Scoliosis in osteogenesis imperfecta: identifying the genetic and non-genetic factors affecting severity and progression from longitudinal data of 290 patients

Abstract

Background Scoliosis is widely prevalent among osteogenesis imperfecta (OI) patients, and is progressive with age. However, factors affecting scoliosis in OI are not well known. Methods We retrospectively retrieved longitudinal radiographic and clinical records of consecutive OI patients seeking treatments at our hospital from 2014 to 2022, graded their pre-operative spinal conditions into four outcome groups, estimated their progression rates, and descriptively and inferentially analyzed the genetic and non-genetic factors that may affect the outcomes and progression rates. Results In all, 290 OI patients met the inclusion criteria, where 221 had genetic records. Of these 221, about 2/3 had mutations in COL1A1 or COL1A2, followed by mutations in WNT1 (9.0%), IFITM5 (9.0%) and other OI risk genes. With an average age of 12.0 years (interquartile range [IQR] 6.9–16.1), 70.7% of the cohort had scoliosis (Cobb angle > 10°), including 106 (36.5%) mild (10°–25°), 40 (13.8%) moderate (25°–50°), and 59 (20.3%) severe (> 50°) scoliosis patients. Patients with either COL1A1 and COL1A2 were strongly biased toward having mild or no scoliosis, whereas patients with mutations in IFITM5, WNT1 and other recessive genes were more evenly distributed among the four outcome grades. Lower-limb discrepancy, bone mineral density (BMD) and age of first drug used were all significantly correlated with severity outcomes. Using multivariate logistic regression, we estimated that each year older adds an odds ratio of 1.13 (95% confidence interval [CI] 1.07–1.2) in progression into advanced stages of scoliosis. We estimated a cohort-wide progression rate of 2.7 degrees per year (95% CI 2.4–3.0). Early-onset patients experienced fast progressions during both infantile and adolescent stages. Twenty-five of the 59 (42.8%) patients with severe scoliosis underwent spinal surgeries, enjoying an average Cobb angle reduction of 33° (IQR 23–40) postoperatively. Conclusion The severity and progression of scoliosis in osteogenesis imperfecta were affected by genetic factors including genotypes and mutation types, and non-genetic factors including age and BMD. As compared with COL1A1, mutations in COL1A2 were less damaging while those on IFITM5 and other recessive genes conferred damaging effects. Progression rates were the fastest in the adolescent adult age-group.

Unraveling the Link of Altered TGFβ Signaling with Scoliotic Vertebral Malformations in Osteogenesis Imperfecta: A Comprehensive Review

“…The study by Patel et al [ 28 ] involving 544 patients with OI reported that subjects suffering from Type III exhibited a higher prevalence of dentinogenesis imperfecta, severe scoliosis, and long bone deformities when compared to those with OI types I and IV. The study by Chen et al reported that patients with the COLI1A1 and COL1A2 genotypes were linked to milder forms of scoliosis, while in patients with IFITM5 mutations, the above pattern was not displayed [ 18 ]. Interestingly, among the two collagen groups, COL1A2 was associated with decreased progression rate to severe scoliotic curves than COL1A1 [ 18 ].…”

“…The study by Chen et al reported that patients with the COLI1A1 and COL1A2 genotypes were linked to milder forms of scoliosis, while in patients with IFITM5 mutations, the above pattern was not displayed [ 18 ]. Interestingly, among the two collagen groups, COL1A2 was associated with decreased progression rate to severe scoliotic curves than COL1A1 [ 18 ]. Similarly, the association between joint hypermobility and scoliosis in severe types of OI was also confirmed by the cross-sectional one-center study by Apronen et al [ 1 ], indicating that spinal joint hypermobility may contribute to the progression of scoliosis in OI.…”

“…Similarly, a study with type III OI patients observed increased expression of TGFβ [ 21 ]. The immunohistological examination of bony tissue also detected increased immunostaining of phosphor -SMAD2 due to the upregulation of TGFβ signaling in OI type III patients [ 18 ]. Moreover, administration of anti- TGFβ antibodies, such as 1D11, in jck mice models with renal osteodystrophy was associated with a decreased pSMAD2/SMAD ratio, TGFβ signaling and bone turnover in the femur [ 57 ].…”

“…Lower leg discrepancy, pelvic obliquity, hypermobility of the spinal ligaments, or microfractures of the vertebrae may also result in spinal malformations in these subjects. Moreover, the severity and progression of scoliotic curves in OI patients are associated with the genotypes and mutations, as well as the age and Bone Mineral Density (BMD) of the affected individuals [ 18 ]. Although the underlying mechanisms of scoliotic development in OI remain unclear, many researchers have examined the implication of several signaling pathways and molecular factors, including growth factors such as insulin-like growth factors (IGF-1), transforming growth factor beta (TGFβ), fibroblast growth factors (FGFs), platelet-derived growth factor (PDGF), or cytokines such as interleukins (ILs) and tumor necrosis factor (TNF).…”