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

Abstract

Objective: Hereditary 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.

Design: Retrospective national cohort study.

Methods: Sanger 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.

Results: Twety-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.

Conclusions: We present the first national cohort of HH in children. The prevalence of XLHR seems to be lower in Norwegian children than reported earlier.

Figure 1

Growth in X-linked hypophosphatemic rickets. Ages at diagnosis and last registered consultation, and the corresponding height z-scores for 19 of the 21 XLHR patients. The two outliers represent two immigrant siblings who had not received any medical care and did not start treatment until age 6 and 15 years respectively. The broken line represents the male treated with growth hormone. Circles represent females and squares represent males.

Figure 2

Complications in X-linked hypophosphatemic rickets. (A) Nephrocalcinosis: the average daily phosphate (given as mg/kg per day elemental phosphorus) dose in patients who developed nephrocalcinosis (NC+) and patients who did not (NC−). The horizontal lines represent the median in each group. (B) Hyperparathyroidism: the relationship between the maximum registered value of serum PTH and phosphate dose (given as mg/kg per day elemental phosphorus) at the same time point.