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

  • 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 SantosEmail author
Original Article

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/m2.7, and four patients, in addition to the obese one, had values greater than 51 g/m2.7, 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.

Keywords

XLH FGF23 Left ventricular hypertrophy PHEX gene Intima-media of carotid artery 

Notes

Acknowledgements

Serum FGF23 determinations were performed in Dr. Mariano Rodríguez’s laboratory (IMIBIC/Hospital Universitario Reina Sofía, Córdoba, Spain), partly funded by the Funfación Nutrición y Crecimiento.

Funding

This study was funded by grants PI12/00987 (National Plan I + D + I 2008–2011) and PI15/02122 (National Plan I + D + I 2013–2016) of the Instituto de Salud Carlos III, by Fondos FEDER, by Fondos Regionales Gobierno del Principado de Asturias (Grupin 14/020), by Foundation of the University of Oviedo (FUO), and funds of University of Oviedo with “Programa de Apoyo y Promoción de la Investigación 2017,” by grant SeveroOcha 2013–2017 of the “Programa Estatal de Promoción del Talento y su Empleabilidad en I + D + I, Subprograma Estatal de Formación” and by Foundation “Nutrición y Crecimiento.”

Compliance with ethical standards

Written inform consent from the participants and approval of the hospital’s ethical committee were obtained.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Conflict of interest

The authors declare that they have no conflict of interest.

Disclosures

Poster presentation in the 51st Annual Scientific Meeting of the European Society for Paediatric Nephrology (ESPN), on October 2018 in Belek, Antalya, Turkey.

References

  1. 1.
    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 CrossRefPubMedGoogle Scholar
  2. 2.
    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 CrossRefPubMedGoogle Scholar
  3. 3.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    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 CrossRefGoogle Scholar
  5. 5.
    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
  6. 6.
    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 CrossRefPubMedGoogle Scholar
  7. 7.
    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 CrossRefPubMedGoogle Scholar
  8. 8.
    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 CrossRefPubMedGoogle Scholar
  9. 9.
    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. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 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 CrossRefPubMedGoogle Scholar
  12. 12.
    Kuro OM (2010) Klotho. Pflugers Arch 459:333–343.  https://doi.org/10.1007/s00424-009-0722-7 CrossRefGoogle Scholar
  13. 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 CrossRefPubMedGoogle Scholar
  14. 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 CrossRefPubMedGoogle Scholar
  15. 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 CrossRefPubMedGoogle Scholar
  16. 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 CrossRefPubMedGoogle Scholar
  17. 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 CrossRefPubMedGoogle Scholar
  18. 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 57:450–458CrossRefGoogle Scholar
  19. 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 CrossRefPubMedGoogle Scholar
  20. 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. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 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 CrossRefPubMedGoogle Scholar
  23. 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 CrossRefPubMedGoogle Scholar
  24. 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 CrossRefPubMedGoogle Scholar
  25. 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. 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 CrossRefPubMedGoogle Scholar
  27. 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 CrossRefPubMedGoogle Scholar
  28. 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 61:1061–1070CrossRefGoogle Scholar
  29. 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 CrossRefPubMedGoogle Scholar
  30. 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 CrossRefPubMedGoogle Scholar
  31. 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 CrossRefPubMedGoogle Scholar
  32. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 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 CrossRefPubMedGoogle Scholar
  34. 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 CrossRefPubMedGoogle Scholar
  35. 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 CrossRefPubMedGoogle Scholar
  36. 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 CrossRefPubMedGoogle Scholar

Copyright information

© IPNA 2019

Authors and Affiliations

  • Olaya Hernández-Frías
    • 1
  • Helena Gil-Peña
    • 2
  • José M. Pérez-Roldán
    • 2
  • Susana González-Sanchez
    • 2
  • Gema Ariceta
    • 3
  • Sara Chocrón
    • 3
  • Reyner Loza
    • 4
  • Francisco de la Cerda Ojeda
    • 5
  • Leire Madariaga
    • 6
  • Inés Vergara
    • 7
  • Marta Fernández-Fernández
    • 8
  • Susana Ferrando-Monleón
    • 9
  • Montserrat Antón-Gamero
    • 10
  • Ángeles Fernández-Maseda
    • 11
  • M. Isabel Luis-Yanes
    • 12
  • Fernando Santos
    • 1
    • 2
    • 13
    Email author return OK on get
  1. 1.University of OviedoOviedoSpain
  2. 2.Hospital Universitario Central de AsturiasOviedoSpain
  3. 3.Hospital Vall d’HebronBarcelonaSpain
  4. 4.Hospital Cayetano HerediaLimaPeru
  5. 5.Hospital Virgen del RocíoSevillaSpain
  6. 6.Hospital de CrucesVizcayaSpain
  7. 7.Complexo Hospitalario Universitario A CoruñaA CoruñaSpain
  8. 8.Complejo Asistencial Universitario de LeónLeónSpain
  9. 9.Hospital de la RiberaValenciaSpain
  10. 10.Hospital Universitario Reina SofíaMadridSpain
  11. 11.Hospital Virgen de la SaludToledoSpain
  12. 12.Hospital Universitario Nuestra Señora de CandelariaSanta Cruz de TenerifeSpain
  13. 13.Nefrología PediátricaHospital Universitario Central de AsturiasOviedoSpain

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