Rachitismo ipofosforemico X-linked

2020 ◽  
Vol 39 (7) ◽  
pp. 430-436
Author(s):  
Laura Lucchetti ◽  
Francesco Emma ◽  
Danilo Fintini ◽  
Marco Cappa
Keyword(s):  
Clinical Symptoms ◽  
Fibroblast Growth Factor 23 ◽  
Vitamin D Supplementation ◽  
Elevated Alkaline Phosphatase ◽  
Dihydroxyvitamin D ◽  
Igg1 Monoclonal Antibody ◽  
Physical Dysfunction ◽  
Phex Gene ◽  
Fgf 23 ◽  
Phosphate Salts

X-linked hypophosphatemia (XLH) is an X-linked disorder with dominant penetration, caused by mutations in the PHEX gene, which encodes for an endopeptidase that is predominantly expressed in osteoblasts, osteocytes and odontoblasts. PHEX mutations cause increased production of fibroblast growth factor 23 (FGF23) that in turn leads to hypophosphatemia by causing inhibition of the renal phosphate reabsorption and of the synthesis of active 1,25-dihydroxyvitamin D. In children XLH is characterised by rickets, bone pain, physical dysfunction, impaired growth, disproportionate short stature, lowerlimb deformities, pathological fractures, dental malposition and dental abscesses. Although phenotype may be variable in severity, early diagnosis and treatment are critical to improve outcome. Laboratory tests show hypophosphatemia associated with hyperphosphaturia and elevated alkaline phosphatase, while parathormone and calcium levels are normal. For decades, patients have been treated with conventional therapy, including active vitamin D supplementation and fractionated daily doses of oral phosphate salts. However, these therapies rarely normalise the phenotype. More recently, burosumab, a recombinant human IgG1 monoclonal antibody against FGF-23, has been introduced for the treatment of XLH. In phase 2 trials, burosumab has been shown to improve significantly clinical symptoms, as well as biological and radiological signs of rickets.

scholarly journals Diagnosis and management of X-linked hypophosphatemia in children and adolescent in the Gulf Cooperation Council countries

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Fahad Al Juraibah ◽  
Elham Al Amiri ◽  
Mohammed Al Dubayee ◽  
Jamal Al Jubeh ◽  
Hessa Al Kandari ◽  
...  
Keyword(s):  
United Arab Emirates ◽  
Fibroblast Growth Factor 23 ◽  
Gulf Cooperation Council ◽  
Hypophosphatemic Rickets ◽  
Etiologic Factor ◽  
Children And Adolescent ◽  
Dihydroxyvitamin D ◽  
Inappropriate Treatment ◽  
Igg1 Monoclonal Antibody ◽  
Wrong Diagnosis

Abstract Introduction X-linked hypophosphatemia (XLH) is a rare inherited cause of hypophosphatemic rickets and osteomalacia. It is caused by mutations in the phosphate-regulating endopeptidase homolog, X-linked (PHEX). This results in increased plasma fibroblast growth factor-23 (FGF23), which leads to loss of renal sodium-phosphate co-transporter expression leading to chronic renal phosphate excretion. It also leads to low serum 1,25-dihydroxyvitamin D (1,25(OH)2D), resulting in impaired intestinal phosphate absorption. Chronic hypophosphatemia in XLH leads to impaired endochondral mineralization of the growth plates of long bones with bony deformities. XLH in children and adolescents also causes impaired growth, myopathy, bone pain, and dental abscesses. XLH is the most frequent inherited cause of phosphopenic rickets/osteomalacia. Hypophosphatemia is also found in calcipenic rickets/osteomalacia as a result of secondary hyperparathyroidism. Thus, chronic hypophosphatemia is a common etiologic factor in all types of rickets. Results There is considerable overlap between symptoms and signs of phosphopenic and calcipenic rickets/osteomalacia. Wrong diagnosis leads to inappropriate treatment of rickets/osteomalacia. Nutritional rickets and osteomalacia are common in the Gulf Cooperation Council countries which include Saudi Arabia, United Arab Emirates, Kuwait, Qatar, Bahrain, and Oman. Due to high levels of consanguinity in the region, genetic causes of phosphopenic and calcipenic rickets/osteomalacia are also common. Conclusion This guideline was developed to provide an approach to the diagnosis of XLH, especially where there is no family history of the disease, and that other related conditions are not mistaken for XLH. We also guide the medical management of XLH with conventional treatment and with burosumab, a recombinant human IgG1 monoclonal antibody to FGF23.

scholarly journals An Overview of FGF-23 as a Novel Candidate Biomarker of Cardiovascular Risk

2021 ◽  
Vol 12 ◽  
Author(s):  
Sara Vázquez-Sánchez ◽  
Jonay Poveda ◽  
José Alberto Navarro-García ◽  
Laura González-Lafuente ◽  
Elena Rodríguez-Sánchez ◽  
...  
Keyword(s):  
Cardiovascular Risk ◽  
Cardiac Fibrosis ◽  
Cardiac Tissue ◽  
Current Knowledge ◽  
Fibroblast Growth Factor 23 ◽  
Experimental Studies ◽  
High Plasma ◽  
Fgf Receptor ◽  
Dihydroxyvitamin D ◽  
Fgf 23

Fibroblast growth factor-23 (FGF)-23 is a phosphaturic hormone involved in mineral bone metabolism that helps control phosphate homeostasis and reduces 1,25-dihydroxyvitamin D synthesis. Recent data have highlighted the relevant direct FGF-23 effects on the myocardium, and high plasma levels of FGF-23 have been associated with adverse cardiovascular outcomes in humans, such as heart failure and arrhythmias. Therefore, FGF-23 has emerged as a novel biomarker of cardiovascular risk in the last decade. Indeed, experimental data suggest FGF-23 as a direct mediator of cardiac hypertrophy development, cardiac fibrosis and cardiac dysfunction via specific myocardial FGF receptor (FGFR) activation. Therefore, the FGF-23/FGFR pathway might be a suitable therapeutic target for reducing the deleterious effects of FGF-23 on the cardiovascular system. More research is needed to fully understand the intracellular FGF-23-dependent mechanisms, clarify the downstream pathways and identify which could be the most appropriate targets for better therapeutic intervention. This review updates the current knowledge on both clinical and experimental studies and highlights the evidence linking FGF-23 to cardiovascular events. The aim of this review is to establish the specific role of FGF-23 in the heart, its detrimental effects on cardiac tissue and the possible new therapeutic opportunities to block these effects.

Circulating Levels of Dickkopf-Related Protein 1 Decrease as Measured GFR Declines and Are Associated with PTH Levels

2020 ◽  
Vol 51 (11) ◽  
pp. 871-880
Author(s):  
Corey M. Forster ◽  
Christine A. White ◽  
Mandy E. Turner ◽  
Patrick A. Norman ◽  
Emilie C. Ward ◽  
...  
Keyword(s):  
Bone Disease ◽  
Mineral Metabolism ◽  
Early Stage ◽  
Fibroblast Growth Factor 23 ◽  
Vitamin D Metabolites ◽  
Related Protein ◽  
Clinical Indicators ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Fgf 23

<b><i>Background:</i></b> The Wnt/β-catenin pathway has been implicated in the development of adynamic bone disease in early-stage chronic kidney disease (CKD). Dickkopf-related protein 1 (DKK1) and sclerostin are antagonists of the Wnt/β-catenin pathway yet have not been widely used as clinical indicators of bone disease. This study characterized levels of DKK1, sclerostin, and other biomarkers of mineral metabolism in participants across a spectrum of inulin-measured glomerular filtration rate (GFR). <b><i>Methods:</i></b> GFR was measured by urinary inulin clearance (mGFR) in 90 participants. Blood samples were obtained for measurement of circulating DKK1, sclerostin, fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), calcium, phosphate, α-klotho, and vitamin D metabolites including 25-hydroxyvitamin D<sub>3</sub> and 1,25-dihydroxyvitamin D<sub>3</sub>. Spearman correlations and linear regressions were used where appropriate to examine the associations between measured values. <b><i>Results:</i></b> The median [IQR] age was 64 years [53.0–71.0], and the median [IQR] mGFR was 32.6 [21.7–60.6] mL/min. DKK1 decreased (<i>r</i> = 0.6, <i>p</i> &#x3c; 0.001) and sclerostin increased (<i>r</i> = −0.4, <i>p</i> &#x3c; 0.001) as kidney function declined, and both were associated with phosphate, PTH, FGF-23, and 1,25-dihydroxyvitamin D<sub>3</sub> in the unadjusted analysis. After adjustment for age and mGFR, DKK1 remained significantly associated with PTH. <b><i>Conclusion:</i></b> The results of this study demonstrate opposing trends in Wnt/β-catenin pathway inhibitors, DKK1 and sclerostin, as mGFR declines. Unlike sclerostin, DKK1 levels decreased significantly as mGFR declined and was independently associated with PTH. Future studies should determine whether measurement of Wnt signaling inhibitors may be useful in predicting bone histomorphometric findings and important clinical outcomes in patients with CKD.

scholarly journals Hypophosphatemic rickets and osteomalacia

2006 ◽  
Vol 50 (4) ◽  
pp. 802-813 ◽  
Author(s):  
Hamilton de Menezes Filho ◽  
Luiz Claudio G. de Castro ◽  
Durval Damiani
Keyword(s):  
Current Knowledge ◽  
Bone Mineralization ◽  
Fibroblast Growth Factor 23 ◽  
Hypophosphatemic Rickets ◽  
Activating Mutations ◽  
Metabolism Regulation ◽  
Autosomal Dominant Hypophosphatemic Rickets ◽  
Phex Gene ◽  
Fgf 23 ◽  
Increased Activity

The hypophosphatemic conditions that interfere in bone mineralization comprise many hereditary or acquired diseases, all of them sharing the same pathophysiologic mechanism: reduction in the phosphate reabsorption by the renal tubuli. This process leads to chronic hyperphosphaturia and hypophosphatemia, associated with inappropriately normal or low levels of calcitriol, causing osteomalacia or rickets in children and osteomalacia in adults. X-linked hypophosphatemic rickets, autosomal-dominant hypophosphatemic rickets, and tumor-induced osteomalacia are the main syndromes involved in the hypophosphatemic rickets. Although these conditions exhibit different etiologies, there is a common link among them: increased activity of a phosphaturic factor, being the fibroblast growth factor 23 (FGF-23) the most studied one and to which is attributed a central role in the pathophysiology of the hyperphosphaturic disturbances. Activating mutations of FGF-23 and inactivating mutations in the PHEX gene (a gene on the X chromosome that codes for a Zn-metaloendopeptidase proteolytic enzyme which regulates the phosphate) involved in the regulation of FGF-23 have been identified and have been implicated in the pathogenesis of these disturbances. Genetic studies tend to show that the phosphorus homeostasis depends on a complex osteo-renal metabolic axis, whose mechanisms of interaction have been poorly understood so far. This paper reviews the current knowledge status concerning the pathophysiology of phosphate metabolism regulation and the pathophysiologic basis of hypophosphatemic rickets. It also analyzes the clinical picture and the therapeutic aspects of these conditions as well.

scholarly journals X-Linked Hypophosphatemia: A New Era in Management

2020 ◽  
Vol 4 (12) ◽  
Author(s):  
Kathryn Dahir ◽  
Mary Scott Roberts ◽  
Stan Krolczyk ◽  
Jill H Simmons
Keyword(s):  
Fibroblast Growth Factor 23 ◽  
Treatment Options ◽  
Human Monoclonal Antibody ◽  
Loss Of Function ◽  
Active Vitamin ◽  
New Era ◽  
Dihydroxyvitamin D ◽  
Conventional Management ◽  
Phex Gene

Abstract X-linked hypophosphatemia (XLH) is a rare, hereditary, progressive musculoskeletal disease that often causes pain and short stature, as well as decreased physical function, mobility, and quality of life. Hypophosphatemia in XLH is caused by loss of function mutations in the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene, resulting in excess levels of the phosphate-regulating hormone fibroblast growth factor 23 (FGF23), which leads to renal phosphate wasting and decreased serum 1,25-dihydroxyvitamin D production. Historically, treatment options were limited to oral phosphate and active vitamin D analogues (conventional management) dosed several times daily in an attempt to improve skeletal mineralization by increasing serum phosphorus. The recent approval of burosumab, a fully human monoclonal antibody to FGF23, has provided a new, targeted treatment option for patients with XLH. This review summarizes our current understanding of XLH, the safety and efficacy of conventional management and burosumab, existing recommendations for managing patients, and unanswered questions in the field.

scholarly journals Dietary and Serum Phosphorus Regulate Fibroblast Growth Factor 23 Expression and 1,25-Dihydroxyvitamin D Metabolism in Mice

Endocrinology ◽  
2005 ◽  
Vol 146 (12) ◽  
pp. 5358-5364 ◽  
Author(s):  
Farzana Perwad ◽  
Nasreen Azam ◽  
Martin Y. H. Zhang ◽  
Takeyoshi Yamashita ◽  
Harriet S. Tenenhouse ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Fold Increase ◽  
Mrna Abundance ◽  
Fibroblast Growth ◽  
Calvarial Bone ◽  
Vitamin D Metabolism ◽  
Dihydroxyvitamin D ◽  
Fgf 23

Fibroblast growth factor-23 (FGF-23) is a novel circulating peptide that regulates phosphorus (Pi) and vitamin D metabolism, but the mechanisms by which circulating FGF-23 itself is regulated are unknown. To determine whether the serum FGF-23 concentration is regulated by dietary intake of Pi, we fed wild-type (WT), Npt2a gene-ablated (Npt2a−/−), and Hyp mice diets containing varying Pi contents (0.02–1.65%). In WT mice, increases in dietary Pi intake from 0.02–1.65% induced a 7-fold increase in serum FGF-23 and a 3-fold increase in serum Pi concentrations. Across the range of dietary Pi, serum FGF-23 concentrations varied directly with serum Pi concentrations (r2 = 0.72; P &lt; 0.001). In Npt2a−/− mice, serum FGF-23 concentrations were significantly lower than in WT mice, and these differences could be accounted for by the lower serum Pi levels in Npt2a−/− mice. The serum concentrations of FGF-23 in Hyp mice were 5- to 25-fold higher than values in WT mice, and the values varied with dietary Pi intake. Fgf-23 mRNA abundance in calvaria was significantly higher in Hyp mice than in WT mice on the 1% Pi diet; in both groups of mice, fgf-23 mRNA abundance in calvarial bone was suppressed by 85% on the low (0.02%) Pi diet. In WT mice fed the low (0.02%) Pi diet, renal mitochondrial 1α-hydroxylase activity and renal 1α-hydroxylase (P450c1α) mRNA abundance were significantly higher than in mice fed the higher Pi diets and varied inversely with serum FGF-23 concentrations (r2 = 0.86 and r2 = 0.64; P &lt; 0.001, respectively). The present data demonstrate that dietary Pi regulates the serum FGF-23 concentration in mice, and such regulation is independent of phex function. The data suggest that genotype-dependent and dietary Pi-induced changes in the serum FGF-23 concentration reflect changes in fgf-23 gene expression in bone.

scholarly journals PENGARUH PEMBERIAN 1,25 DIHYDROXYVITAMIN D (CALCITRIOL) TERHADAP KADAR FIBROBLAST GROWTH FACTOR-23 DAN ALBUMINURIA PADA PASIEN PENYAKIT GINJAL KRONIK STADIUM V YANG MENJALANI HEMODIALISIS

Biomedika ◽  
2017 ◽  
Vol 9 (1) ◽  
Author(s):  
Intan Herlina ◽  
Bambang Purwanto ◽  
Sugiarto Sugiarto
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Drop Out ◽  
Fibroblast Growth ◽  
Angiotensin I ◽  
Chi Square ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Fgf 23

Penyebab utama morbiditas dan mortalitas pada pasien Penyakit Ginjal Kronik adalah insiden kardiovaskuler yang didasari oleh proses aterosklerosis yang menyebabkan meningkatnya morbiditas dan mortalitas. Ginjal merupakan tempat utama sintesa 1,25 Dihydroxyvitamin D (Calcitriol), sehingga dengan adanya kerusakan ginjal menyebabkan defisiensi 1,25 Dihydroxyvitamin D (Calcitriol). Pada pasien Penyakit Ginjal Kronik terjadi peningkatan Fibroblast Growth Factor-23 dan Albuminuria akibat dari aktifitas Renin Angiotensin Aldosteron Sistem. Aktifitas RAAS mempengaruhi 1,25 Dihydroxy vitamin D (Calcitriol), Fibroblast Growth Factor-23 melalui Angiotensin 2 dengan cara menghambat reseptor Angiotensin I (AT1) melalui Nicotinmide Adenine Dinucleotide Phosphate Oxidase (NADPH Oksidase) dan Stress Oxidativ. Beberapa penelitian menyimpulkan pemberian 1,25 Dihydroxyvitamin D (Calcitriol) mempunyai efek renoprotektif, anti inflamasi dan antiproteinuric dengan cara menghambat reseptor Angoitensin I (AT1) sehingga mengakibatkan menurunnya albuminuria. Tujuan Penelitian ini adalah untuk membuktikan pemberian 1,25 Dihydroxyvitamin D (Calcitriol) dapat menurunkan kadar Fibroblas Growth Factor-23 dan albuminuria pada pasien Penyakit Ginjal Kronik stadium V yang menjalani hemodialisis. Penelitian ini merupakan penelitian eksperimen dengan randomisasi, subyek penelitian 30 orang, dibagi dalam dua kelompok sampel, kelompok plasebo 15 orang dan kelompok perlakuan 15 orang. Dalam perjalanan, kelompok placebo drop out 4 pasien karena keluarga pasien tidak menyetujui untuk melanjutkan penelitian dan satu lagi mengalami perburukan, sehingga jumlah sampel menjadi 26 orang, terbagi menjadi kelompok placebo sebanyak 11 orang yang diberi placebo dan kelompok perlakuan 15 orang diberi calcitriol 1x0,5 μg peroral selama 4 minggu. Karakteristik penelitian yang berupa variabel kualitatif, uji homogenitas dilakukan menggunakan uji Chi Square. Uji beda dua Rerata menggunakan uji t pada p<0.005. Pada kelompok plasebo (n=11) ; Kadar Fibroblast Growth Factor-23 sebelum dan sesudah perlakuan (876,24±795,93 RU/mL vs 1235,69±791,71 RU/mL; p=0,059) dan Albuminuria (72,30±195,06 μg/ mg vs 320,14±208,90 μg/mg; p=0,001). Pada kelompok perlakuan (n=15); Kadar Fibroblast Growth Factor-23 sebelum dan sesudah perlakuan (1210,96±845,97 RU/mL vs 612,33±487,32 RU/mL; p=0,002) dan Albuminuria (206,63±327,25 μg/mg vs 192,89±316,00 μg/mg; p=0,001). Terdapat perbedaan yang bermakna pada selisih ratarata kadar Fibroblast Growth Factor-23 (Delta-FGF-23) sebelum dan sesudah perlakuan pada kelompok placebo vs kelompok perlakuan (-359,45±560,23 RU/mL vs 598,63±608,27 RU/mL; p=0,001) dan selisih rata-rata Albuminuria (Delta-albuminuria) sebelum dan sesudah perlakuan pada kelompok placebo vs kelompok perlakuan (-247,84±189,48 μg/mg vs 13,73±23,15μg/mg;p=0,001. Pemberian suplementasi 1,25 Dihydroxyvitamin D (calcitriol) menurunkan kadar FGF-23 albuminuria secara bermakna pada pasien penyakit ginjal kronik stadium V yang menjalani hemodialisisKata Kunci: Penyakit Ginjal Kronis Stadium V, 1,25 Dihydroxyvitamin D (Calcitriol), Fibroblast Growth Factor-23, Albuminuria

scholarly journals THU0421 TUMOR-INDUCED OSTEOMALACIA: DATA FROM A MONOCENTRIC EXPERIENCE ON 16 PATIENTS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 448.2-449
Author(s):  
C. Crotti ◽  
F. Bartoli ◽  
M. Manara ◽  
P. A. Daolio ◽  
F. Zucchi ◽  
...  
Keyword(s):  
Functional Imaging ◽  
Serum Alkaline Phosphatase ◽  
Fibroblast Growth Factor 23 ◽  
Diagnostic Delay ◽  
The Body ◽  
Definitive Treatment ◽  
Surgical Removal ◽  
Tumor Biopsy ◽  
Pet Ct ◽  
Fgf 23

Background:Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome due to a phosphaturic tumor, which overproduces fibroblast growth factor-23 (FGF-23), causing hyperphosphaturia, hypophosphoremia, low 1,25(OH)2VitD3and osteomalacia. Locating the tumor is critical, because lesions are typically small, benign mesenchymal tumors, anywhere in the body; the delay between onset of symptoms and diagnosis ranges from 2.5–28 years. Surgical removal is the only effective therapeutic approach.Objectives:To retrospectively evaluate patients affected by TIO, investigating clinical management and disease outcome.Methods:We retrospectively collected data of patients affected by TIO referred to a tertiary Rheumatology Center between Sep 2000 and Jan 2020.Results:We included 16 patients with a definite diagnosis of TIO, mean age±standard deviation 62.4±14.6 yrs, 56.2% females, mean age at symptoms onset 48.0±14.3 yrs (53.8±13.1 at diagnosis). Mean diagnostic delay between symptoms onset and tumor detection was 6.8±6.4 yrs. All patients complained bone pain, muscle weakness, and fractures before diagnosis of TIO. Biochemical findings were: mean serum Phosphorus (PS) 1.4±0.4 mg/dL (reference range (RR) 2.5-4.6), mean serum Calcium 9.4±0.7 mg/dL (RR 8.4-10.2), mean serum 1,25(OH)2VitD330.5±23.4 ng/L (RR 25-86). Intact-FGF-23 was dosed in 9 patients, always resulting elevated: mean 396.6±707.3 pg/mL (RR 25-45). PTH was increased in 30% of cases, while serum alkaline phosphatase was increased in 87.5%. 24h-Urine Phosphorus (PU) was increased in only 13% of patients, but, when renal phosphate wasting by tubular reabsorption of phosphate (TRP) was calculated, PU resulted increased in all.Tumor was localized in all cases (Fig.1) and were localized in bone and soft tissue, by using functional imaging, followed by anatomical techniques. Before the introduction in routinely practice of68Ga-DOTATATE-PET-CT in 2013, Octreoscan-SPECT/CT and18F FDG-PET were used as imaging modalities. Since 2013, diagnostic delay consistently reduced, from 8.6±8.3 yrs (7 patients) to 4.5±2.6 yrs (9 patients), confirming higher diagnostic accuracy of68Ga-DOTATATE-PET-CT.Figure 1.13 patients underwent surgery; in two cases surgery was not possible due to tumor location, so pharmacological support with phosphate supplements and calcitriol was started; a patient underwent to TC-guided radiofrequency ablation. After surgery, 7 patients experienced a complete remission, 3 had a persistence of the disease, and 3 an overtime relapse, even after a longstanding normalization of PS (6 years). After surgical tumor removal, PS significantly increased in few days (from 1.36±0.39 to 2.9±1.1, p=0.0001), while iFGF-23 levels tended to rapidly decreased (from 396.6±707.3 to 62.8±78.4). Before the introduction of68Ga-DOTATATE-PET-CT, 6 patients underwent to imaging-guided closed biopsy to confirm tumor localization; by using68Ga-DOTATATE-PET-CT only 2 subjects had closed biopsy. Furthermore, in our population only patients who had biopsy to detect the lesion (7 patients) had relapses compared to patients who did not.Conclusion:To our knowledge, this is the widest European cohort of patients affected by TIO reported in the last two decades. We confirm an important delay between symptoms onset and diagnosis. To locate tumor, a stepwise approach is recommended, starting with a thorough medical history and physical examination, followed by functional imaging, preferring68Ga-DOTATATE-PET-CT. Tumor biopsy is not recommended due to the potential cell spilling. Surgery is considered the only definitive treatment, aiming to a wider excision. Active surveillance is always needed, due to the possible relapses, even after a long period of complete clinical and biochemical remission.Disclosure of Interests: :Chiara Crotti: None declared, Francesca Bartoli: None declared, Maria Manara Consultant of: Consultant and/or speaker for Eli-Lilly, MSD, Sanofi-Genzyme, Novartis, Alfa Wasserman and Cellgene, Speakers bureau: Consultant and/or speaker for Eli-Lilly, MSD, Sanofi-Genzyme, Novartis, Alfa Wasserman and Cellgene, Primo Andrea Daolio: None declared, Francesca Zucchi: None declared, Roberto Caporali Consultant of: AbbVie; Gilead Sciences, Inc.; Lilly; Merck Sharp & Dohme; Celgene; Bristol-Myers Squibb; Pfizer; UCB, Speakers bureau: Abbvie; Bristol-Myers Squibb; Celgene; Lilly; Gilead Sciences, Inc; MSD; Pfizer; Roche; UCB, Luigi Sinigaglia: None declared, Massimo Varenna: None declared

scholarly journals The Metabolic Bone Disease X-linked Hypophosphatemia: Case Presentation, Pathophysiology and Pharmacology

Life ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 563
Author(s):  
Jon Vincze ◽  
Brian W. Skinner ◽  
Katherine A. Tucker ◽  
Kory A. Conaway ◽  
Jonathan W. Lowery ◽  
...  
Keyword(s):  
Vitamin D ◽  
Biological Effects ◽  
Fibroblast Growth Factor 23 ◽  
Elevated Serum ◽  
Fractional Excretion ◽  
The United States ◽  
Vitamin D Supplementation ◽  
Loss Of Function ◽  
Case Presentation ◽  
Serum Inorganic Phosphate

The authors present a stereotypical case presentation of X-linked hypophosphatemia (XLH) and provide a review of the pathophysiology and related pharmacology of this condition, primarily focusing on the FDA-approved medication burosumab. XLH is a renal phosphate wasting disorder caused by loss of function mutations in the PHEX gene (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). Typical biochemical findings include elevated serum levels of bioactive/intact fibroblast growth factor 23 (FGF23) which lead to (i) low serum phosphate levels, (ii) increased fractional excretion of phosphate, and (iii) inappropriately low or normal 1,25-dihydroxyvitamin D (1,25-vitD). XLH is the most common form of heritable rickets and short stature in patients with XLH is due to chronic hypophosphatemia. Additionally, patients with XLH experience joint pain and osteoarthritis from skeletal deformities, fractures, enthesopathy, spinal stenosis, and hearing loss. Historically, treatment for XLH was limited to oral phosphate supplementation, active vitamin D supplementation, and surgical intervention for cases of severe bowed legs. In 2018, the United States Food and Drug Administration (FDA) approved burosumab for the treatment of XLH and this medication has demonstrated substantial benefit compared with conventional therapy. Burosumab binds circulating intact FGF23 and blocks its biological effects in target tissues, resulting in increased serum inorganic phosphate (Pi) concentrations and increased conversion of inactive vitamin D to active 1,25-vitD.

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