Abstract：
BACKGROUND: Melorheostosis (MEL) is an exceptionally rare sclerosing bone dysplasia with asymmetrically exuberant bone formation and soft tissue lesions in a segmental distribution. We aimed to summarize the clinical characteristics of Chinese MEL patients and identify their pathogenic cause.
METHODS: In total, 10 Chinese MEL patients were recruited, and clinical manifestations and radiological characteristics were recorded. Sanger sequencing of the LEMD3 gene was performed on peripheral blood samples of all patients, while the exome sequencing of matched peripheral blood, melorheostotic bone, and skin lesion samples was conducted on one patient who provided affected bone and skin tissues. Micro-computed tomography (micro-CT) was also used to scan the melorheostotic bone tissue.
RESULTS: We found the average age of the 10 MEL patients was 29.5 years (range 11-40 years), and the major symptoms were bone pain, restricted movement, and bone deformity. The lesions sites were mainly located in femur (8/10), tibia (8/10), fibula (6/10), and foot (7/10), the next was pelvis (4/10), and the last were patella (1/10), hand (1/10) and spine (1/10). Radiological examinations showed a mixture of hyperostosis consisting of classic \"dripping candle wax,\" \"osteoma-like,\" or \"myositis ossificans-like\" patterns in most patients. No germline pathogenic variants in the LEMD3 gene were found in all patients, but a disease-causing somatic variant of MAP2K1 (c.167A > C, p.Gln56Pro) was detected in melorheostotic bone from one patient. Moreover, the micro-CT analysis showed increased porosity in the melorheostotic bone with somatic MAP2K1 variant.
CONCLUSIONS: This is a summary of the clinical characteristics of Chinese MEL patients and we first identify the somatic MAP2K1 variant in Chinese patients. Our findings validate the molecular genetic mechanism of MEL and broaden its phenotype spectrum in the Chinese population.
METHODS: In total, 10 Chinese MEL patients were recruited, and clinical manifestations and radiological characteristics were recorded. Sanger sequencing of the LEMD3 gene was performed on peripheral blood samples of all patients, while the exome sequencing of matched peripheral blood, melorheostotic bone, and skin lesion samples was conducted on one patient who provided affected bone and skin tissues. Micro-computed tomography (micro-CT) was also used to scan the melorheostotic bone tissue.
RESULTS: We found the average age of the 10 MEL patients was 29.5 years (range 11-40 years), and the major symptoms were bone pain, restricted movement, and bone deformity. The lesions sites were mainly located in femur (8/10), tibia (8/10), fibula (6/10), and foot (7/10), the next was pelvis (4/10), and the last were patella (1/10), hand (1/10) and spine (1/10). Radiological examinations showed a mixture of hyperostosis consisting of classic \"dripping candle wax,\" \"osteoma-like,\" or \"myositis ossificans-like\" patterns in most patients. No germline pathogenic variants in the LEMD3 gene were found in all patients, but a disease-causing somatic variant of MAP2K1 (c.167A > C, p.Gln56Pro) was detected in melorheostotic bone from one patient. Moreover, the micro-CT analysis showed increased porosity in the melorheostotic bone with somatic MAP2K1 variant.
CONCLUSIONS: This is a summary of the clinical characteristics of Chinese MEL patients and we first identify the somatic MAP2K1 variant in Chinese patients. Our findings validate the molecular genetic mechanism of MEL and broaden its phenotype spectrum in the Chinese population.
摘要：
背景：Melorheostosis（MEL）是一种非常罕见的硬化性骨发育不良，具有不对称旺盛的骨形成和段分布的软组织病变。我们旨在总结中国MEL患者的临床特征并确定其病因。
方法：总共，招募了10名中国MEL患者，并记录临床表现和影像学特点。对所有患者的外周血样本进行LEMD3基因的Sanger测序,而匹配外周血的外显子组测序，骨髓增生骨，并对一名提供受影响骨和皮肤组织的患者进行皮肤病变样本。微计算机断层扫描（micro-CT）也用于扫描骨髓增生性骨组织。
结果：我们发现10名MEL患者的平均年龄为29.5岁（范围为11-40岁），主要症状是骨痛，限制移动,骨畸形.病变部位主要位于股骨（8/10），胫骨(8/10),腓骨（6/10），和脚（7/10），下一个是骨盆（4/10），最后一个是髌骨（1/10），手（1/10）和脊柱（1/10）。放射学检查显示，由经典的滴落的蜡烛蜡组成的肥大症混合物，\"\"骨瘤样，大多数患者的\"或\"骨化性肌炎\"模式。在所有患者中均未发现LEMD3基因中的种系致病变异，而是MAP2K1的致病体细胞变体(c.167A>C，p.Gln56Pro）在一名患者的骨髓增生骨中检测到。此外，micro-CT分析显示，具有体细胞MAP2K1变体的骨髓增生骨中的孔隙率增加。
结论：这是中国MEL患者临床特征的总结，我们首先在中国患者中发现了体细胞MAP2K1变异。我们的发现验证了MEL的分子遗传机制，并拓宽了其在中国人群中的表型谱。
方法：总共，招募了10名中国MEL患者，并记录临床表现和影像学特点。对所有患者的外周血样本进行LEMD3基因的Sanger测序,而匹配外周血的外显子组测序，骨髓增生骨，并对一名提供受影响骨和皮肤组织的患者进行皮肤病变样本。微计算机断层扫描（micro-CT）也用于扫描骨髓增生性骨组织。
结果：我们发现10名MEL患者的平均年龄为29.5岁（范围为11-40岁），主要症状是骨痛，限制移动,骨畸形.病变部位主要位于股骨（8/10），胫骨(8/10),腓骨（6/10），和脚（7/10），下一个是骨盆（4/10），最后一个是髌骨（1/10），手（1/10）和脊柱（1/10）。放射学检查显示，由经典的滴落的蜡烛蜡组成的肥大症混合物，\"\"骨瘤样，大多数患者的\"或\"骨化性肌炎\"模式。在所有患者中均未发现LEMD3基因中的种系致病变异，而是MAP2K1的致病体细胞变体(c.167A>C，p.Gln56Pro）在一名患者的骨髓增生骨中检测到。此外，micro-CT分析显示，具有体细胞MAP2K1变体的骨髓增生骨中的孔隙率增加。
结论：这是中国MEL患者临床特征的总结，我们首先在中国患者中发现了体细胞MAP2K1变异。我们的发现验证了MEL的分子遗传机制，并拓宽了其在中国人群中的表型谱。
