Objectives: Hereditary hypophosphatemic rickets (HR) is conventionally treated with phosphate and calcitriol. Exploring genotype and phenotypic spectrum of X-linked hypophosphatemic rickets (XLHR), focusing on short-term, long-term, and pubertal impact of conventional treatment was aimed.
Methods: Sixteen patients from 12 unrelated families with HR were analyzed for phosphate regulating endopeptidase homolog X-linked (PHEX) mutation. Initially Sanger sequencing analysis was performed. If PHEX mutation was not detected, multiplex ligation-dependent probe amplification (MLPA) was performed. If molecular defect was detected, first-degree relatives were analyzed. Thirteen patients (81%) and five first-degree relatives with XLHR were evaluated for genotype-phenotype or gender-phenotype correlation. Clinical characteristics and response to conventional treatment were determined retrospectively.
Results: Nine different PHEX mutations were identified; four splice-site, three point mutations, and two single exon deletions. Four were novel mutations. Despite conventional treatment, median adult height was lower than median height on admission (-3.8 and -2.3 SDS, respectively), metabolic and radiographic recovery were not achieved, adherence was low (30%). Although mean adult height was better in compliant patients than noncompliants (-2.6 vs. -3.7 SDS, respectively), they were still short. Correlation between phenotype and genotype or gender could not be shown. Median phosphate decreased significantly throughout puberty (p=0.014). Median pubertal height was lower than prepubertal height (-4.4 vs. -3.6 SDS; respectively), pubertal growth spurt was not observed. Among five patients with a follow-up longer than five years, three had nephrocalcinosis (60%), two had hyperparathyroidism (40%), 4/6 (33%) required correction osteotomy.
Conclusions: Conventional treatment appears to have limited effect on metabolic, clinical and radiographic recovery in XLHR. Metabolic control and growth worsened during puberty. Although, long-term adverse effects are yet to be seen, introduction of burosumab as first-line treatment may be an alternative after infancy.
Keywords: conventional treatment; genetic variability; growth; hypophosphatemic rickets.
© 2021 Walter de Gruyter GmbH, Berlin/Boston.