The genetic implication of scoliosis in osteogenesis imperfecta: a review
Review Article

The genetic implication of scoliosis in osteogenesis imperfecta: a review

Gang Liu1*, Jia Chen1*, Yangzhong Zhou2, Yuzhi Zuo1, Sen Liu1,2,3, Weisheng Chen1, Zhihong Wu2,3,4, Nan Wu1,2,3

1Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China; 2Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China; 3Research Center of Orthopedics/Rare Disease, Chinese Academy of Medical Sciences, Beijing 100730, China; 4Department of Central Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China

Contributions: (I) Conception and design: G Liu, J Chen, N Wu; (II) Administrative support: N Wu, Z Wu; (III) Provision of study materials or patients: Y Zhou, S Liu; (IV) Collection and assembly of data: Y Zuo, W Chen; (V) Data analysis and interpretation: G Liu, J Chen; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

*These authors contributed equally to this work.

Correspondence to: Nan Wu. Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Beijing 100730, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China. Email:; Zhihong Wu. Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China; Department of Central Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Beijing 100730, China. Email:

Abstract: Osteogenesis imperfecta (OI) is a kind of heritable connective tissue disorder, including blue sclerae, hearing loss, skeletal dysplasia causing bone fragility and deformities. It is typically caused by collagen related gene mutations, which could lead to bone formation abnormalities. Scoliosis is one of the most common and severe spinal phenotype which has been reported in approximately 26–74.5% of all OI patients. Recent breakthroughs have suggested that OI can be divided into more than 16 types based on genetic mutations with different degrees of scoliosis. In this review, we summarize the etiology of scoliosis in OI, especially the genetic studies of different types. We aim to provide a systematic review of the genetic etiology and clinical suggestions of scoliosis in OI.

Keywords: Osteogenesis imperfecta (OI); scoliosis; bone formation; gene

Submitted Sep 06, 2016. Accepted for publication Aug 17, 2017.

doi: 10.21037/jss.2017.10.01


Osteogenesis imperfecta (OI) is a kind of heritable skeletal dysplasia, which is often called “fragile bone”. It affects about 1 in 5,000 to 20,000 births (1), and most cases are caused by mutation of collagen related genes, non-collagen genes account for less than 10% of OI patients (Table 1). The classical phenotypes of OI include frequent long bone fractures, vertebral compression fractures, short stature, blue sclera and dentinogenesis imperfecta (DI) (11). Patients can also have other manifestations, such as scoliosis, unilateral spinal anesthesia (12), among which scoliosis is commonly seen.

Table 1
Table 1 Classification of OI types and vertebral malformations
Full table

According to previous investigations, the prevalence of scoliosis in OI varies from 26% to 74.5% (2,3,5-7,11,13,14). The severity and prevalence of scoliosis in different types of OI is various (Table 1), and the type III patients often had higher prevalence of severe scoliosis than type I and IV (2,3,6).

The outset years of scoliosis in OI cases ranged from 2 to 65 years (15), always the spinal malformation progresses rapidly after 5 years old or after the spinal curve exceeds 50 degrees (16). Although scoliosis was rare before 6 years of age (17), some types of OI can also have scoliosis just after born (18).

The curvature of scoliosis in OI was different varying from 7 to 105 degrees (19). According to a national cross-sectional study by Karbowski (14), 73.7% was mainly mild (<40 degrees), while 10.5% showed moderate (<60 degrees), 9.2% severe (<80 degrees) and 6.6% very severe deformity (>80 degrees). The vertebral deformities included codfish or wedge-shaped vertebrae (20) which were mostly common, and platyspondylia. Another study indicated that there were four types of vertebral body deformities including biconcave, flattened, wedged and unclassifiable vertebrae. The number of biconcave vertebrae (normally six or more) may indicate the severity and possibility of scoliosis (21).

Although scoliosis develops indolently, once the malformations evolve, they tend to be progressive and have numerous influence on the patients’ life, such as pulmonary function and height (22). The treatment is ineffective in severely affected individuals who have minimal cortical bone (23), so it is necessary to prevent spinal curvature progression before severe complications arise (16,17). We are going to explore the tendency and severity of scoliosis, and give some interventions before scoliosis progressing in different types of OI (24). This review will be the first to give an integrated genetic landscape and aim to provide a basic knowledge of scoliosis in OI (25).

Genetic variants and pathogenesis

There are 19 types of OI according to genetic variants, the pathogenesis is not fully understood yet as shown in Figure 1. Based on the mechanism, OI can be divided into five groups (26). According to previous research, all of the groups and 16 types of the 19 types were reported to be manifest with scoliosis.

Figure 1 The pathogenesis of different types of OI with scoliosis. OI, osteogenesis imperfecta; CyPB, cyclophilin B; SPARC, secreted protein, acidic, cysteine-rich; FKBP, FK506-binding protein; P3H1, prolyl3-hydroxylase 1; CRTAP, cartilage-associated protein; PEDF, pigment epithelium-derived factor; IFITM5, interferon-induced transmembrane protein 5.

In the first group, OI is mainly caused by defects in collagen synthesis, structure, or processing including type I–IV and XIII. Most of OI patients have mutations in type I collagen related genes. Based on severity, OI is classified into four types (27). As shown in Table 1, patients with OI type I to IV always have variants in either collagen, type I, alpha-1 (COL1A1) or collagen, type I, alpha-2 (COL1A2). The production of type 1 collagen α1 or α2 chains would decrease. Patients with type I OI always have lower bone mineral density (BMD), thinner cortexes and reduced trabecular number (28) which would cause vertebra compression fracture. Together with joint hypermobility, patients manifested with scoliosis as shown in Table 2. Type II OI is also caused by mutations in COL1A1 or COL1A2, but this type is always too lethal to observe bone change and scoliosis. Type III has severely deforming and higher prevalence of scoliosis with vertebra compression and platyspondyly. Bisphosphonate treatment could decrease Cobb angle progression rates in type III at early age (24). Type IV can also have vertebra compression and severe scoliosis. OI type XIII is mainly caused by BMP1 defects which leads to retention of the C-propeptide (61). Scoliosis with umbilical hernia and platyspondyly were reported at early age (58).

Table 2
Table 2 Gene variants in different types of OI with scoliosis
Full table

In the second group, OI is mainly caused by defects in collagen modification including type VII–IX, XIV and XVII. The collagen prolyl 3-hydroxylation complex which consisted of three proteins in a 1:1:1 ratio of prolyl3-hydroxylase 1 (P3H1), cartilage-associated protein (CRTAP), and cyclophilin B (CyPB) has a significant collagen post-translational over-modification role (62). Each of those protein is encoded by CRTAP, LEPRE1 and PPIB. Defects of these three genes which cause delay of collagen helix folding could lead to OI type VII, VIII and IX (63). Defects of secreted protein, acidic, cysteine-rich (SPARC) which encoded by SPARC also could lead to delay of collagen folding, this type OI is considered to be type XVII (10). Type XIV is caused by TMEM38B mutations. The mechanism has not been completely elucidated. According to recent studies, TMEM38B mutations could inhibit calcium release, abnormal calcium signaling would decrease osteoblast growth and differentiation (64). Meanwhile post-translational modification of collagen would be influenced by calcium alteration of endoplasmic reticulum (26). In those types, patients with scoliosis always have low BMD as shown in Table 2.

In the third group, OI is mainly caused by defects in collagen folding and cross-linking including type X, XI and type caused by PLOD2 mutation. OI type X is mainly caused by mutation of SERPINH1 which encodes HSP47. HSP47 is important in stabilizing folded collagen and transferring to Golgi (49). This type of OI could lead to platyspondyly and scoliosis at early age. Like SERPINH1, FKBP10 is another important gene in procollagen modification (9). Its deficiency could lead to OI type XI. Associated with FKBP10, PLOD2 which encodes LH2 is another gene which could cause OI (54). Scoliosis is also very common in both types.

In the fourth group, OI is mainly caused by defects in bone mineralisation including type V and VI. Mutations of interferon-induced transmembrane protein 5 (IFITM5) could cause autosomal-dominant OI V. IFITM5 has close relationship with osteoblast, which may elucidate hyperplastic callus formation and membrana interossea ossification of forearms after injury (65). Patients with scoliosis could have cystic lesions vertebral bodies or vedge-shaped compression fractures (41). Connected with IFITM5, SERPINF1 which underlying OI type VI encodes protein pigment epithelium-derived factor (PEDF) (41). PEDF plays an important role in osteoprotegerin/RANKLE-pathway (66). Some studies had shown that decreased PEDF level may lead to activated osteoclast increased and thus induced bone resorption (67,68). This type OI could have severe scoliosis (33).

In the fifth group, OI is mainly caused by defects in osteoblast development with collagen insufficiency including type XII, XV and XVI. SP7 which encodes protein Osterix is target gene of Wnt pathway. Scoliosis in OI type XII with SP7 mutation was also reported (57), osteoblast development defects were considered to happen in this progress. Both heterozygous and homozygous WNT1 mutations could lead to OI type XV. As a member of Wnt family, mutations of WNT1 could cause complex signaling pathway defects in bone formation. In this type, scoliosis with early onset osteoporosis was reported (18). Just like WNT1, CREB3L1 mutation could also influence osteoblast development which may cause OI type XVI (69). But no scoliosis was reported yet. As OI type XVI, PLS3 mutation could lead to OI manifesting with osteoporosis and fractures (70). The exact mechanism is not known and report with scoliosis was not found yet.

Mechanism of scoliosis

The mechanism of scoliosis in OI has not been clarified, it is thought that there are some triggering factors such as vertebral microfractures caused by vertebral growth plates injuries or bone fragility. Some other factors like length inequality, pelvic obliquity, ligamentous laxity and inter-vertebral disc abnormalities would lead to scoliotic progression.

The vertebral body malformation may cause abnormal spinal curve in OI. Wedged vertebrae had been reported in OI patients representing kyphosis and quadriparesis (71). Fragile bone and fracture could lead to deformities in some severe OI forms, for example scoliosis (72). Although this is very common in OI, scoliosis patients can have no spinal fracture (32,59).

Osteopenia is also very common in OI patients which might be the pathology of scoliosis because of vertebral fragility (73). Some studies have shown the positive correlation of scoliosis with Z-score BMD and BMI (74). In Col1a1Jrt/+ mice model with OI and Ehlers-Danlos Syndrome (EDS) (75), the scoliosis mice had lower BMD and bone mineral content (BMC) compared with age-matched +/+ littermates which may lead to the early and rapid progressive malformation of vertebrae body.

There were many other factors which may influence scoliosis in OI. According to a retrospective study (11), scoliosis was significantly associated with age, whereas other clinical characteristics such as gender, weight, SDI were not. In some cases (76), scoliosis and vertebral body compression only happened during growth. Engelbert (4) found that the age of first achieving scoliosis was associated with the age of anti-gravity motor milestone, such as “supported sitting”. The connection may be caused by mechanical loads change. Some other studies also shown that the prevalence of scoliosis at maturity was not influenced by bisphosphonate treatment history although the treatment could decrease the progression (24).

Another important reason is increased mechanical strains during childhood. Mechanical loads with osteopenia can cause bone remodeling and progressive deformations, and the pedicle elongation is the most common result. Some OI cases with severe hyperlordosis had been reported to be caused by lumbar pedicle elongation and spondylolisthesis (77). Some other researchers proposed mechanostat model to illustrate bone deformations cause by mechanical forces (78).

Joint hyperlaxity can lead to scoliosis and chest malformations (73). In a subset of OI (79), patients with OI/EDS can have scoliosis because of ligamentous laxity, dislocations of other joints and mild osteopenia, with a few fractures. This may be caused by mutation of exon 6 fromαchain which lead to N-propeptide retention.


Most of the types OI could manifest with scoliosis, with type III patients have higher prevalence and type XV has the earliest scoliosis onset age. The exact mechanism of scoliosis in OI is complex and has not been fully elucidated. Based on current studies, scoliosis is mainly influenced by OI type, osteopenia, age, BMD, BMC, mechanical strains and ligamentous laxity.


Funding: This research was funded by National Natural Science Foundation of China (81501852, 81472046, 81772299), Beijing Natural Science Foundation (7172175), Beijing nova program (Z161100004916123), Beijing nova program interdisciplinary collaborative project (xxjc201717), 2016 Milstein Medical Asian American Partnership Foundation Fellowship Award in Translational Medicine, The Central Level Public Interest Program for Scientific Research Institute (2016ZX310177), PUMC Youth Fund & the Fundamental Research Funds for the Central Universities (3332016006), CAMS Initiative Fund for Medical Sciences (2016-I2M-3-003), the Distinguished Youth foundation of Peking Union Medical College Hospital (JQ201506), the 2016 PUMCH Science Fund for Junior Faculty (PUMCH-2016-1.1).


Conflicts of Interest: The authors have no conflicts of interest to declare.


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Cite this article as: Liu G, Chen J, Zhou Y, Zuo Y, Liu S, Chen W, Wu Z, Wu N. The genetic implication of scoliosis in osteogenesis imperfecta: a review. J Spine Surg 2017;3(4):666-678. doi: 10.21037/jss.2017.10.01