Metaphyseal Chondrodysplasia Schmid type - widening the phenotype: Significant variable expression in two familial cases with heterozygous COL10A1 variants

Abstract

Metaphyseal Chondrodysplasia Schmid Type (SMCD) is a rare dominant form of skeletal dysplasia, caused by heterozygous mutations in the COL10A1 (Collagen Type X alpha 1) gene which codes for α1 chains in type X collagen, and typically results in disproportionate short stature. We report two families with the clinical and radiological diagnosis of SMCD seen in our unit over 4 years. In the first family (A), the proband had a possible pathogenic COL10A1 variant (c.133C>T, p.Pro45Ser). However, his father had the same variant without any obvious signs of SMCD, causing uncertainty whether this mutation was pathogenic. In the second family (B), the proband and her affected father had the same variant. Almost at the same time, a large consanguineous family was reported to have segregation of the variant with SMCD phenotypes in that the homozygosity was related to severer phenotypes and the heterozygosity to milder phenotypes. Hence, we were convinced that the variant was pathogenic. The pathogenic variant (p.Pro45Ser) causes a wide phenotypic spectrum of SMCD and even subclinical features. In this report, we highlight attenuated phenotypes of SMCD, and also discuss the latest therapeutic advances in SMCD and its mechanism of action.