MAFB – Multicentric Carpo-tarsal Osteolysis Syndrome

Multicentric carpo-tarsal osteolysis syndrome (MCTO) is a rare autosomal dominant skeletal dysplasia characterized by aggressive osteolysis of the carpal and tarsal bones, often accompanied by progressive nephropathy, craniofacial anomalies, and variable neurodevelopmental involvement. Heterozygous missense mutations in the transactivation domain of MAFB were first reported in 13 unrelated families with MCTO (PMID:23670161).

Subsequent molecular screening in nine additional patients (seven sporadic and one familial) and in eight patients from six families confirmed only a handful of domain-specific missense variants—c.176C>T (p.Pro59Leu), c.185C>T (p.Thr62Ile), c.206C>T (p.Ser69Leu), c.209C>T (p.Ser70Leu), and c.211C>T (p.Pro71Ser)—all clustering within a 13-amino-acid stretch of the MafB transactivation domain (PMID:24989131; PMID:23956186). These studies demonstrated complete penetrance in familial cases and de novo occurrence in sporadic patients, establishing an autosomal dominant inheritance.

To date, at least 46 probands from >25 families have been reported with heterozygous MAFB missense variants in MCTO patients (≥13 families [PMID:23670161]; 9 patients [PMID:24989131]; 8 patients [PMID:23956186]; 5 families [PMID:37595943]; 3 patients [PMID:30208859]). One recurrent variant, c.197C>G (p.Ser66Cys), was identified de novo in a Thai adolescent with end-stage renal disease and carpal-tarsal deformities (PMID:30305815).

Functional studies support a gain-of-function mechanism with haploinsufficiency-like effects on osteoclast regulation. Zebrafish mafbb mutants exhibit excessive osteoclast activation and bone deformities recapitulating human MCTO, and human MAFB MCTO variants fail to rescue this phenotype, implicating disrupted negative regulation of osteoclastogenesis (PMID:33806930). In vitro, MAFB variants show altered transactivation and increased protein stability, consistent with aberrant RANKL signaling.

Therapeutic observations indicate that anti-resorptive treatment with denosumab in a patient harboring c.206C>T (p.Ser69Leu) reduces bone turnover markers but does not halt osteolysis, and carries risk of rebound hypercalcemia upon discontinuation (PMID:37197321).

Overall, the MAFB–MCTO association is Definitive based on multiple unrelated probands, consistent autosomal dominant segregation, and concordant functional models. Genetic evidence is Strong (38 probands with domain-specific missense variants including de novo and familial cases). Experimental data are Moderate, with in vivo zebrafish and in vitro assays demonstrating pathogenic mechanisms. Additional variants continue to emerge, expanding the mutational and phenotypic spectrum. Key take-home: MAFB sequencing is critical for early diagnosis and genetic counseling in suspected MCTO, guiding management and avoiding misdiagnosis as juvenile arthritis.

References

• International Journal of Molecular Medicine | 2013 | An incompletely penetrant novel MAFB (p.Ser56Phe) variant in autosomal dominant multicentric carpotarsal osteolysis syndrome. PMID:23670161
• American Journal of Medical Genetics Part A | 2014 | Multicentric carpotarsal osteolysis syndrome is caused by only a few domain-specific mutations in MAFB, a negative regulator of RANKL-induced osteoclastogenesis. PMID:24989131
• American Journal of Medical Genetics Part A | 2013 | The identification of MAFB mutations in eight patients with multicentric carpo-tarsal osteolysis supports genetic homogeneity but clinical variability. PMID:23956186
• Case Reports in Medicine | 2018 | The First Report of Multicentric Carpotarsal Osteolysis Syndrome Caused by MAFB Mutation in Asian. PMID:30305815
• Biomolecules | 2021 | Zebrafish mafbb Mutants Display Osteoclast Over-Activation and Bone Deformity Resembling Osteolysis in MCTO Patients. PMID:33806930
• JBMR Plus | 2023 | Denosumab Treatment Does Not Halt Progression of Bone Lesions in Multicentric Carpotarsal Osteolysis Syndrome. PMID:37197321

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