Saito-Hakoda Akiko, Kikuchi Atsuo, Takahashi Tadahisa, Yokoyama Yu, Himori Noriko, Adachi Mika, Ikeda Ryoukichi, Nomura Yuri, Takayama Jun, Kawashima Junko, Katsuoka Fumiki, Fujishima Fumiyoshi, Yamaguchi Takehiko, Ito Akiyo, Hanita Takushi, Kanno Junko, Aizawa Toshimi, Nakazawa Toru, Kawase Tetsuaki, Tamiya Gen, Yamamoto Masayuki, Fujiwara Ikuma, Kure Shigeo
Department of Pediatrics, JR Sendai Hospital, 1-1-5, Itsutsubashi, Aoba-ku, Sendai, Miyagi, 980-8508, Japan.
Department of Pediatrics, Tohoku University Hospital, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
J Bone Miner Metab. 2023 Mar;41(2):193-202. doi: 10.1007/s00774-022-01392-w. Epub 2022 Dec 15.
Paget's disease of bone (PDB) is a skeletal disorder characterized by disorganized bone remodeling due to abnormal osteoclasts. Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A) gene encodes the receptor activator of nuclear factor kappa B (RANK), which has a critical role in osteoclast function. There are five types of rare PDB and related osteolytic disorders due to TNFRSF11A tandem duplication variants so far, including familial expansile osteolysis (84dup18), expansile skeletal hyperphosphatasia (84dup15), early-onset familial PDB (77dup27), juvenile PDB (87dup15), and panostotic expansile bone disease (90dup12).
We reviewed a Japanese family with PDB, and performed whole-genome sequencing to identify a causative variant.
This family had bone symptoms, hyperphosphatasia, hearing loss, tooth loss, and ocular manifestations such as angioid streaks or early-onset glaucoma. We identified a novel duplication variant of TNFRSF11A (72dup27). Angioid streaks were recognized in Juvenile Paget's disease due to loss-of-function variants in the gene TNFRSF11B, and thought to be specific for this disease. However, the novel recognition of angioid streaks in our family raised the possibility of occurrence even in bone disorders due to TNFRSF11A duplication variants and the association of RANKL-RANK signal pathway as the pathogenesis. Glaucoma has conversely not been reported in any case of Paget's disease. It is not certain whether glaucoma is coincidental or specific for PDB with 72dup27.
Our new findings might suggest a broad spectrum of phenotypes in bone disorders with TNFRSF11A duplication variants.
骨佩吉特病（PDB）是一种骨骼疾病，其特征是由于破骨细胞异常导致骨重塑紊乱。肿瘤坏死因子受体超家族成员11A（TNFRSF11A）基因编码核因子κB受体激活剂（RANK），它在破骨细胞功能中起关键作用。迄今为止，由于TNFRSF11A串联重复变异，有五种罕见的PDB及相关溶骨性疾病，包括家族性膨胀性骨溶解症（84dup18）、膨胀性骨高磷酸酶血症（84dup15）、早发性家族性PDB（77dup27）、青少年PDB（87dup15）和全身性膨胀性骨病（90dup12）。
我们对一个患有PDB的日裔家族进行了回顾，并进行了全基因组测序以确定致病变异。
这个家族有骨骼症状、高磷酸酶血症、听力丧失、牙齿脱落以及诸如血管样条纹或早发性青光眼等眼部表现。我们鉴定出一种新的TNFRSF11A重复变异（72dup27）。血管样条纹在因TNFRSF11B基因功能丧失变异导致的青少年佩吉特病中被发现，并被认为是该疾病所特有的。然而，我们家族中血管样条纹的新发现增加了其在因TNFRSF11A重复变异导致的骨骼疾病中出现的可能性，以及RANKL-RANK信号通路作为发病机制的关联性。相反，在任何佩吉特病病例中都未报告过青光眼。尚不确定青光眼是巧合还是72dup27型PDB所特有的。
我们的新发现可能提示TNFRSF11A重复变异导致的骨骼疾病存在广泛的表型谱。
