Multiple Osteochondritis Dissecans as Main Manifestation of Multiple Epiphyseal Dysplasia Caused by a Novel Cartilage Oligomeric Matrix Protein Pathogenic Variant: A Clinical Report

Abstract

Background: Multiple epiphyseal dysplasia (MED) is a clinically and genetically heterogeneous group of skeletal diseases characterized by epiphyseal abnormalities associated with mild short stature. The clinical variability is wide, and the first clinical manifestations still occur in childhood with joint pain and stiffness that evolve into degenerative joint disease. MED, caused by mutations in the Cartilage Oligomeric Matrix Protein (COMP) gene, is the most common form of the disease. COMP-MED usually shows significant involvement of the capital femoral epiphyses and irregular acetabulum; instead, COL9A1-, COL9A2-, and COL9A3-MED appear to have more severe knee involvement than hips, resulting in a milder presentation than COMP-MED cases. Other complications have been reported, in particular osteochondritis dissecans (OCD), which has been described in two large COL9A2-related MED families associated with myopathy.

Methods: Here, we report the case of a 24-year-old man affected by COMP-MED with a positive family history for the disease and a clinical presentation that interestingly is characterized by the presence of multiple OCD.

Results: To our knowledge, this is the first case of COMP mutations related to multiple OCD as the main clinical feature.

Conclusions: This report can expand the clinical phenotype related to the pathogenic variants of the COMP gene, as it shows that multiple OCD can also be present in COMP-related MED as well as in COL9A2-related MED.

Keywords: COMP gene; multiple epiphyseal dysplasia; osteochondritis dissecans; pathogenic mutation.

Figure 1

Coronal ankle MRI showing OCD (arrow) on the medial side of the left talus.

Figure 2

(A) OCD of the capitellum; (B) OCD of the right talus; (C) OCD of the right hip; (D) OCD of the right knee; (E) OCD of the left first metatarsal. Arrows indicate OCD sites.

Figure 3

Timeline of the patient’s diagnostic and treatment.

Figure 4

Family pedigree. III-1: proband (black arrow); II-1: short stature, joint pain with muscle weakness at the age of 3 years, bilateral hip arthroplasty (<50 years). II-2: short stature, early onset multi-joint pain, X-rays in childhood with epiphyseal abnormalities (referred). I-1: significant short stature, multi-joint pain. Affected individuals are in blue.

Figure 5

COMP missense (above) and loss of function (below) variant distribution from Clinvar. The vertical red line indicates this report variant’s location. PLP: pathogenic or likely pathogenic; BLB: benign or likely benign. * ClinVar version of 09.01.2022. ** with AF > max (AF of PLPs). *** Clusters version 21.11.2020.

Figure 6

3D representation of the COMP protein structure through the AlphaFold method. The region of the Thr529 residue is highlighted in the box.