Novel COL2A1 variant (c.619G>A, p.Gly207Arg) manifesting as a phenotype similar to progressive pseudorheumatoid dysplasia and spondyloepiphyseal dysplasia, Stanescu type

Abstract

Progressive pseudorheumatoid dysplasia (PPRD) is a rare, autosomal-recessive condition characterized by mild spondyloepiphyseal dysplasia (SED) and severe, progressive, early-onset arthritis due to WISP3 mutations. SED, Stanescu type, is a vaguely delineated autosomal-dominant dysplasia of unknown genetic etiology. Here, we report three individuals from two unrelated families with radiological features similar to PPRD and SED, Stanescu type who share the same novel COL2A1 variant and were matched following discussion at an academic conference. In the first family, we performed whole-exome sequencing on three family members, two of whom have a PPRD-like phenotype, and identified a heterozygous variant (c.619G>A, p.Gly207Arg) in both affected individuals. Independently, targeted sequencing of the COL2A1 gene in an unrelated proband with a similar phenotype identified the same heterozygous variant. We suggest that the p.Gly207Arg variant causes a distinct type II collagenopathy with features of PPRD and SED, Stanescu type.

Keywords: PPRD; SED; Stanescu; skeletal dysplasia; spondyloepiphyseal dysplasia tarda with progressive arthropathy; type II collagenopathy.

Figure 1

a-c: Proband of Family 1 at 23 years. Note marked joint contractures resulting in Z posture. c: Lateral spine radiograph shows platyspondyly and irregular degenerative changes. d-g: Radiographs of the daughter of the proband of Family 1 at 12 years. d: Mild anterior wedging and platyspondyly of lateral spine. e: Hip and pelvic features include flattened and irregular femoral heads, short femoral necks, and deformed shaft of the left femur secondary to prior trauma. f: Knee radiograph shows joint space narrowing and metaphyseal irregularity. g: Note metaphyseal prominence and joint space narrowing at distal radius and distal ulna. h-m: Radiographs of the proband of Family 2 at 4 years (h) and 8 years (i-m). h: Note irregularity and mild flattening at articular surfaces of capital femoral epiphyses. Acetabulum is flat, and femoral necks are broad with mild coxa valga. i: Capital femoral epiphyses show mild flattening and dysplastic trabeculation. Femoral necks are broad and elongated with further coxa valga. Ilia are somewhat narrowed and elongated. The acetabulum shows deepening with irregularity of its contour. j: Note moderate spinal platyspondyly with anterior wedging and irregularity of the endplates. k: Knee joints show mild flaring of the distal femora and proximal tibiae. Epiphyses are normal. l-m: Hands and feet are normal.