Clinical and Molecular Features of 11 Patients with Different Subtypes of Ehlers-Danlos Syndrome

Ehlers-Danlos syndrome (EDS) comprises a group of clinically and genetically heterogeneous connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and increased tissue fragility. As collagen is present in every organ system, EDS affects multiple body systems, and although its subtypes share overlapping features, each also exhibits distinctive clinical characteristics.

We report 11 EDS patients from eight unrelated families. Whole-exome sequencing, clinical exome sequencing, and Sanger sequencing were performed for genetic diagnosis.

Six EDS subtypes were identified: cardiac valvular EDS, dermatosparaxis EDS, musculocontractural EDS type 1, combined osteogenesis imperfecta/EDS type 2, brittle cornea syndrome type 2, and kyphoscoliotic EDS types 1 and 2. All patients exhibited joint hypermobility and skin hyperextensibility. Eight different variants were detected, including two novel variants; five were classified as pathogenic, two as likely pathogenic, and one as a variant of uncertain significance. Molecular diagnoses influenced clinical management by enabling subtype-specific surveillance, such as cardiologic monitoring in cardiac valvular EDS, early ophthalmologic intervention in brittle cornea syndrome, avoidance of invasive procedures in dermatosparaxis EDS, implementation of fracture-preventive measures in patients with combined osteogenesis imperfecta/EDS, and improved surgical risk management across all EDS subtypes.

This study expands the clinical and molecular spectrum of EDS by identifying two novel pathogenic variants and revealing previously unreported clinical findings. The results emphasize intrafamilial variability and the need to consider possible dual diagnoses, particularly in consanguineous families. Detailed phenotyping combined with comprehensive molecular testing improves subtype delineation and guides patient-specific surveillance and management strategies.