Effect of phosphate supplementation on the expression of the mutant phenotype in murine X-linked hypophosphatemic rickets.

The X-linked Hyp mouse, a murine homologue of X-linked hypophosphatemia in humans, is characterized by rachitic bone disease, hypophosphatemia, impaired renal brush-border membrane Na(+)-phosphate cotransport and abnormal regulation of renal vitamin D metabolism. We demonstrated that short-term phosphate supplementation decreases renal 1,25-dihydroxyvitamin D3 (1,25-(OH)2D) catabolism and increases serum 1,25-(OH)2D levels in Hyp mice (Tenenhouse & Jones 1990). In the present study, we compared several other parameters in normal and Hyp mice fed control (1%) and high (1.6%) phosphate diets for 4 days. Phosphate supplementation significantly raised serum phosphate levels and decreased renal brush-border membrane Na(+)-phosphate but not Na(+)-glucose, cotransport in both genotypes (67% of control diet, p < 0.05). However, under both dietary conditions, the phosphate/glucose transport ratio was significantly reduced in Hyp mice (58% of normal littermates, p < 0.05). Renal PTH-stimulated cAMP accumulation, which was significantly blunted in Hyp mice compared to normal mice under control dietary conditions (p < 0.05), was not altered by phosphate supplementation in either genotype. Serum alkaline phosphatase activity was significantly higher than normal in Hyp mice on the control diet and was further increased in mutants but not in normals fed the high phosphate diet (p < 0.05). Measurements of serum bilirubin and electrophoresis of serum alkaline phosphatase suggested that the elevation in serum alkaline phosphatase activity in phosphate-supplemented Hyp mice represents the bone-derived isozyme.(ABSTRACT TRUNCATED AT 250 WORDS)

[The clinical relevance of phosphorus and calcium in infant nutrition]. / Klinische Relevanz des Phosphors und Kalziums in der Säuglingsernährung.

This paper is an introduction to the clinical part of the symposium and deals with the question of whether and under which circumstances the calcium and phosphorus content in baby formula can provoke pathological conditions. In a healthy baby, high or low mineral intake is efficiently compensated for by Ca-P homeostasis. Both nutritional calcium deficiency and calcium excess are the exception with modern baby feeding practices. However, P-deficiency states resulting in phosphopenic rickets might occur in premature babies and in children with familial hypophosphatemic rickets. These two conditions should be treated and prevented by an alimentary P-supplement. On the other hand, formula with a rich P-content might be a cause of the late form of neonatal hypocalcemia. Therefore, a relatively low-phosphate formula preparation, similar to human milk, is recommended for the first 2 weeks of life of full-term newborns, as well for infants with hyperphosphatemic renal failure.

The occurrence of interglobular dentin in incisors of hypophosphatemic mice fed a high-calcium and high-phosphate diet.

The incisor dentin of hypophosphatemic (Hyp) mice was examined histopathologically to determine whether the multiple occurrences of interglobular dentin would be influenced by the serum phosphate level. Both normal and Hyp mice (12 weeks of age) were divided into two groups. The mice in one group were given a control diet (1.42% Ca, 1.16% P) and the other a high-calcium and high-phosphate diet (2.00% Ca, 3.00% P) for 30 days. Blood was collected from the mice every fifth day for measurement of the calcium and phosphate concentrations in serum. Both ground and decalcified cross-sections were prepared from incisors from the mandible and maxilla for microscopic examination. The levels of serum Ca and P were almost constant in normal mice, regardless of diet. On the other hand, serum P levels in Hyp mice fed the control diet were significantly lower than those in normal mice. The ten days' feeding of the high-Ca/-P diet significantly elevated the serum P level in Hyp mice, and it reached a level similar to that of the normal mice. However, histopathological examination showed no significant changes in incisor dentin of Hyp mice fed the high-Ca/-P diet, and interglobular dentin still occurred. These results suggest that the multiple formations of interglobular dentin, which is the most outstanding feature of X-linked hypophosphatemic vitamin-D-resistant rickets, are not influenced in Hyp mice by the short-time normalization of the serum phosphate level.

Vitamin D-resistant rickets. A prototype of nutritional management of a genetic disorder.

The discovery of the vitamin D endocrine system has opened up many possibilities in our understanding of metabolic bone disease. Of particular importance is the fact that we can now manage certain genetic disorders resulting in vitamin D-resistant rickets or vitamin D-resistant hypocalcemia with the new active hormonal forms of vitamin D and with intelligent dietary management to provide for correction of the mineral difficulty. Thus, in the case of vitamin D dependency, replacement need only be with the missing hormone, 1,25-(OH)2D3. On the other hand, familial hypophosphatemia requires adjustment of the plasma phosphorus by frequent administration of oral phosphate and the adjustment of intestinal calcium absorption by 1,25-(OH)2D3. Renal failure patients require the adjustment of plasma phosphorus concentration and parathyroid hormone status, and the administration of the missing hormone 1,25-(OH)2D3. Hypoparathyroid patients require oral calcium plus 1,25-(OH)2D3, and premature infants require administration of the 1,25-(OH)2D3 because the immature kidneys and immature parathyroid glands fail to produce the required amount of this hormone. Other vitamin D-resistant rachitic conditions cannot be discussed here for lack of space and for lack of information. Undoubtedly, such patients as those having rickets secondary to renal tubular acidosis and rickets secondary to hepatic disorders will eventually come under effecti dietary and hormonal management. In this sense, the vitamin D endocrine system and vitamin D-resistant rickets can serve as a prototype of management of a genetic disorder by dietary means.

Sodium chloride restriction and extracellular fluid volume contraction in hyperphosphatiuric vitamin D resistant rickets in the Lowe syndrome.

A patient with a Lowe syndrome was observed from birth. Progressive hyperchloraemic renal tubular acidosis, hypophosphataemia, hyperphosphaturia and generalized hyperaminoaciduria had developed in infancy. Supplementary vitamin D, alkali and a high intake of dietary phosphate were unsuccessful in controlling the severe phosphate diabetes and rickets. Contraction of the extracellular fluid volume by dietary sodium restriction resulted in correction of the acidosis, hypophosphataemia, hyperaminoaciduria, and hyperphosphaturia, and healing of the rickets.