Dysspondyloenchondromatosis (DSC) associated with COL2A1 mutation: Clinical and radiological overlap with spondyloepimetaphyseal dysplasia‐Strudwick type (SEMD‐S)

Abstract

Dysspondyloenchondromatosis (DSC) is a rare skeletal dysplasia characterized by enchondroma-like lesions and anisospondyly. The former leads to discrepancies in limb length, and the latter, to progressive kyphoscoliosis. Two recent cases have highlighted the genetic heterogeneity of DSC, one demonstrating the presence and, the other, the absence of a COL2A1 mutation. This may have important clinical implications, for example, screening for complications including atlanto-axial instability associated with type II collagenopathies, as well as long-term patient management. We report on a case with radiographic features of DSC with overlap into the type II collagenopathy spondyloepimetaphyseal dysplasia, Strudwick type, who was found to carry a novel heterozygous mutation in the COL2A1 gene. Testing for COL2A1 mutations should be performed in all patients with radiological features of DSC. Further research is needed to identify the underlying molecular cause in cases where no COL2A1 mutation is identified.

Longitudinal Follow-Up of Two Patients with Dysspondyloenchondromatosis due to Novel Heterozygous Mutations in <b><i>COL2A1</i></b>

“…In a study of COL2A1-related dysplasias, Terhal et al [2012] showed that a glycine substitution in the triple helical domain is the most common type of pathogenic mutation in the COL2A1 gene. Missense mutations resulting in substitution of the glycine residue within triple helical domain of COL2A1 with a bulkier amino acid, such as arginine or aspartic acid, are known to be pathogenic [Merrick et al, 2015]. The reported 2 heterozygous missense mutations, c.2258 G>A (p.Gly753Asp) and c.1799 G>A (p.Gly600Asp), by Nakane et al [2011] and Merrick et al [2015] lie within the triple helical domain and cause the substitution of glycine to aspartic acid, as found in our patient 2.…”

“…Missense mutations resulting in substitution of the glycine residue within triple helical domain of COL2A1 with a bulkier amino acid, such as arginine or aspartic acid, are known to be pathogenic [Merrick et al, 2015]. The reported 2 heterozygous missense mutations, c.2258 G>A (p.Gly753Asp) and c.1799 G>A (p.Gly600Asp), by Nakane et al [2011] and Merrick et al [2015] lie within the triple helical domain and cause the substitution of glycine to aspartic acid, as found in our patient 2. Glycine to glutamine substitution, as found in our patient 1, has not been reported in DSC patients before.…”

“…They noted that the chondromatous changes in DSC are expected to be regressive rather than progressive. We compared the clinical and radiological features of the patients in this study to those previously reported 15 patients with DSC in Table 1 [Mainzer et al, 1971;Spranger et al, 1978;Azouz, 1987;Lerman-Sagie et al, 1987;Freisinger et al, 1993;Kozlowski et al, 1994;Nakane et al, 2011;Kenis et al, 2013;Tran Mau-Them et al, 2014;Merrick et al, 2015]. All patients except for the patient of Tran MauThem et al [2014] had asymmetric limb shortening.…”

“…Nakane et al [2011] and Merrick et al [2015] identified novel COL2A1 mutations in 2 patients with DSC, indicating that the condition is a part of type 2 collagenopathies. However, a mutation in COL2A1 could not be detected in a patient described by Tran Mau-Them et al [2014], and they suggested that there might be a possible genetic heterogeneity.…”

“…However, a further case of DSC without unequal limbs was reported in which no pathogenic mutation was identified, suggesting that DSC is genetically heterogeneous [Tran Mau-Them et al, 2014]. Recently, Merrick et al [2015] also reported a mutation in COL2A1 in a patient with DSC.…”