[30-year-old patient with progressive bone pain and muscle weakness. Adult form of phosphate diabetes with secondary hyperparathyroidism].
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Adult↗
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Results for “HYPOPHOSPHATEMIA, FAMILIAL”
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[Rickets. Diagnosis and therapy].
Rickets is caused by deficient mineralization at the level of growth plate and is usually due to a decreased serum calcium/phosphate product. Although the diagnosis of rickets can usually be suspected on the basis of a clinical examination (bone deformities in legs, impaired growth), radiological examination and detailed biochemical work-up are necessary to elucidate the etiology of the underlying disease. It is important to differentiate between calcipenic/vitamin deficient and phosphopenic rickets. The former is due to vitamin D deficiency, and the ultimate cause of this usually lies in altered vitamin D supply; however, impaired synthesis of or resistance to the actions of vitamin D can also be a cause. Phosphopenic rickets is usually related to impaired phosphate reabsorption in the proximal renal tubule. Both calcipenic and phosphopenic rickets can be acquired or hereditary in origin.
Diagnosis, Differential↗
[Deviations in the axes of the lower extremities].
Deviations in the axes can be physiological or pathological. During growth, the axes of the lower extremities undergo significant changes. The femoral neck-shaft-angle decreases from 150 degrees on average at birth to 120 degrees on average at the end of growth. The lower leg is bowed in a varus direction at birth. After a child begins to walk, the knee axis deviates to a slight valgus. This goes back to normal before the age of ten. Pathologic deviations of the axis are rare. They occur in congenital deformations, after trauma or infection, or as a result of metabolic diseases. In association with coxa vara pseudarthrosis of the femoral neck usually develops. Therefore this deformation has to be treated. Correction is best made with a Y-shaped osteotomy according to Pauwels. At the lower leg, a deviation of 15 degrees from the normal axis is usually an indication for operative treatment. In children and adolescents, corrections are best made with (monolateral) external fixators. They allow early weight bearing, which is especially desirable in bilateral corrections.
Adolescent↗
Morphological and functional features of clasts in low phosphate, vitamin D-deficiency rickets.
Focusing on resorption processes, we have extended our previous studies on chondroclasts and osteoclasts in normally developing tissues, using a model of nutritionally induced vitamin D-deficiency rickets. To analyze the resorption process, we investigated the matrix-resorbing cells in this modified and poorly mineralized tissue regarding morphological features and expression of tartrate-resistant acid phosphatase (TRAP) at the subcellular level. Our goal was to test the hypotheses that initiation of resorption is impaired with unmineralized matrix, and that such alterations involve changes in the subcellullar distribution of TRAP, implicating a role for this enzyme in the resorption process. Our results reveal distinctly different morphological appearances of clast-like cells in rickets compared with normal osteoclasts and chondroclasts. Ordinary resorption structures of osteoclasts and chondroclasts at the cell-matrix border, i.e., ruffled borders and clear zones, are profoundly altered in favor of a less well-defined intermediate zone. TRAP distribution at the subcellullar level is also clearly different from that in osteoclasts and chondroclasts from normal rodents, with impaired secretion; consequently, the enzyme is unable to function in the matrix outside the ruffled border. Our ultrastructural observations demonstrate that in rickets, the clasts are incapable of degrading the poorly mineralized cartilage and bone efficiently. Rachitic clasts seem to be recruited to the matrix surface and interaction between cell and matrix is also initiated, but definitive resorption structures at the cell-matrix border are not normally developed. Whether resorption is inhibited by the mere lack of mineral or mineral-associated proteins, or by other mechanisms remains to be settled.
Acid Phosphatase↗
Skeletal casein kinase activity defect in the HYP mouse.
The Hyp mouse, a model for human X-linked hypophosphatemia (XLH), is characterized by phosphate wasting and defective mineralization. Since osteopontin (OPN) is considered pivotal for biological mineralization, we examined the biosynthesis of OPN in osteoblasts of +/Y and Hyp/Y mice. Immunoprecipitation analyses using a specific antibody to OPN revealed that Hyp/Y and +/Y osteoblasts secrete similar levels of OPN as determined by [35S]-methionine biosynthetic labeling, but a reduced phosphorylation was noted after 32P-PO4 biosynthetic labeling. Northern blot hybridization analysis of +/Y and Hyp/Y mice osteoblast mRNAs, using a cDNA probe for mouse OPN, revealed no difference in the steady state levels of osteopontin mRNA. Analysis of casein kinase II activity in +/Y and Hyp/Y mice osteoblast, kidney, heart and liver membrane fractions revealed that casein kinase II activity in the Hyp/Y mice osteoblasts and kidney is only 35%-50%, respectively, of that of the +/Y mice tissues. The accumulated data are consistent with a post-translation defect in the Hyp/Y mouse osteoblast which results in the under-phosphorylation of osteopontin and subsequent under-mineralization of bone matrix.
Animals↗
Lumbar and radial bone mineral density in children and adolescents with X-linked hypophosphatemia: evaluation with dual X-ray absorptiometry.
OBJECTIVE: To evaluate the bone mineral status of children being treated for X-linked hypophosphatemia, including potential differences between cortical bone in the radial diaphysis and combined cortical and trabecular bone in the lumbar spine. DESIGN AND PATIENTS: Forty-four bone mineral evaluations were performed in 11 children and adolescents with X-linked hypophosphatemia. Bone mineral density (BMD) of the lumbar spine and the radial diaphysis were measured by dual X-ray absorptiometry (DXA), second metacarpal cortical thickness was measured on hand radiographs, and these results were expressed as Z-scores (standard deviations from the mean). RESULTS: For the 11 initial examinations, Z-scores (mean+/-SD) were: radial BMD, -2.73+/-1.15, lumbar BMD, +1.28+/-1.53; and cortical thickness, -2.21+/-0.95. Lumbar BMD Z-scores were significantly greater than those for radial BMD and cortical thickness. On follow-up examinations there was a mild increase in radial BMD and decrease in lumbar BMD. Although these changes were statistically significant, they were quite small and the discordance between radial and lumbar BMD was not corrected. CONCLUSIONS: Children and adolescents who are being treated for X-linked hypophosphatemia manifest a bone mineral disorder characterized by decreased BMD in the appendicular skeleton and increased BMD in the lumbar spine. Although current therapy is successful in its anti-rachitic effects, it does not correct this bone mineral disorder and additional therapeutic trials should be considered.
Absorptiometry, Photon↗
Mutation watch: PEX PLUS? Gene(s) for X-linked hypophosphatemia and deafness.
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Animals↗
A simple technique for correction of complicated tibial deformity including rotational deformity.
Although the simplest way to correct bone deformity is one-stage correction, the problem associated with that method is overstretching of the soft tissues, which limits the correction and leads to complications such as compartment syndrome or peripheral nerve palsy. If an adequate amount of tissue necessary for correction is formed in advance, the deformity can be corrected safely at one stage without overstretching of the tissues. A leg lengthening technique was employed to form the necessary tissues. After leg lengthening with an unilateral external fixator (Hifixator), deformities were corrected manually at one stage without anesthesia, and the corrected positions were again secured with the fixator. To correct rotational deformity, two sets of pins were inserted into the proximal bone fragment of the tibia at the time of the operation, and after lengthening the proximal pin clamp of the fixator was disconnected from one pin set and reconnected to the other set. We applied this method to four tibias of three patients without any complications. The tension of the tissues was monitored using a pressure sensor built into a Hifixator to prevent the tissues from overstretching. During and after the correction, the tension of the tissue was maintained at less than before the correction.
Bone Lengthening↗
Novel phosphate-regulating genes in the pathogenesis of renal phosphate wasting disorders.
Over the past decade, three classes of Na/Pi cotransporters have been identified in mammalian kidney. The type IIa Na/Pi cotransporter, Npt2, is the most abundant and is expressed in the brush-border membrane of renal proximal tubular cells where the bulk of filtered inorganic phosphate (Pi) is reabsorbed. Disruption of the Npt2 gene in mice underscored the importance of Npt2 in the overall maintenance of Pi homeostasis and demonstrated that Npt2 is the target for regulation of proximal tubular Pi reabsorption by parathyroid hormone and dietary Pi. The regulation is post-transcriptional and largely occurs by brush-border membrane retrieval and insertion of Npt2 protein. Of great interest is the recent identification of novel Pi regulating genes, PHEX and FGF23, that play a role in the pathophysiology of inherited (X-linked hypophosphatemia and autosomal dominant hypophosphatemic rickets) and acquired (oncogenic hypophosphatemic rickets) disorders characterized by renal Pi wasting and associated skeletal abnormalities. Studies are currently underway to elucidate the molecular basis for impaired renal Pi reabsorption in these disorders and to determine the precise physiological role of PHEX and FGF-23 in the regulation of Pi homeostasis.
Animals↗
Generalized arterial calcification of infancy: two siblings with prolonged survival.
In generalized arterial calcification of infancy (OMIM no. 208000), calcification of the media and proliferation of the intima lead to arterial stenoses. Most affected patients present with untreatable arterial hypertension and die within the first months of life. The disease has recently been linked to mutations in ENPP1. We report two siblings with prolonged survival, both of whom carry the compound heterozygous ENPP1 mutations c.913C>A and c.1164+2T>A. In both siblings, spontaneous regression of arterial calcifications occurred, and antihypertensive treatment could be tapered off gradually. In some patients, the natural course of GACI may be more favourable than previously assumed.
Aorta, Abdominal↗
Growth in X-linked hypophosphatemic rickets.
Growth failure appears frequently in children with X-linked hypophosphatemic rickets (XLHR) due to hypophosphatemia, disease severity, body disproportion, and primary bone abnormality. Recombinant human growth hormone (rhGH) increases phosphate tubular reabsorption and phosphate level in blood and, thus, constitutes an attractive but controversial therapy in short children with XLHR, those efficacy was demonstrated in small uncontrolled series. Our aim was to report our experience regarding growth in XLHR. Twenty-seven children with XLHR--20 girls, seven boys--diagnosed at a median (md) of 1.46 years of age, (range 0.39-8.5 years), were studied at 10.12 years of age (1.58-18.56), md (range). All received oral treatment with phosphate and calcitriol. At the first visit, grouped Z-height was -1; (-4.58; 0.54) md (range). After 5 years' follow-up (0.92-15.6), Z-height was -0.91 (- 4.56; 0.17), not different from that at baseline (P = 0.465). In 16 children entirely controlled in our program upon presentation, a "catch up" phenomenon after the rickets had healed (P = 0.823) or throughout the long-term was not observed (P = 0.995). Eight patients had a Z-height </= -2SD at the last visit, and impaired linear growth was associated with age >2 years at diagnosis, male gender and non-adherence to treatment. Four children, all boys, received rhGH, and in two cases with sufficient follow up stature normalized. No rhGH side effects were observed, and phosphate and calcitriol doses remained stable. Linear growth failure appeared in a third of XLHR children. Efforts need to be made to reduce the age of diagnosis and to improve adherence to treatment. Treatment with rhGH should be considered early, after the rickets has been controlled, in those patients with impaired growth or delayed diagnosis.
Adolescent↗
Epidermal naevus syndrome and hypophosphataemic rickets: description of a patient with central nervous system anomalies and review of the literature.
The epidermal naevus syndrome (ENS) is a rare dermatological condition consisting of congenital epidermal nevi associated with anomalies in the central nervous system, bones, eyes, hear or genito-urinary system. We report a new case of ENS associated with hypophosphataemic rickets. The girl was born with a mixed-type epidermal naevus and skeletal anomalies. Hypophosphataemic rickets was diagnosed at the age of 2.5 years. At 14 years of age. MRI of the head demonstrated right brain hypotrophy, a left temporal arachnoid cyst and asymmetric lateral ventricles. We reviewed the literature and found 13 reported cases of ENS associated with hypophosphataemic rickets. Conclusion We report a further patient with epidermal naevus syndrome and hypophosphataemic rickets, followed from birth to the age of 15 years, who had structural central nervous system anomalies with normal intellectual functioning. A comprehensive neurological work up is recommended in patients with epidermal naevus syndrome.
Adolescent↗
A 3-year-old child with proteinuria and nephrocalcinosis. Suspicion of Dent disease.
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Child, Preschool↗
Megalin and proximal renal tubular dysfunction in Dent disease.
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Chloride Channels↗
Resolution of medullary nephrocalcinosis in children with metabolic bone disorders.
Ultrasonographic resolution of nephrocalcinosis (NC) has been reported in children with furosemide-induced NC, but not in other entities. We report the cases of four children with metabolic bone disease, two with hypophosphatasia and two with X-linked hypophosphatemic rickets, in whom we observed resolution of renal calcifications. At the time of ultrasonographic resolution of NC, 3 of the patients were on anticalciuric diuretics, and all 4 had normal urinalysis, serum creatinine and electrolyte profiles, as well as estimated creatinine clearance. In 3 of the children, evidence of mild tubular dysfunction was found. It thus seems that in some children with bone and mineral disorders who develop NC, ultrasonographic resolution of the renal calcifications can be seen; however, mild tubular dysfunction may remain and require follow-up. Further studies are suggested to explore the possible role of anticalciuric diuretics in promoting the resolution of NC.
Adolescent↗
Hypophosphatemic rickets: results of a long-term follow-up.
This study reports the benefits and side effects of conventional treatment, phosphate and calcitriol supplementation in patients with heritable hypophosphatemic rickets and a long-term follow-up, median of 60.9 months. The group is composed of 17 patients (ten girls). Sixteen patients presented with bone pain and/or deformities, and in one patient the diagnosis was radiological. All the patients had increased alkaline phosphatase, hypophosphatemia, decreased fractional phosphate tubular reabsorption (TRP) and maximum tubular phosphate reabsorption/glomerular filtration rate ratio (TPO4/GFR). Ten of 17 patients had metabolic acidosis, which was corrected only with the conventional treatment. Potassium citrate was prescribed to the patients who developed hypercalciuria. Excluding one patient with pulmonary dysfunction, the remaining 16 patients were divided into two groups according to the age at treatment onset (T0): group I (GI) > or =4 years (n =9) and GII <4 years (n =7). GI and GII had similar follow-up periods and treatment protocols. Seven out of nine GI patients underwent orthopedic surgery, in contrast to none of GII. Anthropometric data results showed that within each group there is no difference in weight and stature z -score at T0 and at the end of the observation (Tf), but, when both groups are compared, GII shows higher z-score for stature at T0 (p <0.05) and at Tf (p <0.05). Nephrocalcinosis developed in three cases and correlated with hypercalciuria (p <0.001) and dose of calcitriol (p =0.03). In conclusion, higher stature z-score is associated with early treatment. A careful protocol is recommended to detect such complications as nephrocalcinosis. We suggest potassium citrate for patients with hypercalciuria to avoid calcium precipitation.
Child, Preschool↗
Effect of dipyridamole on serum and urinary phosphate in X-linked hypophosphatemia.
X-linked hypophosphatemia (XLH) is characterized clinically by rickets, hypophosphatemia and hyperphosphaturia. Conventional treatment of XLH with oral phosphate and vitamin D is associated with hypercalcuria and nephrocalcinosis. Recently, intravenous and oral dipyridamole has been reported to decrease fractional excretion of phosphate in adults with idiopathic hyperphosphaturia. Our objective was to determine whether oral dipyridamole therapy reduces urinary phosphate excretion and increases serum phosphate concentration in children with XLH. A prospective study was performed in six children with XLH. The average age of the patients at the start of the study was 12.5+/-1.0 years. The effects of 12 weeks of oral dipyridamole therapy, at 4.4+/-0.4 mg/kg body weight per day, on serum phosphorous, parathyroid hormone (PTH), 1,25 (OH)2 vitamin D, osteocalcin, tubular maximum for phosphate reabsorption (TmP/GFR), urinary calcium excretion, and cyclic adenosine 3',5'-monophosphate (cAMP) excretion, were compared to baseline levels. Our results show that there was no change in serum phosphorous concentration or TmP/GFR after 12 weeks of dipyridamole therapy. Dipyridamole therapy also had no effect on serum PTH, serum 1,25 (OH)2 vitamin D, alkaline phosphatase, osteocalcin levels, urinary calcium or cAMP excretion. We therefore concluded that in children with XLH, a 12-week course of dipyridamole had no effect on serum phosphorous or its urinary excretion. Dipyridamole therapy is unlikely to improve the bone disease in children with XLH.
Adolescent↗