GARY MATTHEW KIEBZAK, Marquette University


X-linked hypophosphatemia (XLH) is the most common form of vitamin D-resistant rickets. Transmission of this human disease is by X-linked dominant inheritance. XLH is characterized by elevated renal excretion of phosphate, low plasma phosphate (hypophosphatemia) and osteomalacic bone disease. There is no cure for XLH because the etiology of this disease is poorly understood. That is, the primary defect responsible for the elevated renal excretion of phosphate is unknown. Experiments designed to investigate the etiology of XLH became possible in 1976, after the introduction of the mutant XLH (Hyp) mouse (E. Eicher, et al., Proc. Natl. Acad. Sci. USA 73: 4667). Initial work in our laboratory was devoted to more fully characterizing the Hyp mice in order to determine how closely the disease in mice resembled the disease in humans. Hyp mice were found to have elevated renal excretion of phosphate and urinary cAMP, hypophosphatemia, slight hypocalcemia and osteomalacic bone disease. No major deviations from the human disease were found. Among the experiments subsequently performed were studies designed to determine the role of parathyroid hormone (PTH) and calcitonin (CT) in XLH. Essentially, the question being asked was whether PTH and CT were responsible for the elevated phosphate excretion and hypophosphatemia. Two existing hypotheses suggested that the elevated phosphate excretion in XLH is caused by renal hypersensitivity to PTH and/or CT. Since osteomalacic bone may be resistant to the calcemic action of PTH, and possibly CT, it was therefore conceivable that Hyp mice were characterized by both renal hypersensitivity and skeletal resistance to PTH and/or CT. Assuming a classical approach to my research, I performed experiments in which the endogenous source of PTH and CT was removed by thyroparathyroidectomy (TPTX). These studies were followed by experiments in which the response to exogenous PTH and CT was observed in intact and TPTX mice. The major results are as follows. First, no abnormal renal response to PTH or CT was observed. This suggested that renal hypersensitivity to PTH or CT has no role in the etiology of XLH. Second, the PTH- and CT-independent component of renal phosphate and cAMP excretion was significantly elevated in Hyp mice compared to normals after TPTX. This suggested the presence of an intrinsic phosphate transport defect in Hyp mice. Third, Hyp mice were found to display skeletal resistance to PTH. This skeletal resistance could be the cause of the slight hypocalcemia in Hyp mice. The hypocalcemia would cause secondary hyperparathyroidism. Subsequent experiments confirmed that intact Hyp mice did in fact have significantly elevated plasma PTH. Based on the experiments performed in our laboratory, we conclude that Hyp mice are characterized by elevated PTH- and CT-independent renal excretion of phosphate, and secondary hyperparathyroidism.

Recommended Citation

KIEBZAK, GARY MATTHEW, "X-LINKED HYPOPHOSPHATEMIA - THE MOST COMMON FORM OF VITAMIN D RESISTANT RICKETS" (1981). Dissertations (1962 - 2010) Access via Proquest Digital Dissertations. AAI8203768.