Treatment of ear and bone disease in the Phex mouse mutant with dietary supplementation.

HYPOTHESIS: Phosphorus and vitamin D (calcitriol) supplementation in the Phex mouse, a murine model for endolymphatic hydrops (ELH), will improve otic capsule mineralization and secondarily ameliorate the postnatal development of ELH and sensorineural hearing loss (SNHL). BACKGROUND: Male Phex mice have X-linked hypophosphatemic rickets (XLH), which includes osteomalacia of the otic capsule. The treatment for XLH is supplementation with phosphorus and calcitriol. The effect of this treatment has never been studied on otic capsule bone and it is unclear if improving the otic capsule bone could impact the mice's postnatal development of ELH and SNHL. METHODS: Four cohorts were studied: 1) wild-type control, 2) Phex control, 3) Phex prevention, and 4) Phex rescue. The control groups were not given any dietary supplementation. The Phex prevention group was supplemented with phosphorus added to its drinking water and intraperitoneal calcitriol from postnatal day (P) 7-P40. The Phex rescue group was also supplemented with phosphorus and calcium but only from P20 to P40. At P40, all mice underwent auditory brainstem response (ABR) testing, serum analysis, and temporal bone histologic analysis. Primary outcome was otic capsule mineralization. Secondary outcomes were degree of SNHL and presence ELH. RESULTS: Both treatment groups had markedly improved otic capsule mineralization with less osteoid deposition. The improved otic capsule mineralized did not prevent the development of ELH or SNHL. CONCLUSION: Supplementation with phosphorus and calcitriol improves otic capsule bone morphology in the Phex male mouse but does not alter development of ELH or SNHL.

Refractory rickets in the tropics.

Rickets is an important problem in children. The majority of rickets in children is due to deficiency of calcium, phosphorus or vitamin D. However, rickets may also be a feature of renal diseases, e.g. renal tubular acidosis, hypophosphatemic rickets or rickets associated with renal insufficiency. The treatment varies with etiology and hence complete workup is essential before initiating therapy.

Serum parathyroid hormone in X-linked hypophosphatemia.

Serum immunoreactive parathyroid hormone(IPTH) is normal in patients with X-linked hypophosphatemic rickets who are not treated with phosphate salts. Phosphate raises IPTH in these patients. Endogenous IPTH does not influence the existing defect in tubular reabsorption of phosphate in male patients.

FGF23 and disorders of phosphate homeostasis.

It is well known that fibroblast growth factor (FGF) family members are associated with embryonic development and are critical for basic metabolic functions. This review will focus upon fibroblast growth factor-23 (FGF23) and its roles in disorders associated with phosphate handling. The discovery that mutations in FGF23 were responsible for the isolated renal phosphate wasting disorder autosomal dominant hypophosphatemic rickets (ADHR) has ascribed novel functions to the FGF family. FGF23 circulates in the bloodstream, and animal models demonstrate that FGF23 controls phosphate and Vitamin D homeostasis through the regulation of specific renal proteins. The ADHR mutations in FGF23 produce a protein species less susceptible to proteolytic processing. X-linked hypophosphatemic rickets (XLH), tumor-induced osteomalacia (TIO), and fibrous dysplasia of bone (FD) are disorders involving phosphate homeostasis that share phenotypes with ADHR, indicating that FGF23 may be a common denominator for the pathophysiology of these syndromes. Our understanding of FGF23 will help to develop novel therapies for phosphate wasting disorders, as well as for disorders of increased serum phosphate, such as tumoral calcinosis, a rare disorder, and renal failure, a common disorder.

[The Power of Phosphaturia in the Infrequent Hemodialysis]. / L'importanza della Fosfaturia nei pazienti in Emodialisi Infrequente.

INTRODUCTION: Residual renal function (RRF) and phosphaturia had not stimulated particular interest in studies regarding patients on hemodialysis. In the current year the Authors have selected a series of patients with RRF undergoing infrequent hemodialysis treatments. PURPOSE: The Authors have carried out a study of the phosphate balance in patients on infrequent hemodialysis with the hypothesis that the phosphaturia was always neglected in hemodialysis patients, but it could represent a positive impact element on the cardiovascular events and mortality in hemodialysis. METHODS: During 6 months, the Authors have conducted forty urine collections in 10 patients on twice a week hemodialysis (TWH) (age: 69,3 years, dialysis vintage: 42,7 months and 40.9 months on TWH) and eighty urine collections in 8 patients on once a week hemodialysis and low-protein diet (CDDP) (age: 69.6 years, dialysis vintage: 24.7 months and 24 months in CDDP) to determine RRF and phosphaturia. We compared the balance of phosphate compared with a thrice-weekly hemodialysis considering on phosphate removal: dialysis efficiency, phosphate-binders power on the protein- phosphates intake and the extent of phosphaturia. RESULTS: The patients on infrequent hemodialysis have demonstrated a significant share of urinary phosphate output leading to a weekly phosphoric balance equal to zero or even negative. CONCLUSIONS: The phosphoric balance in infrequent hemodialysis patients is a decisive way to remove the phosphates, confirming that this factor could be decisive on the improved survival and reduced cardiovascular mortality compared to patients receiving thrice-weekly hemodialysis. The Authors stress again the need to keep as long as possible the FRR.

Clinical benefits of phosphate control in progression of end stage renal disease.

It is largely agreed that preservation of residual kidney function (RKF) has a directly proportional affect on general, and in particular cardiovascular, mortality. During evaluation of patients on infrequent hemodialysis (ID) as both as once-weekly or twice-weekly hemodialysis it has been frequently underestimated the importance of phosphaturia, Indeed, the native kidney preserves the ability to eliminate not only toxic molecules but also a significative output of phosphate despite of a severe decrease of RKF. This task the modern membranes are as yet not very efficient of reproducing. The hemodialysis patients on ID who adhere accurately to a low protein diet of 0.6-0.8 g/kg/day could reach a draw in the balance of phosphates. In view of the significant impact produced by poor phosphate control on both RKF and the frequency of even severe cardiovascular effects, infrequent dialysis with its negative or neutral weekly phosphate balance, may constitute a valid "bridging" treatment even in the long-term, thus explaining the improved survival rates compared to patients receiving conventional triweekly hemodialysis.

Partial rescue of the Hyp phenotype by osteoblast-targeted PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) expression.

Inactivating mutations and/or deletions of PHEX/Phex (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) are responsible for X-linked hypophosphatemic rickets in humans and in the murine homolog Hyp. The predominant osteoblastic expression of Phex has implicated a primary metabolic osteoblast defect in the pathophysiology of this disorder. By targeting PHEX expression to osteoblasts in the Hyp genetic background, we aimed to correct the corresponding biochemical and morphological abnormalities and obtain information on their pathogenetic mechanism. When transgene Phex expression, driven by a mouse pro-alpha1(I) collagen gene promoter, was crossed into the Hyp background, it improved the defective mineralization of bone and teeth but failed to correct the hypophosphatemia and altered vitamin D metabolism associated with the disorder. Ex vivo bone marrow cultures confirmed the amelioration in the Hyp-associated matrix mineralization defect after Phex expression. These findings suggest that while the Hyp bone and teeth abnormalities partially correct after PHEX gene transfer, additional factors and/or sites of PHEX expression are likely critical for the elaboration of the appropriate molecular signals that alter renal phosphate handling and vitamin D metabolism in this disorder.

Evaluation of stature development during childhood and adolescence in individuals with familial hypophosphatemic rickets.

This review was conducted to study the diagnosis, treatment, and growth progression in infants and adolescents with familial hypophosphatemic rickets. The bibliographic search was carried out utilizing the electronic databases MEDLINE, OVID, and LILACS and by direct research within the last 15 years using the keywords rickets, familial hypophosphatemia, vitamin D deficiency, stature growth, childhood, and adolescence. Article selection was done by comparing the evaluation of the growth in patients with familial hypophosphatemic rickets, including the variables that might affect them, for possible future therapeutic proposals. It is concluded that the most significant fact in the treatment of familial hypophosphatemic rickets in infancy was the magnitude of the final stature. The use of growth hormone can be helpful in these patients. However, research reporting treatments with the use of the growth hormone for rickets are controversial. The majority of the authors agree that treatment using vitamin D and phosphate enables some statural growth in cases of early diagnosis, reflecting a better prognosis.

[Hereditary hypophosphatemia in adults]. / Hypophosphatémies génétiquement déterminées chez l'adulte.

Hereditary hypophosphatemic rickets groups together X-linked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets (ADHR) and hereditary hypophosphatemic rickets with hypercalciuria (HHRH, autosomal recessive). Clinical and biological characteristics and treatment depend on specific etiology. Mutations causing hereditary hypophosphatemic rickets involve PHEX located on Xp11.22 for XLH and FGF-23 located on 12p13 for ADHR. The gene involved in HHRH remains unknown: candidates may encode proteins that modulate phosphate transporter expression or activity. Others forms of rickets must be ruled out: acquired hypophosphatemia due to oncogenic osteomalacia, X-linked recessive hypophosphatemic rickets or Dent's disease, and hereditary 1, 25-dihydroxyvitamin D-resistant rickets with a defect either in the 1-alpha-hydroxylase gene (pseudo-vitamin D deficiency rickets, PDDR) or in the vitamin D receptor (hereditary vitamin D-resistant rickets, HVDRR).

Hypophosphatemic rickets accompanying congenital microvillous atrophy.

This report concerns an 11-year-old boy who manifested hypophosphatemic rickets associated with congenital microvillous atrophy (CMA). He had been suffering from vomiting and severe diarrhea from the first day of life and had been treated with total parenteral nutrition (TPN) since he was 67 days old. At 4 years of age, intestinal biopsy resulted in a diagnosis of CMA. He was admitted to our hospital complaining of leg pain at the age of 11. Laboratory data revealed hypophosphatemia, elevated serum 1, 25-dihydroxyvitamin D (1,25(OH)2D) levels, and hypercalciuria. A roentgenogram showed rickets in the extremities. A balance study of phosphate in urine and stool indicated that the amount of phosphate leaking into the stool was greater than that into the urine. Moreover, the total amount of phosphate leaking from both the intestine and kidney exceeded the amount of phosphate intake from TPN. The rickets was healed by increasing the phosphate concentration in TPN. This case is different from X-linked hypophosphatemic rickets but similar to hereditary hypophosphatemic rickets with hypercalciuria (HHRH) in terms of hypercalciuria and elevated serum 1,25(OH)2D levels. The effectiveness of phosphate treatments used here is also similar to that used for HHRH. However, this type of hypophosphatemic rickets is unique in that phosphate leaking into the intestine plays an important role in its pathogenesis.