Hereditary hypophosphatemia in Norway: a retrospective population-based study of genotypes, phenotypes, and treatment complications

Abstract

ObjectiveHereditary hypophosphatemias (HH) are rare monogenic conditions characterized by decreased renal tubular phosphate reabsorption. The aim of this study was to explore the prevalence, genotypes, phenotypic spectrum, treatment response, and complications of treatment in the Norwegian population of children with HH.DesignRetrospective national cohort study.MethodsSanger sequencing and multiplex ligand-dependent probe amplification analysis of PHEX and Sanger sequencing of FGF23, DMP1, ENPP1KL, and FAM20C were performed to assess genotype in patients with HH with or without rickets in all pediatric hospital departments across Norway. Patients with hypercalcuria were screened for SLC34A3 mutations. In one family, exome sequencing was performed. Information from the patients' medical records was collected for the evaluation of phenotype.ResultsTwety-eight patients with HH (18 females and ten males) from 19 different families were identified. X-linked dominant hypophosphatemic rickets (XLHR) was confirmed in 21 children from 13 families. The total number of inhabitants in Norway aged 18 or below by 1st January 2010 was 1 109 156, giving an XLHR prevalence of ∼1 in 60 000 Norwegian children. FAM20C mutations were found in two brothers and SLC34A3 mutations in one patient. In XLHR, growth was compromised in spite of treatment with oral phosphate and active vitamin D compounds, with males tending to be more affected than females. Nephrocalcinosis tended to be slightly more common in patients starting treatment before 1 year of age, and was associated with higher average treatment doses of phosphate. However, none of these differences reached statistical significance.ConclusionsWe present the first national cohort of HH in children. The prevalence of XLHR seems to be lower in Norwegian children than reported earlier.

Burosumab Improved Histomorphometric Measures of Osteomalacia in Adults with X-Linked Hypophosphatemia: A Phase 3, Single-Arm, International Trial

“…These events, as well as nephrocalcinosis, are known risks associated with conventional therapy. (2,24) In contrast, in the present study, we observed no changes in serum calcium or PTH concentrations, urine calcium excretion, nor renal nephrocalcinosis scores and no incidents of hyperphosphatemia. Burosumab's safety profile was similar to that seen in previous clinical trials, with most adverse events being mild to moderate in severity.…”

“…Sullivan and colleagues reported hypercalciuria and tertiary hyperparathyroidism. These events, as well as nephrocalcinosis, are known risks associated with conventional therapy . In contrast, in the present study, we observed no changes in serum calcium or PTH concentrations, urine calcium excretion, nor renal nephrocalcinosis scores and no incidents of hyperphosphatemia.…”

Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia

“…Several other vitamin D analogues are also available 62,117,121,122 . As in healthy children, 25 reported in 30-70% of patients with XLH 3,48,56,87,[96][97][98][99]118 . Several reports suggest positive associations between daily oral phosphate doses and the risk of developing nephrocalcinosis, whereas the relationship with active vitamin D therapy and/or with the presence of hypercalciuria has been observed less frequently 3,48,96,97,99,118,125 .…”

X-Linked Hypophosphatemia: Uniquely Mild Disease Associated With PHEX 3′-UTR Mutation c.*231A>G (A Retrospective Case–Control Study)

“…X‐linked hypophosphatemia (XLH, OMIM #307800), the most common genetic rickets or osteomalacia, is due to loss‐of‐function mutations of PHEX : “phosphate‐regulating endopeptidase homolog, X‐linked” . Consequently, circulating levels of the phosphatonin fibroblast growth factor 23 (FGF23) increase and affected individuals manifest hypophosphatemia from renal wasting of inorganic phosphate (Pi), diminished kidney synthesis of 1,25‐dihydroxyvitamin D (1,25(OH) 2 D), and decreased intestinal absorption of calcium (Ca) and Pi . XLH accounts for >80% of heritable hypophosphatemic bone disease and occurs in ~1 per 20,000 births .…”

“…Its 22 exons encode a 749–amino acid enzyme that, when compromised, increases circulating FGF23 thereby diminishing expression of two sodium‐Pi cotransporters in renal proximal tubule cells . Furthermore, FGF23 downregulates kidney 1α‐hydroxylase necessary to activate 25‐hydroxyvitamin D to 1,25(OH) 2 D . For decades, conventional medical therapy for XLH has been one or two daily oral doses of bioactive vitamin D 3 (1,25(OH) 2 D 3 or 1α‐hydroxyvitamin D 3 ) with multiple daily oral doses of a Pi salt, at least until linear growth is complete .…”