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Multicentric Carpotarsal Osteolysis: a Contemporary Perspective on the Unique Skeletal Phenotype

  • Rare Bone Disease (CB Langman and E Shore, Section Editors)
  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Multicentric carpotarsal osteolysis (MCTO) is an ultra-rare disorder characterized by osteolysis of the carpal and tarsal bones, subtle craniofacial deformities, and nephropathy. The molecular pathways underlying the pathophysiology are not well understood.

Recent Findings

MCTO is caused by heterozygous mutations in MAFB, which encodes the widely expressed transcription factor MafB. All MAFB mutations in patients with MCTO result in replacement of amino acids that cluster in a phosphorylation region of the MafB transactivation domain and account for a presumed gain-of-function for the variant protein. Since 2012, fewer than 60 patients with MCTO have been described with 20 missense mutations in MAFB. The clinical presentations are variable, and a genotype-phenotype correlation is lacking. Osteolysis, via excessive osteoclast activity, has been regarded as the primary mechanism, although anti-resorptive agents demonstrate little therapeutic benefit.

Summary

This paper appraises current perspectives of MafB protein action, inflammation, and dysfunctional bone formation on the pathogenesis of the skeletal phenotype in MCTO. More research is needed to understand the pathogenesis of MCTO to develop rational therapies.

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Authors and Affiliations

  1. Section of Pediatric Endocrinology, Children’s Hospital Colorado and Department of Pediatrics, University of Colorado School of Medicine, 13123 E. 16th Ave, B265, Aurora, CO, 80045, USA

    Nina S. Ma

  2. Division of Bone and Mineral Diseases, Washington University School of Medicine and Center for Metabolic Bone Disease and Molecular Research, Shriners Children’s, St. Louis, MO, USA

    S. Mumm

  3. Laboratory Animal Resource Center in Transborder Medical Research Center, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan

    S. Takahashi

  4. Center for Bone Health and Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia and the Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    M. A. Levine

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  1. Nina S. Ma
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  4. M. A. Levine
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Contributions

The first draft of the manuscript was written by Nina Ma. Nina Ma and Michael Levine performed the literature search. All authors commented on previous versions of the manuscript. All authors read, critically revised, and approved the final manuscript.

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Correspondence to Nina S. Ma.

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All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

Conflict of Interest

Nina Ma reports grants from Amgen and Ultragenyx, grants and personal fees from Ascendis Pharma, and others from Sophie’s Neighborhood and personal fees from UpToDate.

Steve Mumm reports grants from Shriners Children’s and others from Genomenon, Inc.

Satoru Takahashi reports grants from Sophie's Neighborhood.

Michael Levine reports he has been an investigator on a single-case study of the efficacy of denosumab for MCTO that was funded by Amgen, Inc.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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Ma, N.S., Mumm, S., Takahashi, S. et al. Multicentric Carpotarsal Osteolysis: a Contemporary Perspective on the Unique Skeletal Phenotype. Curr Osteoporos Rep 21, 85–94 (2023). https://doi.org/10.1007/s11914-022-00762-7

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