Inherited Pial Arteriovenous Fistula in Capillary Malformation–Arteriovenous Malformation Family

A 3-year-old girl with a 2-month history of pain and weakness in both legs presented to our clinic. Physical examination showed weakness of bilateral legs (muscle strength: grade 3) and multiple cutaneous red maculae (Fig 1A), which could also be seen in her grandfather and father. Both her grandmother and mother had a miscarriage history in their early pregnancy. Spine magnetic resonance imaging (MRI) revealed extremely thickened and dilated perimedullary vessels below the T8 level, causing severe spinal edema and compression (see Fig 1B). Subsequent digital subtraction angiography (DSA) showed a high-flow perimedullary arteriovenous fistula (AVF; see Fig 1C). Histopathologic examination of maculae indicated epidermal hyperkeratosis and dermal microvascular hyperplasia (see Fig 1D). Six months later, her father (31 years old) returned with a 2-year history of intermittent headache. Physical examination showed red maculae on his scalp and arms (Fig 2A). Abdominal computed tomography revealed multiple hepatic vascular malformations (see Fig 2B). MRI and DSA revealed a high-flow pial AVF in left parieo-occipital sulcus and capillary malformation in scalp (see Fig 2C–E). Genomic DNA samples from the patient and her parents were detected by whole-exome high-throughput sequencing (×100), and heterozygous mutation c.2758+1G>A, inherited from the father, was detected in the RASA1 gene 21 intron. This mutation could cause abnormal gene splicing and loss of coding region, thus affecting protein function. No data were found in the 1000 Genomes Project, ExAC, and gnomAD databases (pathogenic moderate 2 evidence). Conforming to the American College of Medical Genetics and Genomics standards, this variation is a very strong pathogenic variation (pathogenic very strong 1 evidence). Protein function prediction software MutationTaster, GERP++, and CADD were annotated as a functional pathogenic mutation (pathogenic supporting 3 evidence). The RASA1 gene is a known pathogenic gene for capillary malformation–arteriovenous malformation (CM-AVM), encoding the protein p120RasGAP and enhancing the weak intrinsic guanosine triphosphatase activity of RAS proteins, then allowing control of cellular proliferation and differentiation. As reported in our study and the literature, somatic mutations and anomalies of the RAS–mitogen activated protein kinase (MAPK) pathway are the core pathogenic mechanisms of central nervous system (CNS)-AVM.1, 2 We speculated that the abnormal activation of RAS-MAPK pathway in endotheliocytes combined with or caused by germline RASA1 mutation may be the pathogenetic mechanism of AVFs in CM-AVMs. CM-AVM is one of the most common autosomal-dominant cutaneous disorders (incidence is 1/100,000) but receives little attention.3 However, almost one third of patients are associated with fast-flow AVMs/AVFs, which can cause life-threatening complications such as congestive heart failure, intracranial hemorrhage, and neurologic sequelae.4 To our knowledge, inherited CNS pial AVF has not been reported previously, and this is also a newly discovered mutation site of RASA1. Our findings alert clinicians to further investigate for the presence of CNS-AVMs/AVFs in CM-AVM family members. In addition, the newly identified mutation site may suggest that family members with this mutation may have a higher risk of CNS lesions. Funds from the Natural Science Foundation of Beijing (7222081), National Natural Science Foundation of China (No: 82101369), and Xuanwu Hospital Science Program for Fostering Young Scholars (QNPY2020009) were utilized in regard to this article. We thank the patient for participating in this study. J.L., H.Z., and G.L. contributed to study concept and design. J.L., J.Y., and G.L. contributed to data acquisition and analysis. J.L., J.Y., and G.L. contributed to drafting the manuscript or preparing figures. Nothing to report.