The Paradoxical Coexistence of Hypophosphatemic Rickets and Increased Bone Density in Spine of a Subject Carrying a Novel Splice Site Mutation in PHEX
This article presents a detailed case study of a 46-year-old man with a complex clinical presentation involving hypophosphatemic rickets and increased bone density in the spine, associated with a novel splice site mutation in the PHEX gene. The case is part of a larger familial study that reveals significant insights into the genetic and phenotypic characteristics of X-linked hypophosphatemic rickets (XLH).
The patient presented with progressive pain in his left lower extremities for over five years. Physical examination revealed short stature, “O”-type bending in the lower extremities, and a “penguin” gait. Radiographic imaging showed increased bone mass in the spine and a left femoral fracture with sclerosis at the fracture edge. Dual-energy X-ray absorptiometry (DEXA) scans performed in 2018 and 2019 revealed fluctuating bone mass in the spine and femoral neck, indicating a dynamic bone density profile over time.
The family history is notable for similar clinical features in the patient’s mother, brother, and one sister, all of whom exhibited short stature, abnormal lower extremity shape, and gait disturbances. X-rays and DEXA scans of the brother and sister showed varied bone mass patterns, with the brother having increased bone mass in the spine and decreased bone mass in the femoral neck, while the sister had normal bone mass in the spine and a tendency toward decreased bone mass in the femoral neck.
Biochemical analyses revealed hypophosphatemia and elevated parathyroid hormone levels in the proband, his brother, and his nephew. Serum calcium levels were at the lower limit of the normal range, and serum levels of fibroblast growth factor 23 (FGF23) were increased in all affected individuals. The proband and his nephew also exhibited a lower tubular maximum re-absorption threshold of phosphate per glomerular filtration rate.
Whole-exome sequencing (WES) identified a novel splice site mutation (c.1483-1G>C) in intron 13 of the PHEX gene in the proband, his brother, and his sister. This mutation was also found in the proband’s nephew and niece. The mutation is a splice acceptor mutation that has not been previously reported in major genetic databases such as OMIM, Human Gene Mutation Database, Clinvar, 1000 Genomes, dbSNP, Exome Variant Server, or the ExAC Browser. According to the American College of Medical Genetics and Genomics guidelines (2015), this mutation is predicted to be pathogenic.
The presence of increased bone mass in the spine, despite the clinical manifestations of rickets, is a notable feature in this pedigree. Previous studies have suggested that XLH has a site-dependent influence on bone mass, with axial bone mass tending to be increased and peripheral bone mass tending to be decreased. This pattern was observed in the proband and his brother, who showed increased T and Z values in the spine and decreased T and Z values in the femoral neck compared to reference values. The increased axial bone mass in patients with XLH is partially attributable to hyperosteoidosis, and treatments such as calcitriol and phosphate supplementation may play a role in the increased trabecular bone mass observed. However, increased trabecular bone volume has also been found in several untreated subjects, indicating that it may be an intrinsic change caused by the disease process of XLH.
In conclusion, this study reports an XLH pedigree with a novel splice site mutation in the PHEX gene, highlighting the complex interplay between genetic mutations and bone density changes in XLH. The findings underscore the importance of comprehensive genetic and phenotypic analyses in understanding the pathophysiology of XLH and in guiding appropriate therapeutic interventions.
doi.org/10.1097/CM9.0000000000000454
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