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PubMed2001

A new approach to mRNA in proximal tubule cells of patients with CLCN5 channelopathy.

ClC-5 is a chloride channel whose gene mutations have been reported to be associated with X-linked nephrolithiasis (XRN), X-linked recessive hypophosphatemic rickets (XLRH), Dent disease, and idiopathic low-molecular-weight proteinuria (ILMWP) in Japanese children. To establish more efficient screening for CLCN5 abnormalities, we developed a new diagnostic method using reverse transcription and polymerase chain reaction (RT-PCR) of cultured renal tubular cells from the urine of patients. Using this new method, we successfully detected microdeletion of ClC-5 mRNA in a patient and splicing abnormality of the CLCN5 Cl channel.

Cells, Cultured↗
PubMed2000

Renal Fanconi syndrome: first sign of partial respiratory chain complex IV deficiency.

A 2-year-old boy who developed hypophosphatemic rickets without signs of muscular weakness or neurological disturbances is presented. Biochemical findings included hypophosphatemia, metabolic acidosis, hypouricemia, hyperphosphaturia, severe glucosuria, generalized hyperaminoaciduria, hypercalciuria, proteinuria with elevated excretion of IgG, transferrin, albumin and high levels of alpha-1-microglobulin. Urine concentration capacity and creatinine clearance were normal. Lactaturia without elevated levels of plasma lactate and a high urinary excretion of beta-hydroxybutyrate were suggestive for mitochondriopathy. Partial deficiency of cytochrome c oxidase (complex IV of the respiratory chain) was found in skeletal muscle. A renal biopsy specimen demonstrated enlarged mitochondria with abnormal arborization and disorientation of the cristae in the proximal tubular cells. Reduced activity of mitochondrial cytochrome c oxidase in tubular cells could be demonstrated by ultracytochemistry. In conclusion, rickets due to the renal Fanconi syndrome can be the first clinical sign of mitochondrial cytopathies without extra-renal symptoms. Elevated excretion of lactate and ketone bodies in urine may serve as a diagnostic marker.

Child, Preschool↗
PubMed2005

Surgical treatment of femoral bending deformity in a patient with vitamin D-resistant rickets.

Surgical treatment of patients with vitamin D-resistant rickets is reserved for management of severe deformities or pathological fractures of the lower limbs. This case report describes the operative management of a child with vitamin D-resistant rickets suffering from a pathological fracture and a bending deformity of the right femoral bone. A modified technique of fragmentation and realignment by intramedullary fixation was performed using an unreamed humerus nail. We corrected the anatomical proximal femoral shaft angle (aMPFA) from 68 degrees to 84 degrees and achieved three more centimetres of femoral length. The same procedure was performed on the left femur and corrected the aMPFA from 108 degrees to 89 degrees and gained 2.5 more centimetres of femoral length. Thus the legs were almost equal in length. We preferred the modified technique of multiple osteotomies and intramedullary fixation by nailing (originally described by Sofield and Millar) because the correction of angulation and rotation of the femoral shaft in one step appeared to be much easier than with plate fixation. Moreover, this method seems to reduce the number of refractures and enables the patients to approach the normal activities of growing children.

Adolescent↗
PubMed2005

The role of fibroblast growth factor 23 for hypophosphatemia and abnormal regulation of vitamin D metabolism in patients with McCune-Albright syndrome.

McCune-Albright syndrome (MAS) is sometimes complicated by hypophosphatemia and abnormally low levels of 1,25(OH)(2)D in the presence of hypophosphatemia. Recently, fibroblast growth factor 23 (FGF-23) was reported as a phosphaturic and a causal factor of abnormal vitamin D metabolism. This abnormal phosphate and vitamin D metabolism is well known to be found in oncogenic and X-linked hypophosphatemia. We furthermore reported increased circulating plasma FGF-23 levels in patients with oncogenic and X-linked hypophosphatemia. To determine whether FGF-23 may be involved in the pathogenesis of MAS, we measured plasma FGF-23 levels in six MAS patients. As a control for hypophosphatemia, we also investigated the plasma FGF-23 levels in two patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH). We also investigated the correlation of plasma FGF-23 levels with serum phosphate and 1,25(OH)(2)D levels after short-term pamidronate therapy in three MAS patients. Plasma FGF-23 levels were significantly increased in patients with MAS compared to normal controls, whereas they were not increased in HHRH patients. Serum phosphate levels of the MAS patients were significantly lower than those observed in normal controls. Plasma FGF-23 levels showed significant negative correlation with serum phosphate concentrations. In three MAS patients, pamidronate therapy decreased plasma FGF-23 levels, which showed significant negative correlation with serum 1,25(OH)(2)D concentrations. These data suggested that FGF-23 is a possible causal factor for hypophosphatemia and abnormal vitamin D metabolism in MAS.

Adolescent↗
PubMed2005

Comparison of two assays for fibroblast growth factor (FGF)-23.

FGF-23 was recently shown to be involved in the development of several hypophosphatemic diseases, including X-linked hypophosphatemic rickets/osteomalacia (XLH) and tumor-induced rickets/osteomalacia (TIO). FGF-23 is processed between Arg179 and Ser180, and only full-length FGF-23 was shown to cause hypophosphatemia. Two assays for FGF-23 have been reported. One assay detects only full-length FGF-23. In contrast, the C-terminal assay recognizes both full-length and processed C-terminal fragment of FGF-23. However, discrepant results concerning circulatory levels of FGF-23 in patients with TIO and XLH have been reported using these two assays. We simultaneously measured FGF-23 levels in 13 patients with adult-onset hypophosphatemic osteomalacia and 29 patients with XLH by these two assays. The full-length assay indicated that FGF-23 was above the upper limit of the reference range in all patients with osteomalacia and in 24 of 29 patients with XLH. However, the C-terminal assay in dicated that FGF-23 was within the reference range in 3 of 13 patients with osteomalacia and 16 of 29 patients with XLH. In addition, there was no correlation between FGF-23 levels measured by these assays in patients with XLH whose FGF-23 was within the reference range by C-terminal assay. These results indicate that FGF-23 within the reference range by C-terminal assay does not rule out an increase in full-length FGF-23. In addition, because FGF-23 was high in most of these hypophosphatemic patients, these results support the notion that FGF-23 plays a major role in the development of hypophosphatemia in patients with TIO and XLH.

Adolescent↗
PubMed2001

Hypophosphatemic rickets accompanying McCune-Albright syndrome: evidence that a humoral factor causes hypophosphatemia.

McCune-Albright syndrome (MAS) is sometimes complicated by hypophosphatemia. However, it remains unclear whether a humoral factor is associated with the cause of hypophosphatemia. We isolated cells with mutations of the Gsalpha gene from fibrous bone dysplasia tissues of two MAS patients (MAS cells). Severe combined immunodeficiency (SCID) mice were subjected to experiments using from one of these cells patients. Effects of conditioned media (CM) isolated from MAS cells (MAS-CM) on phosphate transport were investigated by using rat renal slices, the renal cell line OK-B, rat intestinal rings and the human intestinal cell line Caco-2. In addition, the effects of MAS-CM on human sodium-dependent phosphate transporter (NPT2) gene promoter activity expression were investigated in the renal cell line OK-B2400 and were compared with the effects of CM isolated from a patient with oncogenic hypophosphatemic osteomalacia (OHO). MAS cells caused significant hypophosphatemia (P < 0.05) and elevated serum alkaline phosphatase activity (P < 0.05) in SCID mice. The MAS-CM significantly inhibited phosphate uptake in everted intestinal rings (P < 0.01), whereas it had no effect on glucose uptake. The MAS-CM had no effect on either phosphate uptake in the kidney or NPT2 gene promoter activity. In contrast, the CM of the OHO patient significantly inhibited phosphate uptake and NPT2 gene promoter activity. These results indicate that the humoral factor derived from fibrous dysplasia cells of the MAS patient is different to that from OHO patients, because the humoral factor from the MAS patient inhibited phosphate transport not in the kidney but in the intestine.

Adolescent↗
PubMedDate not supplied

Phosphaturic mesenchymal tumor-induced rickets.

We describe two prepubertal girls with oncogenic rickets. The first patient, 9 years of age, presented with recent-onset lower-extremity pain. The second girl, presented at 4 years of age following a 9-month period of muscle weakness, bone pain, and poor linear growth. Laboratory analyses in both patients revealed hypophosphatemia and hyperphosphaturia; elevated circulating alkaline phosphatase activity was present in one of them. Radiographic evidence of a generalized rachitic process was evident in both cases. Computerized tomography of the paranasal sinuses and facial bones in patient 1 revealed a small lesion eroding through the inner table of the left mandibular ramus. Microscopic examination of this mass revealed a spindle cell neoplasm with chondroid material, dystrophic calcification, and both osteoclast-like and fibroblast-like cells. Prominent vascularity and marked atypia were present. These features are consistent with a phosphaturic mesenchymal tumor of the mixed connective tissue variant. In the second patient, computerized tomography revealed a lytic lesion located in the right proximal tibia, with histologic features consistent with a phosphaturic mesenchymal tumor of the nonossifying fibroma-like variant. Resection of each tumor resulted in rapid correction of the phosphaturia and healing of the rachitic abnormalities. A careful search for small or occult tumors should be carried out in cases of acquired phosphaturic rickets.

Bone Neoplasms↗
PubMed2005

Serum hyaluronidase aberrations in metabolic and morphogenetic disorders.

Hyaluronidases are endo-glycosidases that degrade both hyaluronan (hyaluronic acid) (HA) and chondroitin sulfates. Deficiency of hyaluronidase activity has been predicted to result in a phenotype similar to that observed in mucopolysaccharidosis (MPS). In the present study, we surveyed a variety of patients with phenotypes similar to those observed in MPS, but without significant mucopolysacchariduria to determine if some are based on aberrations in serum hyaluronidase (Hyal-1) activity. The study included patients with well-characterized dysmorphic disorders occurring on genetic basis, as well as those of unkown etiology. The purpose of the study was to establish how wide spread were abnormalities in levels of circulating Hyal-1 activity. A simple and sensitive semi-quantitative zymographic procedure was used for the determination of activity. Levels of both beta-N-acetylglucosaminidase and beta-glucuronidase whose activities contribute to the total breakdown of hyaluronan (HA) were also measured, as well as the concentration of circulating HA. Among 48 patients with bone or connective tissue abnormalities, low levels of Hyal-1 activity were found in six patients compared to levels in 100 healthy donors (2.0-3.2 units/microL vs 6(+/- 1 SE) units/microL). These six patients exhibited a wide spectrum of clinical abnormalities, in particular shortened extremities: they included three patients with unknown causes of clinical symptoms, one patient with Sanfilippo disease, one of the seven patients with achondroplasia, and one with hypophosphotemic rickets. Normal levels of serum Hyal-1 activities were found in patients with Morquio disease, GM1 gangliosidosis, I cell-disease, 6 of the 7 patients with achondroplasia, Marfan's-syndrome and Ehlers-Danlos syndrome. No patient totally lacked serum Hyal-1 activity. Serum HA concentration was elevated in patients with Sanfilippo A and I-cell disease. Determination of serum and leukocyte Hyal-1 and serum HA may be useful to evaluate patients with metabolic and morphogenetic disorders.

Acetylglucosaminidase↗
PubMed1975

The kidney as an endocrine organ involved in the function of vitamin D.

Vitamin D3 must be metabilically altered first in the liver to 25-hydroxyvitamin D3 (25 OH-D3) and subsequently in the kidney to 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) before it can function. Because 1,25-(OH)2D3 is formed in the kidney and acts in intestine and bone to elevate serum calcium and phosphate concentrations, it can be considered a hormone. The production of 1,25-(OH)2D3 is feedback regulated either directly or indirectly by serum calcium and serum phosphate concentrations. The hypocalcemic regulation is mediated by the parathyroid glands. The hypophosphatemic stimulus, however, does not involve either the parathyroid or thyroid glands. Under conditions whereby the synthesis of 1,25-(OH)2D3 is repressed, 24,25-dihydroxyvitamin D3 (24,25-(OH)2D3 is formed. This metabolite can be converted further to 1,24,25-trihydroxyvitamin D3 (1,24,25-(OH)3D3), which stimulate intestinal calcium transport but not bone calcium mobilization or phosphate transport reactions. A number of vitamin D-resistant bone diseases may be related to defective vitamin D metabolism. For example, bone disease related to choric renal failure likely results from defective formation of 1,25-(OH)2D3 in the kidney. Treatment of this disease with intravenously administered 1,25-(OH)2D3 is effective in correcting the bone lesions. 1Alpha-hydroxyvitamin D3 (1alpha-OH-D3), a new synthetic analog of 1,25-(OH)2D3 which is less expensive to produce than 1,25-(OH)2D3, is effective in anephric animals and may have several advantages over 1,25-(OH)2D3 in treating bone diseases.

Biological Transport↗
PubMed1985

Electrocardiographic finding simulating acute myocardial infarction in a compound metabolic aberration.

A patient with hypokalemic metabolic alkalosis, hypophosphatemia, and hypomagnesemia/hypocalcemia is described. Electrocardiography demonstrated the pattern of acute anterior myocardial infarction. Further evaluation revealed that the patient had not actually had the acute myocardial infarction and that the electrocardiographic change was a mere simulation. The possible role of hypomagnesemia in the pathogenesis of the electrocardiographic change and the interrelation between the metabolic disturbances noted are discussed.

Alkalosis↗
PubMed1985

Development of hypercalcemic hyperparathyroidism after long-term phosphate supplementation in hypophosphatemic osteomalacia. Report of two cases.

Orally administered phosphate supplements are the mainstay of therapy for hypophosphatemic osteomalacia of diverse causes and are generally believed to be free from harmful side effects. Two cases are reported, however, in which long-term therapy (14 and 10 years, respectively) resulted in hypercalcemic hyperparathyroidism associated with surgically proved adenomatous hyperplasia. This complication occurred despite concomitant treatment with pharmacologic doses of vitamin D. Thus, long-term oral phosphate therapy can produce tertiary hyperparathyroidism in susceptible patients.

Adult↗
PubMed1987

Long-term intracaval calcium infusion therapy in end-organ resistance to 1,25-dihydroxyvitamin D.

Two boys aged six and four with the syndrome of hereditary resistance to 1,25-dihydroxyvitamin D3 with rickets alopecia and growth retardation are presented. After unsuccessful therapeutic trials with pharmacologic doses of vitamin D or its active metabolites, the patients were treated by long-term intracaval infusions of calcium through an implantable catheter. A total of 0.5 to 0.9 g of elemental calcium was infused daily for 18 months and the serum calcium concentration was maintained at 9 to 10 mg/dl. Bone pain subsided within one week of treatment. Serum phosphorus, immunoreactive parathyroid hormone, and 1,25-dihydroxyvitamin D concentrations and alkaline phosphatase activity were normalized within four to nine months. Radiographs of the knees and hands revealed progressive healing of rickets with complete resolution after one year of treatment. The patients gained 12 cm and 8 cm per year in height as compared with 3 cm and 2 cm, respectively, in the previous year. A transilial bone biopsy obtained from one patient prior to treatment revealed severe osteomalacia associated with osteitis fibrosa. A follow-up biopsy examined after 12 months of therapy showed almost complete healing of osteomalacia and normal mineralization. These observations indicate the following: (1) Long-term intracaval calcium infusions are an effective mode of therapy for these patients, and (2) When adequate serum calcium and phosphorus concentrations are maintained, healing of rickets and normal growth rate could be achieved even in the absence of a normal 1,25-dihydroxyvitamin D3 receptor-effector system.

Biopsy↗
PubMed1991

X-linked hypophosphatemia: skeletal mass in adults assessed by histomorphometry, computed tomography, and absorptiometry.

PURPOSE AND PATIENTS AND METHODS: X-linked hypophosphatemia (XLH) is the most common inherited form of rickets, yet its influence on skeletal mass in adulthood is controversial and incompletely characterized. Accordingly, we measured bone mass at several skeletal sites using histomorphometric and radiographic techniques in 19 adults (four men) with XLH (age range 20 to 66 years). Most subjects had not received medical therapy for XLH since puberty. RESULTS: Eight of 14 subjects who underwent transiliac bone biopsy had an elevated cancellous bone volume (osteoid and calcified bone), and the group's mean value was supranormal (p less than 0.01). Mineralized bone volume, however, was above normal in only three subjects (NS). Another measure of trabecular bone density, vertebral mineral density by computed tomography, was elevated in three of 13 subjects, and the mean value of the group was increased (p = 0.05). Integral spine bone mineral density (BMD) assessed by dual photon absorptiometry (DPA) was elevated in six of 16 subjects, and the mean was also above normal (p less than 0.01). However, total body calcium, total body BMD (both by DPA), and forearm bone mineral content assessed by single photon absorptiometry (predominantly cortical bone) were normal in almost all subjects, as were the group means for these parameters. Mean regional BMD (by DPA) was below normal in the upper and lower limbs (p less than 0.001) and above normal in the spine (p less than 0.005) and ribs (p less than 0.01). There was no relationship between these indices of bone mass and either biochemical or clinical parameters of disease severity, although men tended to have higher z-scores for axial bone density than premenopausal women whose values, in turn, tended to be higher than those in postmenopausal women (NS). CONCLUSION: We conclude that axial bone mass tends to be increased in adults with XLH, sometimes dramatically so, and this is only partially attributable to hyperosteoidosis. Peripheral bone mass, however, tends to be diminished. Despite these group trends, most adults with untreated XLH have normal indices of bone mass as assessed by a variety of techniques at the commonly used measurement sites. These findings suggest that "osteoporotic" fractures are unlikely to develop as a late complication of XLH in adults.

Absorptiometry, Photon↗
PubMed1982

Deficient nasal bone growth in the X-linked hypophosphataemic (HYP) mouse and its implication in craniofacial growth.

Mice bearing the mutant Hyp gene are characterized by craniofacial abnormalities secondary to their metabolic bone disease. X-ray cephalograms were taken of 40 normal and 29 Hyp mice at 1, 2, 3 and 4 weeks of age in one group and at weeks 6, 9 and 12 in a second. Hyp mice exhibited shorter skulls, shorter mandibles antero-posteriorly and a compressed upper face height. Both the fronto-nasal and the premaxillo-maxillary sutures in the Hyp mice were deformed and failed to close by 12 weeks of age. The deficient linear growth of the nasal bone was the most important measured variable contributing to the overall difference in the skull morphology between Hyp and normal mice. Thus this animal model is promising for elucidating the regulatory mechanisms affecting craniofacial growth.

Animals↗
PubMed1984

Normal handling of phosphate in the salivary glands of X-linked hypophosphataemic mice.

In X-linked hypophosphataemia (Hyp gene) there is reduced renal tubule re-absorption of phosphate and an osteomalacic bone disorder. To determine whether altered phosphate transport also occurs in the salivary gland, saliva was analysed from normal and Hyp mice at 10 weeks of age. The effect of plasma inorganic phosphate on the composition of saliva was controlled by placing both genotypes on either a control diet or a low-P diet for three days. Inorganic phosphate, total phosphate, calcium, sodium, potassium, chloride, amylase, sialic acid, protein, osmotic pressure, percentage water, percentage inorganic solids and sample volume were measured. The Hyp mice fed the control diet showed a significant decrease in salivary-inorganic phosphate, total phosphate, osmotic pressure and sialic acid. These four variables were similarly lower in the normal mice fed the low-phosphate diet. The changes seem to stem from the low plasma inorganic phosphate and not from expression of the Hyp gene in the salivary gland. The total evidence from various organ systems suggests that the altered phosphate transport in X-linked hypophosphataemia may be restricted to the kidney and is not a generalized phosphate-transport deficiency.

Animals↗