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Hereditary hypophosphatemic rickets and tumor-induced osteomalacia

INTRODUCTION

The term vitamin D-resistant rickets (VDRR) originally was used to describe a syndrome of hypophosphatemia and rickets (and/or osteomalacia) that resembled vitamin D deficiency but did not respond to vitamin D replacement or pharmacologic doses of vitamin D. Most of these cases were caused by renal phosphate wasting, leading to the alternate name of "phosphate diabetes." This disorder is now called hereditary hypophosphatemic rickets because the primary problem is phosphate wasting rather than true vitamin D resistance. True vitamin D resistance is characterized by hypocalcemia as well as hypophosphatemia and results from an inherited defect in the metabolism of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D or in the calcitriol receptor that limits the interaction with 1,25-dihydroxyvitamin D. (See "Etiology and treatment of hypocalcemic rickets in children" and "Causes of vitamin D deficiency and resistance".)

Hereditary forms of hypophosphatemic rickets include X-linked, autosomal dominant and autosomal recessive disease, as well as hypophosphatemic rickets with hypercalciuria. The X-linked form is most common; the other forms are rare, with fewer than 100 reported cases. An acquired disorder, tumor-induced (or oncogenic) osteomalacia, has similar clinical manifestations to the familial syndromes. In addition to hypophosphatemia, these disorders all have normal serum levels of calcium and parathyroid hormone. Most of these disorders also have high circulating levels of fibroblast growth factor 23 (FGF23), a circulating hormone that causes renal phosphate wasting and is a common final pathway (graph 1).

The etiology and treatment of hereditary hypophosphatemic rickets and tumor-induced osteomalacia will be reviewed here. The clinical manifestations and evaluation of rickets and osteomalacia are discussed separately. (See "Overview of rickets in children" and "Clinical manifestations and etiology of osteomalacia".)

X-LINKED

X-linked hypophosphatemic rickets (XLH) is a dominant disorder with a prevalence of approximately one case per 20,000 live births [1,2].

Pathogenesis — The pathogenesis of X-linked hypophosphatemic rickets is not fully understood. A number of functional studies indicate that the tubular defect in patients with XLH and in the corresponding mouse model (Hyp mouse) is caused by one or more circulating factors rather than by a defect in the kidney [3,4]. Because these circulating factors promote phosphate excretion and impair bone mineralization, they have been termed "phosphatonins" or "minhibins" [5].
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