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X-Linked Hypophosphatemia: Uniquely Mild Disease Associated With PHEX 3'-UTR Mutation c.*231A>G (A Retrospective
Pamela S Smith1,2, Gary S Gottesman1, Fan Zhang1
1Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children - St. Louis, St. Louis, MO, USA.
Summary
X-linked hypophosphatemia (XLH) with a PHEX 3'-UTR mutation presents a milder form of the disorder, particularly in females. This variant shows improved height and phosphorus levels, challenging traditional XLH recognition and management.
Area of Science:
- Genetics and Molecular Biology
- Endocrinology
- Pediatric Nephrology
Background:
- X-linked hypophosphatemia (XLH) is a prevalent genetic disorder characterized by renal phosphate wasting due to PHEX gene mutations.
- Elevated FGF23 leads to hypophosphatemia, causing rickets in children and osteomalacia in adults.
- A specific non-coding PHEX 3 -UTR mutation (c.*231A>G) was previously identified in individuals with a milder form of XLH.
Purpose of the Study:
- To characterize the clinical and biochemical features of XLH associated with the PHEX 3 -UTR mutation.
- To compare individuals with the UTR mutation to age- and sex-matched XLH patients without this mutation.
- To assess the impact of the UTR mutation on growth, phosphorus metabolism, and bone health.
Main Methods:
- Comparative study of 30 individuals with the PHEX 3 -UTR mutation (UTR group) and 30 age- and sex-matched XLH patients (XLH group).
- Collection and analysis of clinical data including height, arm span, and medical treatment history.
- Biochemical assessments included serum phosphorus (Pi), FGF23, and alkaline phosphatase levels, as well as renal tubular threshold for phosphorus (TmP/GFR).
- Bone mineral density was measured at the lumbar spine.
Main Results:
- The UTR group exhibited significantly better height Z-scores, especially females, and were more proportionate compared to the XLH group.
- Individuals in the UTR group had higher fasting serum Pi and TmP/GFR, with FGF23 levels within the reference range.
- Lumbar spine bone mineral density Z-scores were higher in the UTR group, and fewer individuals in this group received medical treatment.
Conclusions:
- The PHEX 3 -UTR mutation results in a distinctly mild phenotype of XLH, particularly noticeable in girls and women.
- This milder variant presents diagnostic and management challenges due to its less severe presentation.
- Further research is needed to optimize the recognition and therapeutic strategies for this specific XLH subtype.
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