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| | [[User:Muhammad Haider|Muhammad Adnan Haider, M.B.B.S.]][mailto:dr.adnanhaider92@gmail.com] |
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| {{Rickets}}
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| {{CMG}}; {{AE}}
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| {{Rickets}}
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| ==Overview==
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| Rickets is a bony disease due to decreased [[mineralization]] of [[growth plate]], associated with abnormal serum calcium and phosphate level<ref name="pmid23208530">{{cite journal| author=Shore RM, Chesney RW| title=Rickets: Part I. | journal=Pediatr Radiol | year= 2013 | volume= 43 | issue= 2 | pages= 140-51 | pmid=23208530 | doi=10.1007/s00247-012-2532-x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23208530 }} </ref>. This leads to softening of bones.Rickets is more common in children especially in developing countries due to malnutrition and famines. It can also occur in adults and similar presentation in adults is termed as [[osteomalacia]].
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| The origin of the word "rickets" is unknown. The Greek derived word "rachitis" (meaning "inflammation of the spine") was later adopted as the scientific term for rickets, due chiefly to the words' similarity in sound.
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| ==Historical Perspective==
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| ==Classification==
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| There are 3 types of rickets
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| # Nutritional Rickets (due to deficiency of Vit D, calcium, and phosphorous)
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| # Vitamin D dependent rickets (due to defective metabolism of vitamin D)
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| # Vitamin D resistant rickets (hypophosphatemic rickets due renal phosphate wasting)
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| ==Pathophysiology==
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| === Physiology ===
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| Rickets is decreased [[mineralization]] of the [[growth plate]] and is associated with abnormal serum calcium and phosphate level. Viatmin D, [[Fibroblast growth factor 23 (FGF23)]] and [[Parathyroiad hormone (PTH)]] play role in calcium and phosphate homeostasis. Low phosphate level is common pathway in growth plate abnormalities both in calciopenic and phophopenic forms of ricket <ref name="pmid15976027">{{cite journal| author=Sabbagh Y, Carpenter TO, Demay MB| title=Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes. | journal=Proc Natl Acad Sci U S A | year= 2005 | volume= 102 | issue= 27 | pages= 9637-42 | pmid=15976027 | doi=10.1073/pnas.0502249102 | pmc=1172249 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15976027 }} </ref>. Further explained below in pathogeneisis.
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| '''Vitamin D'''
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| Vitamin D in its prohormone forms [[ergocalciferol (vit D2)]] from yeasts and fungi and [[cholecalciferol (vit D3)]] as produced by UV irradiation in human skin from 7-dehydrocholestrol. Vitamin D undergoes [[hydyroxylation]] at 25 position in liver with help of [[25-hydroxylase]] enzyme and hydroxylation at 1 position with help of [[1-''a''-hydroxlase]](encoded by CYP271B)in kidneys. This 25 and 1 hydroxylation activates vitamin D and activated form of vitamin D is 1,25(OH)2D. This 1,25(OH)2D acts on intestine and increases calcium and phosphate absorption and also acts on bone to increase bone [[resorption]]. Metabolic inactivation of 1,25(OH)2D and 25(OH)D occurs in kidneys and intestine by hydroxylation at 24 position with help of enzyme 24-hydroxylase (encoded by CYP24A1) <ref name="pmid24529992">{{cite journal| author=Bikle DD| title=Vitamin D metabolism, mechanism of action, and clinical applications. | journal=Chem Biol | year= 2014 | volume= 21 | issue= 3 | pages= 319-29 | pmid=24529992 | doi=10.1016/j.chembiol.2013.12.016 | pmc=3968073 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24529992 }} </ref>. If there is nutritional deficiency of vitamin D or resistance to action of vitamin D (Vitamin D dependent rickets type 1,2), leads to low serum calcium and phosphate level. This causes increased production of PTH from parathyroid glands. PTH acts on kidneys to increase 1-a-Hydroxylase and calcium absorption and decrease renal phosphate reabsorption leading to hypophosphatemia. Hypophosphatemia is central to development of rickets.
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| '''Fibroblast Growth Factor 23 (FGF23)'''
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| FGF23 is a phosphaturic hormone produced by [[osteocytes]]. FGF23 decreases the renal threshold of phosphate reabsorption by decreasing the sodium dependent phosphate transport protein 2A and 2C (NPT2A and NPT2C) on the apical surfaces of [[proximal renal tubular cells]]<ref name="pmid8113402">{{cite journal| author=Tenenhouse HS, Werner A, Biber J, Ma S, Martel J, Roy S | display-authors=etal| title=Renal Na(+)-phosphate cotransport in murine X-linked hypophosphatemic rickets. Molecular characterization. | journal=J Clin Invest | year= 1994 | volume= 93 | issue= 2 | pages= 671-6 | pmid=8113402 | doi=10.1172/JCI117019 | pmc=293897 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8113402 }} </ref>. So when the level of FGF23 is high, circulating phosphate level will be low in serum. In addition, FGF23 decreases the level of 1,25(OH)2D in blood by increasing the expression of CYP24A1 (inducer of 24-hydroxlase) and down regulating the expression of CYP27B1 (inducer of 1-a-hydroxlase enzyme). The relative deficiency of 1,25(OH)2D decreases serum phosphate level, as normally 1,25(OH)2D increases intestinal phosphate absorption through sodium dependent phosphate transport protein 2B (NPT2B) <ref name="pmid19729436">{{cite journal| author=Sabbagh Y, O'Brien SP, Song W, Boulanger JH, Stockmann A, Arbeeny C | display-authors=etal| title=Intestinal npt2b plays a major role in phosphate absorption and homeostasis. | journal=J Am Soc Nephrol | year= 2009 | volume= 20 | issue= 11 | pages= 2348-58 | pmid=19729436 | doi=10.1681/ASN.2009050559 | pmc=2799172 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19729436 }} </ref>.
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| === Pathogenesis ===
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| [[Growth plate]] (physis) is present between [[epiphysis]] and [[metaphysis]]. There is maturation of [[chondrcytes]] (cartilage cells) progressively occurs from epiphysis to metaphysis. Thickness of growth plate is depending on two opposing factors, proliferation and [[hypertrophy]] of chondrocytes, on one hand, and vascular invasion of growth plate followed by mineralization of physis followed by conversion into [[primary bone spongiosa]], on other hand <ref name="pmid1985332">{{cite journal| author=Pitt MJ| title=Rickets and osteomalacia are still around. | journal=Radiol Clin North Am | year= 1991 | volume= 29 | issue= 1 | pages= 97-118 | pmid=1985332 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1985332 }} </ref>. Hypertrophic chondrocytes undergo [[apoptosis]] and these apoptotic cells and replaced by [[mineralized bone matrix]] by vascular invasion <ref name="pmid1985332">{{cite journal| author=Pitt MJ| title=Rickets and osteomalacia are still around. | journal=Radiol Clin North Am | year= 1991 | volume= 29 | issue= 1 | pages= 97-118 | pmid=1985332 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1985332 }} </ref>. Apoptosis of hypertrophic chondrocytes is induced by extracellualar phosphate via phosphorylation of mitogen-activated-protein-kinase (MAPK) pathway intermediates and downstream inhibition of caspase-9-dependent mitochondrial apoptotic pathway <ref name="pmid15976027">{{cite journal| author=Sabbagh Y, Carpenter TO, Demay MB| title=Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes. | journal=Proc Natl Acad Sci U S A | year= 2005 | volume= 102 | issue= 27 | pages= 9637-42 | pmid=15976027 | doi=10.1073/pnas.0502249102 | pmc=1172249 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15976027 }} </ref>. The decrease in ambient phosphate level impaired the apoptosis of hypertrophic chondrocytes. The ligand 1,25(OH)2D and its receptors also plays a role in this pathway <ref name="pmid20685875">{{cite journal| author=Miedlich SU, Zhu ED, Sabbagh Y, Demay MB| title=The receptor-dependent actions of 1,25-dihydroxyvitamin D are required for normal growth plate maturation in NPt2a knockout mice. | journal=Endocrinology | year= 2010 | volume= 151 | issue= 10 | pages= 4607-12 | pmid=20685875 | doi=10.1210/en.2010-0354 | pmc=2946147 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20685875 }} </ref>. When there is no apoptosis of hypertrophic chondrocytes, growth plate thickens and becomes disorganized. Chondrocytes lose their columnar orientation <ref name="pmid7180943">{{cite journal| author=Lacey DL, Huffer WE| title=Studies on the pathogenesis of avian rickets. I. Changes in epiphyseal and metaphyseal vessels in hypocalcemic and hypophosphatemic rickets. | journal=Am J Pathol | year= 1982 | volume= 109 | issue= 3 | pages= 288-301 | pmid=7180943 | doi= | pmc=1916114 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7180943 }} </ref> with expansion of hypertrophic zone. In the metaphysis, mineralization defect leads to accumulation of osteod <ref name="pmid12964426">{{cite journal| author=Rauch F| title=The rachitic bone. | journal=Endocr Dev | year= 2003 | volume= 6 | issue= | pages= 69-79 | pmid=12964426 | doi=10.1159/000072770 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12964426 }} </ref>.
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| ==Causes==
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| ===Causes of Nutritional Rickets===
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| #Vitamin D deficeincy<ref name="pmid20526242">{{cite journal| author=Unuvar T, Buyukgebiz A| title=Nutritional rickets and vitamin D deficiency in infants, children and adolescents. | journal=Pediatr Endocrinol Rev | year= 2010 | volume= 7 | issue= 3 | pages= 283-91 | pmid=20526242 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20526242 }} </ref>
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| *Lack of supplementation for breast feeding infants
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| *Darker skin color
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| *poor sunlight exposure
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| *Poor vit D intake of lactating mothers<ref name="pmid17951482">Bodnar LM, Catov JM, Roberts JM, Simhan HN (2007) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=17951482 Prepregnancy obesity predicts poor vitamin D status in mothers and their neonates.] ''J Nutr'' 137 (11):2437-42. [http://dx.doi.org/10.1093/jn/137.11.2437 DOI:10.1093/jn/137.11.2437] PMID: [https://pubmed.gov/17951482 17951482]</ref>
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| *High latitude
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| *full boding clothing
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| *restricted intake
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| *[[25-hydroxylase]] deficiency (also known as vitamin-D dependent rickets type 1B)<ref name="pmid25942481">{{cite journal| author=Thacher TD, Fischer PR, Singh RJ, Roizen J, Levine MA| title=CYP2R1 Mutations Impair Generation of 25-hydroxyvitamin D and Cause an Atypical Form of Vitamin D Deficiency. | journal=J Clin Endocrinol Metab | year= 2015 | volume= 100 | issue= 7 | pages= E1005-13 | pmid=25942481 | doi=10.1210/jc.2015-1746 | pmc=4490307 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25942481 }} </ref>
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| *1-a-hydroxylase deficincy (also known as vitamin-D dependent rickets type 1A)owing to renal disease or mutation in CYP27B1
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| *Hereditory 1,25(OH)2D resistant rickets due to mutation in VDR (vitamin-D dependent rickets type 2)<ref name="pmid18694980">{{cite journal| author=Bouillon R, Carmeliet G, Verlinden L, van Etten E, Verstuyf A, Luderer HF | display-authors=etal| title=Vitamin D and human health: lessons from vitamin D receptor null mice. | journal=Endocr Rev | year= 2008 | volume= 29 | issue= 6 | pages= 726-76 | pmid=18694980 | doi=10.1210/er.2008-0004 | pmc=2583388 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18694980 }} </ref> or due to overexpression of vitamin D response element(VDRE)-binding ribonucleoprotein (vitamin D dependent rickets type 2b)
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| #Calcium deficiency
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| *poverty
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| *[[malnutrition]]
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| *intake of competing Oxalate and phosphate intake
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| *extensive breast feeding without complementary calcium containing supplements(extensive breast feeding could be partially protective if no other calcium containing foods source available)<ref name="pmid26745253">{{cite journal| author=Munns CF, Shaw N, Kiely M, Specker BL, Thacher TD, Ozono K | display-authors=etal| title=Global Consensus Recommendations on Prevention and Management of Nutritional Rickets. | journal=J Clin Endocrinol Metab | year= 2016 | volume= 101 | issue= 2 | pages= 394-415 | pmid=26745253 | doi=10.1210/jc.2015-2175 | pmc=4880117 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26745253 }} </ref>
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| ===Causes of Phosphopenic Rickets===
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| This type of rickets is due to serum phosphate deficiency either due to dietary deficiency or due to defects renal reabsorption
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| ====Dietary Causes of Phosphate deficeincy====
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| *breastfed very low weight premature infants<ref name="pmid3385539">{{cite journal| author=Schanler RJ, Abrams SA, Garza C| title=Bioavailability of calcium and phosphorus in human milk fortifiers and formula for very low birth weight infants. | journal=J Pediatr | year= 1988 | volume= 113 | issue= 1 Pt 1 | pages= 95-100 | pmid=3385539 | doi=10.1016/s0022-3476(88)80541-9 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3385539 }} </ref>
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| *[[parenteral nutrition]]
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| *[[Hypoallergenc]] formula feed<ref name="pmid28167344">{{cite journal| author=Gonzalez Ballesteros LF, Ma NS, Gordon RJ, Ward L, Backeljauw P, Wasserman H | display-authors=etal| title=Unexpected widespread hypophosphatemia and bone disease associated with elemental formula use in infants and children. | journal=Bone | year= 2017 | volume= 97 | issue= | pages= 287-292 | pmid=28167344 | doi=10.1016/j.bone.2017.02.003 | pmc=5884631 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28167344 }} </ref>
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| *excessive use of [[phosphate binders]]
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| *gastrointestinal surgeries or disorders
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| ====Rickets caused by Excesssive Renal phosphate wasting====
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| =====FGF23 dependent Renal phosphate wasting=====
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| increased production of decreased degradation of FGF23 lead to excessive renal phosphate loss. Causes are as
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| *[[X-linked]] hypophosphatemia(XLH) due to mutation PHEX gene
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| *[[autosommal recessive]] hypophosphatemic rickets(ARHR)due to mutation in DMP1(ARHR type 1) or ENPP1(ARHR type 2)
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| *[[autosommal dominant]] hypophosphatemic rickets (ADHR) dut to mutation in FGF23
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| *[[Raine syndrome]] due to mutation in FAM20C <ref name="pmid24982027">{{cite journal| author=Takeyari S, Yamamoto T, Kinoshita Y, Fukumoto S, Glorieux FH, Michigami T | display-authors=etal| title=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. | journal=Bone | year= 2014 | volume= 67 | issue= | pages= 56-62 | pmid=24982027 | doi=10.1016/j.bone.2014.06.026 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24982027 }} </ref>
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| *[[polyostotic fibrous dysplasia]]<ref name="pmid12952917">{{cite journal| author=Riminucci M, Collins MT, Fedarko NS, Cherman N, Corsi A, White KE | display-authors=etal| title=FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. | journal=J Clin Invest | year= 2003 | volume= 112 | issue= 5 | pages= 683-92 | pmid=12952917 | doi=10.1172/JCI18399 | pmc=182207 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12952917 }} </ref> or overexpression of a-KLOTHO<ref name="pmid18308935">{{cite journal| author=Brownstein CA, Adler F, Nelson-Williams C, Iijima J, Li P, Imura A | display-authors=etal| title=A translocation causing increased alpha-klotho level results in hypophosphatemic rickets and hyperparathyroidism. | journal=Proc Natl Acad Sci U S A | year= 2008 | volume= 105 | issue= 9 | pages= 3455-60 | pmid=18308935 | doi=10.1073/pnas.0712361105 | pmc=2265125 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18308935 }} </ref>
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| =====FGF23 independent renal phosphate loss=====
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| *fanconi syndrome<ref name="pmid2842681">{{cite journal| author=Tieder M, Arie R, Modai D, Samuel R, Weissgarten J, Liberman UA| title=Elevated serum 1,25-dihydroxyvitamin D concentrations in siblings with primary Fanconi's syndrome. | journal=N Engl J Med | year= 1988 | volume= 319 | issue= 13 | pages= 845-9 | pmid=2842681 | doi=10.1056/NEJM198809293191307 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2842681 }} </ref>
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| *[[Distal Renal tubular acidosis]]
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| *Due to mutation in SLC34A1 (encoding sodium dependent phosphate transport protein 2A (NPT2A)
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| *due to mutation in SLC34A3 (encoding sodium dependent phosphate transport protein 2C (NPT2C)<ref name="pmid16358214">{{cite journal| author=Bergwitz C, Roslin NM, Tieder M, Loredo-Osti JC, Bastepe M, Abu-Zahra H | display-authors=etal| title=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. | journal=Am J Hum Genet | year= 2006 | volume= 78 | issue= 2 | pages= 179-92 | pmid=16358214 | doi=10.1086/499409 | pmc=1380228 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16358214 }} </ref>
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| ===causes of rickets associated with direct inhibition of mineralization at growth plate===
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| *hereditory [[phosphotasia]]
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| *use of etindronate (first generation of bisphosphonates)
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| *flouride excess
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| *aluminium excess
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| ==Genetics==
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| ==Associated Conditions==
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| ==Gross Pathology==
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| There is change in structure of bone with increase in diameters of physis and metaphysis. Bone strength is compromised which is compensated by increase in bone size but overall bone is weak and bowing of bones occurs.
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| ==Microscopic Pathology==
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| Impaired apotosis and mineralization of hypertrophic chondrocytes leads to increase in longitudinal thickness of bone, loss of columnar arrangement of chondrocytes and osteod matrix accumulation in hypertrophic zone between growth plate and metaphysis.<ref name="pmid3616560">{{cite journal| author=Shapiro IM, Boyde A| title=Mineralization of normal and rachitic chick growth cartilage: vascular canals, cartilage calcification and osteogenesis. | journal=Scanning Microsc | year= 1987 | volume= 1 | issue= 2 | pages= 599-606 | pmid=3616560 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3616560 }} </ref>
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| ==References==
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