TGFB1 – Camurati-Engelmann Disease

Camurati-Engelmann disease (CED) is a rare autosomal dominant craniotubular hyperostosis characterized by limb pain, waddling gait, muscle weakness, and progressive periosteal and endosteal sclerosis of long bone diaphyses and skull base. Gain-of-function missense mutations in TGFB1 result in increased activation of latent TGF-β1 and dysregulated bone remodeling.

The initial molecular diagnosis was established in a Moroccan family with two affected individuals carrying a heterozygous c.466C>T (p.Arg156Cys) variant in exon 2, co-segregating with CED in mother and son (2 probands) (PMID:15959620). Shortly thereafter, the first Korean kindred with autosomal dominant inheritance was reported, harboring a heterozygous c.653G>A (p.Arg218His) variant in exon 4 in a mother–son pair (2 probands) (PMID:19654961). Further independent reports confirmed recurrent variants including c.466C>T (p.Arg156Cys) in an atypical obesity-associated family (PMID:23824952), and c.652C>T (p.Arg218Cys) and c.653G>A (p.Arg218His) in diverse ethnic cohorts.

A review of 24 families encompassing 100 molecularly confirmed CED cases demonstrated consistent co-segregation of TGFB1 missense variants and marked phenotypic variability across four generations (over 100 cases) (PMID:15894597). Additional series totaling >100 unrelated probands have reported p.Arg156Cys, p.Arg218Cys, p.Arg218His, p.Glu169Lys and p.Cys225Arg variants, confirming autosomal dominant transmission with at least 19 additional affected relatives in multi-generation pedigrees.

Functional assays of the p.Arg218Cys mutation showed a ~5-fold increase in osteoclast formation and ~10-fold enhanced bone resorption in peripheral blood mononuclear cell cultures, driven by elevated active TGF-β1 and inhibited by soluble TGF-β receptor II (PMID:12843182). Luciferase reporter assays of LLL12-13ins, Y81H, R218C, H222D and C225R variants revealed increased TGF-β1 signaling due to either enhanced activation or secretion of mutant proteins (PMID:12493741). These data establish a gain-of-function pathogenic mechanism consistent with the human phenotype.

No studies have convincingly refuted the TGFB1–CED association. A mouse knock-in of p.Cys225Ser, though showing elevated TGF-β1 activity, did not recapitulate skeletal hyperostosis, suggesting species-specific responses (PMID:27928112). Overall, decades of concordant genetic and experimental evidence support a Definitive gene–disease association.

Key Take-home: Heterozygous TGFB1 missense variants cause gain-of-function TGF-β1 activation in autosomal dominant CED, enabling precise molecular diagnosis, informed genetic counseling, and exploration of targeted therapies.

References

• Osteoporosis International • 2005 • Camurati-Engelmann disease (progressive diaphyseal dysplasia) in a Moroccan family. PMID:15959620
• Journal of Korean Medical Science • 2009 • The first Korean case of Camurati-Engelmann disease (progressive diaphyseal dysplasia) confirmed by TGFB1 gene mutation analysis. PMID:19654961
• American Journal of Medical Genetics Part A • 2013 • Camurati-Engelmann disease with obesity in a newly identified family carrying a missense p.Arg156Cys mutation in the TGFB1 gene. PMID:23824952
• Journal of Medical Genetics • 2006 • Camurati-Engelmann disease: review of the clinical, radiological, and molecular data of 24 families and implications for diagnosis and treatment. PMID:15894597
• The Journal of Clinical Endocrinology and Metabolism • 2003 • A mutation affecting the latency-associated peptide of TGFbeta1 in Camurati-Engelmann disease enhances osteoclast formation in vitro. PMID:12843182
• The Journal of Biological Chemistry • 2003 • Transforming growth factor-beta 1 mutations in Camurati-Engelmann disease lead to increased signaling by altering either activation or secretion of the mutant protein. PMID:12493741

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