CLINICAL REPORT Cardiac valvular Ehlers-Danlos syndrome is a well-defined condition due to recessive null variants in COL1A2 Vito Guarnieri 1 | Silvia Morlino 2 | Giuseppe Di Stolfo 3 | Sandra Mastroianno 3 | Tommaso Mazza 4 | Marco Castori 1 1 Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy 2 Laboratory of Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy 3 Division of Cardiology, Fondazione IRCCS- Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy 4 Unit of Bioinformatics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy Correspondence Marco Castori, Division of Medical Genetics, Foundation IRCCS-Casa Sollievo della Sofferenza, Poliambulatorio “Papa Giovanni Paolo II”, Viale Padre Pio, 7, 71013 San Giovanni Rotondo (FG), Italy. Email: m.castori@operapadrepio.it 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 val- vular 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 eye- lid 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 reces- sive osteogenesis imperfecta and variants in COL1A2, as well as from individuals with autosomal dominant osteogenesis imperfecta and severe cardiac valvular disease. KEYWORDS autosomal recessive, COL1A2, Ehlers-Danlos syndrome, mitral valve, osteogenesis imperfecta 1 | INTRODUCTION Cardiac valvular Ehlers-Danlos syndrome (cvEDS) is an ultrarare Ehlers- Danlos syndrome (EDS) variant characterized by mild–moderate cutane- ous involvement, joint hypermobility and cardiac valvular disease often requiring surgery. Skin features of cvEDS resemble typical manifesta- tions of the more common classical and hypermobile EDS variants (Schwarze et al., 2004; Malfait et al., 2006). The diagnosis of cvEDS is established by the identification of recessive COL1A2 variants leading to a complete deficiency of pro-α2-chain of type I collagen. Only five patients with molecularly confirmed cvEDS have been published to date (Kojima et al., 1988; Schwarze et al., 2004; Malfait et al., 2006). Two further individuals with biochemical demonstration of complete absence of proα2(I) collagen chains and features of EDS plus moderate–severe cardiac valvular involvement have been described before molecular delineation of cvEDS (Sasaki et al., 1987; Hata et al., 1988). Cardiac val- vular EDS diagnostic criteria helping patients' selection were proposed in the 2017 international classification of EDS and related disorders (Malfait et al., 2017). Nevertheless, the extreme paucity of published cases limits our understanding of the phenotypic boundaries and natural history of cvEDS. For example, while severe and progressive cardiac val- vular disease has been originally considered a distinguishing feature of cvEDS (Schwarze et al., 2004), this finding is absent in one of the five published patients (Malfait et al., 2006). Here, we report two additional sisters with cvEDS and the homozygous c.3601G>T transversion in COL1A2. This observation contributes to further delineate cvEDS as a discrete entity within the EDS community. 2 | CLINICAL REPORT The proband (Patient 1) was a 24-year-old woman, first child of appar- ently unrelated parents born in a small town of Southern Italy (~1,000 citizens). The patient was born at term from uneventful pregnancy and delivery. Nevertheless, the mother referred poor perception of fetal moments during pregnancy. The diagnosis of EDS (unclassified variant) was first proposed at 1 year of age for marked and generalized laxity of Received: 9 September 2018 Revised: 15 November 2018 Accepted: 6 February 2019 DOI: 10.1002/ajmg.a.61100 Am J Med Genet. 2019;1–6. wileyonlinelibrary.com/journal/ajmga © 2019 Wiley Periodicals, Inc. 1