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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.
Highlights
Paget’s disease of bone (PDB) is a focal metabolic bone disease characterized by excessive and aberrant bone remodeling that results in bone pain, bone deformity and pathologic fracture, followed by secondary osteoarthritis and nerve compression syndromes [1, 2]
First-degree relatives of PDB patients were asked to fill in the questionnaire and samples of blood were collected for biochemical screening
We mainly focused on missense [D-mis, predicted to be deleterious by SIFT [41] and PolyPhen2 [42]] and loss-of-function (LoF, including splice acceptor/donor and frameshift indels) variants and further excluded those with a minor allele frequency (MAF) higher than 1% registered in ExAC and the 1000 Genomes Project
Summary
Paget’s disease of bone (PDB) is a focal metabolic bone disease characterized by excessive and aberrant bone remodeling that results in bone pain, bone deformity and pathologic fracture, followed by secondary osteoarthritis and nerve compression syndromes [1, 2]. It is well known that there are pronounced geographical and ethnic differences in the prevalence of PDB [3], with the high prevalence in western countries, especially in European descent. Some studies reported intranational regional differences [4–7] and mainly affects people over 55 years [3, 8, 9]. As we know, the literatures on sporadic PDB in Chinese population are confined to case reports [12–15], no systemic study is available with relatively large sample size up to date. In 2012, we reported our study in thirteen sporadic PDB patients [1]. The study focused mainly on the mutation detection in SQSTM1
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