Introduction: X-linked hypophosphatemic rickets (XHR) is the most common form of hereditary rickets, with an estimated incidence of 1: 20.000 individuals. The main characteristic of the disease is excessive renal phosphate loss, which leads to hypophosphatemia with high phosphaturia and defective bone mineralization.
XHR results from mutations in the in the PHEX gene (Phosphate Regulatory Gene with Homology for Endopeptidases located on the X chromosome) located at Xp22.1. PHEX gene has 22 exons and is expressed mainly in the cell membrane of bones and teeth. Currently, at least 364 mutations have been identified, and are registered in the Human Gene Mutation Database.
The PHEX protein has 749 amino acids and three domains: N-terminal cytoplasmic, a single transmembrane region and a large extracellular domain. It functions as a transmembrane endopeptidase, with structure similar to membrane glycoproteins type II.
The protein has an indirect relationship with the hormone FGF23 (Fibroblast Growth Factor 23), which suppresses the action of genes that code for sodium-phosphorus co-transporters and also alters the expression of the vitamin D metabolizing enzyme, resulting in a decrease in the concentration of 1,25-(OH)2D..
Case Report: RRMJ, 2 years, mother G6P2A4, war referred to the pediatric endocrinology service due to reduction of growth rate, irritability, limb pain, skeletal malformations and bowing of legs. The biochemical parameters showed hypophosphatemia, elevated alkaline phosphatase, elevated PTH, normal calcium, increased urinary phosphorus.
Currently he is 6 years of age, and receives treatment with high doses of phosphate and 1,25he-dihydroxyvitamin D3, since he had 2 years and 2 months of age. The patient has difficulty following the prescription correctly due to frequent diarrhea and abdominal pain, and continues to grow at a percentile below the family target.
Molecular Analysis: New generation sequencing of the PHEX gene (OMIN 300550) was performed. We found the variant ChrX: 22.239.768 T>TG (c.1809dupG) which promotes the substitution of the amino acid Serine at position 604 by a Valine and generates a premature stop codon.
Conclusion: A novel pathogenic PHEX mutation was found: c.1809dupG, which caused early termination of translation and produced truncated protein that lead to exuberant clinical expression. Due to poor response to traditional treatment, it is scheduled to start treatment with Burosumabe as soon as the drug is released in our country.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology