A study of the clinical and radiological features in a cohort of 93 patients with a COL2A1 mutation causing spondyloepiphyseal dysplasia congenita or a related phenotype

Abstract

Type 2 collagen disorders encompass a diverse group of skeletal dysplasias that are commonly associated with orthopedic, ocular, and hearing problems. However, the frequency of many clinical features has never been determined. We retrospectively investigated the clinical, radiological, and genotypic data in a group of 93 patients with molecularly confirmed SEDC or a related disorder. The majority of the patients (80/93) had short stature, with radiological features of SEDC (n = 64), others having SEMD (n = 5), Kniest dysplasia (n = 7), spondyloperipheral dysplasia (n = 2), or Torrance-like dysplasia (n = 2). The remaining 13 patients had normal stature with mild SED, Stickler-like syndrome or multiple epiphyseal dysplasia. Over 50% of the patients had undergone orthopedic surgery, usually for scoliosis, femoral osteotomy or hip replacement. Odontoid hypoplasia was present in 56% (95% CI 38-74) and a correlation between odontoid hypoplasia and short stature was observed. Atlanto-axial instability, was observed in 5 of the 18 patients (28%, 95% CI 10-54) in whom flexion-extension films of the cervical spine were available; however, it was rarely accompanied by myelopathy. Myopia was found in 45% (95% CI 35-56), and retinal detachment had occurred in 12% (95% CI 6-21; median age 14 years; youngest age 3.5 years). Thirty-two patients complained of hearing loss (37%, 95% CI 27-48) of whom 17 required hearing aids. The ophthalmological features and possibly also hearing loss are often relatively frequent and severe in patients with splicing mutations. Based on clinical findings, age at onset and genotype-phenotype correlations in this cohort, we propose guidelines for the management and follow-up in this group of disorders.

Recurrent c.G1636A (p.G546S) mutation of COL2A1 in a Chinese family with skeletal dysplasia and different metaphyseal changes: a case report

“…For example, Silveira et al reported clinical and radiological follow-up of six unrelated patients with a R989C mutation that was associated with a severe SEDC phenotype, which was consistent with the phenotypes of twelve other R989C mutation cases [18]. In contrast, three patients with a G504S mutation showed mild SEDC, SEDT, and severe SEDC phenotypes [8, 15]. Likewise, a G513S mutation in a 4-year-old was associated with mild SEDC, but was also associated with a lethal form of SEDC that resulted in neonatal death [15, 19].…”

“…Recurrent COL2A1 mutations have been reported in several studies; some mutations displayed similar phenotypes, while others displayed distinct phenotypes [8, 15–20]. For example, Silveira et al reported clinical and radiological follow-up of six unrelated patients with a R989C mutation that was associated with a severe SEDC phenotype, which was consistent with the phenotypes of twelve other R989C mutation cases [18].…”

“…The X and Y position of the Gly-X-Y repeat are occupied by proline and hydroxyproline residues, respectively [7]. Most COL2A1 mutations are located in the triple-helical region, and glycine to bulky amino acid substitutions (e.g., glycine to serine) in the Gly-X-Y repeat have been identified frequently [8], however, the same COL2A1 mutation may cause different phenotypes and the genotype- phenotype relationship is still poorly understood. In this study, we identified a recurrent c.G1636A (p.G546S) COL2A1 mutation in a Chinese family.…”

Genetics of Short Stature

“…Therefore, mutations in genes that encode matrix collagens, proteoglycans, non-collagenous proteins and their processing enzymes affect growth plate chondrogenesis by several mechanisms and causes growth failure with a wide phenotypic spectrum (Table 1). For example, mutations in collagens [101–108], fibrillin 1 [109], cartilage oligomeric matrix protein [110–111], matrillin-3 [112], aggrecan [113–114] and perlecan [115] have been reported to cause short stature of variable severity. Mutations in genes encoding extracellular matrix proteins may also affect connective tissue beyond the growth plate, causing various degrees of skeletal and joint problems, as well as some conditions with low bone mineral density (Table 1).…”

The expanding spectrum of COL2A1 gene variants IN 136 patients with a skeletal dysplasia phenotype

“…24 Our observations provide a nearly 15% increase in the number of novel variants shown in previous records and illustrate the wide mutability of the COL2A1 gene and its various associated phenotypes. 25 Our results also demonstrate the limits of focusing on a single gene during genetic diagnosis given the lack of clear phenotype to genotype correlations. To address this issue, we are now implementing next-generation sequencing approaches in our routine settings.…”