Unusual Onset of Hereditary Hemorrhagic Telangiectasia Due to Somatic Mutational Mosaicism: Case Report and Review of the Literature

Hereditary Hemorrhagic Telangiectasia (HHT), also known as Rendu–Osler–Weber syndrome, is a disorder of angiogenesis characterized by mucocutaneous telangiectasias and visceral arteriovenous malformations. This rare autosomal dominant disorder is caused by pathogenic variants in the ENG and ACVRL1 genes, and only 1–3% of case variants occur in SMAD4. HHT clinical manifestations include telangiectasias, epistaxis, and arteriovenous malformations in multiple organ systems. Clinical diagnosis is based on Curaçao Criteria. Here, we describe a pauci-symptomatic 10-year-old girl with an orbital and sinus infectious disease. Her clinical history was unremarkable, except for sporadic, self-limiting epistaxis episodes. She showed finger clubbing and low oxygen saturation levels on pulse oximetry, suggesting a chronic lung disease, and a large lung arteriovenous malformation. She also developed acute neurological symptoms, with evidence of multiple cerebral abscess lesions on MRI. HHT was therefore suspected and confirmed by genetic analysis, which revealed a de novo pathogenic variant in the ENG gene [c.1183G>T p.(Glu395Ter)] found in only 15% of the reads from NGS analysis, performed on peripheral blood lymphocytes, indicating a possible mutational mosaicism. This case outlines that HHT could present with unusual clinical symptoms highlighting the importance of diagnosis using both clinical criteria and genetic test.