RADİYAL IŞIN DEFEKTLERİNİN KLİNİK SINIFLANDIRMASI VE ETYOPATOGENEZİNİN ARAŞTIRILMASI

Yıl 2018, Cilt: 81 Sayı: 4, 127 - 138, 01.12.2018

Şahin Avcı , Güven Toksoy Gülenadam Bağırova Umut Altunoğlu Birsen Karaman Seher Başaran Hülya Kayserili Z. Oya Uyguner

Öz

DOI: 10.26650/IUITFD.427250

Amaç: Radiyal ışın defektleri (RID)
1/30.000 prevalansı ile üst ekstremitenin en sık gözlenen konjenital
anomalisidir. Olguların yaklaşık %30’unda RID izole olarak, %70’inde ek
anomaliler veya sendromlar ile birlikte gözlenir. Bu nedenle, olgularda tanının
kesinleşmesi, izlemi, ailelere özgün genetik danışma verilmesi ve sonraki
gebeliklerinde prenatal tanı seçeneğinin sunulabilmesi için önemlidir. Bu
çalışma ile RID olgularının ayırıcı tanısında yol gösterici olması, moleküler
tanıya katkı sağlaması amacıyla yeni nesil dizileme (YND) gen-paneli
oluşturuldu ve panelin moleküler tanıdaki etkinliği araştırıldı.

Gereç ve Yöntem:  Bu çalışmada, 2004-2014 yılları arasında
kliniğimizde RID bulgusu ile değerlendirilen 37 aileden 48 etkilenmiş olgunun
klinik, moleküler ve sitogenetik bulguları değerlendirildi. Karyotipi normal
saptanan ve moleküler tanısı olmayan 31 ailenin indeks olgusunda 14 farklı
fenotip ile ilişkili 43 gen, RID için tasarladığımız hedefe yönelik YND paneli
ile dizilendi.

Bulgular: Sitogenetik analiz ile bir olguda
trizomi 18 ve diğer bir olguda ise ailevi t(2;12)(q31;q24.3) translokasyonu
saptandı. Dört ailede ilişkili genlerdeki (SF3B4, SALL4, TBX5, FANCA)
mutasyonlar çalışma öncesinde moleküler analizlerle belirlenmişti. Tanısı
olmayan 31 indeks olgunun 5’inde (%16), 4 farklı gende (FANCA, NIPBL, ESCO2,
BRIP1) 6 farklı mutasyon saptandı.

Sonuç: RID nedeniyle değerlendirilen 37
ailenin 2’sinde (%5.4) kromozom anomalisi ve 9’unda (%24.3) 7 farklı gende 9
farklı mutasyon saptandı. Bulgularımız, RID olgularında özgün tasarlanan yeni
nesil dizileme panelimizin moleküler tanıya önemli oranda katkı sağladığını; RID’ın
etyopatogenezinde kromozom anomalilerinin de yer aldığını, ayırıcı tanıda yer
alması ve RID-panel çalışmasından önce kromozom anomalilerinin dışlanması
gerektiğini gösterdi.

Anahtar Kelimeler

Fanconi anemisi, radial ışın defektleri, yeni nesil dizileme

CLINICAL CLASSIFICATION OF RADIAL RAY DEFECTS AND RESEARCH INTO ETIOPATHOGENESIS

Öz

DOI: 10.26650/IUITFD.427250

Objective: Radial ray defects (RRDs) are
the most common congenital abnormality of the upper extremities, with a
prevalence of 1:30,000. 70% of RRDs are syndromic or accompanied by additional
malformations, whereas 30% are in isolated form. Definitive diagnosis is
critical for follow-up and provides an opportunity for prenatal diagnosis. The
aim of this study was to provide a guide for the differential diagnosis of
patients with RRD via contributing to their molecular diagnosis by constructing
a next-generation sequencing (NGS) gene-panel test.

Materials and Methods: 48 probands from 37
families, referred for genetic consultation due to RRD, between the years of
2004–2014, were evaluated by cytogenetic and molecular tools following clinical
examinations. 31 probands, with normal karyotype, were screened for 43 RRD
associated genes of 14 syndromes by using in-house-designed targeted NGS
gene-panel.

Results: Chromosomal abnormalities [a
trisomy 18 and a familial reciprocal translocation t(2;12)(q31;q24.3)] in two
families and mutations in related genes (SF3B4, SALL4, TBX5, FANCA) in four
families were known before the initiation of this study. In remaining 31
probands, five families identified to have six different mutations in four
different genes (FANCA, NIPBL, ESCO2, BRIP1).

Conclusion: Chromosomal abnormalities in
two of the 37 families (5.4%) and gene mutations in nine of the 37 families
(24.3%) were identified. Our study demonstrated that an in-house-designed
targeted NGS containing 43 genes made considerable contribution to the
diagnosis of RRD. Moreover, chromosomal abnormalities must always be considered
in the differential diagnosis and excluded before gene-panel screening.

Anahtar Kelimeler

Fanconi anemia, next-generation sequencing, radial ray defects

Kaynakça

• 1. Ashhurst DE. The influence of mechanical conditions on the healing of experimental fractures in the rabbit: a microscopical study. Philos Trans R Soc Lond B Biol Sci 1986;313(1161):271 - 302. 2. Bellaiche N. Imaging in oral implantology. In: Scortecchi GM, Misch CE, Benner KU (eds). Implants and Restorative Dentistry. London, England: Martin Dunitz Ltd, 2001;181. 3. Bouckenooghe T, Remacle C, Reusens B. Is taurine a functional nutrient? Curr Opin Clin Nutr Metab Care 2006;9(6):728-33. 4. Buckwalter JA. Musculoskeletal tissue healing. In: Weinstein SL, Buckwalter JA (eds). Turek’s Orthopaedics, Principles and Their Applications, 6th ed. Philadelphia, Pennsylvania, USA: Lippincott Williams & Wilkins, 2005;57-63. 5. Cetinus E, Kilinc M, Uzel M, et al. Does long-term ischemia affect the oxidant status during fracture healing? Arch Orthop Trauma Surg 2005;125(6):376-80. 6. Demers LM. Bone specific alkaline phosphatase. In: Eastell R, Baumann M, Hoyle NR, Wieczorek L (eds). Bone Markers Biochemical and Clinical Perspectives, London, England: Martin Dunitz Ltd, 2001;57-8. 7. Durak K, Sönmez G, Sarisozen B, Özkan S, Kaya M, Öztürk C. Histological assessment of the effect of alpha-tocopherol on fracture healing in rabbits. J Int Med Res 2003;31(1):26-30. 8. Duygulu F, Yakan B, Karaoğlu S, Kutlubay R, Karahan OI, Özturk A. The effect of zymosan and the protective effect of various antioxidants on fracture healing in rats. Arch Orthop Trauma Surg 2007;127(7):493-501. 9. Frost HM. The biology of fracture healing. An overview for clinicians. Part I. Clin Orthop Relat Res 1989;248:283-93. 10. Garrett IR, Boyce BF, Oreffo RO, Bonewald L, Poser J, Mundy GR. Oxygen-derived free radicals stimulate osteoclastic bone resorption in rodent bone in vitro and in vivo. J Clin Invest 1990;85(3):632-9. 11. Göktürk E, Turgut A, Baycu C, Günal I, Seber S, Gülbaş Z. Oxygen free radicals impair fracture healing in rats. Acta Orthop Scand 1995;66(5):473-5. 12. Goldberg VM, Powell A, Shaffer JW, Zika J, Bos GD, Heiple KG. Bone grafting: role of histocompatibility in transplantation. J Orthop Res 1985;3(4):389-404. 13. Halıcı M, Öner M, Güney A, Canöz Ö, Narin F, Halıcı C. Melatonin promotes fracture healing in the rat model. Eklem Hastalik Cerrahisi 2010;21(3):172-7. 14. Huo MH, Troiano NW, Pelker RR, Gundberg CM, Friedlaender GE. The influence of ibuprofen on fracture repair: biomechanical, biochemical, histologic, and histomorphometric parameters in rats. J Orthop Res 1991;9(3):383-90. 15. Huxtable RJ. Physiological actions of taurine. Physiol Rev 1992;72(1):101-63. 16. Kim JW, Kim C. Inhibition of LPS-induced NO production by taurine chloramine in macrophages is mediated though Ras-ERK-NF-kappaB. Biochem Pharmacol 2005;70(9):1352-60. 17. Lykkesfeldt J. Determination of malondialdehyde as dithiobarbituric acid adduct in biological samples by HPLC with fluorescence detection: comparison with ultraviolet-visible spectrophotometry. Clin Chem 2001;47(9):1725-7. 18. Mohamad S, Shuid AN, Mohamed N, et al. The effects of alpha-tocopherol supplementation on fracture healing in a postmenopausal osteoporotic rat model. Clinics (Sao Paulo) 2012;67(9):1077-85. 19. Mohamadnia AR, Shahbazkia HR, Sharifi S, Shafaei I. Bone-specificalkaline phosphatase as a good indicator of bone formation in sheepdogs. Comp Clin Pathol 2007;16(4):265-70. 20. Park E, Alberti J, Quinn MR, Schuller-Levis G. Taurine chloramine inhibits the production of superoxide anion, IL-6 and IL-8 in activated human polymorphonuclear leukocytes. Adv Exp Med Biol 1998;442:177-82. 21. Park S, Kim H, Kim SJ. Stimulation of ERK2 by taurine with enhanced alkaline phosphatase activity and collagen synthesis in osteoblast-like UMR-106 cells. Biochem Pharmacol 2001;62(8):1107-11. 22. Petrovich YA, Podorozhnaya RP, Kichenko SM, Kozlova MV. Effects of selenium-containing compounds and their metabolism in intact rats and in animals with bone fractures. Bull Exp Biol Med 2004;137(1):74-7. 23. Pincemail J. Free radicals and antioxidants in human diseases. In: Favier AE, Cadet J, Kalyanaraman B, Fontecave M, Pierre JL eds. Analysis of free radicals in biological systems, Basel, Switzerland: Birkhäuser; 1995: 83-98. 24. Roysommuti S, Azuma J, Takahashi K, Schaffer S. Taurine cytoprotection: From cell to system. Thai J Physiol Sci 2003;16(2):17-27. 25. Rozen N, Lewinson D, Bick T, Meretyk S, Soudry M. Role of bone regeneration and turnover modulators in control of fracture. Crit Rev Eukaryot Gene Expr 2007;17(3):197-213. 26. Sarisozen B, Durak K, Dincer G, Bilgen OF. The effects of vitamins E and C on fracture healing in rats. J Int Med Res 2002;30(3):309-13. 27. Schuller-Levis GB, Park E. Taurine and its chloramine: modulators of immunity. Neurochem Res 2004;29(1):117-26. 28. Shuid AN, Mohamad S, Muhammad N, et al. Effects of α-tocopherol on the early phase of osteoporotic fracture healing. J Orthop Res 2011;29(11):1732-8. 29. Silverton SF, Mesaros S, Markham GD, Malinski T. Osteoclast radical interactions: NADPH causes pulsatile release of NO and stimulates superoxide production. Endocrinology 1995; 136(11):5244-7. 30. Sontakke AN, Tare RS. A duality in the roles of reactive oxygen species with respect to bone metabolism. Clin Chim Acta 2002;318(1-2):145-8. 31. Turgut A, Göktürk E, Köse N, Kaçmaz M, Oztürk HS, Seber S, et al. Oxidant status increased during fracture healing in rats. Acta Orthop Scand 1999;70(5):487-90. 32. Turk C, Halici M, Guney A, Akgun H, Sahin V, Muhtaroglu S. Promotion of fracture healing by vitamin E in rats. J Int Med Res 2004;32(5):507-12. 33. Volkmer DL, Sears B, Lauing KL, Nauer RK, Roper PM, Yong S, et al. Antioxidant therapy attenuates deficient bone fracture repair associated with binge alcohol exposure. J Orthop Trauma 2011;25(8):516-21. 34. Wojtecka-Lukasik E, Czuprynska K, Maslinska D, Gajewski M, Gujski M, Maslinski S. Taurine-chloramine is a potent anti-inflammatory substance. Inflamm Res 2006;55 Suppl 1:S17-S18. 35. Yeler H, Tahtabas F, Candan F. Investigation of oxidative stress during fracture healing in the rats. Cell Biochem Funct 2005;23(2):137-9. 36. Yilmaz C, Erdemli E, Selek H, Kinik H, Arikan M, Erdemli B. The contribution of vitamin C to healing of experimental fractures. Arch Orthop Trauma Surg 2001;121(7):426-8. 37. Yuan LQ, Liu W, Cui RR, Wang D, Meng JC, Xie H, et al. Taurine inhibits osteoclastogenesis through the taurine transporter. Amino Acids 2010;39(1):89-99. 38. Yuan LQ, Xie H, Luo XH, Wu XP, Zhou HD, Lu Y, et al. Taurine transporter is expressed in osteoblasts. Amino Acids 2006;31(2):157-63. 39. Zhou C, Zhang X, Xu L, Wu T, Cui L, Xu D. Taurine promotes human mesenchymal stem cells to differentiate into osteoblast through the ERK pathway. Amino Acids 2014;46(7):1673 - 80.