Early XLH Identification, Treatment Crucial to Keeping Quality of Life

Identifying and treating X‐linked hypophosphatemia (XLH) early is key to improving quality of life for people with the disorder, particularly in developing countries, a case report shows.

The report, detailing a child in Columbia with this disease, also highlights the difficulties facing doctors and patients with rare disorders in poorer countries.

The study, “PHEX Gene Mutation in a Patient with X-Linked Hypophosphatemic Rickets in a Developing Country,” was published in the journal The Application of Clinical Genetics.

XLH is a rare genetic disorder in which the kidneys become unable to reabsorb phosphate, leading to chronic hypophosphatemia (low blood levels of phosphate), as well as rickets and osteomalacia — softer and weaker bones more prone to fracture.

The disease is caused by mutations in the PHEX gene — located on the X chromosome — which provides instructions for making an enzyme that controls the production of fibroblast growth factor 23 (FGF23), an enzyme that controls phosphate reabsorption. To date, more than 460 mutations have been associated with XLH.

A 9-year-old girl in Colombia came to a hospital with evident bone deformities in both legs, and large joints; she had also lost several teeth. The girl had started showing symptoms of XLH during her first year of life.

She was initially treated with oral calcium supplements, and instructed to wear leg orthoses (devices that accommodate deformities to support the legs). But her symptoms failed to subside. Apart from a maternal cousin who also had leg deformities, she had no other relatives with bone deformities or growth impairments.

Lab tests showed that her blood levels of phosphorus (2.7 mg/dL; reference range, 2.9–5.1 mg/dL) and the vitamin D analog calcifediol (12.77 ng/mL; reference range, 30–70 ng/mL) were below normal. Her kidney function and electrolyte levels were all within normal range, and she showed no signs of blood or of excess proteins in her urine.

Leg X-rays taken at age 4 revealed several bone abnormalities, including poorly defined contours, and bone widening and deterioration.

“All findings were compatible with a metabolic disorder such as rickets or osteomalacia,” the researchers wrote.

These findings led physicians to suspect the girl might have XLH. A subsequent genetic test revealed a pathogenic (disease-causing) mutation (c.1601C>T; p.Pro534Leu) in one copy of the PHEX gene, confirming an XLH diagnosis.

This mutation leads to an amino acid change from proline to leucine at position 534 of the protein sequence. (Amino acids are the building blocks of proteins.)

According to bioinformatic analyses, this amino acid change is expected to be detrimental to the protein’s structure and function.

“In Colombia, there is an underdiagnosis of this pathology [disease] and we lack molecular characterization of this population. This is in part due to the health system. Many patients cannot access specialty care medicine as they live in rural and disperse areas,” the scientists wrote.

“We emphasize the importance of molecular and genetic confirmation of these pathologies in developing countries in order to offer adequate and early treatment that will improve patients’ quality of life and decrease the economic burden on the health system,” they added.