COL2A1 – Dysspondyloenchondromatosis

Dysspondyloenchondromatosis (DSC) is a rare skeletal dysplasia characterized by metaphyseal and diaphyseal enchondroma-like lesions, anisospondyly, early-onset kyphoscoliosis, and limb length discrepancies. Affected individuals also present with short stature, osteopenia, and recurrent fractures, reflecting impaired cartilage matrix integrity. The condition overlaps radiologically and clinically with type II collagenopathies, notably spondyloepimetaphyseal dysplasia (SEMD) Strudwick type.

In 2011, a single sporadic case of DSC was found to harbor a novel heterozygous COL2A1 missense mutation p.Gly753Asp, confirming allelism with SEMD-Strudwick and establishing an autosomal dominant mechanism ([PMID:22570642]). Subsequent screening of another patient in 2015 identified a heterozygous deletion spanning c.1388_1996-108del in COL2A1, further supporting gene involvement ([PMID:26250472]).

A follow-up study in 2014 described a DSC patient without detectable COL2A1 variants, indicating genetic heterogeneity in a subset of cases ([PMID:24357493]). Nevertheless, the preponderance of COL2A1-positive cases underscores its primary role in DSC pathogenesis.

Longitudinal analysis of two unrelated patients in 2018 revealed novel heterozygous missense variants c.3293G>A (p.Gly1098Glu) and c.1817G>A (p.Gly606Asp) in COL2A1, with clinical progression mirroring classical DSC features and demonstrating variable severity ([PMID:29928178]).

Inheritance is autosomal dominant with de novo heterozygous variants. To date, four unrelated probands with COL2A1 mutations have been reported, each presenting sporadically without affected relatives. Variant spectrum includes glycine substitutions in the triple-helical domain and multi-exon deletions, consistent with dominant-negative effects on cartilage collagen fibrillogenesis.

No specific functional assays for DSC have been published; pathogenicity is inferred from the known structural impact of COL2A1 mutations in type II collagenopathies. One negative case suggests additional loci may underlie a minority of DSC presentations.

In summary, moderate clinical validity supports an autosomal dominant COL2A1-DSC association, with four probands harboring pathogenic COL2A1 variants. Genetic testing for COL2A1 should be prioritized in DSC, and negative cases warrant alternative gene exploration. Key take-home: COL2A1 mutation analysis provides diagnostic confirmation and guides surveillance for collagenopathy-related complications.

References

• Molecular syndromology • 2011 • Dysspondyloenchondromatosis: Another COL2A1-Related Skeletal Dysplasia? PMID:22570642
• American journal of medical genetics. Part A • 2014 • Dysspondyloenchondromatosis without COL2A1 mutation: possible genetic heterogeneity. PMID:24357493
• American journal of medical genetics. Part A • 2015 • Dysspondyloenchondromatosis (DSC) associated with COL2A1 mutation: Clinical and radiological overlap with spondyloepimetaphyseal dysplasia-Strudwick type (SEMD-S). PMID:26250472
• Molecular syndromology • 2018 • Longitudinal Follow-Up of Two Patients with Dysspondyloenchondromatosis due to Novel Heterozygous Mutations in COL2A1. PMID:29928178

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