Novel familial mutation of LRP5 causing high bone mass: Genetic analysis, clinical presentation, and characterization of bone matrix mineralization

Roetzer, Katharina; Uyanık, Gökhan; Brehm, Attila; Zwerina, Jochen; Zandieh, Shahin; Czech, Thomas; Roschger, Paul; Misof, Barbara M.; Klaushofer, Klaus

doi:10.1016/j.bone.2017.12.002

Cited by 21 publications

(29 citation statements)

References 36 publications

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“…Interestingly, our qBEI analysis revealed an even lower degree of mineralization in this compact bone than in the osteonal‐like bone, which is a strong indication that the parallel lamellar bone is younger and thus more recently formed than the remodeled bone. A very similar situation of robust periosteal apposition of lowly mineralized parallel lamellar bone was recently reported in the skull of a patient with an activating LRP5 mutation . It is well known that the inner layer of the periosteum, the cambium, contains numerous blood vessels and osteogenic cells that allow radial bone expansion during skeletal growth.…”

Section: Discussionsupporting

confidence: 66%

“…Melorheostosis is considered as a "sclerosing" bone disorder, often described as "more dense bone," which would suggest more highly mineralized and harder bone as in some other skeletal dysplasia. (23,37,38) This is also supported by clinical observation of an extreme surgical hardness of the bone of the lesion. (11) Our present work suggests that this extreme resistance of the melorheostotic material is not due to abnormal mineral accumulation in the lesion or to a modified and thereby stronger bone matrix, but rather to the periosteal reaction, which covers the lesion with parallel lamellar bone that is known to be resistant against fracturing and cutting and, therefore, likely also against surgical excision.…”

Section: Discussionsupporting

confidence: 53%

“…At first sight, the lower mineralization density combined with nanomechanical properties that depend entirely on mineral content seems counterintuitive, given the clinical description of melorheostosis. Melorheostosis is considered as a “sclerosing” bone disorder, often described as “more dense bone,” which would suggest more highly mineralized and harder bone as in some other skeletal dysplasia . This is also supported by clinical observation of an extreme surgical hardness of the bone of the lesion .…”

Section: Discussionmentioning

confidence: 99%

“…A very similar situation of robust periosteal apposition of lowly mineralized parallel lamellar bone was recently reported in the skull of a patient with an activating LRP5 mutation. (37) It is well known that the inner layer of the periosteum, the cambium, contains numerous blood vessels and osteogenic cells that allow radial bone expansion during skeletal growth. Thus, the periosteal boneforming potential remains throughout life and bone formation is reactivated in metabolically critical situations.…”

Section: Discussionmentioning

confidence: 99%

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Melorheostotic Bone Lesions Caused by Somatic Mutations in MAP2K1 Have Deteriorated Microarchitecture and Periosteal Reaction

Fratzl‐Zelman

Roschger

Kang

et al. 2019

Journal of Bone and Mineral Research

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Melorheostosis is a rare non‐hereditary condition characterized by dense hyperostotic lesions with radiographic “dripping candle wax” appearance. Somatic activating mutations in MAP2K1 have recently been identified as a cause of melorheostosis. However, little is known about the development, composition, structure, and mechanical properties of the bone lesions. We performed a multi‐method phenotype characterization of material properties in affected and unaffected bone biopsy samples from six melorheostosis patients with MAP2K1 mutations. On standard histology, lesions show a zone with intensively remodeled osteonal‐like structure and prominent osteoid accumulation, covered by a shell formed through bone apposition, consisting of compact multi‐layered lamellae oriented parallel to the periosteal surface and devoid of osteoid. Compared with unaffected bone, melorheostotic bone has lower average mineralization density measured by quantitative backscattered electron imaging (CaMean: –4.5%, p = 0.04). The lamellar portion of the lesion is even less mineralized, possibly because the newly deposited material has younger tissue age. Affected bone has higher porosity by micro‐CT, due to increased tissue vascularity and elevated 2D‐microporosity (osteocyte lacunar porosity: +39%, p = 0.01) determined on quantitative backscattered electron images. Furthermore, nano‐indentation modulus characterizing material hardness and stiffness was strictly dependent on tissue mineralization (correlation with typical calcium concentration, CaPeak: r = 0.8984, p = 0.0150, and r = 0.9788, p = 0.0007, respectively) in both affected and unaffected bone, indicating that the surgical hardness of melorheostotic lesions results from their lamellar structure. The results suggest a model for pathophysiology of melorheostosis caused by somatic activating mutations in MAP2K1, in which the genetically induced gradual deterioration of bone microarchitecture triggers a periosteal reaction, similar to the process found to occur after bone infection or local trauma, and leads to an overall cortical outgrowth. The micromechanical properties of the lesions reflect their structural heterogeneity and correlate with local variations in mineral content, tissue age, and remodeling rates, in the same way as normal bone. © 2018 American Society for Bone and Mineral Research

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Section: Discussionsupporting

confidence: 66%

Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Melorheostotic Bone Lesions Caused by Somatic Mutations in MAP2K1 Have Deteriorated Microarchitecture and Periosteal Reaction

Fratzl‐Zelman

Roschger

Kang

et al. 2019

Journal of Bone and Mineral Research

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“…These conditions are also characterized by elevated bone density, hyperostosis with mandibular enlargement, and thickening of the skull (6,7). Roetzer et al (8) reported high bone mass associated with an LRP5 gain-of-function mutation in a 53-year-old mother and her 23-year-old daughter. These patients also had increased calvarial thickness and thickened long bone cortices without any history of fractures (8).…”

Section: Discussionmentioning

confidence: 99%

Adult Osteoporosis With a History of Childhood-Onset Fracture Due to an LRP5 Receptor Variant Mutation

Shin

Shapiro

2019

AACE Clinical Case Reports

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Objective: This case highlights the value of genetic screening for idiopathic osteoporosis with recurrent fractures. Methods: Case report and review of the literature. Results: A 52-year-old Caucasian female with idiopathic osteoporosis with recurrent fractures was identified with a heterozygous low-density lipoprotein receptor related protein 5 (LRP5) mutation. Conclusion: This case highlights the variability in clinical expression of LRP5 polymorphisms and suggests that standard treatment in cases of recurrent fracture may be ineffective.

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Fork‐shaped mandibular incisors as a novel phenotype of LRP5‐associated disorder

Yamada

Kubota

Uchida

et al. 2021

American J of Med Genetics Pt A

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The LRP5 gene encodes a Wnt signaling receptor to which Wnt binds directly. In humans, pathogenic monoallelic variants in LRP5 have been associated with increased bone density and exudative vitreoretinopathy. In mice, LRP5 plays a role in tooth development, including periodontal tissue stability and cementum formation. Here, we report a 14‐year‐old patient with a de novo non‐synonymous variant, p.(Val1245Met), in LRP5 who exhibited mildly reduced bone density and mild exudative vitreoretinopathy together with a previously unreported phenotype consisting of dental abnormalities that included fork‐like small incisors with short roots and an anterior open bite, molars with a single root, and severe taurodontism. In that exudative vitreoretinopathy has been reported to be associated with heterozygous loss‐of‐function variants of LRP5 and that our patient reported here with the p.(Val1245Met) variant had mild exudative vitreoretinopathy, the variant can be considered as an incomplete loss‐of‐function variant. Alternatively, the p.(Val1245Met) variant can be considered as exerting a dominant‐negative effect, as no patients with truncating LRP5 variants and exudative vitreoretinopathy have been reported to exhibit dental anomalies. The documentation of dental anomalies in the presently reported patient strongly supports the notion that LRP5 plays a critical role in odontogenesis in humans, similar to its role in mice.

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Novel familial mutation of LRP5 causing high bone mass: Genetic analysis, clinical presentation, and characterization of bone matrix mineralization

Cited by 21 publications

References 36 publications

Melorheostotic Bone Lesions Caused by Somatic Mutations in MAP2K1 Have Deteriorated Microarchitecture and Periosteal Reaction

Melorheostotic Bone Lesions Caused by Somatic Mutations in MAP2K1 Have Deteriorated Microarchitecture and Periosteal Reaction

Adult Osteoporosis With a History of Childhood-Onset Fracture Due to an LRP5 Receptor Variant Mutation

Fork‐shaped mandibular incisors as a novel phenotype of LRP5‐associated disorder

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