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This Article Full Text Full Text (PDF) All Versions of this Article: EJE-09-0261v1 161/4/647    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Saito, T. Articles by Fujita, T. PubMed PubMed Citation Articles by Saito, T. Articles by Fujita, T.

Familial hypophosphatemic rickets caused by a large deletion in PHEX gene

¹ Division of Pediatrics² Division of Nephrology and Endocrinology, Department of Medicine, University of Tokyo Hospital, Tokyo 113-8655, Japan³ Division of Nephrology and Endocrinology, Department of Medicine, Nagano Municipal Hospital, Nagano, 381-8551, Japan⁴ Division of Pediatrics, National Hospital Organization Chiba Medical Center, Chiba, 260-0042, Japan

(Correspondence should be addressed to S Fukumoto; Email: fukumoto-tky{at}umin.ac.jp)

Abstract

Context: X-linked hypophosphatemic rickets/osteomalacia (XLH), autosomal dominant and recessive hypophosphatemic rickets/osteomalacia (ADHR and ARHR) share common clinical features including high fibroblast growth factor 23 (FGF23) levels. These diseases are caused by mutations in phosphate regulating endopeptidase homolog, X-linked (PHEX), FGF23, and dentin matrix acidic phosphoprotein 1 (DMP1) gene respectively. It remains unclear whether these diseases can be clinically discriminated.

Objective: To clarify the underlying mechanism of patients with hypophosphatemic rickets whose parents showed no physical findings suggesting rickets.

Design and patients: The proband is a 39-year-old woman. She and her 37-year-old brother show the same clinical features such as bowing of legs together with hypophosphatemia (sister: P 1.8 mg/dl, brother: P 1.6 mg/dl) and high FGF23 levels (sister: 542 pg/ml, brother: 96 pg/ml). Physical findings of their parents are normal and ARHR was suspected.

Results: Sequencing of all coding exons and exon–intron junctions of DMP1 and FGF23 genes showed no mutation. Subsequent analysis revealed that there is a deletion of 52 143 bp including exons 1–3 in PHEX gene in the brother. His sister was found to be a heterozygote for the same deletion indicating that they are suffering from XLH. The same deletion was detected in the mother. However, the amount of the wild-type allele was more and that of the mutant one was less in genomic DNA from the mother compared with those from the sister. Single nucleotide polymorphism (SNP) analysis indicated that the mother has three kinds of PHEX alleles suggesting a somatic mosaicism.

Conclusion: Careful genetic analysis is mandatory for correct differential diagnosis of hypophosphatemic rickets with high FGF23 levels.