Autosomal Dominant Hypophosphatemic Rickets Research Articles

Acquired Forms of Fibroblast Growth Factor 23-Related Hypophosphatemic Osteomalacia.

Fibroblast growth factor 23 (FGF23) is a pivotal humoral factor for the regulation of serum phosphate levels and was first identified in patients with autosomal dominant hypophosphatemic rickets and tumor-induced osteomalacia (TIO), the most common form of acquired FGF23-related hypophosphatemic rickets/osteomalacia (FGF23rHR). After the identification of FGF23, many other inherited and acquired forms of FGF23rHR were reported. In this review article, the detailed features of each acquired FGF23rHR are discussed, including TIO, ectopic FGF23 syndrome with malignancy, fibrous dysplasia/McCune-Albright syndrome, Schimmelpenning-Feuerstein-Mims syndrome/cutaneous skeletal hypophosphatemia syndrome, intravenous iron preparation-induced FGF23rHR, alcohol consumption-induced FGF23rHR, and post-kidney transplantation hypophosphatemia. Then, an approach for the differential diagnosis and therapeutic options for each disorder are concisely introduced. Currently, the majority of endocrinologists might only consider TIO when encountering patients with acquired FGF23rHR; an adequate differential diagnosis can reduce medical costs and invasive procedures such as positron emission tomography/computed tomography and venous sampling to identify FGF23-producing tumors. Furthermore, some acquired FGF23rHRs, such as intravenous iron preparation/alcohol consumption-induced FGF23rHR, require only cessation of drugs or alcohol to achieve full recovery from osteomalacia.

Bone characteristics of autosomal dominant hypophosphatemic rickets patients.

Autosomal dominant hypophosphatemic rickets (ADHR) is a rare disease caused by activating mutations in fibroblast growth factor 23 (FGF23) gene. With FGF23 activation, ADHR is a good model to explore the effects of FGF23 on skeletal development and mineralization. However, the bone microarchitecture of ADHR patients is poorly investigated. This study aims to illustrate the bone properties of ADHR patients and clarify the effect of FGF23 on load bearing and non-load bearing bone. Bone microarchitectures of 11 ADHR subjects and sex- and age-matched healthy controls were analyzed by HR-pQCT. The effect of FGF23 mutations on load bearing and non-load bearing bone was explored by comparison of bone microarchitecture in distal radius and distal tibia. The BMD, bone microarchitecture and bone strength were compared between 7 ADHR patients and 7 age- and sex-matched XLH patients. Among 11 subjects with FGF23 mutations, 10 patients presented with obvious symptoms, five of which had received 1-3years of iron supplement, neutral phosphate, and calcitriol treatments. The symptomatic patients presented with low bone density and fractures in X rays, with decreased Z score of aBMD (L1-L4: -1.3±1.4, femoral neck: -2.1±1.8, total hip: -1.85±1.6). Compared with controls, HR-pQCT analysis of 5 untreated ADHR patients showed increased total area (+61.6%, p=0.03) and cortical perimeter (+17.2%, p=0.03) in distal radius. No significant differences were found in other parameters in distal radius. In distal tibia, the patients presented obvious defects in cancellous bone, with decreased trabecular vBMD (-62.9%, p=0.003), trabecular BV/TV (-48.7%, p=0.003) and trabecular number (-42.2%, p=0.001). The trabecular separation (+113.3%, p=0.007) and trabecular network inhomogeneity (+226.7%, p=0.001) were accordingly increased. In addition to another 5 treated patients, the bone microarchitecture changes revealed similar pattern, but the increase of total area and cortical perimeter in distal radius was no longer statistically significant. The non-symptomatic ADHR patient demonstrated slightly decreased total vBMD, trabecular vBMD and trabecular BV/TV in distal tibia. The changing pattern of bone geometry and microarchitecture of ADHR patients were similar to XLH patients but showed less deficit and stronger bone strength. ADHR patients presented increased total area and cortical perimeter in distal radius, and obvious defect in cancellous bone in distal tibia. FGF23 have impairment effect on trabecular bone especially in weight bearing site.

Monogenic causation of pediatric nephrolithiasis

Nephrolithiasis is a condition in which crystals precipitate out of the urine forming kidney stones in the renal calyces and pelvis. Approximately 80% of stones are composed of calcium oxalate and calcium phosphate. In recent years, there has been a significant increase in the prevalence of nephrolithiasis across populations, specifically in that of the pediatric population. The etiology of stone disease is multifactorial, and includes environmental, dietary, hormonal, and genetic factors. Evidence for monogenic causation (also known as Mendelian or single-gene disorders) in nephrolithiasis includes the finding that 30% of children with stone disease report a positive family history, with monogenic nephrolithiasis accounting for approximately 30% of cases. Monogenic nephrolithiasis can occur in isolation or may be the result of an underlying genetic disorder including autosomal dominant hypocalcemia (ADH), primary hyperoxalurias, and hereditary hypophosphatemic rickets with hypercalciuria (HHRH), to name a few. Currently, there are 41 known genes that represent monogenic causes of human nephrolithiasis. Since early detection of these mutations can in some cases prevent the progression to end stage kidney disease in pediatric patients, establishing the genetic basis for nephrolithiasis is increasingly important. Here we provide an overview of kidney stone disease in children with a focus on monogenic causation in the pediatric population.

PSAT228 Hereditary Hypophosphatemic Rickets: Management in Adults

Abstract Introduction Hereditary Hypophosphatemic Rickets (HHR) is a group of rare inherited disorders consisting of X-linked hypophosphatemic rickets (XLHR, prevalence 1 in 20,000 births), autosomal dominant hypophosphatemic rickets (ADHR), and autosomal recessive hypophosphatemic rickets (ARHR). XLHR is caused by loss of function mutation of the PHEX gene, ARHR is caused by loss of function mutation of the DMP1/ENPP1 gene and ADHR is caused by activating point mutations in FGF23. These mutations result in renal phosphate wasting, hypophosphatemia, and impaired bone mineralization. It presents in childhood as skeletal deformities, abnormal gait, skeletal pain, dental abnormalities, and stunted growth. Adults have osteomalacia-related pain, fractures, and arthritis. The diagnosis is made by findings consistent with rickets and normal serum calcium, normal 25-hydroxy vitamin D, low-normal 1,25-dihydroxy vitamin D, elevated alkaline phosphatase activity, and low phosphate levels. Urine studies show low urine calcium and decreased tubular maximum reabsorption of phosphate, confirming renal wasting of phosphate. The goal of treatment in adults is to reduce pain, prevent fractures, enhance mobility, and decrease osteomalacia. Phosphate and vitamin D supplementations are used with close monitoring as it is associated with severe adverse events. It can cause hypercalcemia leading to nephrocalcinosis, nephrolithiasis, chronic kidney disease, and hyperparathyroidism. There is no evidence that the treatment affects long-term skeletal complications. Burosumab, a monoclonal antibody that inhibits FGF23, is approved for the treatment of XLHR. No studies are available about the use of Burosumab in ADHR or ARHR. Case Presentation A 18-year-old male with past medical history of hypophosphatemic rickets with multiple fractures, on oral phosphate tablets and calcitriol, presented to the Endocrinology clinic to establish care. He had been following Pediatric Endocrinology in the past. His blood work showed normal calcium, low phosphate of 1.6 mg/dl (normal: 2.5-4.5 mg/dl), vitamin D 25 hydroxy level of 26 ng/ml (normal: 20-100 ng/ml), vitamin D 1,25-dihydroxy level of 25 pg/ml (normal: 30-80 pg/ml), intact parathyroid hormone level of 549 pg/ml (normal: 15-65 pg/ml), and alkaline phosphatase of 438 U/l (normal: 40-150 U/l). Urine calcium was low and urine phosphorus was elevated with phosphate/creatinine ratio more than 2000 (normal: 60-962), consistent with renal phosphate wasting. Genetic testing in the past was negative for PHEX gene mutation, so he was not a candidate for Burosumab. Conclusion There is limited knowledge about Hereditary Hypophosphatemic Rickets, especially ADHR and ARHR due to limited cases (less than 100 cases reported so far). The current standard of treatment of HHR is sub-optimal and associated with adverse effects. Burosumab has not been tested in ADHR or ARHR, so it is unclear if it will be beneficial in this subgroup. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Pathogenesis of FGF23-Related Hypophosphatemic Diseases Including X-linked Hypophosphatemia

Since phosphate is indispensable for skeletal mineralization, chronic hypophosphatemia causes rickets and osteomalacia. Fibroblast growth factor 23 (FGF23), which is mainly produced by osteocytes in bone, functions as the central regulator of phosphate metabolism by increasing the renal excretion of phosphate and suppressing the production of 1,25-dihydroxyvitamin D. The excessive action of FGF23 results in hypophosphatemic diseases, which include a number of genetic disorders such as X-linked hypophosphatemic rickets (XLH) and tumor-induced osteomalacia (TIO). Phosphate-regulating gene homologous to endopeptidase on the X chromosome (PHEX), dentin matrix protein 1 (DMP1), ectonucleotide pyrophosphatase phosphodiesterase-1, and family with sequence similarity 20c, the inactivating variants of which are responsible for FGF23-related hereditary rickets/osteomalacia, are highly expressed in osteocytes, similar to FGF23, suggesting that they are local negative regulators of FGF23. Autosomal dominant hypophosphatemic rickets (ADHR) is caused by cleavage-resistant variants of FGF23, and iron deficiency increases serum levels of FGF23 and the manifestation of symptoms in ADHR. Enhanced FGF receptor (FGFR) signaling in osteocytes is suggested to be involved in the overproduction of FGF23 in XLH and autosomal recessive hypophosphatemic rickets type 1, which are caused by the inactivation of PHEX and DMP1, respectively. TIO is caused by the overproduction of FGF23 by phosphaturic tumors, which are often positive for FGFR. FGF23-related hypophosphatemia may also be associated with McCune-Albright syndrome, linear sebaceous nevus syndrome, and the intravenous administration of iron. This review summarizes current knowledge on the pathogenesis of FGF23-related hypophosphatemic diseases.

Tumor-Induced Osteomalacia With Normal Fibroblast Growth Factor-23 (FGF23) and Idiopathic Hypercalciuria

Tumor-induced osteomalacia (TIO) is a rare acquired paraneoplastic syndrome characterized by low serum phosphate, phosphaturia, inappropriately low/normal levels of serum calcitriol, and normal or elevated levels of fibroblast growth factor-23 (FGF23). Finding this mesenchymal tumor is challenging since it is usually benign, small, slow-growing, and is localized in the appendicular skeleton. We report a 58-year-old male patient who arrived at the endocrinology outpatient clinic due to slowly progressive low back pain and generalized weakness since the age of 48. On physical examination, only a reduced range of motion was noted. Laboratory tests revealed hypophosphatemia with normal parathyroid hormone (PTH) levels, normal serum calcium, high 24-hour urine calcium, normal 1,25-dihydroxyvitaminD levels, low renal threshold phosphate concentration (TmPO4/GFR), and high FGF23. The 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) reported a hypermetabolic extramedullary lesion in the C1-C2 vertebral bodies measuring 1.5 x 1.1 cm. Two months after the 18F-FDG PET/CT, complete excision of the cervical tumor was performed. The pathology ward reported a histiocytic mesenchymal neoplasm with accumulations of multinucleated giant cells compatible with phosphaturic mesenchymal tumor. After surgery, the patient’s hypophosphatemia was completely resolved. With this, the diagnosis of TIO was confirmed. The patient remains asymptomatic, with normal phosphate levels at one year of follow-up. Hypophosphatemia due to renal losses in an adult patient is a challenging diagnosis and one must consider TIO, autosomal dominant hypophosphatemic rickets, fibrous dysplasia, and even Fanconi syndrome. FGF23 can be extremely useful during the diagnostic approach since acquired dependent hypophosphatemia (FGF23 ≥ 30 RU/mL) highly suggests TIO. In this case report, we want to highlight the paramount importance of adequate tumor screening in adult patients with acquired FGF23-dependent hypophosphatemia. TIO is a reversible cause of hypophosphatemia with potentially disabling consequences if left untreated. These manifestations are non-specific (bone pain and muscle weakness), while others are progressive and severely disabling (bone deformities and multiple fractures). In this case report, we want to highlight the paramount importance of adequate tumor screening in adult patients with acquired hypophosphatemia, and the crucial lead that phosphate and vitamin D regulating hormones (FGF23) have for suspecting TIO.

The Bone Characteristics of Autosomal Dominant Hypophosphatemic Rickets Patients

The Bone Characteristics of Autosomal Dominant Hypophosphatemic Rickets Patients

Jury still out on whether FGF23 is a direct contributor, a useful biomarker, or neither

Fibroblast growth factor 23 (FGF23) is an endocrine hormone that is mainly produced by osteocytes. In patients with chronic kidney disease (CKD), circulating FGF23 levels increase as kidney function declines. This helps maintain normal phosphate balance by enhancing urinary phosphate excretion. As a trade-off, it suppresses biosynthesis of 1,25-dihydroxyvitamin D, favoring the early development of secondary hyperparathyroidism. Besides these canonical renal actions, FGF23 has been identified as an independent predictor of mortality, cardiovascular disease, and other adverse outcomes. 1 Gutiérrez O.M. Mannstadt M. Isakova T. et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med. 2008; 359: 584-592 Crossref PubMed Scopus (1402) Google Scholar , 2 Chonchol M. Greene T. Zhang Y. et al. Low vitamin D and high fibroblast growth factor 23 serum levels associate with infectious and cardiac deaths in the HEMO study. J Am Soc Nephrol. 2016; 27: 227-237 Crossref PubMed Scopus (102) Google Scholar , 3 Komaba H. Fuller D.S. Taniguchi M. et al. Fibroblast growth factor 23 and mortality among prevalent hemodialysis patients in the Japan Dialysis Outcomes and Practice Patterns Study. Kidney Int Rep. 2020; 5: 1956-1964 Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar , 4 Wolf M. Molnar M.Z. Amaral A.P. et al. Elevated fibroblast growth factor 23 is a risk factor for kidney transplant loss and mortality. J Am Soc Nephrol. 2011; 22: 956-966 Crossref PubMed Scopus (226) Google Scholar , 5 Marthi A. Donovan K. Haynes R. et al. Fibroblast growth factor-23 and risks of cardiovascular and noncardiovascular diseases: a meta-analysis. J Am Soc Nephrol. 2018; 29: 2015-2027 Crossref PubMed Scopus (106) Google Scholar Experimental data suggest a direct link between FGF23 and multiple organ injury, particularly cardiac hypertrophy, 6 Grabmer A. Amaral A.P. Schramm K. et al. Activation of cardiac fibroblast growth factor receptor 4 causes left ventricular hypertrophy. Cell Metab. 2015; 22: 1020-1032 Abstract Full Text Full Text PDF Scopus (360) Google Scholar which provides biological plausibility to support the observational findings. Despite these seemingly compelling data, however, it remains unclear whether FGF23 has a causal role in adverse events and whether FGF23 serves as a useful predictor of poor outcomes or a reliable biomarker of disordered phosphate metabolism. In this article, we present various arguments that plead against the role of FGF23 as a causal actor in CKD-associated pathologies. Cardiac hypertrophy elevates serum levels of fibroblast growth factor 23Kidney InternationalVol. 94Issue 1PreviewSeveral experimental studies have shown that fibroblast growth factor 23 (FGF23) induces left ventricular hypertrophy (LVH). However, the opposite directional relationship, namely a potential effect of LVH on FGF23, remains uncertain. Here we evaluated the effects of LVH on FGF23 using cardiomyocyte-specific calcineurin A transgenic mice. At six weeks, these mice showed severe LVH, with elevated levels of serum intact FGF23. FGF23 levels were elevated in cardiomyocytes, but not osteocytes, of the transgenic animals. Full-Text PDF Open ArchiveThe elevation of circulating fibroblast growth factor 23 without kidney disease does not increase cardiovascular disease riskKidney InternationalVol. 94Issue 1PreviewHigh circulating fibroblast growth factor 23 (FGF23) levels are probably a major risk factor for cardiovascular disease in chronic kidney disease. FGF23 interacts with the receptor FGFR4 in cardiomyocytes inducing left ventricular hypertrophy. Moreover, in the liver FGF23 via FGFR4 increases the risk of inflammation which is also found in chronic kidney disease. In contrast, X-linked hypophosphatemia is characterized by high FGF23 circulating levels due to loss of function mutations of the phosphate-regulating gene with homologies to an endopeptidase on the X chromosome (PHEX), but is not characterized by high cardiovascular morbidity. Full-Text PDF Open ArchiveRole of FGF23 in clinical outcomes of patients with chronic kidney diseaseKidney InternationalVol. 100Issue 5PreviewMutations and overexpression of the hormone fibroblast growth factor 23 (FGF23) were discovered 20 years ago as the cause of autosomal dominant hypophosphatemic rickets and tumor-induced osteomalacia, respectively. Subsequently, numerous studies first demonstrated the role of FGF23 in regulating phosphate and calcium homeostasis and second its involvement in inflammation, iron metabolism, and erythropoiesis.1 Moreover, a steadily increasing number of observational studies in patients with advanced stages of chronic kidney disease (CKD) showed associations of increased circulating FGF23 levels with intermediate and hard outcomes, including myocardial hypertrophy and dysfunction, cardiovascular events, and mortality. Full-Text PDF

Role of FGF23 in clinical outcomes of patients with chronic kidney disease

Mutations and overexpression of the hormone fibroblast growth factor 23 (FGF23) were discovered 20 years ago as the cause of autosomal dominant hypophosphatemic rickets and tumor-induced osteomalacia, respectively. Subsequently, numerous studies first demonstrated the role of FGF23 in regulating phosphate and calcium homeostasis and second its involvement in inflammation, iron metabolism, and erythropoiesis.1 Moreover, a steadily increasing number of observational studies in patients with advanced stages of chronic kidney disease (CKD) showed associations of increased circulating FGF23 levels with intermediate and hard outcomes, including myocardial hypertrophy and dysfunction, cardiovascular events, and mortality.

Mutation of SGK3, a novel regulator of renal phosphate transport, causes autosomal dominant hypophosphatemic Rickets

Mutation of <i>SGK3</i>, a novel regulator of renal phosphate transport, causes autosomal dominant hypophosphatemic Rickets

Bone, Growth Plate and Mineral Metabolism

The skeletal research field continues to develop rapidly and has produced several seminal findings in the last year including advances in the treatment of rare skeletal disorders, and an even deeper understanding into the molecular mechanisms that control skeletal development, endochondral bone formation, mineralization of skeletal tissues and skeletal biology. The targeting of the C-type natriuretic peptide (CNP) pathway and options to directly antagonize the overactivity of the FGFR3 pathway in achondroplasia continues to be a subject of high interest and excitement and we here highlight the double-blind, randomized placebo-controlled phase 3 study of a CNP analogue (vosoritide) in children with achondroplasia. We also highlight the identification of a novel gene for autosomal dominant hypophosphatemic rickets, publication of new growth charts for X-linked hypophosphatemia and two large well-designed paediatric vitamin D trials for the prevention of tuberculosis and asthma exacerbation, respectively.

Autosomal Dominant Hypophosphatemic Rickets: A Case Report and Review of the Literature

Autosomal dominant hypophosphatemic rickets (ADHR) is an extremely rare form of genetic rickets caused by mutations in the fibroblast growth factor 23 gene. ADHR is characterized by hypophosphatemia secondary to isolated renal phosphate wasting. Only a few cases of ADHR have been reported in the literature to date. We describe the case of a 17-month-old girl who presented with severe failure to thrive (length: −4.08 standard deviation (SD), weight: −2.2 SD) and hypotonia. Hypophosphatemia, decreased tubular phosphate reabsorption (69%), and rachitic lesions were found. Genetic analysis showed the heterozygous variant c.536G>A (NM_020638.3:c.536G>A) in exon 3 of the FGF23 gene, leading to the diagnosis of ADHR. She was treated with phosphate salts and oral alfacalcidol. After 4 years of treatment, at 5 years of age, the patient’s ADHR resolved spontaneously. Considering the lack of knowledge regarding ADHR, we reviewed the literature to describe the features of this rare and poorly understood disease. Eleven ADHR pediatric cases have been described thus far, with cases tending to be more common in females than males. Similar to the general population, two groups of patients with ADHR can be described depending on the mutations present: patients with an R179 and R176 mutation have early-onset of disease and higher frequency of rickets, and a milder and late-onset of disease, respectively. Symptoms and disease severity may fluctuate. Spontaneous remission may occur during the pediatric age.

Genetic basis of hereditary hypophosphataemic rickets and phenotype presentation in children and adults.

Hypophosphataemic rickets (HR) is a genetic disorder causing defects in the renal handling of phosphorus, resulting in rickets. HR can be classified into two groups. First- those with excess fibroblast growth factor 23(FGF23) levels, which are due to gene mutations in extrarenal factors and include X-linked dominant hypophosphataemic rickets (XLHR), autosomal dominant hypophosphataemic rickets (ADHR), autosomal recessive hypophosphataemic rickets (ARHR), and hypophosphataemic rickets with hyperparathyroidism. Second- those with normal or low FGF23, which are caused by gene mutations in renal tubular phosphate transporters and include hereditary hypophosphataemic rickets with hypercalciuria (HHRH) and X-linked recessive hypophosphataemic rickets. The radiographical changes and clinical features of rickets in various types of HR are similar but not identical. Short stature, bone deformities mainly in the lower limbs, and dental problems are typical characteristics of HR. Although the initial diagnosis of HR is usually based on physical, radiological, and biochemical features, molecular genetic analysis is important to confirm the diagnosis and differentiate the type of HR. In this review, we describe clinical and biochemical features as well as genetic causes of different types of HR. The clinical and biochemical characteristics presented in this review can help in the diagnosis of different types of HR and, therefore, direct genetic analysis to look for the specific gene mutation.

The Effect of Iron Supplementation on FGF23 in Chronic Kidney Disease Patients: a Systematic Review and Time-Response Meta-Analysis.

Fibroblast growth factor 23 (FGF23) gene is found to be responsible for autosomal dominant hypophosphatemic rickets, and is highly expressed in chronic kidney disease (CKD) and end-stage renal disease patients with iron deficiency anemia (IDA). We evaluated the efficacy of different iron treatments on FGF23 levels in dialysis-dependent and non-dialysis-dependent CKD patients with IDA. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing different types of iron treatment versus placebo in CKD patients up to May 2020. We investigated the efficacy of iron treatment on the levels of FGF23 and C-terminal FGF23 (cFGF23) in CKD patients. We estimated weighted mean differences (WMDs) and 95% confidence intervals (CIs) using the random-effects model. Nine studies with 11 arms were included in the meta-analysis. Overall, iron treatment showed a significant reduction in FGF23 levels compared to control group (WMD: - 60.56pg/ml, 95% CI: - 92.17, - 28.95). Compared to placebo, subgroup analysis showed that oral iron therapy (WMD: - 6.98pg/ml, 95% CI: - 10.66, - 3.31) was more effective than intravenous (IV) iron therapy (WMD: 4.90pg/ml, 95% CI: - 12.03, 21.83) on FGF23 levels. There was no significant change in cFGF23 levels between iron treatment and control group (WMD: - 64.72 Ru/ml, 95% CI: - 147.69, 18.25). Subgroup analysis showed that oral iron therapy resulted in a significant reduction in cFGF23 levels compared to control group (WMD: - 150.48 RU/ml, 95% CI: - 151.31, - 149.65). In conclusion, iron treatment was associated with a significant decrease in FGF23 levels in CKD patients.

Iron deficiency plays essential roles in the trigger, treatment, and prognosis of autosomal dominant hypophosphatemic rickets.

Autosomal dominant hypophosphatemic rickets (ADHR) is unique for its incomplete penetrance, variety of disease onsets, and waxing and waning phenotypes. Iron deficiency is a trigger of ADHR. This study aimed to clarify the role of iron deficiency in ADHR. Data of clinical manifestations and laboratory examinations were collected from patients among eight kindreds with ADHR. Multiple regression and Pearson's correlation tests were performed to test the relationships of serum phosphate levels and other laboratory variables during the patients' follow-ups. Among 23 ADHR patients with fibroblast growth factor 23 (FGF23) mutations, 14 patients presented with obvious symptoms. Ten patients had iron deficiency at the onset of ADHR, coinciding with menarche, menorrhagia, pregnancy, and chronic gastrointestinal bleeding. Two patients who did not have their iron status tested presented with symptoms after abortion and pregnancy in one patient each, which suggested that they also had iron deficiency at onset. Patients were treated with ferrous succinate tablets, vitamin C, and neutral phosphate and calcitriol. With correction of the iron status, the patients' symptoms showed notable improvement, with increased serum phosphate levels. Two patients' FGF23 levels also declined to the normal range. There were strong correlations between serum phosphate and serum iron levels (r = 0.7689, p < 0.0001), serum ferritin levels (r = 0.5312, p = 0.002), iron saturation (r = 0.7907, p < 0.0001), and transferrin saturation (r = 0.7875, p < 0.001). We also examined the relationships between serum phosphate levels and hemoglobin-related indices, which were significant (hemoglobin: r = 0.71, p < 0.0001; MCV: r = 0.7589, p < 0.0001; MCH: r = 0.8218, p < 0.0001; and MCHC: r = 0.7751, p < 0.0001). Longitudinal data of six patients' follow-up also showed synchronous changes in serum phosphate with serum iron levels. Iron deficiency plays an important role in triggering ADHR. Monitoring and correcting the iron status are helpful for diagnosing and treating ADHR. Iron metabolism parameters and hemoglobin-related parameters are positively correlated with serum phosphate levels in patients with ADHR and iron deficiency, and these might serve as good indicators of prognosis of ADHR.

New Therapies for Hypophosphatemia-Related to FGF23 Excess.

FGF23 is a hormone produced by osteocytes in response to an elevation in the concentration of extracellular phosphate. Excess production of FGF23 by bone cells, or rarely by tumors, is the hormonal basis for several musculoskeletal syndromes characterized by hypophosphatemia due to renal phosphate wasting. FGF23-dependent chronic hypophosphatemia causes rickets and osteomalacia, as well as other skeletal complications. Genetic disorders of FGF23-mediated hypophosphatemia include X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hypophosphatemic rickets (ARHR), fibrous dysplasia of bone, McCune-Albright syndrome, and epidermal nevus syndrome (ENS), also known as cutaneous skeletal hypophosphatemia syndrome (CSHS). The principle acquired form of FGF23-mediated hypophosphatemia is tumor-induced osteomalacia (TIO). This review summarizes current knowledge about the pathophysiology and clinical presentation of the most common FGF23-mediated conditions, with a focus on new treatment modalities. For many decades, calcitriol and phosphate supplements were the mainstay of therapy. Recently, burosumab, a monoclonal blocking antibody to FGF23, has been approved for treatment of XLH in children and adults, and an active comparator trial in children has shown good efficacy and safety for this drug. The remainder of FGF23-mediated hypophosphatemic disorders continue to be treated with phosphate and calcitriol, although ongoing trials with burosumab for treatment of tumor-induced osteomalacia show early promise. Burosumab may be an effective treatment for the remainder of FGF23-mediated disorders, but clinical trials to support that possibility are at present not available.

MON-338 Severe Hypophosphatemia Induced by Intravenous Ferric Carboxymaltose Therapy for Iron Deficiency Anemia

Background: Ferric carboxymaltose (Injectafer), a newer intravenous iron agent permits larger iron concentrations to be delivered in fewer doses compared to traditional preparations of intravenous iron. However, ferric carboxymaltose has been shown to up-regulate fibroblast growth factor 23 (FGF23) which can result in severe hypophosphatemia. We present a case illustrating this phenomenon. Clinical Case: A 48 year-old Caucasian female was admitted to the emergency department with complaints of gradual onset muscle weakness and severe exhaustion. Over the course of several months she noticed significant muscle weakness in all extremities.Her co-morbidities included morbid obesity (status-post Roux-en-y bypass surgery), asthma, and hereditary angioedema. Due to her history of gastric bypass surgery, the patient required monthly iron sucrose infusions over the previous two years. Her regimen was changed to ferric carboxymaltose (Injectafer) about five months prior to the admission, receiving 750mg treatments twice monthly.On admission, she was found to have severe hypophosphatemia of 1.5 mg/dL (2.1 – 4.7 mg/dL) with 25-OH vitamin D 21 ng/mL and PTH of 155 pg/mL. A random urinary phosphate was 72 mg/dL with a urine creatinine of 45 mg/dL, with calculated fractional excretion of phosphorus of 74%. Further diagnostic tests including EMG / nerve conduction studies, inflammatory markers, autoimmune workup, and creatine kinase were negative. She was found to have a ferritin of 2159 ng/mL (11 – 306 ng/mL) from previous baseline of 12.8 ng/mL with normal ESR and CRP. This was elucidated to be due to iron overload from IV iron infusions out of proportion to her needs. Therefore, ferrric carboxymaltose was discontinued. Her symptoms gradually improved with phosphorus and vitamin D supplementation. Two months later, when seen by Endocrinology, her ferritin was 1220 ng/mL, PTH 44 pg/mL, and phosphorus normalized to 2.6 mg/dL. Conclusion: Ferric carboxymaltose can cause profound phosphaturia and hypophosphatemia by inhibiting the cleavage of intact FGF23 to the inactive form, a mechanism similar to autosomal dominant hypophosphatemic rickets. Previous clinical trials show the incidence of hypophosphatemia to be as high as 41-70%. We conclude that baseline phosphorus and vitamin D levels should be obtained prior to therapy and monitored closely during treatment. Reference: Adkinson NF et al. Comparative safety of intravenous ferumoxytol versus ferric carboxymaltose in iron deficiency anemia: A randomized trial. Am J Hematol. 2018;93(5):683.

SUN-363 Hypophosphatemia Gene Panel Sponsored Program: A High Yield Of Molecular Diagnoses from Clinically Confirmed XLH and Suspected XLH/ Genetic Hypophosphatemia

X-linked hypophosphatemia (XLH), an X-linked dominant disorder caused by a pathogenic change (variant) in the PHEX gene, affects males and females of all ages. Rickets and osteomalacia may be present along with short stature, lower limb deformity, muscle pain and/or weakness/fatigue, bone pain, joint pain/stiffness, hearing difficulty, enthesopathy, osteoarthritis and dental abscesses. Patients with XLH have below-normal serum phosphate and elevated serum FGF23. XLH is one of multiple etiologies of hypophosphatemia; depending on genetic cause, management may differ. The program provides a no-cost test to confirm a clinical XLH diagnosis or to aid diagnosis of suspected XLH or other genetic hypophosphatemia. Methods Program eligibility criteria: >/=1y old and either clinical XLH diagnosis (confirmatory) or suspicion of XLH/ genetic hypophosphatemia (suspected) as evidenced by 2 or more clinical signs/ symptoms. The next generation sequencing gene panel includes 13 genes: ALPL, CLCN5, CYP2R1, CYP27B1, DMP1, ENPP1, FAH, FAM20C, FGF23, FGFR1, PHEX, SLC34A3 and VDR. Copy number variant (CNV) detection was performed. Results 317 unrelated probands have been tested as of October 2, 2019. Of 158 XLH confirmatory samples received, 143 (90.5%) had a PHEX variant: 14 (9.8%) were variants of uncertain significance (VUS) and 129 (90.2%) were either pathogenic or likely pathogenic (P/LP) XLH molecular diagnoses. Of the 15 patients (9.5%) where no PHEX variant was found, one had a P variant in FGF23 (autosomal dominant hypophosphatemic rickets molecular diagnosis) and another had P and LP variants in ENPP1 (autosomal recessive hypophosphatemic rickets Type 2 molecular diagnosis). Of 159 suspected samples, 101 (63.5%) had a PHEX variant: 14 (13.9%) were variants of uncertain significance (VUS) and 87 (86.1%) were P/LP (XLH molecular diagnoses). No PHEX variant was found for 58 (36.5%) of suspected samples; however, 5 of these had other findings: a dominant-negative heterozygous P variant for ALPL was detected in 3 samples (3 hypophosphatasia, HPP, molecular diagnoses); a fourth carried two P variants in ALPL; a fifth had a LP variant and a VUS in ENPP1 (autosomal recessive hypophosphatemic rickets Type 2). Of 121 unique P/LP PHEX variants detected, 59 were deletions duplications or insertions. A complex rearrangement and an Alu-mediated insertion were detected in the full cohort. To date, additional family member testing was performed for 10 probands with original VUS: in 4 cases the VUS was reclassified to P/LP; 2 were reclassified to P/LP due to more clinical info, highlighting the value of family testing and clinical info to resolve VUS. RNA analyses to resolve VUS and unidentified variants may further improve molecular diagnoses of genetic hypophosphatemia. Program results demonstrate a high diagnostic yield for confirmatory and suspected XLH/ genetic hypophosphatemia.

SAT-056 Autosomal Dominant Hypophosphatemic Rickets in Premature Twins Resolved with Iron Supplementation

IntroductionAutosomal dominant hypophosphatemic rickets (ADHR) is a condition with variable phenotype in terms of age of presentation, severity, and possible resolution. ADHR is caused by mutations of FGF23, preventing its cleavage, producing high levels of FGF23, which leads to renal phosphate wasting. Studies in mice and adult humans, have shown a correlation between low iron levels and increased FGF23 levels. To our knowledge, three pediatric patients with ADHR resolved with iron supplementation have been reported in the literature.Clinical caseWe report on identical twins born at 28 weeks and 5 days by cesarean section due to premature rupture of membranes with complicated pregnancy due to twin-to-twin transfusion syndrome. Birth weights were 780 grams (2nd percentile) for twin A, 1,200 grams (50th percentile) for twin B. Hypophosphatemia was documented starting at 2 weeks of life and during the first 6 of months of life, with phosphorus levels between 2.9-3.9 mg/dL for twin A and between 2.4-5.1 mg/dL for twin B.During their NICU admission phosphorus had a positive relationship with the hemoglobin level, which was more severe on twin A. Both were treated with calcitriol and a low dose of phosphorus starting on their 2nd month of life.At 6 months of age, both had persistent hypophosphatemia, more prominently in twin A (2.7mg/dL) with high alkaline phosphatase (1,209 IU/L) and high FGF23 (343 RU/dL). At that time his hemoglobin was 9.8 g/dL and his hematocrit was 29.5%. Both were started on Polyvisol with iron.At 14 months of life phosphorus and calcium were within normal limits, therefore calcitriol and phosphate were discontinued. At 15 months of age their hemoglobin, hematocrit, iron level, and TIBC levels were normal for both twins. Phosphorus was 4.6 and 4.3 mg/dL, alkaline phosphatase reduced significantly to 819 and 413IU/L, and FGF23 normalized to 100 RU/dL and 32 RU/dL on twin A and B respectively.Upon physical examination at 15 months of age, twin A was at the 0.02% for length and weight/length at the 31%; twin B was at the 5% for length and weight/length at the 50%. Both twins had high arched palates. Twin A had craniosynostosis, left renal agenesis, bilateral epicanthal folds, overlapping 2nd toes, and clinodactyly of the fifth digits. Note the donor kid (twin A) had a more severe presentation.Genetic testing showed heterozygous mutation c536G>a (p.Arg179GLN) in the FGF23 gene. This is the same mutation previously reported to be related with ADHR resolved with iron supplementationConclusionThe study of patients with hypophosphatemia and hypophosphaturia should include evaluation of iron status (ferritin, TIBC). Treating iron deficiency on these patients might normalize phosphate levels. This would avoid cumbersome treatment with phosphate and calcitriol.Laboratory valuesPhosphorus:4-8 mg/dLAlkaline Phosphatase: 130-317 IU/LFGF23: 44-215 RU/dL

Contribution of Bone Tissue to Regulation of Calcium and Phosphate Metabolism. Role of FGF23 and Klotho Protein.

Bone tissue actively contributes to the regulation of systemic homoeostasis, and particularly the maintenance of calcium-phosphate balance. The parathyroid hormone-vitamin D feedback axis is balanced by the recently discovered bone-FGF23-kidney hormonal axis. An active complex consisting of FGF23, a receptor and Klotho protein blocks phosphate reabsorption in the proximal tubules, increasing urine phosphate levels and decreasing blood phosphate levels. Mutations of the gene mediating FGF23 transcription lead to a number of diseases, examples including autosomal dominant hypophosphataemic rickets. Klotho protein is a cofactor for FGF23 displaying cardio-, vaso- and nephroprotective activity. It increases calcium reabsorption in the kidneys and inhibits phosphate reabsorption. It also exerts antioxidative and anti-insulin effects and inhibits tissue calcification and apoptosis. As an inhibitor of bone resorption, osteoprotegerin becomes an important contributor to bone remodelling, while RANK/RANKL signalling inhibition is used in the treatment of postmenopausal osteoporosis. Osteocalcin plays an important role in energy metabolism in the human body. Sclerostin exerts a strong catabolic effect on bone tissue. Newly identified contributors to the regulation of calcium and phosphate homoeostasis suggest that bone tissue plays a complex role in the systemic metabolism.