Skip to main content
Top
Published in: Orphanet Journal of Rare Diseases 1/2024

Open Access 01-12-2024 | Scoliosis | Review

Molecular landscape of congenital vertebral malformations: recent discoveries and future directions

Authors: Anna Szoszkiewicz, Ewelina Bukowska-Olech, Aleksander Jamsheer

Published in: Orphanet Journal of Rare Diseases | Issue 1/2024

Login to get access

Abstract

Vertebral malformations (VMs) pose a significant global health problem, causing chronic pain and disability. Vertebral defects occur as isolated conditions or within the spectrum of various congenital disorders, such as Klippel–Feil syndrome, congenital scoliosis, spondylocostal dysostosis, sacral agenesis, and neural tube defects. Although both genetic abnormalities and environmental factors can contribute to abnormal vertebral development, our knowledge on molecular mechanisms of numerous VMs is still limited. Furthermore, there is a lack of resource that consolidates the current knowledge in this field. In this pioneering review, we provide a comprehensive analysis of the latest research on the molecular basis of VMs and the association of the VMs-related causative genes with bone developmental signaling pathways. Our study identifies 118 genes linked to VMs, with 98 genes involved in biological pathways crucial for the formation of the vertebral column. Overall, the review summarizes the current knowledge on VM genetics, and provides new insights into potential involvement of biological pathways in VM pathogenesis. We also present an overview of available data regarding the role of epigenetic and environmental factors in VMs. We identify areas where knowledge is lacking, such as precise molecular mechanisms in which specific genes contribute to the development of VMs. Finally, we propose future research avenues that could address knowledge gaps.
Literature
10.
go back to reference Erol B, Tracy M, Dormans J, Zackai E, Maisenbacher M, O’Brien M, et al. Congenital scoliosis and vertebral malformtions: characterization of segmental defects for genetic analysis. J Pediatr Othop. 2004;24(6):674–82.CrossRef Erol B, Tracy M, Dormans J, Zackai E, Maisenbacher M, O’Brien M, et al. Congenital scoliosis and vertebral malformtions: characterization of segmental defects for genetic analysis. J Pediatr Othop. 2004;24(6):674–82.CrossRef
14.
go back to reference Özek MM, Cinalli G, Maixner WJ. Vertebral Anomalies and Spinal Malformations in Myelomeningocele. The Spina Bifida. 2008; 185–196. Özek MM, Cinalli G, Maixner WJ. Vertebral Anomalies and Spinal Malformations in Myelomeningocele. The Spina Bifida. 2008; 185–196.
22.
go back to reference Groves M, Vivas A, Samdani A. Scoliosis and other congenital vertebral anomalies. Textbook of Pediatric Neurosurgery. 2020:2623–2633 Groves M, Vivas A, Samdani A. Scoliosis and other congenital vertebral anomalies. Textbook of Pediatric Neurosurgery. 2020:2623–2633
26.
go back to reference Tsou P, Yau A, Hodgson A. Embryogenesis and prenatal development of congenital vertebral anomalies and their classification. Clin Orthop Relat Res. 1980;152:211–31.CrossRef Tsou P, Yau A, Hodgson A. Embryogenesis and prenatal development of congenital vertebral anomalies and their classification. Clin Orthop Relat Res. 1980;152:211–31.CrossRef
27.
go back to reference Nasca R, Stelling F, Steel H. Progression of congenital scoliosis due to hemivertebrae and hemivertebrae with bars. J Bone Jt Surg Am. 1975;57(4):456–66.CrossRef Nasca R, Stelling F, Steel H. Progression of congenital scoliosis due to hemivertebrae and hemivertebrae with bars. J Bone Jt Surg Am. 1975;57(4):456–66.CrossRef
35.
go back to reference Lawson ME, Share J, Benacerraf B, Krauss CM. Jarcho-Levin syndrome: prenatal diagnosis, perinatal care, and follow-up of siblings. J Perinatol. 1997;17(5):407–9.PubMed Lawson ME, Share J, Benacerraf B, Krauss CM. Jarcho-Levin syndrome: prenatal diagnosis, perinatal care, and follow-up of siblings. J Perinatol. 1997;17(5):407–9.PubMed
37.
go back to reference Oi S. Malformations of the vertebrae. In: Raimondi ACM, Di Rocco C (eds) Principles of pediatric neurosurgery. 1989; pp 1–18 Oi S. Malformations of the vertebrae. In: Raimondi ACM, Di Rocco C (eds) Principles of pediatric neurosurgery. 1989; pp 1–18
38.
go back to reference Rush BR. Developmental vertebral abnormalities. In: Auer JA, Stick JA, editors. Equine Surgery. 4th ed. St Louis: Elsevier; 2012. p. 693–9.CrossRef Rush BR. Developmental vertebral abnormalities. In: Auer JA, Stick JA, editors. Equine Surgery. 4th ed. St Louis: Elsevier; 2012. p. 693–9.CrossRef
41.
go back to reference Klippel M, Feil A. Un cas d’absence des vertebres cervicales avec cage thoracique remontant jusqu’a la base du crane. Nouv Icon Salpet. 1912;25:223–50. Klippel M, Feil A. Un cas d’absence des vertebres cervicales avec cage thoracique remontant jusqu’a la base du crane. Nouv Icon Salpet. 1912;25:223–50.
43.
go back to reference Krakow D. Spinal abnormalities and Klippel–Feil syndrome. Second Edi. Obstetric Imaging: Fetal Diagnosis and Care. 2nd Edition. Elsevier Inc; 2017;295–297 Krakow D. Spinal abnormalities and Klippel–Feil syndrome. Second Edi. Obstetric Imaging: Fetal Diagnosis and Care. 2nd Edition. Elsevier Inc; 2017;295–297
44.
go back to reference Nouri A, Tetreault L, Zamorano JJ, Mohanty CB, Fehlings MG. Prevalence of Klippel–Feil syndrome in a surgical series of patients with cervical spondylotic myelopathy: analysis of the prospective, multicenter AOSpine North America study. Glob Spine J. 2015;5(4):294–9. https://doi.org/10.1055/s-0035-1546817.CrossRef Nouri A, Tetreault L, Zamorano JJ, Mohanty CB, Fehlings MG. Prevalence of Klippel–Feil syndrome in a surgical series of patients with cervical spondylotic myelopathy: analysis of the prospective, multicenter AOSpine North America study. Glob Spine J. 2015;5(4):294–9. https://​doi.​org/​10.​1055/​s-0035-1546817.CrossRef
45.
go back to reference Jones K, Jones M, del Campo M. Recognizable patterns of human malformations. 7th ed. Elsievier; 2013. p. 796–830. Jones K, Jones M, del Campo M. Recognizable patterns of human malformations. 7th ed. Elsievier; 2013. p. 796–830.
46.
go back to reference Hensinger R, Lang J, MacEwen G. Klippel–Feil syndrome; a costellation of associated anomalies. J Bone Jt Surg Am. 1974;56(6):1246–53.CrossRef Hensinger R, Lang J, MacEwen G. Klippel–Feil syndrome; a costellation of associated anomalies. J Bone Jt Surg Am. 1974;56(6):1246–53.CrossRef
49.
go back to reference Clarke RA, Singh S, McKenzie H, Kearsley JH, Yip MY. Familial Klippel–Feil syndrome and paracentric inversion inv(8)(q22.2q23.3). Am J Hum Genet. 1995;57(6):1364–70.PubMedPubMedCentral Clarke RA, Singh S, McKenzie H, Kearsley JH, Yip MY. Familial Klippel–Feil syndrome and paracentric inversion inv(8)(q22.2q23.3). Am J Hum Genet. 1995;57(6):1364–70.PubMedPubMedCentral
59.
go back to reference Erol B, Tracy MR, Dormans JP, Zackai EH, Maisenbacher MK, Brien MLO, Turnpenny PD, et al. Congenital scoliosis and vertebral malformations characterization of segmental defects for genetic analysis. J Pediatr Orthopaed. 2004;24(6):674–82.CrossRef Erol B, Tracy MR, Dormans JP, Zackai EH, Maisenbacher MK, Brien MLO, Turnpenny PD, et al. Congenital scoliosis and vertebral malformations characterization of segmental defects for genetic analysis. J Pediatr Orthopaed. 2004;24(6):674–82.CrossRef
64.
go back to reference McMaster. The natural history of congenital scoliosis: a study of two hundred and fifty-one patients. J Bone Jt Surg Am. 1982;64(8):1128–47.CrossRef McMaster. The natural history of congenital scoliosis: a study of two hundred and fifty-one patients. J Bone Jt Surg Am. 1982;64(8):1128–47.CrossRef
65.
go back to reference Kose N, Campbell RM. Congenital scoliosis. Med Sci Monit. 2004;10(5):104–10. Kose N, Campbell RM. Congenital scoliosis. Med Sci Monit. 2004;10(5):104–10.
82.
go back to reference Wilkinson D, Bhatt S, Herrmann B. Expression pattern of the mouse T gene and its role in mesorderm formation. Nature. 1990;343(6259):657–9.CrossRefPubMed Wilkinson D, Bhatt S, Herrmann B. Expression pattern of the mouse T gene and its role in mesorderm formation. Nature. 1990;343(6259):657–9.CrossRefPubMed
100.
go back to reference Savini R, Gargiulo G, Cervellati S, Di Silvestre M. Achondroplasia and lumbar spinal stenosis. Ital J Orthop Traumatol. 1991;17(2):199–209.PubMed Savini R, Gargiulo G, Cervellati S, Di Silvestre M. Achondroplasia and lumbar spinal stenosis. Ital J Orthop Traumatol. 1991;17(2):199–209.PubMed
115.
go back to reference Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL. Maternal fever and birth outcome: a prospective study. Teratology. 1998;58(6):251–7.CrossRefPubMed Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL. Maternal fever and birth outcome: a prospective study. Teratology. 1998;58(6):251–7.CrossRefPubMed
116.
117.
go back to reference Shields DC, Ramsbottom D, Donoghue C, Pinjon E, Kirke PN, Molloy AM, et al. Association between historically high frequencies of neural tube defects and the human T homologue of mouse T (Brachyury). Am J Med Genet. 2000;92(3):206–11.CrossRefPubMed Shields DC, Ramsbottom D, Donoghue C, Pinjon E, Kirke PN, Molloy AM, et al. Association between historically high frequencies of neural tube defects and the human T homologue of mouse T (Brachyury). Am J Med Genet. 2000;92(3):206–11.CrossRefPubMed
133.
go back to reference Arth A, Tinker S, Moore C, Canfield M, Agopian A, Reefhuis J. Supplement use and other characteristics among pregnant women with a previous pregnancy affected by a neural tube defect - United States. MMWR Morb Mortal Wkly Rep. 2015;64(1):6–9.PubMedPubMedCentral Arth A, Tinker S, Moore C, Canfield M, Agopian A, Reefhuis J. Supplement use and other characteristics among pregnant women with a previous pregnancy affected by a neural tube defect - United States. MMWR Morb Mortal Wkly Rep. 2015;64(1):6–9.PubMedPubMedCentral
148.
go back to reference Bruce S, Hannula-Jouppi K, Peltonen J, Kere J, Lipsanen-Nyman M. Clinically distinct epigenetic subgroups in Silver–Russell syndrome: the degree of H19 hypomethylation associates with phenotype severity and genital and skeletal anomalies. J Clin Endocrinol Metab. 2009;94(2):579–87. https://doi.org/10.1210/jc.2008-1805.CrossRefPubMed Bruce S, Hannula-Jouppi K, Peltonen J, Kere J, Lipsanen-Nyman M. Clinically distinct epigenetic subgroups in Silver–Russell syndrome: the degree of H19 hypomethylation associates with phenotype severity and genital and skeletal anomalies. J Clin Endocrinol Metab. 2009;94(2):579–87. https://​doi.​org/​10.​1210/​jc.​2008-1805.CrossRefPubMed
164.
go back to reference Xuan JY, Hughes-Benzie RM, MacKenzie AE. A small interstitial deletion in the GPC3 gene causes Simpson–Golabi–Behmel syndrome in a Dutch–Canadian family. J Med Genet. 1999;36(1):57–8.CrossRefPubMedPubMedCentral Xuan JY, Hughes-Benzie RM, MacKenzie AE. A small interstitial deletion in the GPC3 gene causes Simpson–Golabi–Behmel syndrome in a Dutch–Canadian family. J Med Genet. 1999;36(1):57–8.CrossRefPubMedPubMedCentral
166.
go back to reference Handmaker SD, Campbell JA, Robinson LD, Chinwah O, Gorlin RJ. Dyssegmental dwarfism: a new syndrome of lethal dwarfism. Birth Defects Orig Artic Ser. 1977;13(3D):79–90.PubMed Handmaker SD, Campbell JA, Robinson LD, Chinwah O, Gorlin RJ. Dyssegmental dwarfism: a new syndrome of lethal dwarfism. Birth Defects Orig Artic Ser. 1977;13(3D):79–90.PubMed
169.
170.
go back to reference Sobreira N, Modaff P, Steel G, You J, Nanda S, Hoover-Fong J, et al. An anadysplasia-like, spontaneously remitting spondylometaphyseal dysplasia secondary to lamin B receptor (LBR) gene mutations: further definition of the phenotypic heterogeneity of LBR-bone dysplasias. Am J Med Genet A. 2015;167A(1):159–63. https://doi.org/10.1002/ajmg.a.36808.CrossRefPubMed Sobreira N, Modaff P, Steel G, You J, Nanda S, Hoover-Fong J, et al. An anadysplasia-like, spontaneously remitting spondylometaphyseal dysplasia secondary to lamin B receptor (LBR) gene mutations: further definition of the phenotypic heterogeneity of LBR-bone dysplasias. Am J Med Genet A. 2015;167A(1):159–63. https://​doi.​org/​10.​1002/​ajmg.​a.​36808.CrossRefPubMed
178.
182.
go back to reference Stelzer G, Rosen R, Plaschkes I, Zimmerman S, Twik M, et al. The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analysis, Current Protocols in Bioinformatics. 2016;54:1.30.1–1.30.33. GeneCards – the human gene database. www.genecards.org Stelzer G, Rosen R, Plaschkes I, Zimmerman S, Twik M, et al. The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analysis, Current Protocols in Bioinformatics. 2016;54:1.30.1–1.30.33. GeneCards – the human gene database. www.​genecards.​org
200.
go back to reference Yang WT, Lewis MT, Hess K, Wong H, Tsimelzon A, Karadag N, et al. Decreased 741 TGFbeta signaling and increased COX2 expression in high risk women with increased 742 mammographic breast density. Breast Cancer Res Treat. 2010;119(2):305–14.CrossRefPubMed Yang WT, Lewis MT, Hess K, Wong H, Tsimelzon A, Karadag N, et al. Decreased 741 TGFbeta signaling and increased COX2 expression in high risk women with increased 742 mammographic breast density. Breast Cancer Res Treat. 2010;119(2):305–14.CrossRefPubMed
219.
224.
go back to reference Maroteaux P, Spranger J, Opitz JM, Kucera J, Lowry RB, Schimke RN, Kagan SM. Le syndrome campomélique [The campomelic syndrome]. Presse Med. 1893;1971(79):1157–62. Maroteaux P, Spranger J, Opitz JM, Kucera J, Lowry RB, Schimke RN, Kagan SM. Le syndrome campomélique [The campomelic syndrome]. Presse Med. 1893;1971(79):1157–62.
227.
Metadata
Title
Molecular landscape of congenital vertebral malformations: recent discoveries and future directions
Authors
Anna Szoszkiewicz
Ewelina Bukowska-Olech
Aleksander Jamsheer
Publication date
01-12-2024
Publisher
BioMed Central
Keyword
Scoliosis
Published in
Orphanet Journal of Rare Diseases / Issue 1/2024
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/s13023-024-03040-0

Other articles of this Issue 1/2024

Orphanet Journal of Rare Diseases 1/2024 Go to the issue