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Periodontal Ehlers–Danlos syndrome (pEDS) is a rare condition caused by autosomal dominant pathogenic variants in C1R and C1S, characterized by early-onset severe periodontitis with premature tooth loss, easy bruising, pretibial hyperpigmentation and skin fragility. We report 13 novel pEDS patients carrying heterozygous pathogenic variants in C1R and C1S. In addition to the main pEDS clinical signs, including complete tooth loss before the age of 30 years in three patients, three patients and one relative displayed widespread venous insufficiency leading to persistent leg ulcers. One patient suffered an intracranial aneurysm with familial vascular complications including aortic dissection and intracranial aneurysm rupture in several relatives. Brain MRI showed in two patients periventricular white matter hyperintensities. Rare vascular complications exist including venous insufficiency and arterial dissection that can be fatal. More cases with enhanced vascular characterization are required in order to determine if a systematic vascular monitoring, including both arterial and venous assessment, would be recommended.

We provided molecular and clinical findings of five new patients with de novo PPP3CA variants. Interestingly, the two frameshift variants in this study and the six truncating variants previously reported are all clustered within a small 26-amino acid region in the regulatory domain (RD). Genotype-phenotype correlation of the 21 patients with PPP3CA mutations and expression studies on truncating mutations in this study and previous studies suggested that the truncating variants in the RD cause more severe early-onset refractory epilepsy, representing a type of variants distinct from loss-of-function missense variants in the catalytic domain or gain-of-function missense variants in the auto-inhibitory domain.