Study of the prevalence of osteogenesis imperfecta and Ehlers-Danlo syndrome in the Republic of Bashkortostan

BACKGROUND: Osteogenesis imperfecta (Q78.0) and Ehlers-Danlo syndrome (Q79.6) are rare inherited (orphan) connective tissue diseases with variable clinical manifestations and a wide range of molecular defects. Data on the prevalence of these diseases are fragmentary due to the heterogeneous clinical picture and low availability of molecular diagnostics both in the world and in Russia. However, understanding the frequency of these diseases may help to optimize diagnosis and improve the quality of medical care for this category of patients.

AIM: To analyze the prevalence of osteogenesis imperfecta and Ehlers-Danlo syndrome in the Republic of Bashkortostan according to medical records.

MATERIALS AND METHODS: Data on the population of the republic were obtained from the official website of the Federal State Statistics Service for the Republic of Bashkortostan. Information on the incidence of diseases was taken from the reports of the Medical Information and Analytical Center of the Republic of Bashkortostan, analysis of the card file of the Republican Medical and Genetic Center (Ufa) and analysis of the Republican Medical Information and Analytical System «ProMed». Molecular genetic studies were performed by massively parallel sequencing.

RESULTS: A total of 199 patients with osteogenesis imperfecta have been identified in the Republic of Bashkortostan, 69 (34.6%) of them are under active observation. Molecular genetic study was performed for 64 patients (32.1%), and 16 pathogenic changes in the COL1A1 gene, 11 pathogenic mutations in the COL1A2 gene, one mutation each in the P3H1 and IFITM5 genes were detected. 112 males and 87 females were identified. The share of patients under 18 years of age in the whole republic amounted to 36.1%. In Ufa 80 patients were registered, the percentage of patients under active surveillance amounted to 42.5%. In general, 133 patients with Ehlers-Danlo syndrome were registered in the Republic of Bashkortostan, of which 30 patients (22.5%) were under active surveillance. Molecular genetic study was carried out in 43 patients (32.3%), and 5 changes of nucleotide sequence in the COL5A1 gene and 3 in the COL5A2 gene were revealed. There were 71 men and 62 women. As in the case of LE, patients older than 18 years prevail — 89 patients (66.9%), 18 patients (28.6%) were under active surveillance. The overall prevalence of osteogenesis imperfecta in the Republic of Bashkortostan amounted to 5.031 cases per 100,000 population, Ehlers-Danlo syndrome — 3.362 cases per 100,000 population. Patients with osteogenesis imperfecta are more often on active follow-up compared to Ehlers-Danlo syndrome (48.6% and 22.5%, respectively), which is explained by a longer period of work with this group of patients.

CONCLUSION: The prevalence of osteogenesis imperfecta and Ehlers-Danlo syndrome in the Republic of Bashkortostan according to medical records was determined. The total prevalence of osteogenesis imperfecta in the Republic of Bashkortostan amounted to 5.031 cases per 100 thousand population, Ehlers-Danlo syndrome - 3.362 cases per 100 thousand population.

1. Marom R, Lee Y, Grafe I, Lee B. Pharmacological and biological therapeutic strategies for osteogenesis imperfecta. Am J Med Genet Part C Semin Med Genet. 2016;172(4):367-383. doi: https://doi.org/10.1002/ajmg.c.31532

2. Robinson M-E, Rauch F. Mendelian bone fragility disorders. Bone. 2019;126:11-17. doi: https://doi.org/10.1016/j.bone.2019.04.021

3. Peddada KV, Sullivan BT, Margalit A, Sponseller PD. Fracture Patterns Differ Between Osteogenesis Imperfecta and Routine Pediatric Fractures. J Pediatr Orthop. 2018;38(4):e207-e212. doi: https://doi.org/10.1097/BPO.0000000000001137

4. Marini JC, Forlino A, Bächinger HP, et al. Osteogenesis imperfecta. Nat Rev Dis Prim. 2017;3(1):17052. doi: https://doi.org/10.1038/nrdp.2017.52

5. Rossi V, Lee B, Marom R. Osteogenesis imperfecta: advancements in genetics and treatment. Curr Opin Pediatr. 2019;31(6):708-715. doi: https://doi.org/10.1097/MOP.0000000000000813

6. Nadyrshina D, Zaripova A, Tyurin A, Minniakhmetov I, Zakharova E, Khusainova R. Osteogenesis Imperfecta: Search for Mutations in Patients from the Republic of Bashkortostan (Russia). Genes (Basel). 2022. doi: https://doi.org/10.3390/genes13010124

7. Malfait F, Castori M, Francomano CA, Giunta C, Kosho T, Byers PH. The Ehlers–Danlos Syndromes. Nat. Rev. Dis. Prim. 2020; 6. doi: https://doi.org/10.1038/s41572-020-0194-9

8. De Paepe A, Malfait F. The Ehlers–Danlos syndrome, a disorder with many faces. Clin Genet. 2012;82(1):1-11. doi: https://doi.org/10.1111/j.1399-0004.2012.01858.x

9. Eagleton MJ. Arterial complications of vascular Ehlers-Danlos syndrome. J Vasc Surg. 2016;64(6):1869-1880. doi: https://doi.org/10.1016/j.jvs.2016.06.120

10. Pinna R, Cocco F, Campus G, et al. Genetic and developmental disorders of the oral mucosa: Epidemiology; molecular mechanisms; diagnostic criteria; management. Periodontol 2000. 2019;80(1):12-27. doi: https://doi.org/10.1111/prd.12261

11. Malfait F, Wenstrup RJ, De Paepe A. Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type. Genet Med. 2010;12(10):597-605. doi: https://doi.org/10.1097/GIM.0b013e3181eed412

12. Merkuryeva E, Markova T, Tyurin A, et al. Clinical and Genetic Characteristics of Calvarial Doughnut Lesions with Bone Fragility in Three Families with a Reccurent SGMS2 Gene Variant. Int J Mol Sci. 2023;24(9):8021. doi: https://doi.org/10.3390/ijms24098021

13. Tyurin A, Merkuryeva E, Zaripova A, et al. Does the c.-14C>T Mutation in the IFITM5 Gene Provide Identical Phenotypes for Osteogenesis Imperfecta Type V? Data from Russia and a Literature Review. Biomedicines. 2022;10(10):2363. doi: https://doi.org/10.3390/biomedicines10102363

14. Orioli IM, Castilla EE, Barbosa-Neto JG. The birth prevalence rates for the skeletal dysplasias. J Med Genet. 1986;23(4):328-332. doi: https://doi.org/10.1136/jmg.23.4.328

15. Stoll C, Dott B, Roth M, Alembik Y. Birth prevalence rates of skeletal dysplasias. Clin Genet. 1989;35(2):88-92. doi: https://doi.org/10.1111/j.1399-0004.1989.tb02912.x

16. Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis imperfecta. J Med Genet. 1979;16(2):101-116. doi: https://doi.org/10.1136/jmg.16.2.101

17. Andersen PE, Hauge M. Osteogenesis imperfecta: a genetic, radiological, and epidemiological study. Clin Genet. 1989;36(4):250-255. doi: https://doi.org/10.1111/j.1399-0004.1989.tb03198.x

18. Martin E, Shapiro JR. Osteogenesis imperfecta: Epidemiology and pathophysiology. Curr Osteoporos Rep. 2007;5(3):91-97. doi: https://doi.org/10.1007/s11914-007-0023-z

19. Yakhyayeva GT, Namazova-Baranova LS, Margiyeva TV, Chumakova OV. Osteogenesis imperfecta in children in the Russian Federation: Results of the Federal registry audit. Pediatric pharmacology. 2016;13(1):44-48. (In Russ.) doi: https://doi.org/10.15690/pf.v13i1.1514

20. Zinchenko RA, Ginter EK. Osobennosti Medikomediko-Geneticheskogo geneticheskogo Konsul’tirovaniya konsul’tirovaniya v Razlichnyh razlichnyh Populyaciyah populyaciyah i Etnicheskih etnicheskih Gruppahgruppah. Medicinskaya genetika. 2008;7:20-29 (In Russ.)

21. Malfait F, De Paepe A. Molecular genetics in classic Ehlers-Danlos syndrome. Am J Med Genet - Semin Med Genet. 2005. doi: https://doi.org/10.1002/ajmg.c.30070

22. Peterson B, Coda A, Pacey V, Hawke F. Physical and mechanical therapies for lower limb symptoms in children with Hypermobility Spectrum Disorder and Hypermobile Ehlers‐Danlos Syndrome: a systematic review. J Foot Ankle Res. 2018;11(1). doi: https://doi.org/10.1186/s13047-018-0302-1

23. Jansson A, Saartok T, Werner S, Renström P. General joint laxity in 1845 Swedish school children of different ages: Age- and gender-specific distributions. Acta Paediatr Int J Paediatr. 2004. doi: https://doi.org/10.1080/08035250410023971

24. Amelina SS, Shokarev RA, Krivencova NV, Hlebnikova OV, El’chinova GI, Zinchenko RA. Genetiko-Epidemiologicheskoe epidemiologicheskoe Izuchenie izuchenie Rostovskoj Oblastioblasti. Medicinskaya genetika. 2005;4:371-377 (In Russ.)

25. Zinchenko RA, El’chinova GI, Galkina VA, Kirillov AG, i dr. Differenciaciya Etnicheskih Grupp Rossii Po Genam Nasledstvennyh Boleznej. Medicinskaya genetika. 2007;6:29-37 (In Russ.)

26. Zinchenko RA, Ginter EK. Nasledstvennye Bolezni v Populyaciyah Cheloveka. V: «Nacional’noe rukovodstvo. Nasledstvennye bolezni»; Bochkov NP, Ginter EK, Puzyrev VP, Eds.; GEOTAR-Media: Moskva, 2012; S. 662–704 (In Russ.)

27. Mamedova RA, El’chinova GI, Starceva EA, Kozlova SI, i dr. Mediko- i Populyacionno-Geneticheskoe Opisanie Arhangel’skoj Oblasti. Genetika. 1996;32:837-841 (In Russ.)

28. Makaov AH, El’chinova GI, Galkina VA, Kucev SI, Zinchenko RA. Rasprostranennost’ Sindroma Elersa-Danlo v Ryade Populyacij Rossii. Sovremennye problemy nauki i obrazovaniya. 2016 (In Russ.)