XLH is typically caused by mutations in the PHEX gene, which lead to low blood levels of phosphorus, an important component of bones. The disorder typically manifests as delayed growth, rickets (softer-than-normal bones), osteodynia (pain in the bones), and dental problems.
Currently, 567 mutations in PHEX are listed in the Human Gene Mutation Database. However, only a few of these alterations have been discovered in Chinese patients with XLH.
Mutations in other genes can also contribute to the characteristic symptoms of XLH. In particular, variants in the NPR2 gene are known to cause short stature, yet no studies to date have found these mutations in people with XLH.
In the study, researchers described the case of a 40-year-old Chinese man who was admitted to hospital in February 2019 with continuous osteodynia, bowed legs, only four teeth, and a progressive limp.
He was nearly 2 when these symptoms first appeared, and they were initially ignored. Gradual detection of his symptoms started in 2006 after a bone fracture healed poorly due to low blood levels of phosphorus. The patient was first diagnosed with osteoporosis and treated with calcium and vitamin D supplements. However, his symptoms persisted.
The patient’s 63-year-old mother and 42-year-old brother experienced similar complications. All three relatives had short stature (the patient was the tallest at 1.48 m, or 4.85 ft), abnormal bone metabolism, and significantly low bone mineral density indicative of severe osteoporosis.
Laboratory tests showed decreased blood levels of phosphate and calcitriol (the active form of vitamin D), as well as increased urinary phosphorus excretion.
Taken together, these findings were consistent with a diagnosis of XLH.
Genetic analysis revealed that all three patients had the same mutation in PHEX (c.1543C > T), which had already been associated to XLH. As well, a mutation in NPR2 (c.3058C > T) was found in the 40-year-old man, representing the first time this variant has been linked to XLH.
The three family members were given calcitriol and phosphate supplements. Due to the delay in diagnosis and treatment, their osteodynia was only slightly eased.
In turn, the patient’s blood level of phosphorus increased from 0.57 to 0.63 mmol/L at the end of the four-month follow-up, but they were still below the normal range (0.80–1.40 mmol/L).
“We report the familial hypophosphatemic rickets of three patients in a Chinese family caused by a PHEX gene mutation …, which had never been reported in Chinese patients,” the scientists wrote. “We first report an XLH case together with a NPR2 mutation that had never been reported before.”
According to the team, insufficient awareness of XLH may have contributed to the initial misdiagnosis and delayed treatment of these patients.
“We should emphasize the importance of increasing awareness of the disease. Genetic diagnosis and genetic counselling should be paid enough attention to. If early diagnosis and treatment can be made, a lot of patients will benefit,” the researchers said.
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