SAT-360 Out of Sight, out of Mind: PHEX 3’-UTR C.*231A>G X-Linked Hypophosphatemia in Adults: A Case Study of One Family Pedigree with a Widely Variable Phenotype

Abstract

Title: Out of Sight, Out of Mind: PHEX 3’-UTR c.*231A>G X-Linked Hypophosphatemia in Adults: A Case Study of One Family Pedigree with a Widely Variable Phenotype

X-linked hypophosphatemia (XLH) is an inherited form of hypophosphatemia that is part of a group of disorders that leads to impaired bone mineralization, which can manifest as rickets in children and osteomalacia in adults. Mutations in PHEX, DMP1, ENPP1, and activating mutations in FGF23 have each been shown as genetic causes for XLH. PHEX is a zinc metallopeptidase which reduces expression of FGF23 through mechanisms that are not fully understood. Inactivating mutations in the PHEX gene cause elevated levels of FGF23, resulting in renal phosphate-wasting, impaired conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D and impaired bone mineralization with osteomalacia. Though the clinical significance of FGF23 levels is not clearly understood, it has also been shown that FG23 increases with age.

XLH has a reported prevalence of 3.9–5 per 100,000. We speculate that this may be under recognized and that diagnosis may be delayed for many years in those with mild forms of XLH due to non-specific symptoms. Diagnosis may be complicated by normal or low-normal serum phosphorus levels. Adults may be mistakenly diagnosed with ankylosing spondylitis, polyarthritis, osteoarthritis, diffuse idiopathic skeletal hyperostosis and other disorders that cause stiffness. Some clinical manifestations of XLH in adults include dental disease, skeletal and spinal disease, sensorineural hearing loss, kidney stones, renal impairment, and hyperparathyroidism. The PHEX 3’-UTR c.231A>G near the polyadenylation signal has been previously described to cause milder severity in men and seemingly unaffecting women, but data for comparison is limited.

We present a large, multigenerational family with a mutation in the PHEX gene (3’-UTR c.*231A>G) demonstrating variable penetrance in the pedigree. Of the members positive for the mutation, the most common symptoms were sensorineural hearing loss, enthesopathy, and dental disease. Most had normal or low-normal phosphorus levels in both genders. Two patients had prior diagnoses of ankylosing spondylitis/ seronegative spondyloarthropathy. In general, males with the mutation had more severe symptoms than females. However, females with a severe phenotype and low phosphorus was also observed. The disease burden was cumulative over time and correlated with serum phosphorus levels. Musculoskeletal symptoms were increased in the members over the age of 60.

Sources:

Chesher, Douglas et al. Outcome of Adult Patients with X-Linked Hypophosphatemia Caused by PHEX Gene Mutations. Vol. 41. Dordrecht: Springer Netherlands, 2018. Web.

Zhang, Cong et al. Clinical and Genetic Analysis in a Large Chinese Cohort of Patients with X-Linked Hypophosphatemia. Vol. 121. Elsevier Inc, 2019. Web.