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Review
. 2023 Feb;21(1):85-94.
doi: 10.1007/s11914-022-00762-7. Epub 2022 Dec 7.

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

Nina S Ma  1 , S Mumm  2 , S Takahashi  3 , M A Levine  4
Affiliations
Review

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

Nina S Ma et al. Curr Osteoporos Rep. 2023 Feb.

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. 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.

Keywords: Arthritis; Carpal; MAFB; MCTO; Osteolysis; Tarsal.

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Figures

Fig. 1
Fig. 1
A and B Radiographs of the right wrist and ankle of a 4-year–9-month-old child with MCTO. The wrist and mid-foot compartments appear small. The one carpal bone that is present (hamate) is small and irregular in shape. The erosion and tapering of the proximal second and third metacarpal bones are noted. There is a significant deformity of the talus bone and irregularity of the distal calcaneus and proximal cuboid bones. C MAFB is a single exon gene that codes for a 323 amino acid protein. Functional domains of MafB are represented by solid-colored boxes [3]. The numbered residues represent the priming Ser70 and four additional amino acids (Ser54, Thr58, Thr62, Ser66) that are phosphorylation sites. Red circles are underneath codons that are involved in MCTO-causing mutations in MAFB (see Table 1). The grey-shaded amino acids are conserved in proteins encoded by genes related to MAFB (see text) and the small blue, green, and black open boxes indicate the site of missense mutations in these other genes that cause various syndromes (see text)
See this image and copyright information in PMC

References

    1. Tsunakawa Y, Hamada M, Matsunaga Y, Fuseya S, Jeon H, Wakimoto Y, et al. Mice harboring an MCTO mutation exhibit renal failure resembling nephropathy in human patients. Exp Anim 2019;68(1):103–11. 10.1538/expanim.18-0093. - DOI - PMC - PubMed

    2. This paper reports the generation of a mouse harboring a human MCTO mutation using CRISPR/Cas9 technology. The mice develop a renal phenotype that resembles nephropathy in patients with MCTO.

    1. Wu J, Wang L, Xu Y, Zhang Z, Yan X, An Y, et al. Multicentric carpo-tarsal osteolysis syndrome mimicking juvenile idiopathic arthritis: two case reports and review of the literature. Front Pediatr 2021;9:745812. - PMC - PubMed

    2. Overview of the clinical and genetic features of 51 published cases of genetically confirmed MCTO.

    1. Wang PW, Eisenbart JD, Cordes SP, Barsh GS, Stoffel M, Le Beau MM. Human KRML (MAFB): cDNA cloning, genomic structure, and evaluation as a candidate tumor suppressor gene in myeloid leukemias. Genomics. 1999;59(3):275–81. - PubMed
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    2. This paper identified MAFB as the genetic basis for MCTO.

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