Case Report Describes Novel PHEX Mutation Causing XLH in Korean Boy

In cases of suspected familial hypophosphatemia, sequencing the four disease-causing genes at once is a useful approach to determine the exact genetic cause and corresponding disease subtype, a case report suggests.

Using that approach, researchers found a novel mutation in the PHEX gene, which was the cause of X‐linked hypophosphatemia (XLH) in a Korean boy. To date, only 18 other mutations in this gene had been described in Korean patients with the condition.

The study, “Identification of a novel variant in the PHEX gene using targeted gene panel sequencing in a 24-month-old boy with hypophosphatemic rickets,” was published in the journal Annals of Pediatric Endocrinology and Metabolism.

Familial hypophosphatemia is a rare genetic disorder in which the kidneys become unable to reabsorb phosphate, leading to chronic low blood levels of phosphate (hypophosphatemia), as well as rickets and weaker bones.

Its most common form is XLH, caused by mutations in PHEX, but there are three additional forms resulting from mutations in the FGF23, DMP1, or ENPP1 genes.

To date, 18 mutations in the PHEX gene were described in Korean patients, though about 457 alterations in this gene have been reported in the Human Gene Mutation Database.

Researchers now reported the case of a 2-year-old Korean boy suspected of familial hypophosphatemia, who had a previously unknown mutation in the PHEX gene.

The boy went to the department of orthopedics at the Pusan National University Hospital due to outward bowed legs, or genu varum. He had short stature and low weight than normal for his age, but all cognitive and motor assessments were normal.

The boy’s mother, and several other members of her family, also had short stature and had received surgery to correct the outward bowing of their legs.

At examination, the boy showed frontal bossing (protruding forehead) and widening of the femur’s metaphysis, where bone growth occurs.

Blood exams then revealed hypophosphatemia and increased levels of the liver enzyme alkaline phosphatase (which can indicate liver or bone problems), but levels of calcium were within normal range. Vitamin D3 also was slightly above normal.

Despite the low phosphate levels, the patient exhibited deficient absorption of phosphate in his kidneys, which led researchers to suspect an inherited form of hypophosphatemia.

Genetic testing for the four genes associated with the condition then revealed a mutation in the PHEX gene, known as c.1949T>C (p.Leu650Pro). This means that the resulting protein had the amino acid proline instead of leucine in position 650. The boy’s mother had the same mutation.

While this mutation had never been described, prior computer analyses had already modeled changes in this amino acid. Those results suggested that a mutation in this location likely would affect protein function, consistent with findings that this leucine residue is “well-conserved from birds to mammals and humans,” the researchers wrote.

Based on the findings, the mutation now can be classified as likely pathogenic (disease-causing).

After his diagnosis, the boy received treatment with alfacalcidol (a vitamin D analog) combined with phosphate supplements given four times daily. His levels of alkaline phosphatase returned to normal three months later, but one year later, the boy’s weight and height remained low for his age.

At the time of the report, he was 3 years and 10 months, had increased his daily dose of alfacalcidol and phosphate supplements, and had not seen a further increase in leg bowing or experienced treatment side effects.

“In the present study, we report a [novel] variant … in the PHEX gene in a hypophosphatemic rickets patient,” the researchers wrote.

They concluded that “because several genes are related to [familial hypophosphatemia], targeted gene panel sequencing can be a useful molecular diagnostic tool.”