New XLH-causing Gene Mutation Found in Chinese Family, Case Report Suggests

A Chinese man and members of his family carry a previously unknown mutation that caused X-linked hypophosphatemia (XLH), according to a recently published case report. 

The study, “A novel c.2179T>C mutation blocked the intracellular transport of PHEX protein and caused X‐linked hypophosphatemic rickets in a Chinese family,” was published in the journal Molecular Genetics & Genomic Medicine. 

XLH is caused by mutations in the PHEX gene that carries instructions for making the PHEX enzyme. Mutations in this gene lead to excessive activation of a protein called FGF23, greater phosphate excretion in urine, and low levels of phosphate in the blood (hypophosphatemia).

Soft and weak bones (rickets), bowed legs (genu varus), short stature, and dental abnormalities are among the most common symptoms of XLH.

Currently, 369 mutations in the PHEX gene have been identified as causing XLH. However, how most of these mutations drive disease development remains unclear.

Researchers at the Qingdao University, in China, described the case of a 38-year-old man, who was first seen due to fertility problems. While he did not report joint pain, he had visible signs of developmental defects, being only 152 centimeters (4.9 feet) tall, with a forward waist and bowed legs. His first-cousin also had similar symptoms. 

Bone mineral density (BMD) tests of the lower spine (lumbar) and the top of the femur bone (upper leg) were in the normal range compared to men of similar age. 

But blood tests revealed low phosphate levels — 1.76 micrograms per deciliter (mg/dL), normal range is 3.4 to 4.5 mg/dL — and elevated parathyroid hormone levels. Based on these criteria, he was diagnosed with hypophosphatemia. 

The patient’s FGF23 levels in the blood were high — 127.3 picograms (pg)/ml compared to a control range of 26.2 to 66.4 pg/ml, as determined by the analysis of 100 healthy subjects ages 19 to 72 years. 

His cousin also had similar phosphate and FGF23 levels, while his mother, who had slightly bowed legs, had elevated FGF23 (81 pg/ml).

Genetic analysis of the patient uncovered a mutation in the PHEX gene that changed a single amino acid (the building blocks of proteins) in the PHEX enzyme. Specifically, the mutation changed a phenylalanine amino acid to a leucine amino acid. His mother and cousin carried the same mutation. 

Computer analysis predicted the mutation to be disease-related, and an examination of the PHEX enzyme structure suggested the variant likely changed the enzyme’s shape and function. 

Then, cell-based tests revealed that the mutation caused the PHEX enzyme to be improperly processed and transported within the cell.

“In the present study, we identified a novel [mutation] in the PHEX [gene] from an XLH family with two affected individuals,” the researchers wrote. “Our findings expanded the mutation spectrum of the PHEX and provided a genetic basis for the prenatal or postpartum diagnosis of XLH in the future.”