An ACVRL1 gene mutation presenting as vein of Galen malformation at prenatal diagnosis

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant disease.The diagnostic criteria of HHT, or Curaçao criteria, include the following: recurrent epistaxis or nighttime nose bleeding, mucocutaneous telangiectases, visceral arteriovenous malformation, or an appropriate family history. The diagnosis is classified as definite if three criteria are present, possible if two criteria are present, and unlikely if only one is present. Nowadays, the confirmation of HHT diagnosis is based on molecular genetic studies. It has been showed that only mutations of genes encoding proteins within the transforming growth factor beta signaling pathway were responsible for the manifestation of the disease. The vein of Galen malformation (VOGM) as a presenting sign of HHT is rare. The prenatal diagnosis of HHT is even rarer. Herein, we present a case of prenatally diagnosed case of HHT based on the presence of VOGM in the fetus. To our knowledge, it is the first time that the gene mutation discovered in this case manifested as VOGM in the fetal life. K E Y W O R D SACVRL1 gene, hereditary hemorrhagic telangiectasia, prenatal diagnosis, vein of Galen

Recurrent Vein of Galen Aneurysmal Malformation as a Presentation of Hereditary Hemorrhagic Telangiectasia

“…These are usually small, superficial, multiple, and asymptomatic and ascertained primarily in adults either incidentally or due to headache or bleed [Bokhari and Bokhari, 2021]. Rare instances of large bAVMs including VGM have been reported in the literature presenting in the fetal or neonatal period [Tsutsumi et al, 2011;Chida et al, 2013;De Luca et al, 2020]. More than 600 different mutations have been found in ENG or ACVRL1 in HHT families.…”

Hereditary Hemorrhagic Telangiectasia in Pediatric Age: Focus on Genetics and Diagnosis

“…The improvement of methods to detect prenatal malformations led to the diagnosis of HHT even in utero, although only in exceptional cases; Saleh et al [ 48 ] reported the diagnosis of liver AVM with fetal magnetic resonance imaging (MRI), following ultrasound (US) evidence of cardiomegaly at 32 weeks of pregnancy, and De Luca et al [ 49 ] reported on the presence of a huge malformation of the vein of Galen associated with ventriculomegaly detected with US at 26 weeks, then confirmed with MRI.…”

“…In the aftermath of US/MRI diagnosis in both patients, molecular evidence was obtained for mutations in ENG and ACVRL1 respectively. It is regrettable to note that in both cases, familial evidence for HHT was already available [ 49 ] or could have been easily obtained [ 48 ] following the Curaçao criteria, but this evidence did not prompt any genetic counselling about the disease in general, nor any advice to the families about the possibility of observing complications of the disease even in children.…”

“…Prenatal presentation of HHT is possible in cases of severe anatomical abnormalities [ 48 , 49 ], so, in general, any pregnancy in which the fetus is at risk for having inherited the disease should be accurately monitored with repeated US examinations. Our group was involved in genetic testing (unpublished data) after abortion of a fetus because of severe cerebral hemorrhage at the 18th week; no autopsy was performed, but on a sample of fetal tissue, the familial mutation was confirmed.…”

Rare Neurovascular Diseases in Korea: Classification and Related Genetic Variants

“…These malformations are largely sporadic, possibly due to an early insult such as somatic mutations [ 31 ]. However, recent studies reported that some of the VGAMs were associated with germline mutations in RASA1 and EPHB4 , and ACVRL1 genes [ 33 34 35 ].…”