Hereditary hemorrhagic telangiectasia associated with cortical development malformation due to a start loss mutation in
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CASE REPORT
Open Access
Hereditary hemorrhagic telangiectasia associated with cortical development malformation due to a start loss mutation in ENG Davide Villa1, Claudia Cinnante2, Gloria Valcamonica1, Giulia Manenti1, Silvia Lanfranconi3, Annalisa Colombi1, Isabella Ghione3, Maria Cristina Saetti1,3, Mario D’Amico4, Sara Bonato3, Nereo Bresolin1,3, Giacomo Pietro Comi1,5 and Dario Ronchi1*
Abstract Background: Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, is a rare disorder characterized by recurrent epistaxis, telangiectasias and systemic arteriovenous malformations (AVMs). HHT is associated with mutations in genes encoding for proteins involved in endothelial homeostasis such as ENG (endoglin) and ACVRL1 (activin receptor-like kinase-1). Case presentation: Here we describe a 22-year-old male presenting with a transient episode of slurred speech and left arm paresis. Brain MRI displayed polymicrogyria. A right-to-left shunt in absence of an atrial septum defect was noted. Chest CT revealed multiple pulmonary AVMs, likely causing paradoxical embolism manifesting as a transient ischemic attack. The heterozygous ENG variant, c.3G > A (p.Met1lle), was detected in the patient. This variant was also found in patient’s mother and in his younger brother who displayed cortical dysplasia type 2. Conclusions: The detection of cortical development malformations in multiple subjects from the same pedigree may expand the phenotypic features of ENG-related HHT patients. We suggest considering HHT in young patients presenting with acute cerebral ischemic events of unknown origin. Keywords: Cerebrovascular disorders, ENG, Hereditary hemorrhagic telangiectasia, Stroke, Case report
Background Hereditary hemorrhagic telangiectasia (HHT, ORPHA774) or Rendu–Osler–Weber syndrome, is a rare vascular disorder characterized by telangiectasias and arteriovenous malformations (AVMs) of skin, mucosae and internal organs [1]. The incidence, 1:5000–1:8000 worldwide, is likely underestimated because of the reduced age-related * Correspondence: [email protected] 1 Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Via Francesco Sforza 35, 20122 Milan, Italy Full list of author information is available at the end of the article
penetrance and variable clinical expression. Pulmonary and cerebral AVMs have been detected in 24–40% [2, 3] and 10–20% [4] of HHT patients, respectively. Although AVMs often remain clinically silent, cerebral AVMs rupture may cause intracerebral hemorrhage resulting in increased morbidity and mortality. Moreover, HHT patients may experience ischemic stroke or cerebral abscess because of paradoxical embolism due to the right-to-left shunting associated with pulmonary AVMs. Clinical diagnosis can be achieved according to Curaçao criteria: 1) spontaneous and recurrent epistaxis; 2) multiple telangiectasia affecting lips, fingers, and nose; 3)
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