Search

X-linked hypophosphatemia (XLH) is the most common form of inheritable rickets. The disease is caused principally by PHEX mutations leading to increased concentrations of circulating intact FGF23, hence renal phosphate wasting, hypophosphatemia, and decreased circulating levels of 1,25(OH)2 vitamin D. The chronic hypophosphatemia leads to rickets and osteomalacia through a combination of mechanisms, including a lack of endochondral ossification and impaired mineralization. Imaging has a major role in determining the diagnosis of rickets and its cause, detecting complications as early as possible, and helping in treatment monitoring.

International audience; Rare diseases of phosphate/calcium metabolism correspond to a wide and heterogeneous spectrum of diseases. Recent knowledge in physiology and genetics has made it possible to better characterize them and to propose attractive therapeutic approaches based on the underlying pathophysiology. These diseases are often at the interface between nephrology and endocrinology. In this spirit of a multidisciplinary care, each specialty can bring its own critical point of view and its own specificities to improve patient care. The objective of this manuscript is to "read" with a nephrologist's point of view the main frameworks of diseases of phosphate/calcium metabolism, to illustrate the three crucial messages of nephro-protection sent to endocrinologists. First, calciuria must be interpreted both in absolute value (concentration hypercalciuria) and in ratio (flow hypercalciuria). Second, renal monitoring of therapies inducing hypercalciuria on kidneys with normal renal function (e.g. active vitamin D analogs or teriparatide) should be systematic. Last, hyperphosphatemia, often latent in hypoparathyroidism and pseudo-hypoparathyroidism, should be detected and at least benefit from dietary measures, in the context of Western diets rich in phosphate hidden in food additives.

Hypophosphatemic rickets (HR) is a genetic disorder with various types of inheritance. It results mainly from defects in factors that control mineral ion homeostasis such as 1,25(OH)2D (Calcitriol) and FGF23 (Fibroblast Growth Factor 23). The existing bibliography regarding orthodontic treatment in patients with hypophosphatemic rickets is extremely limited. The aim of this case report is to describe the orthodontic treatment of a 9-year old Caucasian female patient suffering from HR. The patient presented a healthy late mixed dentition and periodontium. She suffered from a mild Class III maxillary skeletal pattern. There was a bilateral posterior crossbite, short lingual frenulum, a right maxillary mesioposition with a Class II subdivision on this side and a moderate space deficiency in the dental arches. The disorder was controlled by medication. In specific, patient was taking 1.5mL of phosphate four times per day, 0.3mL of calcitriol twice per day and 50,000 IU of Vitamin D3 on a weekly basis. Given the Class III skeletal pattern, the medical condition and the absence of relevant bibliography, it was decided to perform maxillary expansion, facemask traction and orthodontic treatment with fixed appliances. By the end of treatment, Class I canine and molar relationships were achieved, overjet and overbite were corrected and space deficiency was addressed in both arches. PAR index was 27 at the beginning of treatment and became 2 by the end of treatment (92.5% correction). The aesthetic component of IOTN was 4 and changed to 1, while the dental component used to be 5i and became 2g. With regards to retention, upper and lower fixed retainers from canine to canine and upper and lower vacuum formed appliances were used. In conclusion, a patient with controlled HR was orthodontically treated in a successful way. Orthodontic therapy was performed in a minimally invasive manner. Thus, HR does not constitute a contraindication for orthodontic treatment, when the disorder is kept under control.

Background X-linked hypophosphatemia (XLH) represents the most common genetic form of rickets featuring profound hypophosphatemia with associated skeletal and non-skeletal manifestations. Early onset gait disturbances contribute strongly to the burden of disease. However, no study has comprehensively characterized naturally occurring gait deviations in pediatric patients with XLH. Research questions Can disease-specific gait deviations and potentially influencing factors be identified by gait analysis in non-surgically treated children with XLH? Methods Gait laboratory assessments of 12 pediatric patients with XLH without previous long bone surgery was retrospectively analyzed and compared to age-matched healthy controls. Radiologic and clinical parameters of XLH patients were correlated with kinematic gait variables and gait scores. Results Reduced external knee rotation and increased external hip orientation was ubiquitous in children with XLH. Increased lateral trunk lean, or “waddling gait”, occurred in five children and was associated with varus knee deformities. Overall, children with XLH showed a reduced Gait Deviation Index (GDI) compared to controls. Radiologic and gait analysis revealed complex combined frontal and torsional deformity of the lower limbs as a common feature in XLH. Higher Body Mass Index (BMI) was associated with both lateral trunk lean and impaired GDI. Significance Gait analysis is feasible to quantify gait deviations and lower limb deformities in pediatric patients with XLH. Specific gait characteristics including internal knee rotation and external hip rotation are common among patients with XLH and contribute to impaired gait scores. Our data suggest the use of gait and deformity data assessment as outcome parameters in future observational and interventional studies. Standardized assessment might contribute to targeted treatments to improve life quality in XLH patients.

X-linked hypophosphatemic rickets (XLH) is a skeletal disorder with spontaneous appearance of a periapical abscess in clinically healthy-like teeth a typical dental finding. A 1Y5M boy came to our clinic with spontaneous pain in the maxillary anterior region. Clinical examinations led to diagnosis of acute periapical periodontitis in the maxillary left primary central incisor, for which root canal treatment was performed. Thereafter, a pediatrician diagnosed XLH based on elevated ALP in a blood test at 1Y10M. We should have been suspected XLH in this case even with the absence of periapical abscess.

X-linked hypophosphatemia (XLH) is associated with a pervasive, severe degenerative osteoarthritis. We conducted a retrospective chart review/patient survey using the Knee or Hip Osteoarthritis Outcome Score Physical Function Short Form. Fourteen total knee arthroplasties and 7 total hip arthroplasties among 11 patients were included. The mean KOOS-PS score was 31.4 ± 9.7 with a mean follow up of 6.9 years. Mean HOOS-PS score was 14.8 ± 12.9 at a mean follow up of 7.6 years. One knee failed due to aseptic loosening and one hip was revised due to polyethylene wear. In conclusion, total joint arthroplasty is beneficial in XLH.

Hereditary hypophosphatemia with increased FGF23 levels are rare inherited metabolic diseases characterized by low serum phosphate because of impaired renal tubular phosphate reabsorption. The most common form is X-linked hypophosphatemia (XLH), secondary to a mutation in the PHEX gene. In children, XLH is often manifested by rickets, delayed development of gait, lower limb deformities, growth retardation, craniosynostosis, and spontaneous dental abscesses. In adults, patients present diffuse musculoskeletal pain (bone and joints), early osteoarthritis, entesopathies, pseudo-fractures, muscular weakness, and severe dental damage. Conventional medical management is based on the combined administration of oral phosphate supplementation with active vitamin D analogs. Treatment with the recently approved anti-FGF23 burosumab is an alternative, especially in severe forms. Burosumab restores phosphate reabsorption in the proximal tubule and stimulates the endogenous synthesis of calcitriol. In Europe, burosumab has been approved for the treatment of XLH with radiographic evidence of bone disease in pediatric patients from one year of age and in adults. This manuscript will discuss the specific management of burosumab in children and adolescents in daily practice.

Tumor-induced osteomalacia (TIO), caused by phosphaturic mesenchymal tumors (PMTs), is a rare paraneoplastic syndrome characterized by frequent bone fractures, bone pain, muscle weakness, and affected gait. These tumors typically secrete high levels of Fibroblastic Growth Factor 23 (FGF23), a hormone which acts on the kidney to cause hypophosphatemia, ultimately impairing bone mineralization. In this case report, we present a 41-year-old female with FGF23-mediated hypophosphatemia with a 26-year delay in TIO diagnosis and a concurrent misdiagnosis of X-linked hypophosphatemic rickets (XLH). Given an absence of family history of hypophosphatemia, a 13-gene hypophosphatemia panel including XLH (PHEX gene) was performed and came back negative prompting a diagnostic search for a PMT causing TIO. A 68Ga-DOTATATE PET/CT scan revealed the presence of a 9th right rib lesion, for which she underwent rib resection. The patient's laboratory values (notably serum phosphorus, calcium, and vitamin D) normalized, with FGF23 decreasing immediately after surgery, and symptoms resolving over the next three months. Chromogenic in situ hybridization (CISH) and RNA-sequencing of the tumor were positive for FGF23 (CISH) and the transcriptional marker FN1-FGFR1, a novel fusion gene between fibronectin (FN1) and Fibroblast Growth Factor Receptor 1 (FGFR1), previously determined to be present in the majority of TIO-associated tumors. This case demonstrates the notion that rare and diagnostically challenging disorders like TIO can be undiagnosed and/or misdiagnosed for many years, even by experienced clinicians and routine lab testing. It also underscores the power of novel tools available to clinicians such as gene panels, CISH, and RNA sequencing, and their ability to characterize TIO and its related tumors in the context of several phenotypically similar diseases., Graphical abstract (A) CT (white arrows = mass). (B) PET (white arrows = activity). (C) 68 Ga-DOTATE Scan Axial (red arrows = activity). (D) 68 Ga-DOTATE Scan Coronal (A/P) (red arrows = activity). (E) Post-operative image of 9th right rib removed during the second, successful surgery. White stars (*) denote the two areas of abnormality, red arrow denotes the primary lesion of concern for PMT shown histologically in F and G. (F) Histological appearance of the Phosphaturic Mesenchymal Tumor (PMT) specifically showing infiltration of rib bone and proliferation of uniform short spindle to ovoid cells with a rich vascular background and cystic changes. (G) FGF23 Chromogenic in situ hybridization (CISH) of the PMT.Unlabelled Image, Highlights • TIO is caused by FGF23 hypersecretion by phosphaturic mesenchymal tumors (PMTs). • TIO can go undiagnosed and/or be misdiagnosed with similar disorders (e.g. XLH). • Family history, biochemistry, gene panels, and imaging may help distinguish TIO. • FN1-FGF1 and FN1-FGFR1 are transcribed and synthesized by the majority of PMTs. • Burosumab (anti-FGF23) and FGF/R inhibitors show promise; resection is preferred.

Hypophosphatasia (HPP) is the inborn-error-of-metabolism caused by loss-of-function mutation(s) of the ALPL gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). TNSALP in healthy individuals is on cell surfaces richly in bone, liver, and kidney. Thus, TNSALP natural substrates accumulate extracellularly in HPP, including inorganic pyrophosphate (PPi), a potent inhibitor of hydroxyapatite crystal formation and growth. Superabundance of extracellular PPi (ePPi) in HPP impairs mineralization of bones and teeth, often leading to rickets during childhood and osteomalacia in adult life and to tooth loss at any age. HPP’s remarkably broad-ranging severity is largely explained by nearly four hundred typically missense mutations throughout the ALPL gene that are transmitted as an autosomal dominant or autosomal recessive trait. In the clinical laboratory, the biochemical hallmark of HPP is low serum ALP activity (hypophosphatasemia). However, our experience indicates that hyperphosphatemia from increased renal reclamation of filtered inorganic phosphate (Pi) is also common. Herein, from our prospective single-center study, we document throughout the clinical spectrum of non-lethal pediatric HPP that hyperphosphatemia reflects increased renal tubular threshold maximum for phosphorus adjusted for the glomerular filtration rate (TmP/GFR). To explore its pathogenesis, we studied mineral metabolism and quantitated circulating levels of three phosphatonins [fibroblast growth factor 23 (FGF23), secreted frizzled-related protein 4 (sFRP4), and fibroblast growth factor 7 (FGF7)] in 41 pediatric patients with HPP, 73 with X-linked hypophosphatemia (XLH), and 15 healthy pediatric control (CTR) subjects. The HPP and XLH cohorts had normal serum total and ionized calcium and parathyroid hormone levels (Ps > 0.10) and uncompromised glomerular filtration. In XLH, serum FGF23 was characteristically elevated (P < 0.0001) and despite hypophosphatemia sFRP4 was normal (P > 0.4) while FGF7 was low (P < 0.0001). In HPP, despite hyperphosphatemia serum FGF23 and sFRP4 were normal (Ps > 0.8) while FGF7 was low (P < 0.0001). Subsequently, in rats, we confirmed that FGF7 is phosphaturic. Thus, hyperphosphatemia in non-lethal pediatric HPP is associated with phosphatonin insufficiency together with, as we discuss, ePPi excess and diminished renal TNSALP activity.

Objective: To present a serious complication of X-linked hereditary hypophosphatemia.Methods: The authors present the case of a 49-year-old man who presented to the hospital with back pain and was found to have a thoracic myelopathy caused by hypertrophy of the ligamentum flavum.Results: The treating physicians found that the patient had calcification and hypertrophy of the ligamentum flavum that compressed the thoracic spinal cord and caused incomplete paraplegia. The patient's symptoms improved with decompression of the spinal cord.Conclusion: Patients with X-linked hereditary hypophosphatemia are at risk for compression of the spinal cord. Patients with this syndrome who present with back pain need to be examined carefully for evidence of spinal cord compression.Abbreviations: FGF23 = fibroblast growth factor 23 PTH = parathyroid hormone XLH = X-linked hypophosphatemia

The Hyp mouse is a murine homolog of human X-linked hypophosphatemic rickets and displays hypo-mineralization in bone and dentin due to a defect of the phosphate-regulating gene with homology to endopeptidase on the X chromosome (Phex) gene. It has long been considered that the bone and dentin defects in Hyp mice are caused by hypophosphatemia alone, however, several recent studies have indicated the possibility that intrinsic defects are present in Hyp mice osteoblasts. Further, we previously found a hyper-expression of osteocalcin (OC) mRNA in Hyp mouse odontoblasts and suggested the possibility of the presence of intrinsic defects. In the present study, we evaluated morphological features and OC mRNA expression levels in tooth germs of Nor mice with a normal phex gene and a low concentration of serum phosphate, and compared them to those in Hyp and wild-type mice. Nor mice exhibited low serum phosphate levels, however, did not show the characteristic features of dentin defects seen in Hyp mice, such as widened predentin and hyper-expression of OC mRNA. These results suggest that the hypo-mineralization of dentin in Hyp mice is not dependent on serum phosphate level, but rather is affected by intrinsic defects in odontoblasts.

We describe the clinical, genetic, biochemical, and molecular characterization of a mouse that arose in the first generation (G(1)) of a random mutagenesis screen with the chemical mutagen ethyl-nitrosourea. The mouse was observed to have skeletal abnormalities inherited with an X-linked dominant pattern of inheritance. The causative mutation, named Skeletal abnormality 1 (Ska1), was shown to be a single base pair mutation in a splice donor site immediately following exon 8 of the Phex (phosphate-regulating gene with homologies to endopeptidases located on the X-chromosome) gene. This point mutation caused skipping of exon 8 from Phex mRNA, hypophosphatemia, and features of rickets. This experimentally induced phenotype mirrors the human condition X-linked hypophosphatemia; directly confirms the role of Phex in phosphate homeostasis, normal skeletal development, and rickets; and illustrates the power of mutagenesis in exploring animal models of human disease.

Nephrocalcinosis (NC) detected by ultrasound is a recognized abnormality for some patients with X-linked hypophosphatemia (XLH) who received vitamin D2 and inorganic phosphate therapy, but is commonly observed in XLH patients treated with 1,25-dihydroxyvitamin D3 and inorganic phosphate supplementation. Nevertheless, long-term follow-up of kidney function in XLH patients with NC detected ultrasonographically has not been reported. We investigated two women with XLH, ages 31 (patient 1) and 39 (patient 2) years, each of whom had suffered at least one documented episode of vitamin D2-induced hypercalcemia and renal azotemia during childhood. Patient 2 had also been treated with inorganic phosphate. No medications for XLH had been taken during adulthood. Renal ultrasonography at our institution demonstrated marked bilateral medullary NC in both women. No other explanation was found for their NC that apparently occurred several decades earlier from medical therapy for XLH. Detailed studies (including creatinine clearance, beta2-microglobulin excretion, and fasting urinary osmolality and acidification) revealed no impairment of kidney function in either patient. Our findings indicate that subradiographic medullary NC acquired during medical therapy for XLH may persist for decades, but with no adverse renal sequelae. Definitive (long-term) assessment of kidney function in the XLH population with NC, however, will be necessary to fully understand the risk of current medical treatment for this most common heritable form of rickets.

X-linked hypophosphatemia (XLH), which is a heritable metabolic bone disease characterized biochemically by selective renal phosphate (Pi) wasting, is associated with mutations in the PEX ( P hosphate-regulating gene with homologies to E ndopeptidases on the X -chromosome) gene. To further explore the physiologic role of PEX and define its effect in XLH we have determined the expression and tissue distribution. Northern analysis found abundant PEX mRNA in a restricted pattern, predominantly in adult ovary and fetal lung. In addition, PEX expression was also found in adult lung and fetal liver. A PEX cDNA of 2550 basepairs, which contains the full PEX coding region, was isolated from a human ovary cDNA library. The PEX cDNA shows high homology to other membrane-bound zinc metallopeptidases. The presence of PEX in non-osseous tissues strongly suggests features of a systemic role, rather than a unique function in bone development.

X-linked hypophosphatemia is a metabolic bone disease occurring in both humans and mice. In mice, two different mutations (Hyp and Gy), occurring at separate but closely linked loci, have been proposed as models for this disease. Varying reports of the Vitamin D status of these two mutants has led us to reexamine the influence of diet on circulating calcitrophic hormones and mineral metabolism in both mutants. Hyp and Gy mice were raised on the B6C3H background, and both normal females and heterozygous mutant females were studied at 10 weeks of age. Animals were fed one of three diets at random: high (1.5% Ca and 1.0% P); medium (0.6% Ca and 0.6% P); or low (0.0% Ca and 0.6% P). After 3 days, serum and urine samples were collected. In comparison to mutant mice fed the high diet, both Hyp and Gy mice fed the low diet had decreased serum calcium levels, and further elevations in both serum alkaline phosphatase and serum parathyroid hormone (PTH). Serum 1,25-dihydroxyvitamin D levels were elevated by both the medium and low diets in all groups of mice over values obtained with the high diet. Mutant mice were significantly higher in serum PTH on all diets compared to normal mice fed the same diet. Mutant mice were not elevated in serum 1,25-dihydroxyvitamin D over normal mice when fed the high diet. However, both Hyp and Gy mice fed the medium and low diets were elevated in serum 1,25-dihydroxyvitamin D over normal mice. Serum PTH levels were correlated to serum 1,25-dihydroxyvitamin D levels with Hyp and Gy mice lying on the same line (r = 0.86; p < 0.0001). In summary, when Hyp and Gy mice are studied on the same genetic background and fed the same diet, similar responses are seen in PTH levels and 1,25-dihydroxyvitamin D levels. Both mutants should be useful in elucidating the pathophysiology of this poorly understood human disease.

The Hyp mouse is an established animal model of X-linked hypophosphatemia, one of the most common genetic forms of metabolic bone disease in humans. This study describes the first determination of whole bone mechanical behavior in the heterozygous male and female Hyp mouse. Femora from 12-week-old mice were tested in torsion. The contribution of structural and material properties to mechanical behavior was determined by geometrical evaluation prior to testing and by analysis of the diaphyseal mineral after testing. The male and female Hyp femora were found to undergo significantly more angular deformation at failure than the same sex normal femora (36.02 ± 10.64 vs. 9.88 ± 3.50 rad/m for the females and 56.29 ± 16.18 vs. 9.95 ± 3.16 rad/m for the males) and to have a significantly lower structural stiffness (0.854 ± 0.297 x 10 -3 vs. 3.04 ± 0.87 x 10 -3 [N-m/(rad/m)] for the females and 0.382 ± 0.239 x 10 -3 vs. 3.66 ± 1.15 x 10 -3 [N-m/(rad/m)] for the males). The male Hyp femora had a significantly lower failure torque than male normal femora (1.58 ± 0.62 x 10 -2 vs. 3.44 ± 1.57 x 10 -2 N-m). Because the polar movement of inertia, a geometrical property that affects torsional behavior, was not significantly different between the Hyp femora and the same sex normals, differences in mechanical behavior were attributed to material properties. Ground Hyp diaphyseal bone had a significantly lower mineral (ash) content (59.94 ± 2.07% vs. 68.88 ± 0.68% for the females and 56.09 ± 0.17% vs. 68.41 ± 0.65% for the males) and a higher calcium-to-phosphorus molar ratio (1.672 ± 0.008 vs. 1.621 ± 0.012 for the females and 1.692 ± 0.002 vs. 1.625 ± 0.022 for the males) than the same sex normal bones. A reduction in carbonate content of the mineral in the Hyp femora was also noted. These results are indicative of increased bone turnover. In addition, the mineral content of the Hyp female femora was significantly greater than that of the Hyp male femora. Analysis by Fourier transform infrared microscopy in conjunction with light microscopy and scanning electron microscopy revealed hypomineralized periosteocytic and perivascular lesions in the Hyp femora that penetrated through the endosteal and periosteal surfaces. It was concluded that the altered mechanical properties of the Hyp femora are attributed to the reduced quantity and quality of mineral.

XLH is an important disease, it is the subject of several classic articles in the medical sciences (Scriver et al., 1991), and it has been an important stimulus to study renal hypophosphatemias and how they are involved in rickets and osteomalacia (Scriver, 1974; Scriver and Tenenhouse, 1991). Renal transport is the major determinant of phosphate homeostasis in mammals and it is unlikely that this important biochemical parameter would have been left by evolution to a single renal transport system. Together physiologists and geneticists found that the mammalian kidney has several gene products dedicated to phosphate transport. That has implications for biochemists in search of a membrane protein to clone and explain XLH, for example. Let us suppose the transporter affected in XLH is cloned. Will it be the product of the XLH (or Hyp or Gy) locus? One will not know until the transporter gene is mapped. There is no question of the X-chromosome locus product being protein kinase C for example, since it maps to autosomes. But where does one start in the search for the X-chromosome locus? With the elusive putative diffusible factor or with the transporter, or perhaps with an enzyme in vitamin D hormone metabolism? Which goes to say that it is necessary to know the phenotype to arrive at the right locus. Or is it? Sufficient physical mapping of region Xp22.31-p21.3 will eventually lead to positional cloning of the Hyp gene. What will it be?(ABSTRACT TRUNCATED AT 250 WORDS)