Atrophic violaceus pretibial plaques: when the clue is the oral mucosa

Periodontal Ehlers–Danlos syndrome (pEDS) is an autosomal-dominant disorder, caused by a disturbed classic complement pathway and characterized by early-onset periodontitis. We report a family with pEDS, who had been misdiagnosed for years. The patients’ medical history, physical examination, radiological studies and skin biopsy results are described in Table 1. The father had hypertension and the siblings had recurrent articular lesions. All had gingivitis since childhood, and all three had the typical periodontal presentation (Fig. 1) and pretibial plaques (Fig. 2). Laboratory studies, including full blood count, serum biochemistry and serology profile, all gave normal results. The clinical presentation suggested pEDS. The genetic mutations underlying pEDS are alterations in the genes C1R and C1S, which encode complement 1 subunits C1r and C1s, respectively. Following informed consent, a genetic study was performed. As most of the variants described in the C1R and C1S genes alter residues of CUB1, CUB2, Sushi CCP1 and Sushi CCP2 domains in the C1r protein, and Sushi CCP1 domain in C1s protein, the genetic analysis was limited to those regions. Therefore, exons 2, 6, 7, 8, 9 and 10 of C1R and exon 8 of C1S were analysed by Sanger sequencing using standard methods. All three patients were heterozygous for the missense mutation c.1014C>G in the C1R gene (NM_001733.7). Kapferer-Seebacher et al. reported on 93 patients with pEDS; our family’s clinical features were similar (Table 1). Dental implants have been reported to be successful in patients with other forms of EDS, but pEDS has shown worse results, as in the father of our family, whose implants lasted < 1 year. Leucoencephalopathy appears to be part of the clinical spectrum of pEDS with C1R mutations. We performed brain magnetic resonance imaging (MRI) of the father in our family, and the results were suggestive of a leucoencephalopathy pattern, which could be related to small vessel abnormalities, but might also be related to his hypertension. The extent of the MRI changes seems to be disproportionate to the presence of neurological disease features. In both siblings, we found dural ectasia in both siblings, which is a widening of the dural sac surrounding the spinal cord; this has been reported in 23.5% of patients with EDS, but has not been described in pEDS. Both of the siblings had mitral valve prolapse, which has been reported previously in just one case. It has been shown that the classic complement pathway is centrally involved in periodontal host defence, and its overactivation may excessively amplify inflammation and contribute to the immunopathology of periodontal disease. Recent research has reported that all known C1R variants causing pEDS result in an uncontrolled cleavage of C1S and thus a gain of function for uncontrolled protease activity against C4, and that they are incapable of forming the C1 complex because of the missing C1q binding site. In this family, we found the variant p.Cys338Trp in the C1R gene in all three members. The variant causes a cytosine to tryptophan change in residue 338 of the protein (p.Cys338Thr). This is the first time this variant has been described in any human disease, Correspondence: Dr Constanza Martinez Mera, Department of Dermatology, Hospital Universitario Puerta de Hierro. Majadahonda, Manuel de Falla 1, Majadahonda, Madrid, 28222, Spain E-mail: c.martinezmera@gmail.com