ESPE Yearbook of Paediatric Endocrinology

Hum Mol Genet ddac107 (2022)Abstract: https://pubmed.ncbi.nlm.nih.gov/35567544/

In Brief: Disproportionate tall stature represents a hallmark feature of Marfan syndrome, although specific mechanisms underlying linear bone overgrowth are unclear. This study used an ex vivo model system to identify dysregulation of TGFβ-binding proteins in the outer perichondrium as causative for the bone overgrowth phenotype in fibrillin-1-deficiency.

Commentary: Marfan syndrome is associated with fibrillin-1 deficiency and represents one of the most common genetic causes for tall stature. While the management of cardiovascular complications has improved substantially over the last decades, skeletal manifestations – in particular long bone overgrowth – remain poorly understood and therefore lack causative treatment options.

Sedes et. al combined data on the role of fibrillin-1 in TGF beta signalling as well as evidence on the role of perichondral tissue in the regulation of the beneath growth plate chondrocytes. By use of a conditional knockout system, fibrilin-1 deficiency in various mesenchymal tissues was shown to affect limb length differentially. Interestingly, growth promoting effects in mice lacking Fibrillin 1 in perichondrium and tendons was exclusively exerted by effects on the hypertrophic zone. Ingenuity pathway analysis of perchondrial RNAseq data allowed an in silicoprediction of TGF beta signalling to be downregulated in fibrilin-1 knockout animals. Similar to previous findings in aortic tissue, a redcued expression of LTBP3 and 4 exclusively in the outer perichondrium could be demonstrated by IHC. In metatarsal bone cultures, the authors could finally prove a reversal of bone overgrowth in perichondrium/tendon specific fibrillin-1 deficiency by TGF beta treatment.

This study, for the first time, implicates perichondrial tissue in TGF beta signalling mediated overgrowth at the level of the growth plates. In contrast to previous studies on TGFb-receptor defects featuring shorter bones, the particular association of local fibrillin-1 deficiency most likely caused by deficient binding protein expression and complex formation revealed an opposite phenotype resembling tall stature in patients. While a role of TGF beta bioavailability in the affection of growth plate tissue in Marfan syndrome been suggested before, the current study enables a more specific understanding of the mechanisms causing overgrowth and often extreme tall stature in patients with Marfan syndrome.