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ObjectiveTo investigate in extremely low birthweight (ELBW; <1000 g) babies the associations between refeeding syndrome (serum phosphate <1.4 mmol·L-1 and serum total calcium>2.8 mmol·L-1) and hypophosphataemia in the first week and death or neurodisability at 2 years’ corrected age (CA).DesignSecondary cohort analysis of the ProVIDe trial participants with serum biochemistry within 7 days of birth. At 2 years’ CA, neurodisability was assessed by Bayley Scales of Infant Development Edition III and neurological examination. Associations between neurodisability and other variables were analysed using t-tests and logistic regression adjusted for sex and smallness-for-gestational age.SettingSix tertiary neonatal intensive care units (NICUs) in New Zealand.Participants352 ELBW babies born between 29 April 2014 and 30 October 2018.Main outcome measureDeath or neurodisability at 2 years’ CA.ResultsFifty-nine babies died, two after discharge from the NICU. Of the 336 babies who survived to 2 years’ CA, 277 had neurodevelopmental assessment and 107 (39%) had a neurodisability. Death or neurodisability was more likely in babies who had refeeding syndrome (aOR 1.96 (95% CI 1.09 to 3.53), p=0.02) and in babies who had hypophosphataemia (aOR 1.74 (95% CI 1.09 to 2.79), p=0.02). Hypophosphataemia was associated with increased risk of death (aOR 2.07 (95% CI 1.09 to 3.95), p=0.03)) and severe hypophosphataemia (<0.9 mmol·L-1) with increased risk of death (aOR 2.67 (95% CI 1.41 to 5.00), p=0.002) and neurodisability (aOR 2.31 (95% CI 1.22 to 4.35), p=0.01).ConclusionsIn ELBW babies, refeeding syndrome and hypophosphataemia in the first week are associated with death or neurodisability. Until optimal phosphate requirements are determined through further research, monitoring for hypophosphataemia and mitigation strategies are indicated.Trial registration numberACTRN12612001084875

The association between intravenous iron substitution therapy and hypophosphatemia was previously reported in patients with iron deficiency anemia. However, the extent of hypophosphatemia is thought to depend on the type of iron supplementation. We hypothesized that the intravenous application of ferric carboxymaltose and iron sucrose leads to a different longitudinal adaptation in serum phosphate levels. In this open-label pilot study, a total of 20 patients with inflammatory bowel diseases or iron deficiency anemia were randomly assigned to one of two study groups (group 1: ferric carboxymaltose, n = 10; group 2: iron sucrose, n = 10). Serum values were controlled before iron substitution therapy, as well as 2, 4, and 12 weeks after the last drug administration. The primary objective of the study was the longitudinal evaluation of serum phosphate levels after iron substitution therapy with ferric carboxymaltose and iron sucrose. The secondary objective was the longitudinal investigation of calcium, 25-hydroxyvitamin D (25(OH)D), intact parathyroid hormone, procollagen type 1 amino-terminal propeptide (P1NP), beta-CrossLaps (CTX), hemoglobin (Hb), iron, ferritin, and transferrin saturation levels. Two weeks after drug administration, phosphate levels were significantly lower (p < 0.001) in group 1 and ferritin levels were significantly higher (p < 0.001) in group 1. Phosphate levels (0.8–1.45 mmol/L) were below the therapeutic threshold and ferritin levels (10–200 ng/mL for women and 30–300 ng/mL for men) were above the therapeutic threshold in group 1. P1NP (15–59 µg/L) and CTX (<0.57 ng/mL) levels were above the therapeutic threshold in group 2. Four weeks after drug administration, significant differences were still observed between both study groups for phosphate (p = 0.043) and ferritin (p = 0.0009). All serum values except for Hb were within the therapeutic thresholds. Twelve weeks after drug administration, no differences were observed in all serum values between both study groups. Hb values were within the therapeutic threshold in both study groups. Serum 25(OH)D levels did not differ between both study groups throughout the whole study period and remained within the therapeutic threshold.

Hypophosphatemia, Hyperphosphaturia, and Bisphosphonate Treatment Are Associated With Survival Beyond Infancy in Generalized Arterial Calcification of Infancy Frank Rutsch, MD ; Petra Böyer, MS ; Yvonne Nitschke, MS ; Nico Ruf, PhD ; Bettina Lorenz-Depierieux, PhD ; Tanja Wittkampf, PhD ; Gabriele Weissen-Plenz, PhD ; Rudolf-Josef Fischer, MD, PhD ; Zulf Mughal, MBChB, FRCPCH, DCH ; John W. Gregory, MD ; Justin H. Davies, MD, FRCPCH, MRCP ; Chantal Loirat, MD ; Tim M. Strom, PhD ; Dirk Schnabel, MD ; Peter Nürnberg, PhD ; Robert Terkeltaub, MD and the GACI Study Group From the Department of General Pediatrics (F.R., P.B., Y.N., T.W.), University Children’s Hospital, Münster, Germany; Laboratory of Developmental Genetics and Imprinting (N.R.), The Babraham Institute, Cambridge, United Kingdom; Institute of Human Genetics (B.L.-D., T.M.S.), Helmholtz Zentrum München, Munich, Germany; Institute of Human Genetics (B.L.-D., T.M.S.), Klinikum rechts der Isar, Technical University, Munich, Germany; Department of Cardiothoracic Surgery (G.W.-P.), University Hospital, Münster, Germany; Department of Medical Informatics and Biomathematics (R.-J.F.), Münster University Hospital, Münster, Germany; Department of Paediatrics (Z.M.), Saint Mary’s Hospital for Women and Children, Manchester, United Kingdom; Department of Pediatric Endocrinology (J.W.G.), Wales School of Medicine, Cardiff University, Cardiff, United Kingdom; Department of Pediatric Endocrinology (J.H.D.), Southampton University Hospital, Southampton, United Kingdom; Department of Pediatric Nephrology (C.L.), Hôpital Robert Debré, Paris, France; Pediatric Endocrinology (D.S.), Otto Heubner Center, Charité, Berlin, Germany; Cologne Center for Genomics (P.N.), University of Cologne, Germany; and Department of Rheumatology Allergy/Immunology (R.T.), VA Medical Center, UCSD, San Diego, Calif. Correspondence to Dr Frank Rutsch, Klinik und Poliklinik für Kinder-und Jugendmedizin, Universitätsklinikum Münster, Albert-Schweitzer Strasse 33, D-48149 Münster, Germany. E-mail rutschf{at}mednet.uni-muenster.de Received June 9, 2008; accepted October 15, 2008. Background— Generalized arterial calcification of infancy has been reported to be frequently lethal, and the efficiency of any therapy, including bisphosphonates, is unknown. A phosphate-poor diet markedly increases survival of NPP1 null mice, a model of generalized arterial calcification of infancy. Methods and Results— We performed a multicenter genetic study and retrospective observational analysis of 55 subjects affected by generalized arterial calcification of infancy to identify prognostic factors. Nineteen (34%) patients survived the critical period of infancy. In all 8 surviving patients tested, hypophosphatemia due to reduced renal tubular phosphate reabsorption developed during childhood. Eleven of 17 (65%) patients treated with bisphosphonates survived. Of 26 patients who survived their first day of life and were not treated with bisphosphonates only 8 (31%) patients survived beyond infancy. Forty different homozygous or compound heterozygous mutations, including 16 novel mutations in ENPP1 , were found in 41 (75%) of the 55 patients. Twenty-nine (71%) of these 41 patients died in infancy (median, 30 days). Seven of the 14 (50%) patients without ENPP1 mutations died in infancy (median, 9 days). When present on both alleles, the mutation p.P305T was associated with death in infancy in all 5 cases; otherwise, no clear genotype-phenotype correlation was seen. Conclusion— ENPP1 coding region mutations are associated with generalized arterial calcification of infancy in 75% of subjects. Except for the p.P305T mutation, which was universally lethal when present on both alleles, the identified ENPP1 mutations per se have no discernable effect on survival. However, survival seems to be associated with hypophosphatemia linked with hyperphosphaturia and also with bisphosphonate treatment. Key Words: genetics • mortality • pediatrics • prognosis • survival The online-only Data Supplement is available at http://circgenetics.ahajournals.org/cgi/content/full/CIRCGENETICS.108.797704/DC1. Home | Subscriptions | Archives | Feedback | Authors | Help | Circulation Journals Home | AHA Journals Home | Search Copyright © 2008 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. var _rsCI=\"us-lippincott\"; var _rsCG=\"0\"; var _rsDN=\"//secure-us.imrworldwide.com/\"; var _rsSE=1; var _rsSM=1.0;

Fibrous dysplasia (FD) is sometimes accompanied by extraskeletal manifestations that can include any combination of café-au-lait macules, hyperfunctioning endocrinopathies, such as gonadotropin-independent precocious puberty, hyperthyroidism, growth hormone excess, FGF23-mediated renal phosphate wasting, and/or Cushing syndrome, as well as other less common features. The combination of any of these findings, with or without FD, is known as McCune-Albright syndrome (MAS). The broad spectrum of involved tissues and the unpredictable combination of findings owe to the fact that molecular defect is due to dominant activating mutations in the widely expressed signaling protein, G s α, and the fact these mutations arises sporadically, often times early in development, prior to gastrulation, and can distribute across many or few tissues. The complexity can be mastered by a systematic screening of potentially involved tissues and cognizance that the pattern of involved tissues is established, to some degree, in utero. Thorough testing allows the clinician to establish, often times at presentation, the full extent of the disease, and importantly as well what tissues are unaffected. Treatment and follow-up can then be focused on affected systems and a meaningful prognosis can be offered to the patient and family. The authors outline screening and treatment strategies that allow for effective management of the extraskeletal manifestations of FD.

Background Research on the association of serum phosphate levels with the severity and prognosis of neonatal diseases is limited. Neonatal sepsis is the primary cause of neonatal mortality. Therefore, in this study, we aimed to investigate the association between serum phosphate levels and neonatal sepsis outcomes. Methods This retrospective cohort study was conducted using the Pediatric Intensive Care (PIC) database (2010–2018). Neonatal sepsis was diagnosed based on ICD-10 codes. Serum phosphate levels within 72 h of sepsis diagnosis were selected. Outcomes were severe sepsis, in-hospital mortality, length of hospital stay (hospital Los.), and ICU stay (ICU Los.). Covariates included demographic and clinical characteristics as well as serum biomarkers. Multi-variable regression and subgroup analyses were performed to explore the association between serum phosphate levels and neonatal sepsis outcomes. Results A total of 120 infants with neonatal sepsis were included, and their characteristics were analyzed according to serum phosphate tertiles. The median age was 3.0 (1.0, 17.0) days. The proportion of male infants was 62.5% (75/120). The proportion of preterm infants was 44.2% (53/120). The incidence of late-onset sepsis was 60.8% (73/120). Multivariate linear regression analysis showed that the serum phosphate level at sepsis diagnosis was associated with hospital Los. and remained so after adjustment for all covariates. Each 1 mmol/L decrease in serum phosphate level prolonged the length of hospital stay by 7.53 days. The low serum phosphate group had an 11.75-day longer hospital stay than the high serum phosphate group. Curve fitting showed a negative linear correlation between serum phosphate levels and hospital Los. in infants with neonatal sepsis and no significant interactions were observed in the subgroup analysis; however, serum phosphate levels were not independently associated with ICU Los. In addition, no correlation was found between serum phosphate levels and mortality or the severity of sepsis in neonates. Conclusions Hypophosphatemia is highly prevalent in neonates with sepsis. Lower serum phosphate levels are associated with prolonged hospital stay in neonates with sepsis. Strengthening the monitoring of serum phosphate levels in neonates with sepsis and maintaining the homeostasis of phosphate in the body can promote refined management of neonatal sepsis and help improve the prognosis of the patients.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by hypophosphatemia, bone mineralization disorders with increased risk of fragility fractures, muscle pain, and progressive weakness. TIO has been associated with increased production of the phosphaturic hormone Fibroblast Growth Factor 23 (FGF23) usually by mesenchymal tumors of soft tissue or bone (Phosphaturic Mesenchymal Tumors—PMTs). In rare cases TIO may be observed in association with other malignancies. We report the case of a 66-year-old woman with an occasional diagnosis of both a PMT and an ovarian cancer during the evaluation of TIO. We also systematically review the literature to discover possible correlations between osteomalacia, FGF23 production, and ovarian cancer. Four studies were eligible for the analysis. Two case reports described an association between TIO development and ovarian cancer, whereas the two case-control studies hypothesized a possible correlation between FGF/FGF receptor axis and cancer development. Although it does not provide conclusive evidence regarding the association between TIO and ovarian cancer, this case report highlights the possibility that in the diagnostic workup of suspected TIO, both FGF23-secreting tumors distinct from PMT and tumors unrelated to the clinical presentation of TIO could be identified. This information is important for guiding successful tumor staging and determining the necessity for surgical intervention and/or eventual adjuvant therapy.

Phosphaturic mesenchymal tumors (PMTs) are extremely rare mesenchymal tumors of soft tissue and bone that cause tumor-induced osteomalacia (TIO). Some of these tumors are completely asymptomatic and may grow undetected unless they become large enough to cause pain or discomfort. This type of tumor is crucial to diagnose in patients being treated for phosphate metabolism disorders and are a rare reason why patients seek medical help owing to pain. Here, we report the details of a patient with progressive bone pain caused by a PMT originating in the left femur.

Tumour-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare paraneoplastic disorder caused by tumours that secrete fibroblast growth factor 23 (FGF23). Owing to the role of FGF23 in renal phosphate handling and vitamin D synthesis, TIO is characterized by decreased renal tubular reabsorption of phosphate, by hypophosphataemia and by low levels of active vitamin D. Chronic hypophosphataemia ultimately results in osteomalacia (that is, inadequate bone mineralization). The diagnosis of TIO is usually suspected when serum phosphate levels are chronically low in the setting of bone pain, fragility fractures and muscle weakness. Locating the offending tumour can be very difficult, as the tumour is often very small and can be anywhere in the body. Surgical removal of the tumour is the only definitive treatment. When the tumour cannot be located or when complete resection is not possible, medical treatment with phosphate salts or active vitamin D is necessary. One of the most promising emerging treatments for unresectable tumours that cause TIO is the anti-FGF23 monoclonal antibody KRN23. The recent identification of a fusion of fibronectin and fibroblast growth factor receptor 1 (FGFR1) as a molecular driver in some tumours not only sheds light on the pathophysiology of TIO but also opens the door to a better understanding of the transcription, translocation, post-translational modification and secretion of FGF23, as well as suggesting approaches to targeted therapy. Further study will reveal if the FGFR1 pathway is also involved in tumours that do not harbour the translocation. Tumour-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare paraneoplastic disorder caused by tumours that secrete fibroblast growth factor 23. Clinically, TIO is associated with hypophosphataemia and skeletal abnormalities. This Primer focuses on the epidemiological, pathophysiological, diagnostic and clinical aspects of TIO.

Refeeding syndrome (RFS) is a life-threatening metabolic complication caused by refeeding in malnourished patients and is a barrier to early nutritional supplementation. Hypophosphatemia is a hallmark of RFS; however, its detailed pathogenic mechanism remains unclear. In this study, we aimed to unravel the underlying mechanism by generating a novel rat model that exhibits a decrease in plasma inorganic phosphorus levels comparable to that in patients with severe RFS and developing a mathematical model that reproduces the results. Although insulin is believed to be implicated in hypophosphatemia, we found a crucial role of amino acids. Furthermore, we inferred the dynamics of associated factors that play important roles in the regulation of hypophosphatemia, such as phosphate diuretic hormones, intracellular phosphorus content, and mTOR signaling, and experimentally confirmed them. Our findings provide new insights into the mechanisms underlying hypophosphatemia in RFS and should contribute to advancements in the prevention and intervention of RFS.

Rickets, historically referred to as “the English disease”, is common worldwide. Absence of phosphate at the growth plate and mineralising bone surfaces due to inadequate vitamin D supply either from sunlight exposure or diet is the main cause. Inherited disorders causing hypophosphataemia have shown the intricacies of phosphate metabolism. Present advice about the provision of vitamin D to young infants needs to be clarified; the existing guidance is fragmentary and contradictory, and will not help to eradicate the disease.