Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 independent families comprising 107 individuals with pEDS to identify the locus, characterize the clinical details in those with defined genetic causes, and try to understand the physiological basis of the condition. In 17 of these families, we identified heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (2 families), contiguous genes in the mapped locus that encode subunits C1r and C1s of the first component of the classical complement pathway. These two proteins form a heterotetramer that then combines with six C1q subunits. Pathogenic variants involve the subunit interfaces or inter-domain hinges of C1r and C1s and are associated with intracellular retention and mild endoplasmic reticulum enlargement. Clinical features of affected individuals in these families include rapidly progressing periodontitis with onset in the teens or childhood, a previously unrecognized lack of attached gingiva, pretibial hyperpigmentation, skin and vascular fragility, easy bruising, and variable musculoskeletal symptoms. Our findings open a connection between the inflammatory classical complement pathway and connective tissue homeostasis.

Histologic sections of seven squamous cell carcinomas (SCC), 13 basal cell carcinomas (BCC), and a Bowenoid actinic keratoses were examined for expression of HLA class 1 antigens (HLA-ABC) using a monoclonal antibody and an immunoperoxidase technique. Expression of beta 2-microglobulin was examined with a polyclonal antibody method. Neither cell marker was detected within the Bowenoid actinic keratoses. Squamous cell carcinomas and basal cell carcinomas exhibited decreased expression of both HLA-ABC and beta 2-microglobulin and often did not express these antigens at all. HLA-ABC was present in only two of 13 basal cell carcinomas and four of seven squamous cell carcinomas. beta 2-microglobulin was present in one of 13 basal cell carcinomas and two of seven squamous cell carcinomas. When present, these antigens often were present in a few areas of the tumor, but absent in others. In both SCC and BCC, both antigens were usually lost simultaneously. In all tumors with beta 2-microglobulin, HLA-ABC also was retained. There was no apparent relationship of anatomic site or type of tumor with retention of surface antigens. Since some tumors or portions of tumors retained HLA-ABC and beta 2-microglobulin on their surfaces, the absence of these antigens is not an absolute marker for malignancy.

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