A De Novo Deleterious PHEX Variant Without Clinical Features of X-Linked Hypophosphatemia

X-linked hypophosphatemia (XLH), the most common form of hereditary rickets, is due to inactivation of PHEX, resulting in increased circulating fibroblast growth factor 23. Consequent renal phosphate loss leads to hypophosphatemia, rickets, and progressive bow deformity. Inheritance is X-linked dominant, such that heterozygous females are affected, as well as hemizygous males. A 10-month-old girl was referred for potential treatment for presumed XLH. Amniocentesis, performed following prenatal identification of duodenal atresia, polyhydramnios, and intrauterine growth restriction, revealed a de novo X-chromosomal deletion encompassing 10 genes, including PHEX. Postnatal genetic testing confirmed presence of the deletion in the baby. She demonstrated no phenotypic, biochemical, or radiographic features of XLH. Neither parent had features of XLH, nor carried the deletion. Given the discordance between genotype and phenotype, evaluation for skewed X-inactivation was pursued. Methylation analysis via the androgen receptor locus was inconclusive, thus RNA sequencing was pursued. Analysis of 12 high-quality single nucleotide polymorphisms (SNPs) that are expressed in mRNA revealed skewed X-inactivation. Heterozygous disruption of PHEX typically confers a diagnosis of XLH. Skewed X-inactivation, whereby one X chromosome is preferentially silenced, appears to have protected this patient from the expected expression of an X-linked dominant disorder.