AUTHOR=Tao Xiaohui , Liu Li , Yang Xingguang , Wei Zhe , Chen Zhongzhong , Zhang Ge , Zhang Zhenlin , Yue Hua 

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

JOURNAL=Frontiers in Endocrinology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.850462

DOI=10.3389/fendo.2022.850462

ISSN=1664-2392

ABSTRACT=<sec><title>Objective</title><p>To evaluate the clinical features of sporadic Paget’s disease of bone (PDB) in China and further explore the underlying genetic abnormalities of the disease.</p></sec><sec><title>Methods</title><p>Clinical 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.</p></sec><sec><title>Results</title><p>A 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 <italic>SQSTM1</italic> gene (c.1211T&gt;C, M404T) and one novel heterozygous missense mutation in <italic>HNRNPA2B1</italic> gene (c.989C&gt;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 <italic>WNT16</italic>, <italic>RYR3</italic> and <italic>RYR1</italic> genes) and amyotrophic lateral sclerosis (ALS, including <italic>NUP205</italic>, <italic>CAPN2</italic>, and <italic>NUP214</italic> genes).</p></sec><sec><title>Conclusion</title><p>In contrast to Western patients, Chinese patients have an earlier onset age, more severe symptoms, and lower frequency of <italic>SQSTM1</italic> gene mutation (4.0%). Moreover, a novel heterozygous missense mutation in <italic>HNRNPA2B1</italic> gene was identified in one male patient with isolated bone phenotype. As for other genetic factors, it was indicated that <italic>WNT16</italic>, <italic>RYR3</italic>, <italic>RYR1</italic>, <italic>NUP205</italic>, <italic>CAPN2</italic> and <italic>NUP214</italic> genes may be potential pathogenic genes, pathways of neurodegeneration and ALS may play a vital role in the pathogenesis of PDB.</p></sec>