Study Finds Rare Mutation Linked to Mild XLH Disease That Affects Mainly Girls

A mutation in a region of the PHEX gene — a region containing no information to make proteins — leads to mild X-linked hypophosphatemia (XLH), especially in females, compared to variants in other regions of the same gene, researchers have found.

This finding presents challenges for diagnosis and disease management, they added.

The study, “X-Linked Hypophosphatemia: Uniquely Mild Disease Associated With PHEX 3ʹ-UTR Mutation c.*231A>G (A Retrospective Case-Control Study),” was published in the Journal of Bone and Mineral Research.

XLH is caused by mutations in PHEX that lead to excessive production of fibroblast growth factor 23 (FGF23). This hormone prevents kidneys from reabsorbing phosphate, leading to chronic hypophosphatemia, or low blood levels of phosphate.

In a previous study, the team from Shriners Hospitals for Children in St. Louis described six children and four of their mothers carrying a rare mutation in PHEX — known as c.*231A>G — which is located in a gene region that does not contain information to make the PHEX protein. Still, the mutation may affect how messenger RNA (which is derived from DNA in protein production) is processed and ultimately affect the resulting protein.

The six children had mild XLH compared to boys with mutations located in other parts of the PHEX gene.

Aiming to better characterize the impact of this mutation, the researchers compared 30 patients with this variant (UTR group) to participants with a different XLH-causing genetic change. Patients were followed at the Center for Metabolic Bone Disease and Molecular Research at the hospital.

Both groups included 13 adults (ages 23 to 63) and 17 children (2 to 17). In the UTR group, 17 participants, including 13 females, received no medical treatment. In the other group, 27 of the 30 patients received conventional medical treatment, including 11 of the 13 females.

Patients in the UTR group were significantly taller than those in the other group, particularly the women. People with XLH typically have abnormalities in their lower extremities as well as short stature. As such, the researchers assessed a computer-generated arm to height score, which was compared to a height Z-score. Results showed that both scores were below average in the two groups. A measure of body proportionality then showed that the UTR group was more proportional than the comparison group.

In lab tests, the UTR group had significantly higher levels of fasting blood phosphate compared to the XLH group — 3.0 vs 2.5 mg/dl — and enhanced phosphate reabsorption in the kidneys (2.5 vs. 2.0 mg/dL).

Blood levels of FGF23 were available for 10 patients in the UTR group and seven in the comparison group. Nine participants in the UTR group had FGF23 levels within the reference range (44–215 RU/ml). In contrast, all but one patient with other mutations had FGF23 levels above normal.

Blood levels of an enzyme called alkaline phosphatase (typically elevated in people with XLH) were similar between the two groups.

Bone mineral density — a measure of the mineral content in bones, namely calcium — of the lower back was significantly higher in the UTR group than in the other XLH patients.

Overall, the results suggest that the rare variant is linked with mild disease, especially in girls and women, “posing challenges for its recognition and management,” the scientists wrote.

“Management strategies must consider if treatment is warranted, timing of interventions, duration of pharmacologic therapy, and regimen options,” they added.

“However, the natural history of this XLH variant remains unclear, and perhaps severe late-onset problems can emerge,” the investigators said