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

Silje Rafaelsen,Robert Bjerknes,Stefan Johansson,Helge Ræder

doi:10.1530/eje-15-0515

Silje Rafaelsen, Robert Bjerknes + Show 2 more

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https://doi.org/10.1530/eje-15-0515

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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.

Highlights

Hereditary hypophosphatemia (HH) is a group of rare diseases with disordered phosphate metabolism and decreased renal tubular phosphate reabsorption (1)
ARHR1 is caused by mutations in the DMP1 gene, encoding the dentin matrix protein 1 (7, 8), ARHR2 is caused by mutations in the ENPP1 gene encoding the ectonucleotide pyrophosphatase/phosphodiesterase 1 (9, 10), whereas we have recently shown an association between biallelic mutations in FAM20C and FGF23dependent ARHR3 in a Norwegian family (11)
During the period from 1st January 2010 to 31st December 2014, we included another four patients, two of which immigrated to Norway in 2014 and two patients born to X-linked dominant hypophosphatemic rickets (XLHR) mothers after 2010

Summary

Introduction

Hereditary hypophosphatemia (HH) is a group of rare diseases with disordered phosphate metabolism and decreased renal tubular phosphate reabsorption (1). In hypophosphatemic rickets (HR), the hypophosphatemia is associated with rickets and osteomalacia, whereas syndromes with hypophosphatemia combined with osteosclerosis and ectopic calcifications, and not rickets or osteomalacia, are recognized (1). HR can be classified as either dependent or independent of the bone derived fibroblast growth factor 23 (FGF23) (1).

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