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      Novel SLC34A3 mutation causing hereditary hypophosphataemic rickets with hypercalciuria in a Gambian family

      a , * , b , a , c

      Bone

      Elsevier Science

      HHRH, Rickets, SLC34A3, Gene mutation, Africa

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          Abstract

          Three siblings, aged 12, 4 and 2 years, presented at a Gambian clinic with bone deformities. Radiographs of knees and wrists confirmed the presence of florid rickets. The family (including 2 unaffected siblings and the mother) were investigated for hereditary rickets.

          The three affected siblings had biochemical features of hereditary hypophosphataemic rickets with hypercalciuria (HHRH) with normal plasma calcium and 25-hydroxyvitamin D concentrations, elevated 1,25-dihydroxyvitamin D, hypophosphataemia, hyperphosphaturia and hypercalciuria. At presentation, two of the three affected siblings had an elevated fibroblast growth factor-23 (FGF23) concentration. The mother and clinically unaffected siblings had largely normal biochemistry.

          Genetic analysis of the SLC34A3 gene, encoding the type IIc sodium-phosphate cotransporter, in DNA samples from the siblings and their mother was conducted. Three single nucleotide polymorphisms (SNPs) S168F, E513V and L599L were identified. E513V and L599L had been previously identified as benign polymorphisms. S168F however, is a previously unreported variant. In silico mutation evaluation predicted that the S168F mutation causes changes in the protein product which are damaging to its function. In addition, the three clinically affected siblings were homozygous in the S168F variant whereas the unaffected family members were carriers.

          This study describes a biochemical profile and complementary gene data consistent with a rare genetic hypophosphataemic rickets disease in a family from rural Gambia. To our knowledge, this study reports the first cases of HHRH in Africa and describes a novel causal mutation within the SLC34A3 gene.

          Highlights

          ► A Gambian family of 5 children where 3 siblings had florid rickets with suspected HHRH ► Biochemical profile of hypophosphataemia with elevated urinary phosphate and calcium excretion. ► Genetic analysis of the SLC34A3 gene indicated a novel mutation of S168F. ► The siblings with rickets were homozygous in S168F, the unaffected siblings were carriers. ► We report the first cases of hereditary hypophosphataemic rickets with hypercalciuria in Africa.

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          Most cited references 6

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          Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice.

          Autosomal dominant hypophosphatemic rickets (ADHR) is unique among the disorders involving Fibroblast growth factor 23 (FGF23) because individuals with R176Q/W and R179Q/W mutations in the FGF23 (176)RXXR(179)/S(180) proteolytic cleavage motif can cycle from unaffected status to delayed onset of disease. This onset may occur in physiological states associated with iron deficiency, including puberty and pregnancy. To test the role of iron status in development of the ADHR phenotype, WT and R176Q-Fgf23 knock-in (ADHR) mice were placed on control or low-iron diets. Both the WT and ADHR mice receiving low-iron diet had significantly elevated bone Fgf23 mRNA. WT mice on a low-iron diet maintained normal serum intact Fgf23 and phosphate metabolism, with elevated serum C-terminal Fgf23 fragments. In contrast, the ADHR mice on the low-iron diet had elevated intact and C-terminal Fgf23 with hypophosphatemic osteomalacia. We used in vitro iron chelation to isolate the effects of iron deficiency on Fgf23 expression. We found that iron chelation in vitro resulted in a significant increase in Fgf23 mRNA that was dependent upon Mapk. Thus, unlike other syndromes of elevated FGF23, our findings support the concept that late-onset ADHR is the product of gene-environment interactions whereby the combined presence of an Fgf23-stabilizing mutation and iron deficiency can lead to ADHR.
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            Renal tubular reabsorption of phosphate (TmP/GFR): indications and interpretation.

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              Radiographic scoring method for the assessment of the severity of nutritional rickets.

              Radiographic changes of rickets are well characterized, but no method of grading the severity of these changes has been in general use. Consequently, it is difficult to compare objectively or follow radiographic improvement. We prospectively evaluated the utility and reproducibility of a scoring method for measuring the severity of rickets. A 10-point score for radiographs of wrists and knees was devised to assess the degree of metaphyseal fraying and cupping and the proportion of the growth plate affected. The score progresses in half point increments from zero (normal) to 10 points (severe). Four trained physicians independently scored radiographs on two separate occasions from 67 children with active rickets. A broad representation of mean radiographic scores was moderately correlated with alkaline phosphatase (r = 0.58). Interobserver correlation of radiographic scores was 0.84 or greater for all observer pairs and intraobserver correlation was 0.89 or greater for each observer. Researchers and clinicians should find the score useful to assess objectively the severity of rickets.
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                Author and article information

                Contributors
                Journal
                Bone
                Bone
                Bone
                Elsevier Science
                8756-3282
                1873-2763
                1 March 2013
                March 2013
                : 53
                : 1
                : 216-220
                Affiliations
                [a ]MRC Human Nutrition Research, Elsie Widdowson Laboratory, Cambridge, UK
                [b ]MRC/Wits Developmental Pathways for Health Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
                [c ]MRC Keneba, Keneba, West Kiang, The Gambia
                Author notes
                [* ]Corresponding author at: MRC Human Nutrition Research, Elsie Widdowson Laboratory, Cambridge, UK, CB1 9NL. Fax: + 44 1223 437515. vickie.braithwaite@ 123456mrc-hnr.cam.ac.uk
                Article
                S8756-3282(12)01410-X
                10.1016/j.bone.2012.12.003
                3557384
                23246670
                © 2013 Elsevier Inc.

                Open Access under CC BY 3.0 license

                Categories
                Case Report

                Human biology

                africa, hhrh, rickets, slc34a3, gene mutation

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