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15.12.2022 | Original Article

Familial Paget’s disease of bone with ocular manifestations and a novel TNFRSF11A duplication variant (72dup27)

verfasst von: Akiko Saito-Hakoda, Atsuo Kikuchi, Tadahisa Takahashi, Yu Yokoyama, Noriko Himori, Mika Adachi, Ryoukichi Ikeda, Yuri Nomura, Jun Takayama, Junko Kawashima, Fumiki Katsuoka, Fumiyoshi Fujishima, Takehiko Yamaguchi, Akiyo Ito, Takushi Hanita, Junko Kanno, Toshimi Aizawa, Toru Nakazawa, Tetsuaki Kawase, Gen Tamiya, Masayuki Yamamoto, Ikuma Fujiwara, Shigeo Kure

Erschienen in: Journal of Bone and Mineral Metabolism | Ausgabe 2/2023

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Abstract

Introduction

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).

Materials and methods

We reviewed a Japanese family with PDB, and performed whole-genome sequencing to identify a causative variant.

Results

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.

Conclusion

Our new findings might suggest a broad spectrum of phenotypes in bone disorders with TNFRSF11A duplication variants.

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Titel: Familial Paget’s disease of bone with ocular manifestations and a novel TNFRSF11A duplication variant (72dup27)
verfasst von: Akiko Saito-Hakoda
Atsuo Kikuchi
Tadahisa Takahashi
Yu Yokoyama
Noriko Himori
Mika Adachi
Ryoukichi Ikeda
Yuri Nomura
Jun Takayama
Junko Kawashima
Fumiki Katsuoka
Fumiyoshi Fujishima
Takehiko Yamaguchi
Akiyo Ito
Takushi Hanita
Junko Kanno
Toshimi Aizawa
Toru Nakazawa
Tetsuaki Kawase
Gen Tamiya
Masayuki Yamamoto
Ikuma Fujiwara
Shigeo Kure
Publikationsdatum: 15.12.2022
Verlag: Springer Nature Singapore
Erschienen in: Journal of Bone and Mineral Metabolism / Ausgabe 2/2023
Print ISSN: 0914-8779
Elektronische ISSN: 1435-5604
DOI: https://doi.org/10.1007/s00774-022-01392-w

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Familial Paget’s disease of bone with ocular manifestations and a novel TNFRSF11A duplication variant (72dup27)