Genetic Causes of Rickets

Demir, Korcan; Acar, Sezer; SHİ, Yufei

Genetic Causes of Rickets

Sezer ACAR, (Dokuz Eylül University Faculty of Medicine, Department of Pediatric Endocrinology, İzmir, Turkey)

Korcan DEMİR, (Dokuz Eylül University Faculty of Medicine, Department of Pediatric Endocrinology, İzmir, Turkey)

Yufei SHİ (King Faisal Specialist Hospital & Research Centre, Department of Genetics, Riyadh, Saudi Arabia)

Journal of Clinical Research in Pediatric Endocrinology

4 1

Yıl: 2017 Cilt: 9 Sayı: 2 (Özel) Sayfa Aralığı: 88 - 105 Metin Dili: İngilizce İndeks Tarihi: 29-07-2022

Genetic Causes of Rickets

Öz:

Genetic Causes of Rickets

Anahtar Kelime:

Konular: Endokrinoloji ve Metabolizma Pediatri

Öz:

Rickets is a metabolic bone disease that develops as a result of inadequate mineralization of growing bone due to disruption of calcium, phosphorus and/or vitamin D metabolism. Nutritional rickets remains a significant child health problem in developing countries. In addition, several rare genetic causes of rickets have also been described, which can be divided into two groups. The first group consists of genetic disorders of vitamin D biosynthesis and action, such as vitamin D-dependent rickets type 1A (VDDR1A), vitamin D-dependent rickets type 1B (VDDR1B), vitamin D-dependent rickets type 2A (VDDR2A), and vitamin D-dependent rickets type 2B (VDDR2B). The second group involves genetic disorders of excessive renal phosphate loss (hereditary hypophosphatemic rickets) due to impairment in renal tubular phosphate reabsorption as a result of FGF23-related or FGF23-independent causes. In this review, we focus on clinical, laboratory and genetic characteristics of various types of hereditary rickets as well as differential diagnosis and treatment approaches

Anahtar Kelime:

Konular: Endokrinoloji ve Metabolizma Pediatri

Belge Türü: Makale Makale Türü: Araştırma Makalesi Erişim Türü: Erişime Açık

1. Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M; Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society. Vitamin D deficiency in children and its management: review of current knowledge and recommendations. Pediatrics 2008;122:398-417.
2. Hatun Ş, Ozkan B, Bereket A. Vitamin D deficiency and prevention: Turkish experience. Acta Paediatr 2011;100:1195-1199. Epub 2011 Jul 4
3. 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;160:491-497. Epub 2008 Dec 18
4. Miller WL. Genetic disorders of Vitamin D biosynthesis and degradation. J Steroid Biochem Mol Biol 2017;165:101-108. Epub 2016 Apr 6
5. Bastepe M, Jüppner H. Inherited hypophosphatemic disorders in children and the evolving mechanisms of phosphate regulation. Rev Endocr Metab Disord 2008;9:171-180. Epub 2008 Mar 26
6. Peacock M. Calcium metabolism in health and disease. Clin J Am Soc Nephrol 2010;5(Suppl 1):S23-30.
7. Wang L, Nancollas GH, Henneman ZJ, Klein E, Weiner S. Nanosized particles in bone and dissolution insensitivity of bone mineral. Biointerphases 2006;1:106-111.
8. Robertson WG, Marshall RW. Calcium measurements in serum and plasma--total and ionized. CRC Crit Rev Clin Lab Sci 1979;11:271-304.
9. Pavone V, Testa G, Gioitta Iachino S, Evola FR, Avondo S, Sessa G. Hypophosphatemic rickets: etiology, clinical features and treatment. Eur J Orthop Surg Traumatol 2015;25:221-226. Epub 2014 Jun 24
10. Wagner CA, Hernando N, Forster IC, Biber J. The SLC34 family of sodiumdependent phosphate transporters. Pflugers Arch 2014;466:139-153. Epub 2013 Dec 19
11. Forster IC, Hernando N, Biber J, Murer H. Proximal tubular handling of phosphate: A molecular perspective. Kidney Int 2006;70:1548-1559. Epub 2006 Sep 6
12. Shaikh A, Berndt T, Kumar R. Regulation of phosphate homeostasis by the phosphatonins and other novel mediators. Pediatr Nephrol 2008;23:1203-1210. Epub 2008 Feb 21
13. Masi L. Phosphatonins: new hormones involved in numerous inherited bone disorders. Clin Cases Miner Bone Metab 2011;8:9-13.
14. Kato S, Yoshizazawa T, Kitanaka S, Murayama A, Takeyama K. Molecular genetics of vitamin D- dependent hereditary rickets. Horm Res 2002;57:73-78.
15. Wan LY, Zhang YQ, Chen MD, Liu CB, Wu JF. Relationship of structure and function of DNA-binding domain in vitamin D receptor. Molecules 2015;20:12389-12399.
16. Glorieux FH. Pseudo-vitamin D deficiency rickets. J Endocrinol 1997;154(Suppl):S75-78.
17. Fraser D, Kooh SW, Kind HP, Holick MF, Tanaka Y, DeLuca HF. Pathogenesis of hereditary vitamin-D-dependent rickets. An inborn error of vitamin D metabolism involving defective conversion of 25-hydroxyvitamin D to 1 alpha,25-dihydroxyvitamin D. N Engl J Med 1973;289:817-822.
18. Kitanaka S, Takeyama K, Murayama A, Sato T, Okumura K, Nogami M, Hasegawa Y, Niimi H, Yanagisawa J, Tanaka T, Kato S. Inactivating mutations in the 25-hydroxyvitamin D3 1alpha-hydroxylase gene in patients with pseudovitamin D-deficiency rickets. N Engl J Med 1998;338:653-661.
19. Tahir S, Demirbilek H, Ozbek MN, Baran RT, Tanriverdi S, Hussain K. Genotype and Phenotype Characteristics in 22 Patients with Vitamin D-Dependent Rickets Type I. Horm Res Paediatr 2016;85:309-317.
20. Demir K, Kattan WE, Zou M, Durmaz E, BinEssa H, Nalbantoğlu Ö, Al-Rijjal RA, Meyer B, Özkan B, Shi Y. Novel CYP27B1 Gene Mutations in Patients with Vitamin D-Dependent Rickets Type 1A. PLoS One 2015;10:e0131376.
21. Durmaz E, Zou M, Al-Rijjal RA, Bircan I, Akçurin S, Meyer B, Shi Y. Clinical and genetic analysis of patients with vitamin D-dependent rickets type 1A. Clin Endocrinol (Oxf) 2012;77:363-369.
22. Alzahrani AS, Zou M, Baitei EY, Alshaikh OM, Al-Rijjal RA, Meyer BF, Shi Y. A novel G102E mutation of CYP27B1 in a large family with vitamin D-dependent rickets type 1. J Clin Endocrinol Metab 2010;95:4176- 4183. Epub 2010 Jun 9
23. Kitanaka S, Murayama A, Sakaki T, Inouye K, Seino Y, Fukumoto S, Shima M, Yukizane S, Takayanagi M, Niimi H, Takeyama K, Kato S. No enzyme activity of 25-hydroxyvitamin D3 1alpha-hydroxylase gene product in pseudovitamin D deficiency rickets, including that with mild clinical manifestation. J Clin Endocrinol Metab 1999;84:4111-4117.
24. Wang JT, Lin CJ, Burridge SM, Fu GK, Labuda M, Portale AA, Miller WL. Genetics of vitamin D 1alpha-hydroxylase deficiency in 17 families. Am J Hum Genet 1998;63:1694-1702.
25. Wang X, Zhang MY, Miller WL, Portale AA. Novel gene mutations in patients with 1alpha-hydroxylase deficiency that confer partial enzyme activity in vitro. J Clin Endocrinol Metab 2002;87:2424-2430.
26. Root AW, Diamond FB. Disorders of Mineral Homeostasis in Children and Adolescents. in: Sperling M. (ed). Pediatric Endocrinology Vol 4th edition. Philadelphia, Saunders-Elsevier, 2014;734-845.
27. Lo SF. Nelson Textbook of Pediatrics. 20th ed. Philadelphia, Elsevier, 2016;3464-3472.
28. Baştuğ F, Gündüz Z, Tülpar S, Poyrazoğlu H, Düşünsel R. Urolithiasis in infants: evaluation of risk factors. World J Urol 2013;31:1117-1122. Epub 2012 Jan 19
29. Casella SJ, Reiner BJ, Chen TC, Holick MF, Harrison HE. A possible genetic defect in 25-hydroxylation as a cause of rickets. J Pediatr 1994;124:929-932.
30. Cheng JB, Motola DL, Mangelsdorf DJ, Russell DW. De-orphanization of cytochrome P450 2R1: a microsomal vitamin D 25-hydroxilase. J Biol Chem 2003;278:38084-38093. Epub 2003 Jul 16
31. Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW. Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc Natl Acad Sci U S A 2004;101:7711-7715. Epub 2004 May 5
32. Zhu J, DeLuca HF. Vitamin D 25-hydroxylase - Four decades of searching, are we there yet? Arch Biochem Biophys 2012;523:30-36. Epub 2012 Jan 31
33. Tosson H, Rose SR. Absence of mutation in coding regions of CYP2R1 gene in apparent autosomal dominant vitamin D 25-hydroxylase deficiency rickets. J Clin Endocrinol Metab 2012;97:E796-801. Epub 2012 Mar 14
34. Brooks MH, Bell NH, Love L, Stern PH, Orfei E, Queener SF, Hamstra AJ, DeLuca HF. Vitamin-D-dependent rickets type II. Resistance of target organs to 1,25-dihydroxyvitamin D. N Engl J Med 1978;298:996-999.
35. Marx SJ, Bliziotes MM, Nanes M. Analysis of the relation between alopecia and resistance to 1,25-dihydroxyvitamin D. Clin Endocrinol (Oxf) 1986;25:373-381.
36. Li M, Indra AK, Warot X, Brocard J, Messaddeq N, Kato S, Metzger D, Chambon P. Skin abnormalities generated by temporally controlled RXRalpha mutations in mouse epidermis. Nature 2000;407:633-636.
37. Wan LY, Zhang YQ, Chen MD, Du YQ, Liu CB, Wu JF. Relationship between Structure and Conformational Change of the Vitamin D Receptor Ligand Binding Domain in 1alpha,25-Dihydroxyvitamin D3 Signaling. Molecules 2015;20:20473-20486.
38. Malloy PJ, Pike JW, Feldman D. The vitamin D receptor and the syndrome of hereditary 1,25-dihydroxyvitamin D-resistant rickets. Endocr Rev 1999;20:156-188.
39. Nicolaidou P, Tsitsika A, Papadimitriou A, Karantana A, Papadopoulou A, Psychou F, Liakopoulou D, Georgouli H, Kakourou T, Chrousos G. Hereditary vitamin D-resistant rickets in Greek children: genotype, phenotype, and long-term response to treatment. J Pediatr Endocrinol Metab 2007;20:425-430.
40. Tiosano D, Hadad S, Chen Z, Nemirovsky A, Gepstein V, Militianu D, Weisman Y, Abrams SA. Calcium absorption, kinetics, bone density, and bone structure in patients with hereditary vitamin D-resistant rickets. J Clin Endocrinol Metab 2011;96:3701-3709. Epub 2011 Sep 14
41. Takeda E, Yokota I, Kawakami I, Hashimoto T, Kuroda Y, Arase S. Two siblings with vitamin-D-dependent rickets type II: no recurrence of rickets for 14 years after cessation of therapy. Eur J Pediatr 1989;149:54-57.
42. Malloy PJ, Zhu W, Zhao XY, Pehling GB, Feldman D. A novel inborn error in the ligand-binding domain of the vitamin D receptor causes hereditary vitamin D-resistant rickets. Mol Genet Metab 2001;73:138- 148.
43. al-Aqeel A, Ozand P, Sobki S, Sewairi W, Marx S. The combined use of intravenous and oral calcium for the treatment of vitamin D dependent rickets type II (VDDRII). Clin Endocrinol (Oxf) 1993;39:229-237.
44. Ersoy B, Kiremitci S, Isojima T, Kitanaka S. Successful intermittent intravenous calcium treatment via the peripheral route in a patient with hereditary vitamin D-resistant rickets and alopecia. Horm Res Paediatr 2015;83:67-72. Epub 2015 Jan 6
45. Ma NS, Malloy PJ, Pitukcheewanont P, Dreimane D, Geffner ME, Feldman D. Hereditary vitamin D resistant rickets: identification of a novel splice site mutation in the vitamin D receptor gene and successful treatment with oral calcium therapy. Bone 2009;45:743- 746. Epub 2009 Jun 10
46. Celbek G, Gungor A, Albayrak H, Kir S, Guvenc SC, Aydin Y. Bullous skin reaction seen after extravasation of calcium gluconate. Clin Exp Dermatol 2013;38:154-155. Epub 2012 Jul 25
47. Huang K, Malloy P, Feldman D, Pitukcheewanont P. Enteral calcium infusion used successfully as treatment for a patient with hereditary vitamin D resistant rickets (HVDRR) without alopecia: a novel mutation. Gene 2013;512:554-559. Epub 2012 Sep 28
48. Akıncı A, Dündar İ, Kıvılcım M. The Effectiveness of Cinacalcet as an Adjunctive Therapy for Hereditary 1,25 Dihydroxyvitamin D3-Resistant Rickets. J Clin Res Pediatr Endocrinol 2017;9:172-178. Epub 2016 Oct 31
49. Srivastava T, Alon US. Cinacalcet as adjunctive therapy for hereditary 1,25-dihydroxyvitamin D-resistant rickets. J Bone Miner Res 2013;28:992-996.
50. Hewison M, Rut AR, Kristjansson K, Walker RE, Dillon MJ, Hughes MR, O’Riordan JL. Tissue resistance to 1,25-dihydroxyvitamin D without a mutation of the vitamin D receptor gene. Clin Endocrinol (Oxf) 1993;39:663-670.
51. Giraldo A, Pino W, Garcia-Ramirez LF, Pineda M, Iglesias A. Vitamin D dependent rickets type II and normal vitamin D receptor cDNA sequence. A cluster in a rural area of Cauca, Colombia, with more than 200 affected children. Clin Genet 1995;48:57-65.
52. Chen H, Hewison M, Hu B, Adams JS. Heterogeneous nuclear ribonucleoprotein (hnRNP) binding to hormone response elements: a cause of vitamin D resistance. Proc Natl Acad Sci U S A 2003;100:6109- 6114. Epub 2003 Apr 25
53. Chen H, Hewison M, Adams JS. Functional characterization of heterogeneous nuclear ribonuclear protein C1/C2 in vitamin D resistance: a novel response element-binding protein. J Biol Chem 2006;281:39114-39120. Epub 2006 Oct 27
54. 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;160:491-497. Epub 2008 Dec 18
55. Guven A, Al-Rijjal RA, BinEssa HA, Dogan D, Kor Y, Zou M, Kaya N, Alenezi AF, Hancili S, Tarim Ö, Baitei EY, Kattan WE, Meyer BF, Shi Y. Mutational analysis of PHEX, FGF23 and CLCN5 in patients with hypophosphataemic rickets. Clin Endocrinol (Oxf) 2017;87:103-112. Epub 2017 May 11
56. Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266-281.
57. Bergwitz C, Jüppner H. Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Annu Rev Med 2010;61:91-104.
58. Prié D, Friedlander G. Genetic disorders of renal phosphate transport. N Engl J Med 2010;362:2399-2409.
59. Li H, Martin A, David V, Quarles LD. Compound deletion of Fgfr3 and Fgfr4 partially rescues the Hyp mouse phenotype. Am J Physiol Endocrinol Metab 2011;300:E508-517. Epub 2010 Dec 7
60. Hu MC, Shiizaki K, Kuro-o M, Moe OW. Fibroblast growth factor 23 and Klotho: physiology and pathophysiology of an endocrine network of mineral metabolism. Annu Rev Physiol 2013;75:503-533.
61. Martin A, David V, Quarles LD. Regulation and function of the FGF23/ klotho endocrine pathways. Physiol Rev 2012;92:131-155.
62. Razali NN, Hwu TT, Thilakavathy K. Phosphate homeostasis and genetic mutations of familial hypophosphatemic rickets. J Pediatr Endocrinol Metab 2015;28:1009-1017.
63. Turan S, Topcu B, Gökçe İ, Güran T, Atay Z, Omar A, Akçay T, Bereket A. Serum alkaline phosphatase levels in healthy children and evaluation of alkaline phosphatase z-scores in different types of rickets. J Clin Res Pediatr Endocrinol 2011;3:7-11. Epub 2011 Feb 23
64. Yu ASL, Stubbs JR. Evaluation and treatment of hypophosphatemia. In: Lam AQ, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www. uptodate.com (Accessed on October 27, 2017).
65. Barth JH, Jones RG, Payne RB. Calculation of renal tubular reabsorption of phosphate: the algorithm performs better than the nomogram. Ann Clin Biochem 2000;37:79-81.
66. Payne RB. Renal tubular reabsorption of phosphate (TmP/GFR): indications and interpretation. Ann Clin Biochem 1998;35:201-206.
67. Rowe PS, Oudet CL, Francis F, Sinding C, Pannetier S, Econs MJ, Strom TM, Meitinger T, Garabedian M, David A, Macher MA, Questiaux E, Popowska E, Pronicka E, Read AP, Mokrzycki A, Glorieux FH, Drezner MK, Hanauer A, Lehrach H, Goulding JN, O’Riordan JL. Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP). Hum Mol Genet 1997;6:539-549.
68. Rowe PS. Regulation of bone-renal mineral and energy metabolism: the PHEX, FGF23, DMP1, MEPE ASARM pathway. Crit Rev Eukaryot Gene Expr 2012;22:61-86.
69. Jonsson KB, Zahradnik R, Larsson T, White KE, Sugimoto T, Imanishi Y, Yamamoto T, Hampson G, Koshiyama H, Ljunggren O, Oba K, Yang IM, Miyauchi A, Econs MJ, Lavigne J, Jüppner H. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med 2003;348:1656-1663.
70. Durmaz E, Zou M, Al-Rijjal RA, Baitei EY, Hammami S, Bircan I, Akçurin S, Meyer B, Shi Y. Novel and de novo PHEX mutations in patients with hypophosphatemic rickets. Bone 2013;52:286-291. Epub 2012 Oct 16
71. Zou M, Buluş D, Al-Rijjal RA, Andıran N, BinEssa H, Kattan WE, Meyer B, Shi Y. Hypophosphatemic rickets caused by a novel splice donor site mutation and activation of two cryptic splice donor sites in the PHEX gene. J Pediatr Endocrinol Metab 2015;28:211-216.
72. Shimada T, Muto T, Urakawa I, Yoneya T, Yamazaki Y, Okawa K, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T. Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology 2002;143:3179-3182.
73. Econs MJ, McEnery PT. Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder. J Clin Endocrinol Metab 1997;82:674-681.
74. Imel EA, Hui SL, Econs MJ. FGF23 concentrations vary with disease status in autosomal dominant hypophosphatemic rickets. J Bone Miner Res 2007;22:520-526.
75. Wolf M, White KE. Coupling fibroblast growth factor 23 production and cleavage: iron deficiency, rickets, and kidney disease. Curr Opin Nephrol Hypertens 2014;23:411-419.
76. Farrow EG, Yu X, Summers LJ, Davis SI, Fleet JC, Allen MR, Robling AG, Stayrook KR, Jideonwo V, Magers MJ, Garringer HJ, Vidal R, Chan RJ, Goodwin CB, Hui SL, Peacock M, White KE. Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice. Proc Natl Acad Sci U S A 2011;108:E1146-1155. Epub 2011 Oct 17
77. Imel EA, Peacock M, Gray AK, Padgett LR, Hui SL, Econs MJ. Iron modifies plasma FGF23 differently in autosomal dominant hypophosphatemic rickets and healthy humans. J Clin Endocrinol Metab 2011;96:3541-3549. Epub 2011 Aug 31
78. Lorenz-Depiereux B, Bastepe M, Benet-Pagès A, Amyere M, Wagenstaller J, Müller-Barth U, Badenhoop K, Kaiser SM, Rittmaster RS, Shlossberg AH, Olivares JL, Loris C, Ramos FJ, Glorieux F, Vikkula M, Jüppner H, Strom TM. DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat Genet 2006;38:1248-1250. Epub 2006 Oct 8
79. Feng JQ, Ward LM, Liu S, Lu Y, Xie Y, Yuan B, Yu X, Rauch F, Davis SI, Zhang S, Rios H, Drezner MK, Quarles LD, Bonewald LF, White KE. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet 2006;38:1310-1315. Epub 2006 Oct 8
80. Mäkitie O, Pereira RC, Kaitila I, Turan S, Bastepe M, Laine T, Kröger H, Cole WG, Jüppner H. Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation. J Bone Miner Res 2010;25:2165-2174.
81. Levy-Litan V, Hershkovitz E, Avizov L, Leventhal N, Bercovich D, Chalifa-Caspi V, Manor E, Buriakovsky S, Hadad Y, Goding J, Parvari R. Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. Am J Hum Genet 2010;86:273-278. Epub 2010 Feb 4
82. Rutsch F, Ruf N, Vaingankar S, Toliat MR, Suk A, Höhne W, Schauer G, Lehmann M, Roscioli T, Schnabel D, Epplen JT, Knisely A, Superti-Furga A, McGill J, Filippone M, Sinaiko AR, Vallance H, Hinrichs B, Smith W, Ferre M, Terkeltaub R, Nürnberg P. Mutations in ENPP1 are associated with ‘idiopathic’ infantile arterial calcification. Nat Genet 2003;34:379- 381.
83. Lorenz-Depiereux B, Schnabel D, Tiosano D, Häusler G, Strom TM. Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets. Am J Hum Genet 2010;86:267-272. Epub 2010 Feb 4
84. Mackenzie NC, Zhu D, Milne EM, van ‘t Hof R, Martin A, Darryl Quarles L, Millán JL, Farquharson C, MacRae VE. Altered bone development and an increase in FGF-23 expression in Enpp1(-/-) mice. PLoS One 2012;7:e32177. Epub 2012 Feb 16
85. Brownstein CA, Adler F, Nelson-Williams C, Iijima J, Li P, Imura A, Nabeshima Y, Reyes-Mugica M, Carpenter TO, Lifton RP. A translocation causing increased alpha-klotho level results in hypophosphatemic rickets and hyperparathyroidism. Proc Natl Acad Sci U S A 2008;105:3455-3460. Epub 2008 Feb 28
86. Imura A, Tsuji Y, Murata M, Maeda R, Kubota K, Iwano A, Obuse C, Togashi K, Tominaga M, Kita N, Tomiyama K, Iijima J, Nabeshima Y, Fujioka M, Asato R, Tanaka S, Kojima K, Ito J, Nozaki K, Hashimoto N, Ito T, Nishio T, Uchiyama T, Fujimori T, Nabeshima Y. Alpha-Klotho as a regulator of calcium homeostasis. Science 2007;316:1615-1618.
87. Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997;390:45-51.
88. Woudenberg-Vrenken TE, van der Eerden BC, van der Kemp AW, van Leeuwen JP, Bindels RJ, Hoenderop JG. Characterization of vitamin D-deficient klotho(-/-) mice: do increased levels of serum 1,25(OH)2D3 cause disturbed calcium and phosphate homeostasis in klotho(-/-) mice? Nephrol Dial Transplant 2012;27:4061-4068. Epub 2012 Jul 9
89. White KE, Cabral JM, Davis SI, Fishburn T, Evans WE, Ichikawa S, Fields J, Yu X, Shaw NJ, McLellan NJ, McKeown C, Fitzpatrick D, Yu K, Ornitz DM, Econs MJ. Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation. Am J Hum Genet 2005;76:361-367. Epub 2004 Dec 28
90. Schwindinger WF, Francomano CA, Levine MA. Identification of a mutation in the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase in McCune-Albright syndrome. Proc Natl Acad Sci U S A 1992;89:5152-5156.
91. Riminucci M, Collins MT, Fedarko NS, Cherman N, Corsi A, White KE, Waguespack S, Gupta A, Hannon T, Econs MJ, Bianco P, Gehron Robey P. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Invest 2003;112:683-692.
92. Raine J, Winter RM, Davey A, Tucker SM. Unknown syndrome: microcephaly, hypoplastic nose, exophthalmos, gum hyperplasia, cleft palate, low set ears, and osteosclerosis. J Med Genet 1989;26:786-788.
93. Simpson MA, Hsu R, Keir LS, Hao J, Sivapalan G, Ernst LM, Zackai EH, Al-Gazali LI, Hulskamp G, Kingston HM, Prescott TE, Ion A, Patton MA, Murday V, George A, Crosby AH. Mutations in FAM20C are associated with lethal osteosclerotic bone dysplasia (Raine syndrome), highlighting a crucial molecule in bone development. Am J Hum Genet 2007;81:906-912. Epub 2007 Sep 14
94. Simpson MA, Scheuerle A, Hurst J, Patton MA, Stewart H, Crosby AH. Mutations in FAM20C also identified in non-lethal osteosclerotic bone dysplasia. Clin Genet 2009;75:271-276.
95. Wang X, Hao J, Xie Y, Sun Y, Hernandez B, Yamoah AK, Prasad M, Zhu Q, Feng JQ, Qin C. Expression of FAM20C in the osteogenesis and odontogenesis of mouse. J Histochem Cytochem 2010;58:957-967. Epub 2010 Jul 19
96. Wang X, Wang S, Li C, Gao T, Liu Y, Rangiani A, Sun Y, Hao J, George A, Lu Y, Groppe J, Yuan B, Feng JQ, Qin C. Inactivation of a novel FGF23 regulator, FAM20C, leads to hypophosphatemic rickets in mice. PLoS Genet 2012;8:e1002708. Epub 2012 May 17
97. Rafaelsen SH, Raeder H, Fagerheim AK, Knappskog P, Carpenter TO, Johansson S, Bjerknes R. Exome sequencing reveals FAM20c mutations associated with fibroblast growth factor 23-related hypophosphatemia, dental anomalies, and ectopic calcification. J Bone Miner Res 2013;28:1378-1385.
98. Takeyari S, Yamamoto T, Kinoshita Y, Fukumoto S, Glorieux FH, Michigami T, Hasegawa K, Kitaoka T, Kubota T, Imanishi Y, Shimotsuji T, Ozono K. Hypophosphatemic osteomalacia and bone sclerosis caused by a novel homozygous mutation of the FAM20C gene in an elderly man with a mild variant of Raine syndrome. Bone 2014;67:56- 62. Epub 2014 Jun 27
99. Kinoshita Y, Hori M, Taguchi M, Fukumoto S. Functional analysis of mutant FAM20C in Raine syndrome with FGF23-related hypophosphatemia. Bone 2014;67:145-151. Epub 2014 Jul 12
100. Zonana J, Rimoin DL, Lachman RS, Cohen AH. A unique chondrodysplasia secondary to a defect in chondroosseous transformation. Birth Defects Orig Artic Ser 1977;13:155-163.
101. Maroteaux P, Stanescu V, Stanescu R, Le Marec B, Moraine C, Lejarraga H. Opsismodysplasia: a new type of chondrodysplasia with predominant involvement of the bones of the hand and the vertebrae. Am J Med Genet 1984;19:171-182.
102. Below JE, Earl DL, Shively KM, McMillin MJ, Smith JD, Turner EH, Stephan MJ, Al-Gazali LI, Hertecant JL, Chitayat D, Unger S, Cohn DH, Krakow D, Swanson JM, Faustman EM, Shendure J, Nickerson DA, Bamshad MJ; University of Washington Center for Mendelian Genomics. Whole-genome analysis reveals that mutations in inositol polyphosphate phosphatase-like 1 cause opsismodysplasia. Am J Hum Genet 2013;92:137-143. Epub 2012 Dec 27
103. Khwaja A, Parnell SE, Ness K, Bompadre V, White KK. Opsismodysplasia: Phosphate Wasting Osteodystrophy Responds to Bisphosphonate Therapy. Front Pediatr 2015;3:48.
104. Zeger MD, Adkins D, Fordham LA, White KE, Schoenau E, Rauch F, Loechner KJ. Hypophosphatemic rickets in opsismodysplasia. J Pediatr Endocrinol Metab 2007;20:79-86.
105. Rafaelsen S, Johansson S, Ræder H, Bjerknes R. Hereditary hypophosphatemia in Norway: a retrospective population-based study of genotypes, phenotypes, and treatment complications. Eur J Endocrinol 2016;174:125-136. Epub 2015 Nov 5
106. Bhatia V, Kulkarni A, Nair VV. Disorders of Mineral and Bone Metabolism. in: Zacharin M. (ed). Practical Pediatric Endocrinology in a Limited Resource Setting 1st ed. New York, Elsevier, 2013;171-184.
107. Taylor A, Sherman NH, Norman ME. Nephrocalcinosis in X-linked hypophosphatemia: effect of treatment versus disease. Pediatr Nephrol 1995;9:173-175.
108. 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;325:1843-1848.
109. Patzer L, van’t Hoff W, Shah V, Hallson P, Kasidas GP, Samuell C, de Bruyn R, Barratt TM, Dillon MJ. Urinary supersaturation of calcium oxalate and phosphate in patients with X-linked hypophosphatemic rickets and in healthy schoolchildren. J Pediatr 1999;135:611-617.
110. Kooh SW, Binet A, Daneman A. Nephrocalcinosis in X-linked hypophosphataemic rickets: its relationship to treatment, kidney function, and growth. Clin Invest Med 1994;17:123-130.
111. Alon US, Levy-Olomucki R, Moore WV, Stubbs J, Liu S, Quarles LD. Calcimimetics as an adjuvant treatment for familial hypophosphatemic rickets. Clin J Am Soc Nephrol 2008;3:658-664. Epub 2008 Feb 6
112. Mäkitie O, Kooh SW, Sochett E. Prolonged high-dose phosphate treatment: a risk factor for tertiary hyperparathyroidism in X-linked hypophosphatemic rickets. Clin Endocrinol (Oxf) 2003;58:163-168.
113. Alon US, Monzavi R, Lilien M, Rasoulpour M, Geffner ME, Yadin O. Hypertension in hypophosphatemic rickets--role of secondary hyperparathyroidism. Pediatr Nephrol 2003;18:155-158. Epub 2003 Jan 18
114. Novais E, Stevens PM. Hypophosphatemic rickets: the role of hemiepiphysiodesis. J Pediatr Orthop 2006;26:238-244.
115. Quinlan C, Guegan K, Offiah A, Neill RO, Hiorns MP, Ellard S, Bockenhauer D, Hoff WV, Waters AM. Growth in PHEX-associated X-linked hypophosphatemic rickets: the importance of early treatment. Pediatr Nephrol 2012;27:581-588. Epub 2011 Nov 20
116. Mäkitie O, Doria A, Kooh SW, Cole WG, Daneman A, Sochett E. Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets. J Clin Endocrinol Metab 2003;88:3591-3597.
117. Santos F, Fuente R, Mejia N, Mantecon L, Gil-Peña H, Ordoñez FA. Hypophosphatemia and growth. Pediatr Nephrol 2013;28:595-603. Epub 2012 Nov 22
118. Fuente R, Gil-Peña H, Claramunt-Taberner D, Hernández O, Fernández-Iglesias A, Alonso-Durán L, Rodríguez-Rubio E, Santos F. X-linked hypophosphatemia and growth. Rev Endocr Metab Disord 2017;18:107-115.
119. Rothenbuhler A, Esterle L, Gueorguieva I, Salles JP, Mignot B, Colle M, Linglart A. Two-year recombinant human growth hormone (rhGH) treatment is more effective in pre-pubertal compared to pubertal short children with X-linked hypophosphatemic rickets (XLHR). Growth Horm IGF Res 2017;36:11-15. Epub 2017 Aug 15
120. Wöhrle S, Henninger C, Bonny O, Thuery A, Beluch N, Hynes NE, Guagnano V, Sellers WR, Hofmann F, Kneissel M, Graus Porta D. Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets. J Bone Miner Res 2013;28:899-911.
121. Imel EA, Zhang X, Ruppe MD, Weber TJ, Klausner MA, Ito T, Vergeire M, Humphrey JS, Glorieux FH, Portale AA, Insogna K, Peacock M, Carpenter TO. Prolonged Correction of Serum Phosphorus in Adults With X-Linked Hypophosphatemia Using Monthly Doses of KRN23. J Clin Endocrinol Metab 2015;100:2565-2573. Epub 2015 Apr 28
122. Carpenter TO, Imel EA, Ruppe MD, Weber TJ, Klausner MA, Wooddell MM, Kawakami T, Ito T, Zhang X, Humphrey J, Insogna KL, Peacock M. Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia. J Clin Invest 2014;124:1587-1597. Epub 2014 Feb 24
123. Zhang X, Imel EA, Ruppe MD, Weber TJ, Klausner MA, Ito T, Vergeire M, Humphrey J, Glorieux FH, Portale AA, Insogna K, Carpenter TO, Peacock M. Pharmacokinetics and pharmacodynamics of a human monoclonal anti-FGF23 antibody (KRN23) in the first multiple ascending-dose trial treating adults with X-linked hypophosphatemia. J Clin Pharmacol 2016;56:176-185. Epub 2015 Aug 11
124. Bergwitz C, Roslin NM, Tieder M, Loredo-Osti JC, Bastepe M, AbuZahra H, Frappier D, Burkett K, Carpenter TO, Anderson D, Garabedian M, Sermet I, Fujiwara TM, Morgan K, Tenenhouse HS, Juppner H. SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis. Am J Hum Genet 2006;78:179-192. Epub 2005 Dec 9
125. Abe Y, Nagasaki K, Watanabe T, Abe T, Fukami M. Association between compound heterozygous mutations of SLC34A3 and hypercalciuria. Horm Res Paediatr 2014;82:65-71. Epub 2014 Jun 11
126. Chi Y, Zhao Z, He X, Sun Y, Jiang Y, Li M, Wang O, Xing X, Sun AY, Zhou X, Meng X, Xia W. A compound heterozygous mutation in SLC34A3 causes hereditary hypophosphatemic rickets with hypercalciuria in a Chinese patient. Bone 2014;59:114-121. Epub 2013 Nov 16
127. Tencza AL, Ichikawa S, Dang A, Kenagy D, McCarthy E, Econs MJ, Levine MA. Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3/type IIc sodium-phosphate cotransporter: presentation as hypercalciuria and nephrolithiasis. J Clin Endocrinol Metab 2009;94:4433-4438. Epub 2009 Oct 9
128. Courbebaisse M, Leroy C, Bakouh N, Salaün C, Beck L, Grandchamp B, Planelles G, Hall RA, Friedlander G, Prié D. A new human NHERF1 mutation decreases renal phosphate transporter NPT2a expression by a PTH-independent mechanism. PLoS One 2012;7:e34764. Epub 2012 Apr 10
129. Prié D, Huart V, Bakouh N, Planelles G, Dellis O, Gérard B, Hulin P, Benqué-Blanchet F, Silve C, Grandchamp B, Friedlander G. Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium-phosphate cotransporter. N Engl J Med 2002;347:983-991.
130. Beck L, Karaplis AC, Amizuka N, Hewson AS, Ozawa H, Tenenhouse HS. Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities. Proc Natl Acad Sci U S A 1998;95:5372-5377.
131. Magen D, Berger L, Coady MJ, Ilivitzki A, Militianu D, Tieder M, Selig S, Lapointe JY, Zelikovic I, Skorecki K. A loss-of-function mutation in NaPi-IIa and renal Fanconi’s syndrome. N Engl J Med 2010;362:1102- 1109.
132. Schlingmann KP, Ruminska J, Kaufmann M, Dursun I, Patti M, Kranz B, Pronicka E, Ciara E, Akcay T, Bulus D, Cornelissen EA, Gawlik A, Sikora P, Patzer L, Galiano M, Boyadzhiev V, Dumic M, Vivante A, Kleta R, Dekel B, Levtchenko E, Bindels RJ, Rust S, Forster IC, Hernando N, Jones G, Wagner CA, Konrad M. Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia. J Am Soc Nephrol 2016;27:604- 614. Epub 2015 Jun 5
133. Lapointe JY, Tessier J, Paquette Y, Wallendorff B, Coady MJ, Pichette V, Bonnardeaux A. NPT2a gene variation in calcium nephrolithiasis with renal phosphate leak. Kidney Int 2006;69:2261-2267. Epub 2006 May 10
134. Wagner CA, Rubio-Aliaga I, Biber J, Hernando N. Genetic diseases of renal phosphate handling. Nephrol Dial Transplant 2014;29:iv45-54.
135. Tieder M, Arie R, Modai D, Samuel R, Weissgarten J, Liberman UA. Elevated serum 1,25-dihydroxyvitamin D concentrations in siblings with primary Fanconi’s syndrome. N Engl J Med 1988;319:845-849.
136. Demir K, Yildiz M, Bahat H, Goldman M, Hassan N, Tzur S, Ofir A, Magen D. Clinical Heterogeneity and Phenotypic Expansion of NaPiIIa-Associated Disease. J Clin Endocrinol Metab 2017;102:4604-4614.
137. Wang B, Yang Y, Friedman PA. Na/H exchange regulatory factor 1, a novel AKT-associating protein, regulates extracellular signal-regulated kinase signaling through a B-Raf-mediated pathway. Mol Biol Cell 2008;19:1637-1645. Epub 2008 Feb 13
138. Karim Z, Gérard B, Bakouh N, Alili R, Leroy C, Beck L, Silve C, Planelles G, Urena-Torres P, Grandchamp B, Friedlander G, Prié D. NHERF1 mutations and responsiveness of renal parathyroid hormone. N Engl J Med 2008;359:1128-1135.
139. Lloyd SE, Pearce SH, Fisher SE, Steinmeyer K, Schwappach B, Scheinman SJ, Harding B, Bolino A, Devoto M, Goodyer P, Rigden SP, Wrong O, Jentsch TJ, Craig IW, Thakker RV. A common molecular basis for three inherited kidney stone diseases. Nature 1996;379:445-449.
140. Devuyst O, Thakker RV. Dent’s disease. Orphanet J Rare Dis 2010;5:28.
141. Wrong OM, Norden AG, Feest TG. Dent’s disease; a familial proximal renal tubular syndrome with low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, metabolic bone disease, progressive renal failure and a marked male predominance. QJM 1994;87:473-493.
142. Lloyd SE, Pearce SH, Günther W, Kawaguchi H, Igarashi T, Jentsch TJ, Thakker RV.. Idiopathic low molecular weight proteinuria associated with hypercalciuric nephrocalcinosis in Japanese children is due to mutations of the renal chloride channel (CLCN5). J Clin Invest 1997;99:967-974.
143. Hoopes RR Jr, Raja KM, Koich A, Hueber P, Reid R, Knohl SJ, Scheinman SJ. Evidence for genetic heterogeneity in Dent’s disease. Kidney Int 2004;65:1615-1620.
144. Scheinman SJ. X-linked hypercalciuric nephrolithiasis: clinical syndromes and chloride channel mutations. Kidney Int 1998;53:3-17.
145. Hoopes RR Jr, Shrimpton AE, Knohl SJ, Hueber P, Hoppe B, Matyus J, Simckes A, Tasic V, Toenshoff B, Suchy SF, Nussbaum RL, Scheinman SJ. Dent Disease with mutations in OCRL1. Am J Hum Genet 2005;76:260-267. Epub 2004 Dec 30
146. Levin-Iaina N, Dinour D. Renal disease with OCRL1 mutations: Dent-2 or Lowe syndrome? J Pediatr Genet 2012;1:3-5.

APA	Acar S, Demir K, SHİ Y (2017). Genetic Causes of Rickets. , 88 - 105.
Chicago	Acar Sezer,Demir Korcan,SHİ Yufei Genetic Causes of Rickets. (2017): 88 - 105.
MLA	Acar Sezer,Demir Korcan,SHİ Yufei Genetic Causes of Rickets. , 2017, ss.88 - 105.
AMA	Acar S,Demir K,SHİ Y Genetic Causes of Rickets. . 2017; 88 - 105.
Vancouver	Acar S,Demir K,SHİ Y Genetic Causes of Rickets. . 2017; 88 - 105.
IEEE	Acar S,Demir K,SHİ Y "Genetic Causes of Rickets." , ss.88 - 105, 2017.
ISNAD	Acar, Sezer vd. "Genetic Causes of Rickets". (2017), 88-105.

APA	Acar S, Demir K, SHİ Y (2017). Genetic Causes of Rickets. Journal of Clinical Research in Pediatric Endocrinology, 9(2 (Özel)), 88 - 105.
Chicago	Acar Sezer,Demir Korcan,SHİ Yufei Genetic Causes of Rickets. Journal of Clinical Research in Pediatric Endocrinology 9, no.2 (Özel) (2017): 88 - 105.
MLA	Acar Sezer,Demir Korcan,SHİ Yufei Genetic Causes of Rickets. Journal of Clinical Research in Pediatric Endocrinology, vol.9, no.2 (Özel), 2017, ss.88 - 105.
AMA	Acar S,Demir K,SHİ Y Genetic Causes of Rickets. Journal of Clinical Research in Pediatric Endocrinology. 2017; 9(2 (Özel)): 88 - 105.
Vancouver	Acar S,Demir K,SHİ Y Genetic Causes of Rickets. Journal of Clinical Research in Pediatric Endocrinology. 2017; 9(2 (Özel)): 88 - 105.
IEEE	Acar S,Demir K,SHİ Y "Genetic Causes of Rickets." Journal of Clinical Research in Pediatric Endocrinology, 9, ss.88 - 105, 2017.
ISNAD	Acar, Sezer vd. "Genetic Causes of Rickets". Journal of Clinical Research in Pediatric Endocrinology 9/2 (Özel) (2017), 88-105.