Abstract No. 598 Clinical manifestations of patients with novel mutations associated with hereditary hemorrhagic telangiectasia and related vascular anomalies

Abstract

In this series, 4 patients with HHT were identified with novel GDF2 mutations. They were compared to an individual with capillary malformation-arteriovenous malformation syndrome (CM-AVM) secondary to a RASA1 mutation to highlight the clinical similarity between the two diseases. With IRB exemption, the electronic medical record was searched with the search term HHT, genetic mutation, pulmonary arteriovenous malformation. The eligibility criteria included only those patients with a novel mutation in the GDF2 and RASA1 locus. The initial search resulted in 776 total patients with a suspected diagnosis of HHT. 162 patients had genetic testing done. We derived 5 patients with HHT-like clinical presentations found to have a novel (GDF2, n = 4) or related (RASA1, n = 1) mutation. 5 patients were included with a mean age of 17 years (range, < 1–37) with 60% female. 4 patients had a mutation or deletion in the GDF2 gene, and 1 patient had a RASA1 mutation and was diagnosed with CM-AVM. See Table. All GDF2 patients reported childhood nosebleeds, but only 1/ 4 patients continue to experience epistaxis by adulthood. 2/4 patients reported self-limited nosebleeds that resolved by adulthood. Mucocutaneous telangiectasia was observed only in 1/4 patients and in an atypical location. Unlike classic HHT, AVM and telangiectasia were not observed in the pulmonary or the hepatic vasculatures of GDF2 patients. 1 patient with a missense GDF2 mutation was found to have a hepatic focal nodular hyperplasia. The patient with CM-AVM also did not exhibit pulmonary or hepatic vascular involvement. GDF2 mutations predominately affected the cerebrovasculature. 2/4 GDF2 mutated patients suffered from brain vascular malformation. A third patient presented for evaluation after her daughter was diagnosed with a brain AVM. A frontal AVM and macrocephaly were diagnosed in the CM-AVM patient.3 patients with GDF2 mutations and one with RASA1 mutation were found to have some form of cardiac abnormalities. Clinical manifestations of HHT secondary to GDF2 mutations presented differently and exhibit overlapping features as CM-AVM due to RASA1 mutation.Tabled 1SexAge (years)DiagnosisGeneNucleotide ChangeProtein ChangeMutation TypeSignificanceF3CM-AVMRASA1c.2131C >Tp.Arg711TerNonsensePathogenicF37HHTGDF2c.1063G >Cp.Glu355GlnMissenseUnknownM32HHTGDF2c.1207G >Ap.Val403IleMissenseUnknownF13HHTGDF25.10-Mb deletion of 10q11.22 to 10q11.2336 genes deletedDeletionLikely pathogenicM0HHTGDF25.5-Mb deletion of 10q11.22 to 10q11.23UndeterminedDeletionLikely pathogenic Open table in a new tab