Cardiac valvular Ehlers-Danlos syndrome is a well-defined condition due to recessive null variants in COL1A2

Cardiac valvular Ehlers-Danlos syndrome (EDS) is a rare EDS subtype, caused by specific recessive variants in the gene encoding pro-α2-chain of type I collagen (COL1A2). Cardiac valvular EDS is mainly characterized by generalized/peripheral joint hypermobility, moderate-severe cardiac valvular disease, skin hyperextensibility and other minor soft tissues features. Only five molecularly confirmed patients have been reported to date. Here, we describe two additional affected sisters, who share the homozygous c.3601G>T nonsense variant in COL1A2. Clinical data and literature review allowed to better define the clinical spectrum of cardiac valvular EDS which now emerges as a more recognizable EDS variant with progressive heart valve disease firstly affecting the mitral valve. Possibly distinguishing features include bilateral flatfeet with hindfoot pronation, lower eyelid ptosis and hypoplasia of the interphalangeal creases. The absence of bone fragility in our patients indicates that cardiac valvular EDS is also separated from patients with autosomal recessive osteogenesis imperfecta and variants in COL1A2, as well as from individuals with autosomal dominant osteogenesis imperfecta and severe cardiac valvular disease.