Clinical and Molecular Findings in a Cohort of Children with Central Nervous System Arteriovenous Fistulas

Background: To assess the spectrum of genetic anomalies in a cohort of children presenting with at least one cerebral or medullary pial fistula, and to describe their baseline clinical characteristics.

Methods: From 1988 to 2016, all consecutive patients with at least one cerebral or spinal arteriovenous pial fistula were screened for genetic analysis. All patients less than 18 years of age with at least one cerebral or spinal arteriovenous pial fistula were included in this study. Symptoms, associated with the AVF were recorded: cardiac failure, neurological deficit/seizure, hemorrhage. In case of cerebral location of the fistula, the minimum transverse diameter of the venous collector was assessed. Patients having a venous collector diameter greater than 3 cm were considered as having a giant draining venous pouch. When a mutation was identified, other signs related to a specific gene deficiency were investigated, including dermal examination. The outcome was assessed using the mRS and school level in cases involving cerebral AVFs and the ASIA impairment scale in cases involving spinal cord AVFs.

Results: A germline mutation was identified in 23 out of 43 probands (52.3%±14.7%): 8 in ENG (34.8%±14.1%), 1 in ACVRL1 (4.3%±6%) leading to HHT molecular diagnosis and 14 in RASA1 (60.9%±14.4%) leading to CM-AVM molecular diagnosis. No differences in age at onset or gender were detected between mutation carriers and non-carriers. HHT patients, had significantly fewer cases of cardiac failure at onset (p = 0.035). There was no difference in the percentage of multiple and single cerebrospinal AV shunts in each of the three genotype groups. However, in HHT, AV shunts tended to be located more frequently in the spinal cord (p = 0.069) with an increased rate of hemorrhaging at presentation (p = 0.069). The presence of a giant venous pouch was significantly higher if no mutation was identified (p = 0.033). In cases associated with skin capillary haemangioma, there was a strong association with RASA1 mutation (p-value<0.0001).

Conclusion: Our results highlight the importance of genetic testing in this setting in view of the high frequency of gene mutations in pediatric cerebrospinal AVFs, and show the predominance of Rasa1 over HHT mutations. Clinical symptoms associated with the neurovascular lesions can guide the molecular diagnosis but current sequencing techniques does allow a parallel sequencing of all known genes for the disease, thereby accelerating the diagnosis.