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01-06-2019 | Original Article

Risk of cardiovascular involvement in pediatric patients with X-linked hypophosphatemia

Authors: Olaya Hernández-Frías, Helena Gil-Peña, José M. Pérez-Roldán, Susana González-Sanchez, Gema Ariceta, Sara Chocrón, Reyner Loza, Francisco de la Cerda Ojeda, Leire Madariaga, Inés Vergara, Marta Fernández-Fernández, Susana Ferrando-Monleón, Montserrat Antón-Gamero, Ángeles Fernández-Maseda, M. Isabel Luis-Yanes, Fernando Santos

Published in: Pediatric Nephrology | Issue 6/2019

Abstract

Objective

To find out if cardiovascular alterations are present in pediatric patients with X-linked hypophosphatemia (XLH).

Study design

Multicentre prospective clinical study on pediatric patients included in the RenalTube database (www.renaltube.com) with genetically confirmed diagnosis of XLH by mutations in the PHEX gene. The study’s protocol consisted of biochemical work-up, 24-h ambulatory blood pressure monitoring (ABPM), carotid ultrasonography, and echocardiogram. All patients were on chronic treatment with phosphate supplements and 1-hydroxy vitamin D metabolites.

Results

Twenty-four patients (17 females, from 1 to 17 years of age) were studied. Serum concentrations (X ± SD) of phosphate and intact parathyroid hormone were 2.66 ± 0.60 mg/dl and 58.3 ± 26.8 pg/ml, respectively. Serum fibroblast growth factor 23 (FGF23) concentration was 278.18 ± 294.45 pg/ml (normal < 60 pg/ml). Abnormally high carotid intima media thickness was found in one patient, who was obese and hypertensive as revealed by ABPM, which disclosed arterial hypertension in two other patients. Z scores for echocardiographic interventricular septum end diastole and left ventricular posterior wall end diastole were + 0.77 ± 0.77 and + 0.94 ± 0.86, respectively. Left ventricular mass index (LVMI) was 44.93 ± 19.18 g/m^2.7, and four patients, in addition to the obese one, had values greater than 51 g/m^2.7, indicative of left ventricular hypertrophy. There was no correlation between these echocardiographic parameters and serum FGF23 concentrations.

Conclusions

XLH pediatric patients receiving conventional treatment have echocardiographic measurements of ventricular mass within normal reference values, but above the mean, and 18% have LVMI suggestive of left ventricular hypertrophy without correlation with serum FGF23 concentrations. This might indicate an increased risk of cardiovascular involvement in XLH.

Beck-Nielsen SS, Brock-Jacobsen B, Gram J, Brixen K, Jensen TK (2009) Incidence and prevalence of nutritional and hereditary rickets in southern Denmark. Eur J Endocrinol 160:491–497. https://doi.org/10.1530/EJE-08-0818 CrossRefPubMed

Bastepe M, Jüppner H (2008) Inherited hypophosphatemic disorders in children and the evolving mechanisms of phosphate regulation. Rev Endocr Metab Disord 9:171–180. https://doi.org/10.1007/s11154-008-9075-3 CrossRefPubMed

Rowe PSN (2012) Regulation of bone-renal mineral and energy metabolism: the PHEX, FGF23, DMP1, MEPE ASARM pathway. Crit Rev Eukaryot Gene Expr 22:61–86. https://doi.org/10.1111/j.1743-6109.2008.01122.x.Endothelial CrossRefPubMedPubMedCentral

Martos Moreno GÁ, Aparicio C, de Lucas C, Gil Peña H, Argente J (2016) X-linked hypophosphatemic rickets due to mutations in PHEX: clinical and evolutionary variability. An Pediatr (Barc) 85:41–43. https://doi.org/10.1016/j.anpedi.2016.04.012 CrossRef

Fuente R, Gil-Peña H, Claramunt-Taberner D, Hernandez O, Fernandez-Iglesias A, Alonso-Duran L, Rodrigues-Rubio E, Santos F (2017) X-linked hypophosphatemia and growth. GeneReviews(®) 1–23. https://doi.org/10.1007/s11154-017-9408-1

Coyac BR, Falgayrac G, Penel G, Schmitt A, Schinke T, Linglart A, McKee MD, Chaussain C, Bardet C (2018) Impaired mineral quality in dentin in X-linked hypophosphatemia. Connect Tissue Res 59:91–96. https://doi.org/10.1080/03008207.2017.1417989 CrossRefPubMed

Vakharia JD, Matlock K, Taylor HO, Backeljauw PF, Topor LS (2018) Craniosynostosis as the presenting feature of X-linked hypophosphatemic rickets. Pediatrics 141:S515–S519. https://doi.org/10.1542/peds.2017-2522 CrossRef

Vega RA, Opalak C, Harshbarger RJ, Fearon JA, Ritter AM, Collins JJ, Rhodes JL (2016) Hypophosphatemic rickets and craniosynostosis: a multicenter case series. J Neurosurg Pediatr 17:694–700. https://doi.org/10.3171/2015.10.PEDS15273 CrossRef

Ruppe MD X-linked hypophosphatemia. 2012 Feb 9 [updated 2017 Apr 13]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A (eds) GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2018. Available from http://www.ncbi.nlm.nih.gov/books/NBK83985/. Accessed 27 Nov 2018

10.

Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, Gutiérrez OM, Aguillon-Prada R, Lincoln J, Hare JM, Mundel P, Morales A, Scialla J, Fischer M, Soliman EZ, Chen J, Go AS, Rosas SE, Nessel L, Townsend RR, Feldman HI, St John Sutton M, Ojo A, Gadegbeku C, Di Marco GS, Reuter S, Kentrup D, Tiemann K, Brand M, Hill JA, Moe OW, Kuro-O M, Kusek JW, Keane MG, Wolf M (2011) FGF23 induces left ventricular hypertrophy. J Clin Invest 121:4393–4408. https://doi.org/10.1172/JCI46122.ease CrossRefPubMedPubMedCentral

11.

Leifheit-Nestler M, Siemer RG, Flasbart K, Richter B, Kirchhoff F, Ziegler WH, Klintschar M, Becker JU, Erbersdobler A, Aufricht C, Seeman T, Fischer DC, Faul C, Haffner D (2016) Induction of cardiac FGF23/FGFR4 expression is associated with left ventricular hypertrophy in patients with chronic kidney disease. Nephrol Dial Transplant 31:1088–1099. https://doi.org/10.1093/ndt/gfv421 CrossRefPubMed

12.

Kuro OM (2010) Klotho. Pflugers Arch 459:333–343. https://doi.org/10.1007/s00424-009-0722-7 CrossRef

13.

Urbina E, Alpert B, Flynn J, Hayman L, Harshfield GA, Jacobson M, Mahoney L, McCrindle B, Mietus-Snyder M, Steinberger J, Daniels S, American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee (2008) Ambulatory blood pressure monitoring in children and adolescents: recommendations for standard assessment: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee of the Council on Cardiovas. Hypertension 52:433–451. https://doi.org/10.1161/HYPERTENSIONAHA.108.190329 CrossRefPubMed

14.

Urbina EM, Williams RV, Alpert BS, Collins RT, Daniels SR, Hayman L, Jacobson M, Mahoney L, Mietus-Snyder M, Rocchini A, Steinberger J, McCrindle B, American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee of the Council on Cardiovascular Disease in the Young (2009) Noninvasive assessment of subclinical atherosclerosis in children and adolescents: recommendations for standard assessment for clinical research: a scientific statement from the American Heart Association. Hypertension 54:919–950. https://doi.org/10.1161/HYPERTENSIONAHA.109.192639 CrossRefPubMed

15.

Jourdan C, Wühl E, Litwin M, Fahr K, Trelewicz J, Jobs K, Schenk JP, Grenda R, Mehls O, Tröger J, Schaefer F (2005) Normative values for intima-media thickness and distensibility of large arteries in healthy adolescents. J Hypertens 23:1707–1715. https://doi.org/10.1097/01.hjh.0000178834.26353.d5 CrossRefPubMed

16.

Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, Lancellotti P, Muraru D, Picard MH, Rietzschel ER, Rudski L, Spencer KT, Tsang W, Voigt JU (2015) Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 16:233–270. https://doi.org/10.1093/ehjci/jev014 CrossRefPubMed

17.

Pettersen MD, Du W, Skeens ME, Humes RA (2008) Regression equations for calculation of Z scores of cardiac structures in a large cohort of healthy infants, children, and adolescents: an echocardiographic study. J Am Soc Echocardiogr 21:922–934. https://doi.org/10.1016/j.echo.2008.02.006 CrossRefPubMed

18.

Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, Reichek N (1986) Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 57:450–458CrossRefPubMed

19.

Foster BJ, MacKie AS, Mitsnefes M, Ali H, Mamber S, Colan SD (2008) A novel method of expressing left ventricular mass relative to body size in children. Circulation 117:2769–2775. https://doi.org/10.1161/CIRCULATIONAHA.107.741157 CrossRefPubMed

20.

Flynn J, Kaelber D, Baker-Smith C, Blowey D, Carroll AE, Daniels SR, de Ferranti SD, Dionne JM, Falkner B, Flinn SK, Gidding SS, Goodwin C, Leu MG, Powers ME, Rea C, Samuels J, Simasek M, Thaker VV, Urbina EM, SUBCOMMITTEE ON SCREENING AND MANAGEMENT OF HIGH BLOOD PRESSURE IN CHILDREN (2018) Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics 142. https://doi.org/10.1542/peds.2018-1739

21.

Yamazaki Y, Imura A, Urakawa I, Shimada T, Murakami J, Aono Y, Hasegawa H, Yamashita T, Nakatani K, Saito Y, Okamoto N, Kurumatani N, Namba N, Kitaoka T, Ozono K, Sakai T, Hataya H, Ichikawa S, Imel EA, Econs MJ, Nabeshima Y (2010) Establishment of sandwich ELISA for soluble alpha-klotho measurement: age-dependent change of soluble alpha-klotho levels in healthy subjects. Biochem Biophys Res Commun 398:513–518. https://doi.org/10.1016/j.bbrc.2010.06.110 CrossRefPubMedPubMedCentral

22.

Santos F, Carbajo-Pérez E, Rodríguez J, Fernández-Fuente M, Molinos I, Amil B, García E (2005) Alterations of the growth plate in chronic renal failure. Pediatr Nephrol 20:330–334. https://doi.org/10.1007/s00467-004-1652-4 CrossRefPubMed

23.

Marthi A, Donovan K, Haynes R, Wheeler DC, Baigent C, Rooney CM, Landray MJ, Moe SM, Yang J, Holland L, di Giuseppe R, Bouma-de Krijger A, Mihaylova B, Herrington WG (2018) Fibroblast growth factor-23 and risks of cardiovascular and noncardiovascular diseases: a meta-analysis. J Am Soc Nephrol 29:2015–2027. https://doi.org/10.1681/ASN.2017121334 CrossRefPubMedPubMedCentral

24.

Haffner D, Leifheit-Nestler M (2017) Extrarenal effects of FGF23. Pediatr Nephrol 32:753–765. https://doi.org/10.1007/s00467-016-3505-3 CrossRefPubMed

25.

Czaya B, Seeherunvong W, Singh S, Yanucil C, Ruiz P, Quiroz Y, Grabner A, Katsoufis C, Swaminathan S, Abitbol C, Rodriguez-Iturbe B, Faul C, Freundlich M (2018) Cardioprotective effects of paricalcitol alone and in combination with FGF23 receptor inhibition in chronic renal failure: experimental and clinical studies. Am J Hypertens. https://doi.org/10.1093/ajh/hpy154

26.

Chinali M, Emma F, Esposito C, Rinelli G, Franceschini A, Doyon A, Raimondi F, Pongiglione G, Schaefer F, Matteucci MC (2016) Left ventricular mass indexing in infants, children, and adolescents: a simplified approach for the identification of left ventricular hypertrophy in clinical practice. J Pediatr 170:193–198. https://doi.org/10.1016/j.jpeds.2015.10.085 CrossRefPubMed

27.

Takashi Y, Kinoshita Y, Hori M, Ito N, Taguchi M, Fukumoto S (2017) Patients with FGF23-related hypophosphatemic rickets/osteomalacia do not present with left ventricular hypertrophy. Endocr Res 42:132–137. https://doi.org/10.1080/07435800.2016.1242604 CrossRefPubMed

28.

Yilmaz G, Ustundag S, Temizoz O, Sut N, Demir M, Ermis V, Sevinc C, Ustundag A (2015) Fibroblast growth factor-23 and carotid artery intima media thickness in chronic kidney disease. Clin Lab 61:1061–1070CrossRefPubMed

29.

Hu X, Ma X, Luo Y, Xu Y, Xiong Q, Pan X, Bao Y, Jia W (2017) Contribution of fibroblast growth factor 23 to Framingham risk score for identifying subclinical atherosclerosis in Chinese men. Nutr Metab Cardiovasc Dis 27:147–153. https://doi.org/10.1016/j.numecd.2016.11.009 CrossRefPubMed

30.

Sarmento-Dias M, Santos-Araujo C, Poinhos R, Santos-Araújo C, Poínhos R, Oliveira B, Silva IS, Silva LS, Sousa MJ, Correia F, Pestana M (2016) Fibroblast growth factor 23 is associated with left ventricular hypertrophy, not with uremic vasculopathy in peritoneal dialysis patients. Clin Nephrol 85:135–141. https://doi.org/10.5414/CN108716 CrossRefPubMed

31.

Matsui I, Oka T, Kusunoki Y, Mori D, Hashimoto N, Matsumoto A, Shimada K, Yamaguchi S, Kubota K, Yonemoto S, Higo T, Sakaguchi Y, Takabatake Y, Hamano T, Isaka Y (2018) Cardiac hypertrophy elevates serum levels of fibroblast growth factor 23. Kidney Int 94:60–71. https://doi.org/10.1016/j.kint.2018.02.018 CrossRefPubMed

32.

Andrukhova O, Slavic S, Smorodchenko A, Zeitz U, Shalhoub V, Lanske B, Pohl EE, Erben RG (2014) FGF23 regulates renal sodium handling and blood pressure. EMBO Mol Med 6:744–759. https://doi.org/10.1002/emmm.201303716 CrossRefPubMedPubMedCentral

33.

Nakamura Y, Takagi M, Takeda R, Miyai K, Hasegawa Y (2017) Hypertension is a characteristic complication of X-linked hypophosphatemia. Endocr J 64:283–289. https://doi.org/10.1507/endocrj.EJ16-0199 CrossRefPubMed

34.

Nehgme R, Fahey JT, Smith C, Carpenter TO (1997) Cardiovascular abnormalities in patients with X-linked hypophosphatemia. J Clin Endocrinol Metab 82:2450–2454. https://doi.org/10.1210/jcem.82.8.4181 CrossRefPubMed

35.

Vered I, Vered Z, Perez JE, Jaffe AS, Whyte MP (1990) Normal left ventricular performance in children with X-linked hypophosphatemic rickets: a Doppler echocardiography study. J Bone Miner Res 5:469–474. https://doi.org/10.1002/jbmr.5650050508 CrossRefPubMed

36.

Alon US, Monzavi R, Lilien M, Rasoulpour M, Geffner ME, Yadin O (2003) Hypertension in hypophosphatemic rickets--role of secondary hyperparathyroidism. Pediatr Nephrol 18:155–158. https://doi.org/10.1007/s00467-002-1044-6 CrossRefPubMed

Title: Risk of cardiovascular involvement in pediatric patients with X-linked hypophosphatemia
Authors: Olaya Hernández-Frías
Helena Gil-Peña
José M. Pérez-Roldán
Susana González-Sanchez
Gema Ariceta
Sara Chocrón
Reyner Loza
Francisco de la Cerda Ojeda
Leire Madariaga
Inés Vergara
Marta Fernández-Fernández
Susana Ferrando-Monleón
Montserrat Antón-Gamero
Ángeles Fernández-Maseda
M. Isabel Luis-Yanes
Fernando Santos
Publication date: 01-06-2019
Publisher: Springer Berlin Heidelberg
Published in: Pediatric Nephrology / Issue 6/2019
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-018-4180-3

At a glance: The STEP trials

Springer Medicine

Risk of cardiovascular involvement in pediatric patients with X-linked hypophosphatemia

Abstract

Objective

Study design

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Objective

Study design

Results

Conclusions

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