Chronic Atrial Intestinal Dysrhythmia Syndrome Is Associated with Cerebral Small Vessel Disease and Predominantly Cerebellar Microbleeds

Shortcutting the diagnostic odyssey: the multidisciplinary Program for Undiagnosed Rare Diseases in adults (UD-PrOZA)

“…Patients typically present with sick sinus syndrome requiring cardiac pacemakers and intestinal myogenic and neurogenic pseudo-obstruction. Recently, a novel association was reported between CAID syndrome and cerebral small vessel disease [ 24 ]. It was hypothesized that this cerebral vascular phenotype is a consequence of upregulated TGF-β signaling leading to vessel wall fibrosis and premature senescence of cerebellar arterioles due to mitotic dysregulation [ 23 , 24 ].…”

“…Recently, a novel association was reported between CAID syndrome and cerebral small vessel disease [ 24 ]. It was hypothesized that this cerebral vascular phenotype is a consequence of upregulated TGF-β signaling leading to vessel wall fibrosis and premature senescence of cerebellar arterioles due to mitotic dysregulation [ 23 , 24 ]. Our patient is the third CAID patient in the literature in which cerebral small vessel disease is reported.…”

“…WES identified a homozygous splice region variant in RIPPLY2 (c.240-4T>G) (Additional file 2 : Table S3), a known founder mutation associated with spondylocostal dysostosis 6 (MIM: 616566) [ 25 ]. Although a clear effect on splicing in postnatal tissue has never been proven due to the embryonic expression of this gene, we classified this gene as likely pathogenic since in the literature, seven patients have been reported presenting with congenital posterior cervical spine malformations in which this splice region mutation was identified in homozygous or compound heterozygous state [ 24 ]. In only one patient a Klippel-Feil syndrome (fusion of the cervical vertebrae) was reported, all other patients presented with agenesis of the posterior vertebral elements.…”