Familial hypophosphatemic rickets caused by a large deletion in PHEX gene.
BACKGROUND
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.


METHODS
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.


CONCLUSIONS
Careful genetic analysis is mandatory for correct differential diagnosis of hypophosphatemic rickets with high FGF23 levels.
Saito
Tasuku
T
Division of Pediatrics, Department of Medicine, University of Tokyo Hospital, Tokyo 113-8655, Japan.
Nishii
Yutaka
Y
Yasuda
Toshiyuki
T
Ito
Nobuaki
N
Suzuki
Hisanori
H
Igarashi
Takashi
T
Fukumoto
Seiji
S
Fujita
Toshiro
T
D000328:Adult; D000368:Aged; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D005091:Exons / Q000235:genetics; D053098:Familial Hypophosphatemic Rickets / Q000235:genetics*; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics; D017353:Gene Deletion; D005799:Genes, Dominant; D005808:Genes, Recessive; D040181:Genetic Diseases, X-Linked; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D010018:Osteomalacia / Q000209:etiology / Q000235:genetics; D053402:PHEX Phosphate Regulating Neutral Endopeptidase / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025842:SUMO-1 Protein / Q000235:genetics
C000717427:FGF23 protein, human; D025842:SUMO-1 Protein; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506231:PHEX protein, human