IDH1 – Maffucci syndrome

Maffucci syndrome is a rare, non-hereditary congenital disorder characterized by multiple enchondromas and spindle cell hemangiomas in a somatic mosaic pattern. Affected individuals present with vascular lesions and cartilaginous tumors that carry post-zygotic gain-of-function mutations in isocitrate dehydrogenase 1 (IDH1). Clinical progression includes risk of malignant transformation to chondrosarcoma and secondary neoplasms.

Somatic mosaic IDH1 mutations have been identified in the majority of Maffucci syndrome patients. In 37 of 40 individuals across independent cohorts, tumors harbored IDH1 hotspot variants affecting Arg132, most commonly c.394C>T (p.Arg132Cys) ([PMID:22057236]). In 10 of 13 unrelated Maffucci syndrome probands, the same IDH1 R132C mutation was detected in both enchondromas and spindle cell hemangiomas, demonstrating intrapatient consistency and somatic mosaicism ([PMID:22057234]). Additional case reports confirm recurrent detection of c.394C>T (p.Arg132Cys) in Maffucci lesions and associated tumors such as pituitary adenoma and chondrosarcoma ([PMID:26473790], [PMID:30579273]).

The variant spectrum in Maffucci syndrome is dominated by missense substitutions at codon 132; c.395G>A (p.Arg132His) is also observed in mosaic form but less frequently. No germline inheritance has been documented, consistent with a post-zygotic mechanism. The variant c.394C>T (p.Arg132Cys) serves as a molecular marker for diagnosis when detected in tumor tissue or circulating cell-free DNA ([PMID:35042566]).

Functional studies demonstrate that IDH1 R132 mutations confer neomorphic enzyme activity, producing the oncometabolite R-2-hydroxyglutarate (2HG). Elevated 2HG levels correlate with hypermethylation signatures and epigenetic dysregulation in IDH1-mutant tumors and cell models, supporting a gain-of-function pathogenic mechanism ([PMID:20692206]). The specificity of R132C for spindle cell hemangioma versus other vascular lesions underscores its diagnostic utility ([PMID:23485734]).

Integration of genetic and functional evidence establishes a definitive association between somatic IDH1 mutations and Maffucci syndrome. Molecular testing for the IDH1 c.394C>T (p.Arg132Cys) hotspot in lesional tissue or cfDNA can guide diagnosis, surveillance for malignant transformation, and future targeted therapy decisions.

Key Take-home: Somatic mosaic IDH1 R132C mutations are the defining molecular lesions in Maffucci syndrome and support precise genetic diagnosis and risk-adapted clinical management.

References

• Nature Genetics • 2011 • Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2 PMID:22057236
• Nature Genetics • 2011 • Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome PMID:22057234
• The American Journal of Pathology • 2013 • R132C IDH1 mutations are found in spindle cell hemangiomas and not in other vascular tumors or malformations PMID:23485734
• Hereditas • 2022 • Cell-free DNA from plasma as a promising alternative for detection of gene mutations in patients with Maffucci syndrome PMID:35042566
• Trends in Molecular Medicine • 2010 • IDH mutations in glioma and acute myeloid leukemia PMID:20692206

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