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dc.contributor.authorRafaelsen, Silje Hjorth
dc.date.accessioned2018-01-11T13:51:28Z
dc.date.available2018-01-11T13:51:28Z
dc.date.issued2016-05-03
dc.identifier.isbn978-82-308-3339-1
dc.identifier.urihttp://hdl.handle.net/1956/17202
dc.description.abstract<p>Background: Hereditary hypophosphatemia (HH) is a group of diseases characterized by monogenic hypophosphatemia due to reduced tubular maximum reabsorption of phosphate per glomerular filtration rate (TmP/GFR). This group includes X-linked dominant hypophosphatemic rickets (XLHR), caused by deactivating mutations in PHEX, autosomal dominant HR (ADHR), caused by activating mutations in FGF23 and autosomal recessive HR, caused by deactivating mutation in DMP1 (ARHR1) or ENPP1 (ARHR2), and all these conditions involve elevated levels of the phosphate regulating, bone-derived hormone FGF23. Combined therapy with phosphate and active vitamin D partially corrects rickets, osteomalacia and suboptimal growth in children, but the therapeutic window is narrow, with a risk of nephrocalcinosis and hyperparathyroidism.</p> <p>Hyperphosphatemic familial tumoral calcinosis (HFTC) and hyperphosphatemia hyperostosis syndrome (HHS) are caused by reduced levels of FGF23, due to deactivating mutations in FGF23, GALNT3 or KL. Phosphate lowering treatment only partially reduces the abnormal soft tissue calcifications characteristic for these conditions.</p> <p>Aims: To study hereditary disorders of phosphate metabolism in Norwegian patients, including the prevalence, phenotype and outcome of hereditary hypophosphatemia (HH) in the Norwegian pediatric population. Moreover, to study the genetic causes, including mutations in novel genes, associated with hypo- or hyperphosphatemia in Norwegian families.</p> <p>Materials and methods: Patients were recruited by contact with all pediatric and medical departments in Norwegian hospitals during the years 2009-2015. Inclusion criteria for HH were hypophosphatemia and reduced TmP/GFR, and for HFTC/HHS hyperphosphatemia and increased TmP/GFR. Clinical data were retrieved from the patients’ medical records. If the genotype was not already known, we performed Sanger sequencing of the PHEX, FGF23, DMP1, ENPP1, GALNT3, KL and FAM20C genes. Whole exome sequencing was performed in three families where the genetic screening was negative.</p> <p>Results: In Paper I we found a prevalence of genetically verified XLHR in Norway of 1 in 60.000. PHEX mutations were confirmed in 21 of the 28 included patients with HH, FAM20C mutations in two, and SLC34A3 mutations in one patient. We found a trend for XLHR males to be more growth restricted and more often having dental involvement than females. In XLHR children, 10 of 15 patients had elevated PTH before the start of treatment and nine of 21 had low-grade nephrocalcinosis during treatment with phosphate and alfacalcidol, but only one case of transiently compromised renal function.</p> <p>In Paper II we identified novel combined heterozygous mutations in FAM20C in two male siblings with hyperphosphatemia and reduced TmP/GFR, and elevated levels of FGF23. They did not demonstrate rickets, but rather generalized osteosclerosis and intracerebral calcifications.</p> <p>In Paper III we identified a novel homozygous mutation in GALNT3 in two siblings with HFTC and HHS. We showed the phenotypic diversity within the same family, and the fluctuation of symptoms over time. We also reviewed all cases of genetically verified HFTC and HHS, and showed that the combined HFTC/HHS phenotype is more common than previously recognized.</p> <p>Conclusions: We have shown that the prevalence of XLHR in Norwegian children seems to be lower than reported in other cohorts. In XLHR children, males seem to have a more severe mineralization phenotype than females. Adequate treatment partially corrects rickets, skeletal axis deviation and longitudinal growth, but gives an increased risk of low-grade nephrocalcinosis, although without renal dysfunction. We have also identified two patients with FAM20C mutations and shown that they have pathological serum levels of FGF23, and that FAM20C mutations are associated with autosomal recessive FGF23-dependent hereditary hypophosphatemia. Finally, we have brought further support to theory that HFTC and HHS are two syndromes in a clinical spectrum of FGF23 related hereditary hyperphosphatemias.</p>eng
dc.language.isoengeng
dc.publisherThe University of Bergeneng
dc.relation.haspartPaper 1: Rafaelsen S, Johansson S, Raeder H, Bjerknes R. Hereditary hypophosphatemia in Norway; a retrospective population-based study of genotypes, phenotypes and treatment complications. Eur J Endocrinol. 2016;174(2):125-36. <a href="http://hdl.handle.net/1956/15294" target="blank">http://hdl.handle.net/1956/15294</a>eng
dc.relation.haspartPaper II: Rafaelsen SH, Raeder H, Fagerheim AK, Knappskog P, Carpenter TO, Johansson S, Bjerknes R. Exome sequencing reveals FAM20C mutations associated with fibroblast growth factor 23-related hypophosphatemia, dental anomalies, and ectopic calcification. J Bone Miner Res. 2013;28(6):1378-85. Full-text not available in BORA due to publisher restrictions. <a href="https://doi.org/10.1002/jbmr.1850" target="blank">https://doi.org/10.1002/jbmr.1850</a>eng
dc.relation.haspartPaper III: Rafaelsen S, Johansson S, Raeder H, Bjerknes R. Long-term clinical outcome and phenotypic variability in hyperphosphatemic familial tumoral calcinosis and hyperphosphatemic hyperostosis syndrome caused by a novel GALNT3 mutation; case report and review of the literature. BMC Genet. 2014;15:98. <a href="http://hdl.handle.net/1956/8579" target="blank"> http://hdl.handle.net/1956/8579</a>eng
dc.titleHereditary phosphate balance disorders in Norwegian childreneng
dc.typeDoctoral thesiseng
dc.rights.holderCopyright the author. All rights reserved.eng
bora.peerreviewedNot peer reviewedeng
noa.nsiVDP::Medisinske Fag: 700::Klinisk medisinske fag: 750eng


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