Disorders of Renal Phosphate Transport

Disorders of Renal Phosphate Transport

Myra L. Chiang

Phosphorus plays a critical role in skeletal development, mineralization, and cellular functions. The kidney regulates phosphate homeostasis by tubular reabsorption of filtered phosphates (TRP) and by 1-alpha-hydroxylation of calcidiol into the active form, 1,25-dihydroxyvitamin D3 (calcitriol). Genetic defects that lead to renal phosphate wasting and abnormal vitamin D metabolism and function are the most common causes of inherited rickets (Table 336.1).


X-linked hypophosphatemic rickets (XLHR) is the most common type of hereditary rickets, with an incidence of 1 in 20,000 births. It is characterized by rachitic bone disease, hypophosphatemia, phosphaturia caused by reduced activity of the
renal brush-border membrane sodium-phosphate cotransporter in the proximal tubule, and abnormal regulation of the renal 1-alpha-hydroxylase activity resulting in an inappropriately low serum concentration of 1,25-dihydroxyvitamin D3, relative to the degree of hypophosphatemia. Although the disease is completely penetrant, substantial interfamilial and intrafamilial variations in severity of disease exist. Male and female patients appear to be affected similarly despite the X-linked dominant inheritance.


  Primary Defect Gene Locus
Phosphopenic rickets
X-linked hypophosphatemia Mutations in PHEX Chromosome Xp22.1
Autosomal dominant hypophosphatemia Mutations in FGF23 Chromosome 12p13
Hereditary hypophosphatemic rickets with hypercalciuria ? ?
Calcipenic rickets
Vitamin D–dependent type 1 Mutations in 1-alpha-hydroxylase Chromosome 12q14
Vitamin D–dependent type 2 Mutations in vitamin D receptor ?
?, Unknown.


Functional studies indicate that the tubular defect and impaired synthesis of calcitriol in patients with XLHR are probably related to a circulating phosphaturic substance rather than an intrinsic defect in the kidney. A primary osteoblast abnormality also may exist. The gene responsible for XLHR was mapped to chromosome Xp22.1 and was named PHEX (phosphate regulating gene with homologies to endopeptidases on the X chromosome). PHEX is expressed predominantly in bones and teeth. Mutations in the PHEX gene cause decreased degradation of the hormone-like substances called phosphatonins, leading to abnormally high circulating concentrations of these factors and consequent renal phosphate wasting and abnormal mineralization.


Type Calcium Phosphate Alkaline Phosphatase Parathyroid Hormone 25-(OH)D3 1,25-(OH)2D3 Urine Calcium
Vitamin D–deficient ↓ or N ↓ or N ↓ or N ↓ or N
Vitamin D–dependent type 1 ↓ or N ↑↑ N ↓↓
Vitamin D–dependent type 2 ↓ or N ↑↑ N ↑↑
X-linked hypophosphatemia N ↓↓ N N N or ↓
Hereditary hypophosphatemic rickets with hypercalciuria N ↓↓ N or ↓ N
↑, increased; ↓, decreased; N, normal.

Clinical and Radiologic Findings

During early infancy, patients with XLHR appear to be clinically normal, although frontal bossing may be present. As the child begins to walk, bowing of the lower extremities becomes evident. Because of genu varum and coxa vara, patients walk with a waddling gait. Occasionally, genu valgum instead of genu varum is observed. Spontaneous periapical tooth abscesses associated with defective dentin formation develop with advancing age. Craniotabes, rachitic rosary, and deformity of the upper extremities occur less frequently than in vitamin D–deficient or vitamin D–dependent rickets. In addition, patients with XLHR do not have tetany and severe myopathy, which may occur in the other two forms of rickets. Growth retardation is marked in untreated male patients, who seldom reach a height of 5 feet. Bone pain, degenerative joint disease, and dental problems extend into the patient’s adult life. Continuing treatment seems to ameliorate some of these symptoms.

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Jul 24, 2016 | Posted by in ORTHOPEDIC | Comments Off on Disorders of Renal Phosphate Transport
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