Negative autoregulation of fibroblast growth factor receptor 2 expression characterizing cranial development in cases of Apert (P253R mutation) and Pfeiffer (C278F mutation) syndromes and suggesting a basis for differences in their cranial phenotypes

Object. Heterogeneous mutations in the fibroblast growth factor receptor 2 gene (FGFR2) cause a range of craniosynostosis syndromes. The specificity o f the Apert syndrome-affected cranial phenotype reflects its narrow mutatio nal range: 98% of cases of Apert syndrome result from an Ser252Trp or Pro25 3Arg mutation in the immunoglobulin-like (Ig)IIIa extracellular subdomain o f FGFR2. In contrast, a broad range of mutations throughout the extracellul ar domain of FGFR2 causes the overlapping cranial phenotypes of Pfeiffer an d Crouzon syndromes and related craniofacial dysostoses. Methods. In this paper the expression of FGFR1, the IgIIIa/c and IgIIIa/b i soforms of FGFR2, and FGFR3 is investigated in Apert syndrome (P253R mutati on)- and Pfeiffer syndrome (C278F mutation)-affected fetal cranial tissue a nd is contrasted with healthy human control tissues. Both FGFR1 and FGFR3 a re normally expressed in the differentiated osteoblasts of the periosteum a nd osteoid, in domains overlapped by that of FGFR2, which widely include pr eosseous cranial mesenchyme. Expression of FGFR2, however, is restricted to domains of advanced osseous differentiation in both Apert syndrome- and Pf eiffer syndrome-affected cranial skeletogenesis in the presence of fibrobla st growth factor (FGF)2, but not in the presence of FGF4 or FGF7. Whereas e xpression of the FGFR2-IgIIIa/b (KGFR) isoform is restricted in normal huma n cranial osteogenesis, there is preliminary evidence that KGFR is ectopica lly expressed in Pfeiffer syndrome-affected cranial osteogenesis. Conclusions. Contraction of the FGFR2-IgIIIa/c (BEK) expression domain in c ases of Apert syndrome- and Pfeiffer syndrome-affected fetal cranial ossifi cation suggests that the mutant activation of this receptor, by ligand-depe ndent or ligand-independent means, results in negative autoregulation. This phenomenon, resulting from different mechanisms in the two syndromes, offe rs a model by which to explain differences in their cranial phenotypes.