New PHEX Mutation Causing XLH Found in Japanese Family

Researchers found a new mutation in the PHEX gene that causes X-linked hypophosphatemia (XLH) in a Japanese family, according to a case report.

Titled “Phenotypes of a family with XLH with a novel PHEX mutation,” the report was published in the journal Human Genome Variation.

XLH is characterized by low levels of phosphate in the body, resulting in stunted growth, bone deformities, pain, rickets, and weaker bones. This condition is caused by mutations in the PHEX gene, with more than 220 identified to date.

In the report, researchers described the case of a 4-year-old boy who was brought to the endocrinology unit of a Japanese hospital due to concerns over his short stature. Like both his parents, grandmother, and sister, the boy also had genu valgum, commonly known as “knock-knees,” a condition that occurs when a person has a large gap between their feet when standing with their knees together. However, unlike his family members, he also had scaphocephaly (an abnormality in skull formation).

He underwent a series of laboratory tests, showing low blood levels of phosphate and vitamin D, as well as a higher-than-normal amount of parathyroid hormone.

A brain CT scan found another skull anomaly called craniosynostosis, while X-rays revealed bone bowing.

The researchers suspected XLH based on these laboratory findings, so the patient and his family underwent genetic analysis. They found that the boy, as well as his mother and sister (who both had low phosphate levels in the blood), had a new mutation in intron 17 of PHEX, known as c.1769-2delA. This confirmed the XLH diagnosis.

Protein-coding genes, such as PHEX, are made up of exons — the part of the gene that actually provides instructions for making the protein — and introns, regions between exons normally spliced out during protein production.

The researchers then employed a type of software that predicts splicing patterns. Results suggested altered gene splicing due to this mutation. Other mutations in PHEX with this kind of impact have been previously reported, accounting for nearly a fifth of identified variants in this gene.

The boy was started on nutritional supplements, with daily doses of 55 mg/kg of phosphate and 35 nanograms/kg of the vitamin D metabolite alfacalcidol.

“In summary, we herein described the novel splicing of and a familial mutation in PHEX,” the researchers wrote.

“Since we detected the same mutation in the younger sister of the patient in our report, she underwent regular follow-ups,” they added. “We will also carefully monitor symptoms and disease progression in this family in the future.”