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X-Linked Hypophosphatemia (XLH) is characterized by impaired renal phosphate reabsorption and diminished Vitamin-D metabolism. In addition, intestinal calcium and phosphate absorption is also impaired.

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Familial Hypophosphatemia; Hypophosphatemic Vitamin D-Resistant Rickets type I; X-Linked Vitamin D-Resistant Rickets; Hereditary Hypophosphatemia type I; Phosphate Diabetes.

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XLH is the most common form of rickets in industrialized countries. It affects males and females in equal numbers; however, males are usually more severely affected than females. Worldwide approximately 1 in 20,000 live births suffers from the disease.

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In most cases, XLH is inherited as a dominant X-linked trait. However, autosomal dominant and recessive traits have also been reported. The X-linked defect seems to be the result of a mutation in the PHEX (X-linked phosphate regulating endopeptidase homolog) gene and has been mapped to Xp22.2-22.1. The autosomal dominant form of familial hypophosphatemia (sometimes associated with decreased glucose tolerance) seems to be caused by a mutation of gene 12p13.3.

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The two pathogenetic mechanisms involved in this disorder are the failure of the proximal renal tubule to reabsorb phosphate and to convert calcidiol (25-hydroxy-cholecalciferol) to calcitriol (1,25-dihydroxy-choleclaciferol). The defect is characterized by low calcium serum levels in combination with hypophosphatemia not resulting in increased levels of calcitriol. Decreased concentration of inorganic phosphate leads to osteomalacia secondary to impaired function of osteoblasts, since mature bone formation requires the precipitation of hydroxyapatite, which has a high phosphate content (chemical formula {Ca[Ca3(PO4)2]3} 2+· 2 OH-).

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In the absence of a family history of XLH, the diagnosis is made clinically. Nevertheless, the diagnosis is sometimes difficult. This is especially true in the first year of life, since the phosphate levels may be normal even in an infant with an affected parent. In addition, the range of normal serum phosphorus levels in children is significantly higher than in adults. Abnormal bowing of the long bones is usually the first sign, but does not appear before 12 to 18 months of age. Elevated serum alkaline phosphatase levels (often the first laboratory sign), mild hypocalcemia, and moderate hypophosphatemia with significant hyperphosphaturia in the absence of severe secondary hyperparathyroidism are typical. Serum calcitriol levels are inappropriately normal. In contrast to Hereditary Vitamin D-Resistant Rickets (HVDRR), aminoaciduria and bicarbonaturia are not present.

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The clinical signs of XLH are quite variable. Major symptoms of XLH include skeletal malformations, bone pain, abnormally bowed legs (see below), and generalized, but usually mild muscle weakness. Affected infants may experience failure to thrive resulting in low weight and a short, stocky stature (with an adult height of usually less than 165 cm). However, most often the symptoms appear at the age of 12 to 18 months and affected infants show a waddling gait, bowing of the legs with coxa vara, genua vara or genus valga (all secondary to the weight-bearing function). Dolichocephaly, Arnold-Chiari Syndrome, and sensorineural hearing loss ...

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