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The molecular background to hypophosphataemic rickets
  1. P S N ROWE
  1. Royal Free and University College Medical School, Department of Biochemistry and Molecular Biology, Centre for Molecular Osteo-Renal Research, Rowland Hill Street, Hampstead, London NW3 2PF, UK
  1. Dr Rowe email: p.rowe{at}rfc.ucl.ac.uk

https://doi.org/10.1136/adc.83.3.192

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    Bone mineral loss disorders are major, worldwide health concerns, and can be familial, idiopathic, oncogenic, dietary, or hormonal. The mechanisms controlling bone integrity are complex. Extensive research has been directed towards the characterisation of the key factors involved in bone mineral regulation and two specific bone diseases, X-linked hypophosphataemic rickets (HYP) and oncogenic hypophosphataemic osteomalacia (OHO). The primary defect in HYP is a defective zinc metalloendopeptidase (PHEX),1-4 and a new candidate glycoprotein (MEPE) has been proposed as the phosphaturic factor released by OHO tumours.5 ,6 Both diseases cause severe changes in bone morphology and have an overlapping pathophysiology. This review will discuss the recent molecular advances in our understanding of the role of the kidney and other organs in bone mineral homeostasis, with emphasis on X-linked hypophosphataemic rickets and tumour osteomalacia.

    Clinical features of HYP and tumour osteomalacia

    Classic, vitamin D resistant HYP(MIM #307800), is characterised by:

    • Hypophosphataemia

    • Renal phosphate leak as expressed as a lowered transfer maximum of phosphate per unit volume of glomerular filtrate (TMPO4/GFR)

    • Inappropriate vitamin D metabolism in the presence of low serum phosphate (low to normal serum 1,25 dihydroxy vitamin D3; calcitriol)

    • High alkaline phosphatase

    • Skeletal defects.7

    OHO shares many clinical, biochemical, and physiological features with HYP.8 ,9 The tumours are mainly of mesenchymal origin, although a number of different tumour types have been reported.10 ,11 Evidence indicates that changes in renal phosphate handling, vitamin D metabolism, and skeletal mineralisation are caused by factor(s) secreted by OHO tumours.8-10 12-19 The resection of OHO tumours results in the disappearance of disease symptoms and bone healing and is a key observation that supports this.8 ,12 ,20

    Cloning of the rickets gene

    The rickets gene PHEX (phosphate regulating gene with endopeptidase activity on the X chromosome),1 ,2 is a zinc metalloendopeptidase with close homologies to an …

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