Clinical Characteristics and Pathogenic Gene Identification in Chinese Patients With Paget’s Disease of Bone

Abstract

ObjectiveTo evaluate the clinical features of sporadic Paget’s disease of bone (PDB) in China and further explore the underlying genetic abnormalities of the disease.MethodsClinical characteristics, biochemical indices, bone turnover markers and radiographic examinations of the patients were collected. Genomic DNA was extracted from peripheral blood and whole-exome sequencing was carried out to identify the potential pathogenic genes. The pathogenicity of the variants was thereafter investigated by bioinformatics analysis.ResultsA total of 50 patients (57.20 ± 15.52 years, male/female: 1.63: 1) with PDB were included and the mean onset age was 48.34 years (48.34 ± 17.24 years). 94.0% of the patients exhibited symptomatic patterns described as bone pain (86.0%), elevated skin temperature at the lesion site (26.0%), bone deformity (22.0%) and local swelling (18.0%). The most frequently involved lesion sites were pelvis (52.0%), femur (42.0%), tibia (28.0%), skull (28.0%) and spine (18.0%), respectively. Additionally, 40.0% of them accompanied with osteoarthritis, 14.0% with pathological fractures, and the misdiagnosis rate of PDB was as high as 36.0%. Serum level of alkaline phosphatase was significantly increased, with the mean value of 284.00 U/L (quartiles, 177.00-595.00 U/L). Two heterozygous missense mutations of SQSTM1 gene (c.1211T>C, M404T) and one novel heterozygous missense mutation in HNRNPA2B1 gene (c.989C>T, p. P330L) were identified in our study. Moreover, several potential disease-causing genes were detected and markedly enriched in the pathways of neurodegeneration (including WNT16, RYR3 and RYR1 genes) and amyotrophic lateral sclerosis (ALS, including NUP205, CAPN2, and NUP214 genes).ConclusionIn contrast to Western patients, Chinese patients have an earlier onset age, more severe symptoms, and lower frequency of SQSTM1 gene mutation (4.0%). Moreover, a novel heterozygous missense mutation in HNRNPA2B1 gene was identified in one male patient with isolated bone phenotype. As for other genetic factors, it was indicated that WNT16, RYR3, RYR1, NUP205, CAPN2 and NUP214 genes may be potential pathogenic genes, pathways of neurodegeneration and ALS may play a vital role in the pathogenesis of PDB.

Bone scan findings of Paget's disease of bone in patients with VCP Multisystem Proteinopathy 1 (MSP1)

“…There is currently no de nitive treatment for the neuromuscular and neurological manifestations of MSP1. However, treatment with bisphosphonates such as alendronate and zoledronic acid has been noted to provide relief from bone pain in the majority of patients with PDB [14,33,34]. In our cohort, only one patient (ID 4) reported to be taking bisphosphonates who had ve active PDB regions and an ALP level of 234 IU/L.…”

Bone scan findings of Paget’s disease of bone in patients with VCP Multisystem Proteinopathy 1

“…There is currently no definitive treatment for the neuromuscular and neurological manifestations of MSP1. However, treatment with bisphosphonates such as alendronate and zoledronic acid has been noted to provide relief from bone pain in the majority of patients with PDB 14 , 33 , 34 . In our cohort, only one patient (ID 4) reported to be taking bisphosphonates who had five active PDB regions and an ALP level of 234 IU/L.…”

The role of microscopic properties on cortical bone strength of femoral neck

“…In response to this mechanical need, the femoral neck cross-section is oval in shape, with the cortical bone forming a ring—shaped shell and the interior filled with cancellous bone to ensure the overall bone mechanical properties of the femoral neck [ 38 , 39 ]. The femoral neck was made of 80% cortical bone and 20% trabecular bone, thus the cortical bone has been reported to be the main determinant of the femoral neck bone strength [ 40 ]. Existing studies also support this conclusion.…”