Long-term effect of conventional phosphate and calcitriol treatment on metabolic recovery and catch-up growth in children with PHEX mutation


ALİKAŞİFOĞLU A., ÜNSAL Y., GÖNÇ E. N. , ÖZÖN Z. A. , KANDEMİR N., ALİKAŞİFOĞLU M.

JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM, vol.34, no.12, pp.1573-1584, 2021 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 34 Issue: 12
  • Publication Date: 2021
  • Doi Number: 10.1515/jpem-2021-0387
  • Journal Name: JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, CAB Abstracts, EMBASE, MEDLINE
  • Page Numbers: pp.1573-1584
  • Keywords: conventional treatment, genetic variability, growth, hypophosphatemic rickets, X-LINKED HYPOPHOSPHATEMIA, D-RESISTANT RICKETS, VITAMIN-D, FINAL HEIGHT, THERAPY, MANAGEMENT, COHORT
  • Hacettepe University Affiliated: Yes

Abstract

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 amplifi-cation (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.