Introduction. Osteogenesis imperfecta (OI) is etiologically heterogeneous disorder characterized by childhood osteoporosis. A subtype OI type V is caused by the same c.-14C>T mutation in the IFITM5 gene. Nevertheless, there is a marked interindividual phenotypic variability in clinical presentation; however, response to bisphosphonates is reported to be good.
Methods. Two individuals with OI type V had multiple recurrent fractures with hypertrophic calluses, scoliosis and ossifications of the forearm interosseous membranes. Sequencing of IFITM5, genotyping of variants rs2297480 in farnesyl diphosphate synthase gene (FDPS), and rs3840452 in geranylgeranyl diphosphate synthase 1 gene (GGPS1), both involved in bisphosphonate metabolism, was performed.
Results. In patient 1 BMD reached normal values during bisphosphonate treatment and remained normal four years after the treatment discontinuation. In patient 2 no increase in BMD after five years of bisphosphonate treatment was observed and callus formation continued. The c.-14C>T IFITM5 mutation in heterozygous state was detected in both individuals. Additionally, both patients carried FDPS variant rs2297480 in homozygous state, and were heterozygous for GGPS 1 variant rs3840452.
Conclusions. The paper presents a short overview of childhood osteoporosis with a special emphasis on OI type V by presenting two cases. Both OI type V patients had identical disease-causing mutation, but marked interindividual phenotypic variability. The striking failure in response to bisphosphonate treatment in one of the patients could not be explained by the variants in genes involved in bisphosphonate metabolism.
1. Bachrach LK, Hastie T, Wnag M-C, Narasimhan B, Marcus R. Bone mineral acquisition in healthy Asian, Hispanic, Black, and Caucasian youth: a longitudinal study. J Clin Endocrinol Metab 1999; 84: 4702-12.
2. Manolagas SC, Jilka RL. Bone marrow, cytokines, and bone remodeling. N Engl J Med 1995; 332: 305-11.
3. Blake GM, Naeem M, Boutros M. Comparison of effective dose to children and adults from dual X-ray absorptiometry examinations. Bone 2006; 38: 935-42.
4. World Health Organization. WHO scientific group assessement of the osteoporosis at the primary care level. Geneva: WHO, 2004.
5. Bachrach L, Sills I. Clinical report-bone densitometry in children and adolescents. Pediatrics 2011; 127: 189-94.
6. Zemel BS, Leonard MB, Kelly A, Lappe JM, Gilsanz V, Oberfield S. et al. Height adjustment in assessing dual energy X-ray absorptiometry measurements of bone mass and density in children. J Clin Endocrinol Metab 2010; 95: 1265-73.
7. Landin LA. Epidemiology of children’s fractures. J Pediatr Orthop B 1997; 6: 79-83.
8. Goulding A, Jones IE, Taylor RW, Manning PJ, Williams SM. More broken bones: a 4-year double cohort study of young girls with and without distal forearm fractures. J Bone Miner Res 2000; 15: 2011-8.
9. Shaw NJ. Osteoporosis in paediatrics. Arch Dis Child Educ Pract Ed 2007; 92: 169-75
10. Warman ML, Cormier-Daire V, Hall C, Krakow D, Lachman R, LeMerrer M. et al. Nosology and classification of genetic skeletal disorders: 2010 revision. Am J Med Genet A 2011; 155A: 943-68.
11. Valadares ER, Carneiro TB, Santos PM, Oliveira AC, Zabel B. What is new in genetics and osteogenesis imperfecta classification? J Pediatr (Rio J) 2014; 90: 536-41.
12. Marini JC, Reich A, Smith SM. Osteogenesis imperfecta due to mutations in non-collagenous genes: lessons in the biology of bone formation. Curr Opin Pediatr 2014; 26: 500-7.
13. van Dijk FS, Zillikens MC, Micha D, Riessland M, Marcelis CL, de Die- Smulders CE. et al. PLS3 mutations in X-linked osteoporosis with fractures. N Engl J Med 2013; 369: 1529-36.
14. Glorieux F, Rauch F, Plotkin H, Ward L, Travers R, Roughley P. et al. Type V osteogenesis imperfecta: a new form of brittle bone disease. J Bone Miner Res 2000; 15: 1650-8.
16. Cheung MS, Glorieux FH, Rauch F. Natural history of hyperplastic callus formation in osteogenesis imperfecta type V. J Bone Miner Res 2007; 22: 1181-6.
17. Vieira RL, Amaral DT, Jesus-Garcia FR, Saraiva G, Fernandes AR, Resnick D. Hyperplastic callus formation in osteogenesis imperfecta type V mimicking osteosacroma: 4-year follow-up with resolution. Skeletal Radiol 2006; 35: 402-5.
18. Rieker O, Kreitner KF, Karbowski A. Hyperplastic callus formation in osteogenesis imperfecta: CT and MRI findings. Eur Radiol 1998; 8: 1137-9.
19. Dobrocky I, Seidl G, Grill F. MRI and CT features of hyperplastic callus in osteogenesis imperfecta tarda. Eur Radiol 1999; 9: 665-8.
20. Cheung MS, Azouz EM, Glorieux FH, Rauch F. Hyperplastic callus formation in osteogenesis imperfecta type V: follow-up of three generations over ten years. Skeletal Radiol 2008; 37: 465-7.
21. Cho TJ, Lee KE, Lee SK, Song SJ, Kim KJ, Jeon D. et al. A single recurrent mutation in the 5’-UTR of IFITM5 causes osteogenesis imperfecta type V. Am J Hum Genet 2012; 91: 343-8.
22. Semler O, Garbes L, Keupp K, Swan D, Zimmermann K, Becker J. et al. A mutation in the 5’-UTR of IFITM5 creates an in-frame start codon and causes autosomal-dominant osteogenesis imperfecta type V with hyperplastic callus. Am J Hum Genet 2012; 91: 349-57.
23. Rauch F, Moffatt P, Cheung M, Roughley P, Lalic L, Lund AM. et al. Osteogenesis imperfecta type V: marked phenotypic variability despite the presence of the IFITM5 c.-14C>T mutation in all patients. J Med Genet 2013; 50: 21-4.
24. Shapiro JR, Lietman C, Grover M, Lu JT, Nagamani SC, Dawson BC. et al. Phenotypic variability of osteogenesis imperfecta type V caused by IFITM5 mutation. J Bone Miner Res 2013; 28: 1523-30.
25. Balasubramanian M, Parker MJ, Dalton A, Giunta C, Lindert U, Peres LC. et al. Genotype-phenotype study in type V osteogenesis imperfecta. Clin Dysmorphol 2013; 22: 93-101
26. Lamovec J, Možina E, Baebler B. Hyperplastic callus formation in osteogenesis imperfecta. Ann Diag Pathol 2003; 7: 231-5.
27. Lee DY, Cho TJ, Choi IH, Chung CY, Yoo WY, Kim JH. et al. Clinical and radiological manifestations of osteogenesis imperfecta type V. J Korean Med Sci 2006; 21: 709-14.
28. Zeitlin L, Rauch F, Travers R, Munns C, Glorieux FH. The effect of cyclical intravenous pamidronate in children and adolescents with osteogenesis imperfecta Type V. Bone 2006; 38; 13-20.
29. Fleming F, Woodhead HJ, Briody JN, Hall J, Cowell CT, Ault J. et al. Cyclic bisphosphonate therapy in osteogenesis type V. J Pediatr Child Health 2005; 41: 147-51.
30. Vuorimies I, Toiviainen-Salo S, Hero M, Mäkitie O. Zoledronic acid treatment in children with osteogenesis imperfecta. Horm Res Paediatr 2011; 75: 346-53.
31. Zacharin M, Bateman J. Pamidronate treatment of osteogenesis imperfecta-lack of correlation between clinical severity, age at onset of treatment, predicted collagen mutation and treatment response. J Pediatr Endocrinol Metab 2002; 15: 163-74.
32. Marini F. Falchetti A, Silvestri S, Bagger Y, Luzi E, Tanini A. et al. Modulatory effect of farnesyl pyrophosphate synthase (FDPS) rs2297480 polymorphism on the response to long-term aminobisphosphonate treatment in postmenopausal osteoporosis. Curr Med Res Opin 2008; 24: 2609-15.
33. Choi HJ, Choi JY, Cho SW, Kang D, Han KO, Kim SW. et al. Genetic polymorphism in geranylgeranyl diphosphate synthase (GGSP1) predicts bone density response to bisphosphonate therapy in Korean women. Yonsei Med J 2010; 51: 231-8.