The paradoxical coexistence of hypophosphatemic rickets and increased bone density in spine of a subject carrying a novel splice site mutation in PHEX

0
0
0

The paradoxical coexistence of hypophosphatemic rickets and increased bone density in spine of a subject carrying a novel splice site mutation in PHEX

Imagine living with leg pain for years, only to discover your bones tell a conflicting story—weakened legs from rickets, yet unusually dense spine bones. That’s the paradox a 46-year-old man and his family faced, linked to a never-before-seen genetic mutation in the PHEX gene, which regulates phosphate in the body.

The man, part of a family with a history of short stature and abnormal gait, had been dealing with progressive left leg pain for over five years. A physical exam revealed short stature, “O-type” (bowed) legs, and a “penguin gait”—a waddling walk common in bone disorders. X-rays and dual-energy X-ray absorptiometry (DEXA) scans painted a confusing picture: his spine had increased bone density, but he had a fractured left femur with hardening at the break. A follow-up DEXA scan a year later showed his spine density dropped while his femoral neck density rose—adding to the mystery.

His mother, brother, and one sister shared similar symptoms: short stature, bowed legs, and gait issues. Testing showed several family members had low blood phosphate (hypophosphatemia), high parathyroid hormone (a hormone that regulates calcium and phosphate), and elevated fibroblast growth factor 23 (FGF23)—a hormone that reduces the kidneys’ ability to absorb phosphate. The man and his nephew also had weaker kidney phosphate reabsorption, a key sign of X-linked hypophosphatemic rickets (XLH)—a genetic disorder that causes soft bones in children and bone pain in adults.

To solve the puzzle, researchers from the Laboratory of Endocrinology and Metabolism at West China Hospital, Sichuan University, used whole-exome sequencing (a test that reads most of a person’s genes) on the man, his brother, and sister. They found a novel splice site mutation (c.1483-1G>C) in intron 13 of the PHEX gene—never before reported in major databases like OMIM, ClinVar, or 1000 Genomes. Splice site mutations disrupt how genes are “cut and pasted” into functional proteins, often leading to non-working or faulty proteins. Genetic guidelines from the American College of Medical Genetics and Genomics classified this mutation as pathogenic (disease-causing).

The mutation ran in the family: the man and his brother (males, who have one X chromosome) had one mutated copy (hemizygous), while his sister, nephew, niece, and grandniece (females, who have two X chromosomes) had one mutated and one healthy copy (heterozygous carriers). This aligns with XLH’s X-linked inheritance—males are more severely affected because they lack a healthy backup X chromosome.

What makes this case stand out? The man and his brother had XLH symptoms—bowed legs, bone pain—but their spines had increased bone density. Previous studies show XLH affects bones differently by location: axial bones (like the spine) often get denser, while peripheral bones (like the femur) get weaker. This is partly due to excess unmineralized bone tissue (hyperosteoidosis) and may be an intrinsic part of XLH, even without treatment.

This study adds a new piece to the XLH puzzle with a novel PHEX mutation and highlights the paradox of dense spine bones in people with rickets. For families with XLH, understanding these bone differences could improve care—especially since dense spine bones don’t cancel out the risk of fractures in other areas.

All participants provided written informed consent for their clinical information and images to be published. The study was funded by the National Natural Science Foundation of China (Nos. 81770875 and 81572639), Science and Technology Department of Sichuan Province (No. 2018SZ0142), Sichuan University (No. 2018SCUH0093), and the National Clinical Research Center for Geriatrics of West China Hospital (No. Z2018B05).

References

  1. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405–424. doi: 10.1038/gim.2015.30
  2. Cheung M, Roschger P, Klaushofer K, Veilleux LN, Roughley P, Glorieux FH, et al. Cortical and trabecular bone density in X-linked hypophosphatemic rickets. J Clin Endocrinol Metab 2013;98:E954–E961. doi: 10.1210/jc.2012-4133
  3. Beck-Nielsen SS, Brixen K, Gram J, Molgaard C. High bone mineral apparent density in children with X-linked hypophosphatemia. Osteoporos Int 2013;24:2215–2221. doi: 10.1007/s00198-013-2286-9
  4. Beck-Nielsen SS, Brusgaard K, Rasmussen LM, Brixen K, Brock-Jacobsen B, Poulsen MR, et al. Phenotype presentation of hypophosphatemic rickets in adults. Calcif Tissue Int 2010;87:108–119. doi: 10.1007/s00223-010-9373-0
  5. Reid IR, Murphy WA, Hardy DC, Teitelbaum SL, Bergfeld MA, Whyte MP. X-linked hypophosphatemia: skeletal mass in adults assessed by histomorphometry, computed tomography, and absorptiometry. Am J Med 1991;90:63–69. doi: 10.1016/0002-9343(91)90507-t

doi.org/10.1097/CM9.0000000000000454

Was this helpful?

0 / 0