A proposed nosology of inherited disorders of the extracellular matrix (ECM): Insights from the IEMbase and dyadic classification.

We have identified 252 inherited disorders of the extracellular matrix (ECM) caused by 154 different gene defects and have proposed a classification system in 8 categories based on their mode of action: 1. Disorders of ECM glycoproteins, 2. Disorders of ECM proteoglycans, 3. Disorders of proteins in TGF-beta signaling pathway, 4. Disorders of fibrillar collagens, 5. Disorders of fibrillar collagen processing and maturation, 6. Disorders of non-fibrillar collagens, 7. Other disorders of connective tissue with bone fragility and 8. Other disorders of connective tissue. Additionally, using information from IEMbase, we have described the clinical involvement of 18 organs and systems, as well as essential laboratory investigations for each type of ECM disorder. Skeletal, ocular, neurological and dysmorphic manifestations were the most prevalent, occurring in 18 %, 12 %, 10 %, and 10 % of ECM disorders, respectively. This was followed by cardiovascular, dermatological, ear-related, muscular, digestive, endocrine, and hematological symptoms (3-7 %). Among the skeletal symptoms, those affecting joints, spine, upper limbs, lower limbs and mineralization were the most common with rates of 25.8 %, 18.0 %, 14.3 %, 14.1 % and 11.5 %, respectively. 27.4 % of the disorders display a single phenotype, with skeletal issues being the most common at 17.8 % and ocular abnormalities 12.2 %. Conversely, 72.6 % of disorders have multiple phenotypes, with LTBP4-related Cutis laxa (10 phenotypes) and SMAD4- related Myhre Syndrome (gain of function) at the end of the spectrum with up to 11 phenotypes. The information provided in this study, including our proposed dyadic classification system for ECM disorders, may be useful for healthcare providers caring for individuals with conditions associated with ECM problems.