasia that remains stable. Interestingly, the patient with CM-AVM also did not exhibit pulmonary or hepatic vascular involvement. GDF2 mutations predominately affected the cerebrovasculatures. 2 of the 4 patients with GDF2 variants suffered from vascular malformations in the frontal lobe and midbrain. Although no cerebral vascular anomalies were identified in patient 2, she presented for evaluation after her daughter was diagnosed with a brain AVM. A frontal mesial AVM and macrocephaly were diagnosed in the patient with CM-AVM. 3 patients with GDF2 mutations/deletions and one with RASA1 mutation were found to have some form of cardiac abnormalities including arrhythmias, valvular disease, and congenital complex anomalies.

Clinical manifestations of the GDF2 phenotypic variant present differently from classical HHT. CM-AVM due to RASA1 mutation exhibit overlapping features as HHT caused by a GDF2 mutation/deletion.