COL1-related overlap disorder: Recent published paper

Posted December 18, 2019

There are currently 14 subtypes of Ehlers-Danlos syndromes (EDS). In 13 of these (i.e. all except the hypermobile subtype), the diagnosis is confirmed by the combination of clinical features, and the identification of a mutation in corresponding disease-genes. Among them, the current classification identifies 3 subtypes of EDS that are associated with mutations in the two genes encoding for collagen I (named COL1A1 and COL1A2). These 3 subtypes are classical EDS (cEDS) with arterial fragility, arthrochalasia EDS (aEDS) and cardiac-valvular EDS (cvEDS). 

Collagen 1 is the most abundant collagen molecule in the human body, and is found in almost all tissues and organs. Abnormalities of Collagen I are also found in another disorder, osteogenesis imperfecta.  In this condition there is an increased risk of fractures and related bony malformations. Recently, a small number of individuals with features of both osteogenesis imperfecta and EDS have been described with mutations in COL1A1 and COL1A2. This condition was originally defined as “osteogenesis imperfecta/Ehlers-Danlos syndrome overlap”. However, the existence of this entity is debated. It is not recognized by the current classification of EDS and related disorders, or the 2019 nosology of skeletal disorders. 

In a recently published paper, COL1-related overlap disorder: A novel connective tissue disorder incorporating the osteogenesis imperfecta/Ehlers-Danlos syndrome overlapa group of 21 individuals from 13 families are reported. All of them had a features of EDS and “mild” osteogenesis imperfecta (such as short stature, bluish sclerae, and fractures). The clinical diagnosis of EDS was supported by generalized joint hypermobility, related musculoskeletal manifestations and minor skin features. In all families, a mutation in COL1A1 or COL1A2 was documented, demonstrating that there is a subgroup of individuals with mutations in COL1A1 and COL1A2, who cannot be classified as affected by cEDS, aEDS or cvEDS. Equally the diagnosis of osteogenesis imperfecta does not fit for the predominance of soft tissue manifestations. 

The term “collagen I-related overlap disorder” has been proposed for these individuals. This term has been preferred because the clinical picture reported in these 21 individuals is broader than previously described in the “osteogenesis imperfecta/Ehlers-Danlos syndrome overlap” and because the latter term might generate confusion by giving the false impression that a person has two co-existing disorders (i.e. osteogenesis imperfecta AND Ehlers-Danlos syndrome). ​

Given the predominance of soft tissue manifestations in these individuals we will be asking that ‘collagen I-related overlap disorder’ be considered as a new entry in further revisions of the classification of Ehlers-Danlos syndromes.

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