Comparative study of children with calciopaenic and phosphopaenic rickets seen at Chris Hani Baragwanath Hospital

Transcription

1 SA Orthopaedic Joural Summer 2016 Vol 15 No 4 Page 37 Comparative study of childre with calciopaeic ad phosphopaeic rickets see at Chris Hai Baragwaath Hospital Dr F Agaba MBBCh, FCPaed(SA), MMed Departmet of Paediatrics, Charlotte Maxeke Academic Hospital ad Faculty of Health Scieces, Uiversity of the Witwatersrad, Johaesburg, South Africa Dr JM Pettifor MBBCh, FCPaed(SA), PhD(Med) Departmet of Paediatrics ad MRC/Wits Developmetal Pathways for Health Research Uit, Chris Hai Baragwaath Academic Hospital ad Faculty of Health Scieces, Uiversity of the Witwatersrad, Johaesburg, South Africa Dr K Thadraye MBBCh, FCPaed(SA), MMed, PhD, Certificate i Edocriology ad Metabolism (Paeds) Departmet of Paediatrics, Chris Hai Baragwaath Academic Hospital ad Faculty of Health Scieces, Uiversity of the Witwatersrad, Johaesburg, South Africa Correspodig author: Dr K Thadraya PO Box Bassoia Cell: Tel: (office) Fax: kebashi.thadraye@wits.ac.za This research was coducted i partial fulfilmet of the requiremets for the degree of Masters of Medicie i the brach of Paediatrics to the Faculty of Health Scieces, Uiversity of the Witwatersrad, Johaesburg, Abstract Itroductio: The majority of causes of rickets ca be divided ito two large pathogeic groups, amely calciopaeic ad phosphopaeic. Few studies have compared the cliical ad biochemical presetatios of the two forms of rickets. The aim of this study was to compare the demographic, cliical ad biochemical presetatios ad respose to therapy of childre with calciopaeic ad phosphopaeic rickets. Methodology: The study is a retrospective chart review of childre diagosed with rickets at Chris Hai Baragwaath Academic Hospital (CHBAH) i Johaesburg, South Africa, betwee 2006 ad The radiological respose to therapy was evaluated usig the Thacher scorig system to assess the severity of rickets. Results: The study comprises 112 patiets from 2 moths to 18 years of age diagosed with rickets (53% with calciopaeic rickets ad 47% with phosphopaeic rickets). The calciopaeic group was youger tha the phosphopaeic group (20 [7 26] vs 36 [24 51] moths; p<0.001), but the phosphopaeic group was more severely stuted tha the calciopaeic group at presetatio (HAZ scores 3.3 [ 4.5 to 2.1] vs 2 [ 3.4 to 0.7]; p<0.001). Followig treatmet, 75% of patiets i the calciopaeic group had biomarkers that had ormalised completely withi a media of 13 (9 18) weeks while oly 10% i the phosphopaeic group had ormalised withi a media of 17 (17 50) weeks. Radiological healig i respose to treatmet was better i the calciopaeic group compared to the phosphopaeic group (67.5% vs 18%; p-value <0.01). Coclusio: Calciopaeic rickets (maily vitami D deficiecy) preseted at a youger age ad respose to therapy was better compared to phosphopaeic rickets (maily X-liked hypophosphataemic rickets). This study highlights the sigificat differeces betwee calciopaeic ad phosphopaeic rickets, which may be helpful to attedig orthopaedic surgeos ad paediatricias i differetiatig betwee these two groups of rickets ad i the maagemet thereof. Summary of abstract: This study highlights the differeces betwee calciopaeic ad phosphopaeic rickets, which may be of assistace to attedig orthopaedic surgeos ad paediatricias i the maagemet of rickets. The study shows that i childre with calciopaeic rickets, the majority are vitami D deficiet, ad preset at a youger age with craiotabes ad less severe lower limb deformities compared to childre with phosphopaeic rickets who maily have X-liked hypophosphataemic rickets ad are severely short i stature ad have geu valgum deformities. The medical maagemet of the two types of rickets differs ad respose to medical therapy is better i the calciopaeic compared to the phosphopaeic group. Key words: rickets, calciopaeic, phosphopaeic, Thacher score, Johaesburg, X-liked hypophosphataemic rickets, vitami D deficiecy

2 Page 38 SA Orthopaedic Joural Summer 2016 Vol 15 No 4 Itroductio With the discovery of the role of vitami D i the pathogeesis of rickets early a cetury ago, the various causes were divided ito those resposive to ad those resistat to vitami D therapy. 1 As the pathogeesis of various types of rickets became more apparet, the uderlyig mechaisms were classified ito those associated primarily with disturbaces i calcium (calciopaeic rickets) ad those related to perturbed phosphate homeostasis (phosphopaeic rickets). 2 Table I lists the differet causes of these two forms of rickets. 2,3 table i: the causes of calciopaeic ad phosphopaeic rickets Calciopaeic causes a. Abormalities i vitami D metabolism Nutritioal rickets dietary deficiecy of vitami D iadequate exposure to sulight Impaired absorptio of vitami D steatorrhea, e.g. coeliac disease biliary obstructio, e.g. biliary atresia Impaired hydroxylatio of vitami D to 25-hydroxyvitami D liver immaturity prematurity Icreased metabolism of vitami D aticovulsat drugs, e.g. pheobarbitoe Decreased real sythesis of 1,25-dihydroxy-vitami D real failure vitami D-depedecy rickets (type I) Ed-orga resistace to 1,25-dihydroxy-vitami D vitami D-depedecy rickets (Type II) b. Dietary deficiecy of calcium Diets deficiet i dairy products table ii: Biochemical differeces betwee calciopaeic ad phosphopaeic rickets Biochemistry Calciopaeic rickets Phosphopaeic rickets Serum calcium ( mmol/l) or N N Serum iorgaic phosphate ( mmol/L)* or N Serum 25(OH)D (>30 mol/l) (vitami D deficiecy oly) Serum alkalie phosphatase ( IU/L)* Serum parathyroid hormoe ( pmol/l) N or slightly Normal values show withi brackets; *Age-depedet Phosphopaeic causes Decreased itake of phosphate prematurity Decreased itestial absorptio of phosphate igestio of large amouts of alumiium hydroxide Icreased real losses of phosphate hypophosphataemic vitami D- resistat rickets: X-liked or sporadic Facoi sydrome mesechymal tumours N The biochemical fidigs differ betwee the two groups of rickets while the skeletal chages are cliically similar 3,4 although there are some differeces i cliical presetatio. Maagemet of rickets depeds o the uderlyig cause. Previous studies suggest that calciopaeic rickets presets earlier tha phosphopaeic rickets. 5,6 The severe calciopaeic form of rickets usually presets with delayed motor milestoes, severe boe pai ad deformities, ad hypotoia, 7 while the commo form of phosphopaeic rickets presets with short stature ad leg deformities. Table II shows the importat differeces i the biochemical fidigs betwee calciopaeic ad phosphopaeic rickets. 1,3,4,8 The commoest cause of calciopaeic rickets is vitami D deficiecy which is easily corrected by oral admiistratio of vitami D. 3 X-liked hypophosphataemic rickets is the most commo form of phosphopaeic rickets ad is curretly treated with calcitriol ad phosphate supplemets. 9,10 I South Africa, there are little published data o the prevalece ad presetatio of the differet types of rickets i childre. The cliical, biochemical ad radiological differeces betwee calciopaeic ad phosphopaeic rickets may ot be easily recogised by the attedig health care workers i primary ad secodary health care facilities. This study aims to describe the demographic, cliical, biochemical ad radiological fidigs together with the maagemet of these childre presetig with calciopaeic ad phosphopaeic rickets to the Metabolic Boe Disease Cliic i Johaesburg. Methodology The study was a retrospective, descriptive study of all the rachitic patiets (a total of 112 patiets from 1 moth to 18 years of age) referred to the cliic. No patiets were excluded from the study. The records of patiets who were reviewed were see at the Paediatric Metabolic Boe Disease Cliic at Chris Hai Baragwaath Academic Hospital (CHBAH), the major referral hospital for the commuities of Soweto, Johaesburg ad surroudig areas from Jauary 2006 util December The classificatio of calciopaeic ad phosphopaeic rickets was based o the fial diagosis of the attedig cliicias. The fial diagosis was based o the biochemical chages o presetatio ad o the respose of the rickets to the prescribed therapy as these two types of rickets are treated differetly. The diagosis of rickets was cofirmed o radiographs of the wrists or kees.

3 SA Orthopaedic Joural Summer 2016 Vol 15 No 4 Page 39 Iformatio o the demographic, cliical, radiological ad biochemical fidigs were collected. Radiological fidigs were evaluated by FA ad thereafter checked by KT usig the Thacher scorig system for severity of rickets. 11 Data was aalysed usig Statistica statistical software versio 10.0 (Stat soft, USA). Cotiuous variables were described usig medias ad iterquartile rages (IQR) because they were ot ormally distributed. Categorical variables were described usig percetages. Comparisos betwee patiets with calciopaeic ad phosphopaeic rickets were doe usig chi-squared or Fisher s exact statistical methods for categorical data ad Ma-Whitey U test for cotiuous variables. A p-value of <0.05 was cosidered to be statistically sigificat. Height for age Z score (HAZ) ad weight for age Z score (WAZ) were calculated usig the WHO Athroplus software ( The study was approved by the Huma Research Ethics Committee (HREC) of the Uiversity of the Witwatersrad (approval umber M130225). Permissio from the Chief Executive Officer at CHBAH was obtaied to coduct the study. Results Demographic data This study comprised 112 patiets aged betwee 2 moths ad 18 years diagosed with rickets. Fifty-ie patiets were classified as havig calciopaeic rickets (52.7%) ad 53 with phosphopaeic rickets (47.3%). There was a greater umber of males compared to females i the calciopaeic group (38 [64%] vs 21 [36%]; p<0.01) ad a greater umber of females compared to males i the phosphopaeic group (35 [66%] vs 18 [34%]; p<0.01). I both the calciopaeic ad phosphopaeic groups, the majority of childre were black Africa (51 [87%] ad 45 [84%] respectively) with the remaiig 13% ad 16% comprisig Idia/Pakistai, white or mixed acestry ethic groups. I both groups, more tha 80% of childre were from Gauteg ad the rest from other provices withi South Africa. I both the groups, more tha two-thirds of the patiets were referred from peripheral hospitals or a paediatricia, followed by orthopaedic surgeos, cliics ad geeral practitioers. I the calciopaeic group, two (3%) patiets had a family history of rickets (oe patiet had a elder siblig with vitami D deficiecy ad the other patiet had a ucle who had had a possible diagosis of rickets but had ot bee treated). I the phosphopaeic group, 22 (42%) had a family history of rickets. Age ad athropometric measuremets at presetatio ad referral The ages at iitial referral ad at the most recet follow-up visit together with the athropometric measuremets at the iitial referral of the patiets are show i Table III. The calciopaeic group preseted at a youger age compared to the phosphopaeic group (20 [7 26] vs 36 [24 51] moths; p<0.001), but the phosphopaeic group were more stuted (HAZ scores 3.3 [ 4.5 to 2.1] vs 2 [ 3.4 to 0.7] respectively; p<0.001). Pathogeesis of rickets i the calciopaeic ad phosphopaeic groups I the calciopaeic group, the majority of patiets (54/59) preseted with vitami D deficiecy rickets; two preseted with probably dietary calcium deficiecy rickets; two patiets were diagosed as havig vitami D depedecy rickets (VDDR) type I (oe of whom was cofirmed o geetic testig); ad oe child had real osteodystrophy. table iii: Chroological ages ad athropometric measuremets i the calciopaeic ad phosphopaeic groups Chroological ages ad athropometric measuremets All patiets (=112) Calciopaeic rickets (=59) Phosphopaeic rickets (=53) Age at diagosis or at iitial presetatio (moths) 24 (16 41) 20 (7 26) 36 (24-51) <0.001 Age at first cosultatio at Metabolic Boe Disease Cliic (moths) 26 ( ) 20 (7 26) 41 (25 71) <0.001 Age at most recet follow-up (moths) 42 (24 93) 27 (15 36) 89 (50 132) <0.001 Weight (kg) 10.3 ( ) 9.2 ( ) 12 (9.4 16) <0.001 WAZ score 1.6 ( 2.9 to -0.4) 1.2 ( 3 to -0.01) 1.9 ( 2.7 to 1.3) 0.05 Height (cm) 80 ( ) 76 (64 83) 85 (77 96) <0.001 HAZ score 2.9 ( 3.9 to 1.4) 2 ( 3.4 to 0.7) 3.3 ( 4.5 to 2.1) <0.001 Head circumferece (cm) 48 ( ) 46.7 ( ) 50 (48 51) <0.001 *Ma-Whitey U test

4 Page 40 SA Orthopaedic Joural Summer 2016 Vol 15 No 4 I the phosphopaeic group, 33/53 patiets (62%) preseted with a cliical diagosis of X-liked hypophosphataemic rickets. The remaiig 20 patiets (38%) i the phosphopaeic group preseted with rickets secodary to other real tubulopathies (proximal RTA 9 [17%], distal RTA 4 [8%]) ad sporadic hypophosphataemic rickets (7 [13%]). Cliical characteristic features of rickets The most commo cliical presetig features i both groups were wideed wrists, rachitic rosary ad frotal bossig i more tha 80% of patiets. There was a greater umber of patiets i the phosphopaeic group presetig with geu valgum of the lower limbs compared to those patiets with calciopaeic rickets (64% vs 32%; p<0.01). Craiotabes ad a lack of lower limb deformities were the two cliical features more prevalet i the calciopaeic group compared to the phosphopaeic group (27% vs 11%; p<0.05 ad 27% vs 4%; p<0.01 respectively). Results of biomarkers o presetatio ad o follow-up or discharge Table IV shows the baselie biochemical variables o referral ad o oe-year follow-up or at discharge (after therapy) of the calciopaeic ad phosphopaeic groups of patiets. Total serum calcium levels were sigificatly lower i the calciopaeic group (2.1 [2 2.3] mmol/l) compared to the phosphopaeic group (2.3 [ ] mmol/l). I the calciopaeic group, 41% (24/58) had hypocalcaemia, while i the phosphopaeic group, 27% (14/52) were hypocalcaemic. The calciopaeic group also had sigificatly higher serum parathyroid hormoe (PTH) ad alkalie phosphatase (ALP) levels. The media phosphate level was lower i the phosphopaeic group tha the calciopaeic group (p<0.001). I the phosphopaeic group, 96% (50/52) were phosphopaeic compared to the 60% (34/57) i the calciopaeic group. The ioised calcium ad 25-hydroxyvitami D (25(OH)D) levels were ot sigificatly differet, but the umber of patiets with measuremets was small i both groups. At oe-year follow-up or o discharge after therapy, total serum calcium levels i both groups were withi the ormal referece rage but serum iorgaic phosphate levels remaied low i the phosphopaeic group (p<0.001). After treatmet, data were available o 96 childre, 35/47 (75%) i the calciopaeic group had biochemical markers of rickets that had ormalised completely withi a media of 13 (9 18) weeks while oly 5/49 (10%) i the phosphopaeic group had withi a media of 17 (17 50) weeks (75% vs 10%; p value <0.001). table iv: Baselie measuremets of biomarkers o referral ad o oe-year follow-up or at discharge (after therapy) i patiets with calciopaeic ad phosphopaeic rickets Biomarkers o referral All groups Calciopaeic rickets Phosphopaeic rickets Calcium (ioised) (mmol/l) ( ) ( ) ( ) 0.05 Total serum calcium (mmol/l) ( ) ( ) ( ) <0.01 Phosphate (mmol/l) ( ) ( ) ( ) < Serum alkalie phosphatase (IU/L) ( ) ( ) ( ) 0.03 Serum parathyroid Hormoe (pmol/l) ( ) (12 36) ( ) < Serum 25(OH)D (mol/l) ( ) (32 82) (34 85) 0.3 Biomarkers at 1-year follow-up or discharge Calcium (Ioised) (mmol/l) ( ) ( ) ( ) 0.4 Total serum calcium (mmol/l) ( ) ( ) ( ) 0.2 Phosphate (mmol/l) ( ) ( ) ( ) < Serum alkalie phosphatase (IU/L) ( ) ( ) ( ) < Serum parathyroid hormoe (pmol/l) ( ) (3 8.6) ( ) 0.5 Thacher score Iitial Thacher score 94 9 (6 10) 47 9 (4 10) (6 10) 0.1 Thacher score at 1-year follow-up or o discharge 78 2 (0 7) 40 0 (0 2) 38 6 (1.5 8) < *Ma-Whitey U test used

5 SA Orthopaedic Joural Summer 2016 Vol 15 No 4 Page 41 The gradig of radiological fidigs of rickets usig the Thacher scorig system The Thacher scorig system was utilised to assess the severity of the radiological features of rickets at the wrist ad/or kee o iitial presetatio ad at oe-year follow-up or o discharge (Table IV). The iitial media Thacher score for all patiets was 9 (IQR 6 10). There was o differece i the Thacher score at presetatio betwee the phosphopaeic ad calciopaeic groups of patiets (media 10 [IQR 6 10] vs 9 [IQR 4 10]; p = 0.12). At oeyear follow-up or o discharge, the Thacher score had falle but remaied high i the phosphopaeic group while i the calciopaeic group it had retured to early ormal (<1.5) (media 6 [IQR 1.5 8] ad 0 [IQR 0 2] respectively; p<0.001). I the calciopaeic group of patiets, 27 (67.5%) patiets had resolutio of the radiological features (Thacher score 1.5) at the time of discharge. Not all childre had a radiographic assessmet o discharge, especially if they had improved cliically ad biochemically. Some were also discharged before complete healig because the cliical ad biochemical respose had bee good. At follow-up i the phosphopaeic group, seve (18%) had resolutio of radiological features of rickets while 31 (82%) did ot show complete resolutio of radiological features. Thus, radiological healig i respose to treatmet was better i the calciopaeic group compared to the phosphopaeic group (67.5% vs 18%; p-value <0.001). Treatmet of the rickets Of the 112 patiets, 41 (37%) had bee started o treatmet prior to their referral to our cliic as show i Figure 1. Twety-five of the 41 patiets referred o treatmet had calciopaeic rickets ad the remaiig 16 had phosphopaeic rickets. Of the 16 patiets with phosphopaeic rickets, 50% (8) were beig treated as calciopaeic rickets o vitami D at the time of referral. Discussio Although the curret literature o rickets does highlight the saliet features ad maagemet of the various forms of rickets, this study provides a overview of the differeces betwee calciopaeic ad phosphopaeic rickets so that these patiets ca be more easily recogised early i the disease process ad thereafter treated or referred to a tertiary cetre for further maagemet if warrated. This retrospective study compares a almost equal umber of calciopaeic ad phosphopaeic patiets (52.7% vs 47.3%) presetig to the Paediatric Metabolic Boe Disease Cliic at CHBAH betwee 2006 ad The majority of patiets were referred by paediatricias (36.6%), peripheral hospitals (33%) ad by the orthopaedic surgeos withi the hospital s major referral area. The prepoderace of female patiets i the hypophosphataemic group (66% female) is i keepig with the majority of patiets i that group beig diagosed with X-liked hypophosphataemic rickets, 42% of whom had a family history. These fidigs are similar to studies from the Republic of Korea ad orth Idia, 5,12 which foud a greater umber of female patiets (82% ad 70.5% respectively) tha male patiets with hypophosphataemic rickets. I these studies, a positive family history was oted i 29% ad 35.3% respectively. I the calciopaeic group of rickets, the most commo cause of rickets was vitami D deficiecy. I the phosphopaeic group, 75% of patiets preseted with suspected X-liked hypophosphataemia (XLH) ad sporadic hypophosphataemic rickets while the remaiig 25% preseted with phosphopaeic rickets secodary to a uderlyig real tubular dysfuctio. Ulike a Idia study, i which two-thirds of patiets with refractory rickets were foud to have real tubular acidosis (RTA), the majority beig distal RTA, 13 i the preset study oly a quarter had RTA. The youger age of the calciopaeic patiets (20 moths compared to 36 moths i the phosphopaeic group) reflects the characteristically earlier age of presetatio of vitami D deficiecy rickets. As was oted i Mumbai (wester Idia), childre with vitami D deficiecy rickets or real tubular acidosis more frequetly preseted i the first 2 years of life while those with X-liked hypophosphataemic rickets after 2 years of age, 13 fidigs similar to the patters described i this study. The phosphopaeic group of childre were also more stuted tha the calciopaeic group at the time of referral (HAZ score 3.3 vs 2; p<0.001), reflectig the more chroic ature of X-liked hypophosphataemic rickets (XLH) compared to vitami D deficiecy rickets. 22 Fial diagosis: calciopaeic 30 o vitami D 8 Fial diagosis: phosphopaeic 41 treatmet started prior to referral Figure 1. Flow diagram demostrates treatmet at the time of referral of childre with suspected rickets to the Paediatric Metabolic Boe Disease cliic 8 N=112 8 o combiatio therapy Leolax, oe alpha, mist KCL ifats ad scholls solutio Fial diagosis: phosphopaeic 71 ot o treatmet prior to referral 3 o oe alpha or titralac 3 Fial diagosis: calciopaeic

6 Page 42 SA Orthopaedic Joural Summer 2016 Vol 15 No 4 The most commo cliical presetig features i both calciopaeic ad phosphopaeic groups of rickets were wideed wrists, rachitic rosary ad frotal bossig (>80% of patiets), which is similar to that reported by Solima et al. 14 who studied ifats ad youg childre with vitami D deficiecy rickets. Aother study o utritioal rickets i Keya also reported o the most commo cliical fidigs beig swellig of the wrists (89%), frotal bossig (67%) ad rachitic rosary of the chest (54%). 15 Thacher et al. screeed Nigeria childre with rickets ad foud that there were five cliical features of rickets that idepedetly predicted active rickets of which wrist ad costochodral elargemet had the highest positive predictive values for active rickets which supports the cliical fidigs of this study. 16 Surprisigly i this study, 25(OH)D levels were foud to be i the ormal rage (>50 mol/l) i the majority of childre with both types of rickets. The most likely explaatio for these apparetly iappropriate levels of 25(OH)D i the calciopaeic group is because over oe-third of patiets were o vitami D treatmet o referral. Furthermore, oly 24 of 59 patiets with calciopaeic rickets had their vitami D status assessed. Usig the Thacher scorig system, the radiological severity of rickets at presetatio was similar i the two groups, but at the time of discharge or at 12 moths, radiological healig was less evidet i the phosphopaeic group tha the calciopaeic group (18% vs 67.5%; p-value <0.001). These fidigs suggest that the majority of patiets with phosphopaeic rickets do ot heal completely with therapy. This fidig highlights the chroic ature of the uderlyig causes of phosphopaeic rickets ad helps differetiate the two types of rickets. The retrospective ature of this study has limitatios, as ot all relevat data could be traced. Furthermore, ot all cliical fidigs may have bee reported or looked for at the time of iitial assessmet, thus ifluecig the prevalece of cliical fidigs. Fially, 18 (16%) patiets at iitial cosultatio did ot have X-rays ad 34 (30%) patiets did ot have X-rays after oe year of follow-up, thus possibly ifluecig the iterpretatio of the radiographic fidigs. Coclusio I coclusio, this study highlights the differeces betwee calciopaeic ad phosphopaeic rickets, which may be of assistace to the attedig orthopaedic surgeos ad paediatricias i the maagemet of rickets. The study shows that i childre with calciopaeic rickets, the majority are vitami D deficiet, ad preset at a youger age with craiotabes ad less severe lower limb deformities compared to childre with phosphopaeic rickets who maily have X-liked hypophosphataemic rickets ad are severely short i stature ad have geu valgum deformities. The medical maagemet of the two types of rickets differs ad respose to medical therapy is better i the calciopaeic compared to the phosphopaeic group. Compliace with ethics guidelies Drs F Agaba, JM Pettifor ad K Thadraye have o coflicts of iterest to declare. This study was self-fuded ad thus there is o eed for disclosure of fudig by the authors. The study was approved by the Huma Research Ethics Committee (HREC) of the Uiversity of the Witwatersrad (approval umber M130225). Permissio from the Chief Executive Officer at CHBAH was obtaied to coduct the study. Refereces 1. Pettifor JM. Nutritioal rickets: deficiecy of vitami D, calcium, or both? Am J Cli Nutr. 2004;80(6 Suppl):1725S-9S. 2. Pettifor JM. Nutritioal rickets i developig coutries. Forum Nutr. 2003;56: Pettifor JM, Thadraye K. Rickets ad metabolic boe disorders. I: Gree RJ, editor. Coovadia s paediatrics ad child health. 7th ed. South Africa: Oxford Uiversity Press Souther Africa Limited; 2014: Jagtap VS, Sarathi V, Lila AR, Badgar T, Meo P, Shah NS. Hypophosphatemic rickets. Idia J Edocriol Metab. 2012;16(2): Bhadada SK, Bhasali A, Upreti V, Dutta P, Satosh R, Das S, et al. Hypophosphataemic rickets/osteomalacia: a descriptive aalysis. Idia J Med Res. 2010;131: Tezer H, Siklar Z, Dallar Y, Dogakoc S. Early ad severe presetatio of vitami D deficiecy ad utritioal rickets amog hospitalized ifats ad the effective factors. Turk J Pediatr. 2009;51(2): Naude CE, Carey PD, Laubscher R, Fei G, Seekal M. Vitami D ad calcium status i South Africa adolescets with alcohol use disorders. Nutriets. 2012;4(8): Pettifor JM. Calcium ad vitami d metabolism i childre i developig coutries. A Nutr Metab. 2014;64 Suppl 2: Holm IA, Ecos MJ, Carpeter TO. Familial hypophosphatemia ad related disorders. I: Glorieux FH, Pettifor JM, Jupper H, editors. Pediatric boe: biology ad diseases. Lodo: Elsevier; 2012: Liglart A, Biosse-Dupla M, Briot K, Chaussai C, Esterle L, Guillaume-Czitrom S, et al. Therapeutic maagemet of hypophosphatemic rickets from ifacy to adulthood. Edocr Coect. 2014;3(1):R Thacher TD, Fischer PR, Pettifor JM, Lawso JO, Maaster BJ, Readig JC. Radiographic scorig method for the assessmet of the severity of utritioal rickets. J Trop Pediatr. 2000;46(3): Cho HY, Lee BH, Kag JH, Ha IS, Cheog HI, Choi Y. A cliical ad molecular geetic study of hypophosphatemic rickets i childre. Pediatr Res. 2005;58(2): Joshi RR, Patil S, Rao S. Cliical ad etiological profile of refractory rickets from wester Idia. Idia J Pediatr. 2013;80(7): Solima A, De Sactis V, Adel A, El Awwa A, Bedair S. Cliical, biochemical ad radiological maifestatios of severe vitami d deficiecy i adolescets versus childre: respose to therapy. Georgia Med News. 2012(210): Edwards JK, Thiogo A, Va de Bergh R, Kizito W, Kosgei RJ, Sobry A, et al. Prevetable but eglected: rickets i a iformal settlemet, Nairobi, Keya. Public Health Actio. 2014;4(2): Thacher TD, Fischer PR, Pettifor JM. The usefuless of cliical features to idetify active rickets. A Trop Paediatr. 2002;22(3): This article is also available olie o the SAOA website ( ad the SciELO website ( Follow the directios o the Cotets page of this joural to access it. SAOJ