Dysspondyloenchondromatosis: Another COL2A1-Related Skeletal Dysplasia

Abstract

Dysspondyloenchondromatosis (DSC) is a rare skeletal dysplasia that has currently been classified into the group of spondylometaphyseal dysplasias. To date, only 12 affected individuals have been reported. All cases are sporadic, and the etiology remains unknown. Distinctive features of DSC are anisospondyly and enchondroma-like lesions in the metaphyseal and diaphyseal portions of the long tubular bones. Affected individuals usually develop kyphoscoliosis and asymmetric limb shortening at an early age. Interestingly, some of the skeletal changes overlap with spondyloepimetaphyseal dysplasia (SEMD) Strudwick type, a rare type II collagen disorder. Based on this resemblance we postulated that DSC may be allelic to SEMD Strudwick type and therefore performed a COL2A1 analysis in an affected boy who was diagnosed as having DSC at the age of 3 years. The identification of a novel heterozygous COL2A1 missense mutation (p.Gly753Asp) in the proband confirms our hypothesis and suggests that DSC may be another type II collagen disorder.

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

“…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.…”

“…Craniofacial involvement with cleft palate, vitreoretinal degeneration, severe myopia, hearing impairment, and atlantoaxial instability are other characteristic features of type 2 collagenopathies [Kannu et al, 2012]. Cleft palate in DSC has been reported only by Kozlowski et al [1994] and Nakane et al [2011]. Our patients had normal ophthalmic and hearing examinations and no cleft palate.…”

“…In our patients, the localization of enchondromatous lesions on long bones was in proximal parts of humeri, femurs, and tibias as well as distal parts of ulnae, radii, and femurs. Patients of Nakane et al [2011] and Merrick et al [2015] showed similar localization patterns of enchondromatous lesions. The patient of Tran Mau-Them et al [2014] had enchondromatous lesions on distal ulnae, distal radii, and vertebrae showing a different localization pattern compared to other DSC patients.…”

“…The majority of DSC patients had severe scoliosis, even within the first years of life [Mainzer et al, 1971;Nakane et al, 2011]. Patient 1 reported here developed progressive scoliosis, which began at the age of 2 years.…”

“…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.…”