GUIDELINES ON THE DIAGNOSIS AND MANAGEMENT OF X-LINKED HYPOPHOSPHATEMIA

Year 2020, Volume: 83 Issue: S-1, 1 - 16, 13.05.2020

Serap Turan

Abstract

X-linked hypophosphatemia (XLH) is the most common cause of rickets related to inherited renal phosphate wasting. XLH is associated with lower limb deformities, pain, poor mineralization of the teeth, and disproportionate short stature in children as well as hyperparathyroidism, osteomalacia, enthesopathies, osteoarthritis, and pseudofractures in adults. The characteristics and severity of XLH vary between patients. Because of its rarity, the diagnosis and specific treatment of XLH are frequently delayed, which has a detrimental effect on patient outcomes. The diagnosis of XLH is based on signs of rickets and/or osteomalacia in association with hypophosphatemia and renal phosphate wasting in the absence of vitamin D or calcium deficiency. Whenever possible, the diagnosis should be confirmed by molecular genetic analysis or measurement of levels of fibroblast growth factor 23 (FGF23) before treatment. An evidence-based guideline was published for recommendation on the diagnosis, treatment, and follow-up of XLH by a multidisciplinary team organized by a metabolic bone disease expert. In this article, the current recommendations - based on the published guideline was summarized and adapted for our country.

Keywords

X-linked hypophosphatemia, XLH, rickets, hypophosphatemic rickets, PHEX, concensus, guidelines, treatment, conventional, burosumab

X’E BAĞLI HİPOFOSFATEMİDE TANI VE TEDAVİ UZLAŞISI

Abstract

X’e bağlı hipofosfatemi (XLH) kalıtsal renal fosfat kaybına bağlı raşitizmin en sık nedenidir. Çocuklarda alt ektremite deformiteleri, orantısız boy kısalığı, ektremite ağrısı, diş problemlerinin yanı sıra erişkin yaş grubunda hiperparatiroidi, osteomalazi, entesopati, osteoartrit ve psödofraktürlere neden olur. Hastalar arasında hastanın klinik seyri ve etkilenme düzeyi farklılıklar gösterebilir. XLH nadir bir hastalık olması nedeniyle hastalığın tanısı sıklıkla gecikmekte ve tedavi gecikmesinin hasta sonlanımına olumsuz etkileri bulunmaktadır. XLH; D vitamini eksikliği/ hipokalsemi veya hiperparatriodinin eşlik etmediği renal fosfat kaybına bağlı gelişen hipofosfatemi ve raşitizm durumunda akla gelmelidir. Mümkün olduğu durumlarda tanı, moleküler genetik testler ile veya tedavi öncesi alınan fibroblast growth factor 23 (FGF23) ölçümü ile doğrulanmalıdır. Metabolik kemik hastalıkları konusunda uzman hekimlerin önderliğinde multidisipliner bir ekip tarafından kanıta dayalı olarak hazırlanıp 2019 yılında yayınlanan uzlaşı raporu ile XLH hastalarının tanı ve tedavi kriterleri belirlenmiştir. Yazımızda bu uzlaşı raporu temel alınarak ülkemiz için XLH’de tanı, tedavi ve takip prensipleri verilmiştir.

Keywords

X’e bağlı hipofosfatemi, XLH, raşitizm, hipofosfatemik raşitizm, PHEX, uzlaşı, rehber, tedavi, konvasiyonel, burosumab

References

• 1. Haffner D, Emma F, Eastwood DM, Duplan MB, Bacchetta J, Schnabel D, et al. Clinical practice recommendations for the diagnosis and management of X- linked hypophosphatemia. Nat Rev Nephrol 2019;15:435-55.
• 2. Beck-Nielsen SS, Brock-Jacobsen B, Gram J, Brixen K, Jensen TK. Incidence and prevalence of nutritional and hereditary rickets in southern Denmark. Eur J Endocrinol 2009;160:491-7.
• 3. Endo I, Fukumoto S, Ozono K, Namba N, Inoue D, Okazaki R, et al. Nationwide survey of fibroblast growth factor 23 (FGF23)-related hypophosphatemic diseases in Japan: prevalence, biochemical data and treatment. Endocr J 2015;62:811-6.
• 4. Rafaelsen S, Johansson S, Ræder H, Bjerkneset R. Hereditary hypophosphatemia in Norway: a retrospective population- based study of genotypes, phenotypes, and treatment complications. Eur J Endocrinol 2016;174:125-36.
• 5. Liu S, Zhou J, Tang W, Jiang X, Rowe DW, Quarleset LD. Pathogenic role of Fgf23 in Hypmice. Am J Physiol Endocrinol Metab 2006;291:E38-49.
• 6. Feng JQ, Clinkenbeard EL, Yuan B, White KE, Drezner MK. Osteocyte regulation of phosphate homeostasis and bone mineralization underlies the pathophysiology of the heritable disorders of rickets and osteomalacia. Bone 2013;54:213-21.
• 7. Carpenter TO, Insogna KL, Zhang JH, Ellis B, Nieman S, Simpson C, et al. Circulating levels of soluble klotho and FGF23 in X- linked hypophosphatemia: circadian variance, effects of treatment, and relationship to parathyroid status. J Clin Endocrinol Metab 2010;95:E3527.
• 8. Abe K, Ooshima T, Lily TS, Yasufuku Y, Sobue S. Structural deformities of deciduous teeth in patients with hypophosphatemic vitamin D- resistant rickets. OralSurg Oral Med Oral Pathol 1988;65:191-8.
• 9. Chaussain-Miller C, Sinding C, Septier D, Wolikow M, Goldberg M, Garabedianet M. Dentin structure in familial hypophosphatemic rickets: benefits of vitamin D and phosphate treatment. Oral Dis 2007;13:482-9.
• 10. Verge CF, Lam A, Simpson JM, Cowell CT, Howard NJ, Silink M. Effects of therapy in X- linked hypophosphatemic rickets. N Engl J Med 1991;325:1843-8.
• 11. Zivicnjak M, Schnabel D, Billing H, Staude H, Filler G, Querfeld U, et al. Age-related stature and linear body segments in children with X-linked hypophosphatemic rickets. Pediatr Nephrol 2011;26:223-31.
• 12. Haffner D, Waldegger S. In: Geary DF, Schaefer F, editors. Pediatric Kidney Disease 2nd edn Ch 35. Springer:Verlag Berlin Heidelberg; 2016.p.953-72.
• 13. Ruppe MD, Brosnan PG, Au KS, Tran PX, Dominguez BW, Northrup H. Mutational analysis of PHEX, FGF23 and DMP1 in a cohort of patients with hypophosphatemic rickets. Clin Endocrinol 2011;74:312-8.
• 14. Beck- Nielsen SS, Brixen K, Gram J, Brusgaard K. Mutationalanalysis of PHEX, FGF23, DMP1, SLC34A3 and CLCN5 in patients with hypophosphatemic rickets. J Hum Genet 2012;57:453-8.
• 15. Christie PT, Harding B, Nesbit MA, Whyte MP, Thakker RV. X- Linked hypophosphatemia attributable to pseudoexons of the PHEX gene. J Clin Endocrinol Metab 2001;86:3840-4.
• 16. Carpenter TO, Shaw NJ, Portale AA, Ward LM, Abrams SA, Pettifor JM. Rickets. Nat Rev Dis Primers 2017;3:17101.
• 17. Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL. A clinician’s guide to X- linked hypophosphatemia. J Bone Miner Res 2011;26:1381-8.
• 18. Linglart A, Biosse-Duplan M, Briot K, Chaussain C, Esterle L, Guillaume-Czitrom S, et al. Therapeutic management of hypophosphatemic rickets from infancy to adulthood. Endocr Connect 2014;3:R13-30.
• 19. Yamazaki Y, Okazaki R, Shibata M, Hasegawa Y, Satoh K, Tajima T, et al. Increased circulatory level of biologically active full- length FGF-23 in patients with hypophosphatemic rickets / osteomalacia. J Clin Endocrinol Metab 2002;87:4957-60.
• 20. Souberbielle JC, Prié D, Piketty ML, Rothenbuhler A, Delanaye P, Chanson P, et al. Evaluation of a new fully automated assay for plasma intact FGF23. Calcif Tissue Int 2017;101:510-8.
• 21. Carpenter TO, Olear EA, Zhang JH, Ellis BK, Simpson CA, Cheng D, et al. Effect of paricalcitol on circulating parathyroid hormone in X- linked hypophosphatemia: a randomized, double- blind, placebo- controlled study. J Clin Endocrinol Metab 2014;99:3103-11.
• 22. Bettinelli A, Bianchi ML, Mazzucchi E, Gandolini G, Appiani AC. Acute effects of calcitriol and phosphate salts on mineral metabolism in children with hypophosphatemic rickets. J Pediatr 1991;118:372-6.
• 23. Blydt- Hansen TD, Tenenhouse HS, Goodyer P. PHEX expression in parathyroid gland and parathyroid hormone dysregulation in X- linked hypophosphatemia. Pediatr Nephrol 1999;13:607-11.
• 24. Whyte MP, Schranck FW, Armamento- Villareal R. X- Linked hypophosphatemia: a search for gender, race, anticipation, orparent of origin effects on disease expression in children. J Clin Endocrinol Metab 1996;81:4075-80.
• 25. Gaucher C, Walrant- Debray O, Nguyen TM, Esterle L, Garabedian M, Jehan F. PHEX analysis in 118 pedigrees reveals new genetic clues in hypophosphatemic rickets. Hum Genet 2009;125:401-11.
• 26. Flynn JT, Kaelber DC, Baker-Smith CM, Blowey D, Carroll AE, Daniels SR, et al. Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics 2017;140: e20171904.
• 27. Kiattisunthorn K, Wutyam K, Indranoi A, Vasuvattakul S. Randomized trial comparing pulse calcitriol and alfacalcidol for the treatment of secondary hyperparathyroidism in haemodialysis patients. Nephrology 2011;16:277-84.
• 28. Melhem E, Assi A, El Rachkidi R, Ghanem I. EOS(®) biplanar X- ray imaging: concept, developments, benefits, and limitations. J Child Orthop 2016;10:1-14.
• 29. European Medicines Agency. Crysvita. Annex I —summary of product characteristics. EMA https://www.ema.europa. eu/en/documents/product- information/crysvita- eparproduct- information_en.pdf (2018).
• 30. US Food&Drug Administration. CRYSVITA (prescribinginformation). FDA.gov https://www.accessdata. fda.gov/drugsatfda_docs/label/2018/61068s000lbl.pdf (2018).
• 31. Carpenter TO, Whyte MP, Imel EA, Boot AM, Högler W, Linglart A, et al. Burosumab therapy in children with X- linked hypophosphatemia. N Engl J Med 2018;378:1987-98.
• 32. Carpenter TO, Imel EA, Ruppe MD, Weber TJ, Klausner MA, Wooddell MM, et al. Randomized trial of the anti- FGF23 antibody KRN23 in X- linked hypophosphatemia. J Clin Invest 2014;124:1587-97.
• 33. Aono Y, Yamazaki Y, Yasutake J, Kawata T, Hasegawa H, Urakawa I, et al. Therapeutic effects of anti- FGF23 antibodies in hypophosphatemic rickets / osteomalacia. J Bone Miner Res 2009;24:1879-88.
• 34. Insogna KL, Briot K, Imel EA, Kamenický P, Ruppe MD, Portale AA, et al. A randomized, double- blind, placebo- controlled, phase 3 trial evaluating the efficacy of burosumab, an anti- FGF23 antibody, in adults with X- linked hypophosphatemia: week 24 primary analysis. J Bone Miner Res 2018;33:1383-93.
• 35. Imel EA, Glorieux FH, Whyte MP, Munns CF, Ward LM, Nilsson O, et al. Burosumab versus conventional therapy in children with X-linked hypophosphatemia: a randomised, active-controlled, open-label, phase 3 trial. Lancet 2019;393(10189):2416-27.