Crouzon’s syndrome: a new surgical approach

Crouzon’s syndrome is a rare genetic disorder characterized by distinctive malformations of the skull and facial region, premature cranial suture closure is the most common skull abnormality, optic disc edema and proptosis are among the most common ocular findings. It is a genetic disorder of gene FGFR-2 (Fibroblast Growth Factor Receptor-2) in 95% of cases, and in 5% of cases, FGFR-3 (Fibroblast Growth Factor Receptor-3) mutation occurs.Once a suture becomes fused, growth perpendicular to that suture becomes restricted and the fused bones act as a single body structure. Compensatory growth occurs at the remaining open sutures to allow continued brain growth, resulting in abnormal bone growth and producing facial deformities.In the new born child, some potential problems that may need to be addressed include respiratory difficulties, feeding problems, neurologic complications such as hydrocephalus and the potential risk of developmental delay.We represent a literature review and a rare case of Crouzon’s Syndrome, who wanted facial correction to be done at the age of 24years. We planned two stage surgical procedure, for correction of facial deformity.

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In vitro and in vivo characterization of Recifercept, a soluble fibroblast growth factor receptor 3, as treatment for achondroplasia

PLoS ONE ◽

10.1371/journal.pone.0244368 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0244368

Author(s):

Diogo Gonçalves ◽

Guylène Rignol ◽

Pierre Dellugat ◽

Guido Hartmann ◽

Stephanie Sarrazy Garcia ◽

...

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Bone Growth ◽

Fibroblast Growth Factor Receptor ◽

Genetic Disorder ◽

Growth Factor Receptor ◽

Model Systems ◽

Long Bone ◽

Fibroblast Growth

Achondroplasia is a rare genetic disorder caused by mutations in the Fibroblast Growth Factor receptor 3 (FGFR3). These mutations lead to aberrant increase of inhibitory signaling in proliferating chondrocytes at the growth plate. Recifercept is a potential treatment for this disease using a decoy approach to sequester FGFR3 ligands subsequently normalizing activation of the mutated FGFR3 receptor. Recifercept binds to FGF isoforms in vitro and in cellular model systems and reduces FGFR3 signaling. In addition, in a transgenic mouse model of achondroplasia, Recifercept restores reduced body weight and long bone growth in these mice. These data suggest that Recifercept treatment could lead to clinical benefits in children treated with this molecule.

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Chimeras of the native form or achondroplasia mutant (G375C) of human fibroblast growth factor receptor 3 induce ligand-dependent differentiation of PC12 cells.

Molecular and Cellular Biology ◽

10.1128/mcb.17.7.4169 ◽

1997 ◽

Vol 17 (7) ◽

pp. 4169-4177 ◽

Cited By ~ 17

Author(s):

L M Thompson ◽

S Raffioni ◽

J J Wasmuth ◽

R A Bradshaw

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Pc12 Cells ◽

Human Fibroblast ◽

Bone Growth ◽

Fibroblast Growth Factor Receptor ◽

Growth Factor Receptor ◽

Extracellular Domain ◽

Platelet Derived Growth Factor ◽

Fibroblast Growth

Mutations in the gene for human fibroblast growth factor receptor 3 (hFGFR3) cause a variety of skeletal dysplasias, including the most common genetic form of dwarfism, achondroplasia (ACH). Evidence indicates that these phenotypes are not due to simple haploinsufficiency of FGFR3 but are more likely related to a role in negatively regulating skeletal growth. The effects of one of these mutations on FGFR3 signaling were examined by constructing chimeric receptors composed of the extracellular domain of human platelet-derived growth factor receptor beta (hPDGFR beta) and the transmembrane and intracellular domains of hFGFR3 or of an ACH (G375C) mutant. Following stable transfection in PC12 cells, which lack platelet-derived growth factor (PDGF) receptors, all clonal cell lines, with either type of chimera, showed strong neurite outgrowth in the presence of PDGF but not in its absence. Antiphosphotyrosine immunoblots showed ligand-dependent autophosphorylation, and both receptor types stimulated strong phosphorylation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase, an event associated with the differentiative response of these cells. In addition, ligand-dependent phosphorylation of phospholipase Cgamma and Shc was also observed. All of these responses were comparable to those observed from ligand activation, such as by nerve growth factor, of the native PC12 cells used to prepare the stable transfectants. The cells with the chimera bearing the ACH mutation were more rapidly responsive to ligand with less sustained MAPK activation, indicative of a preactivated or primed condition and consistent with the view that these mutations weaken ligand control of FGFR3 function. However, the full effect of the mutation likely depends in part on structural features of the extracellular domain. Although FGFR3 has been suggested to act as a negative regulator of long-bone growth in chrondrocytes, it produces differentiative signals similar to those of FGFR1, to which only positive effects have been ascribed, in PC12 cells. Therefore, its regulatory effects on bone growth likely result from cellular contexts and not the induction of a unique FGFR3 signaling pathway.

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Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3

Development ◽

10.1242/dev.125.24.4977 ◽

1998 ◽

Vol 125 (24) ◽

pp. 4977-4988 ◽

Cited By ~ 10

Author(s):

M.C. Naski ◽

J.S. Colvin ◽

J.D. Coffin ◽

D.M. Ornitz

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Signaling Pathway ◽

Growth Plate ◽

Bone Growth ◽

Fibroblast Growth Factor Receptor ◽

Growth Factor Receptor ◽

Fibroblast Growth ◽

Growth Plate Cartilage ◽

Bmp4 Expression

Fibroblast growth factor receptor 3 (FGFR3) is a key regulator of skeletal growth and activating mutations in Fgfr3 cause achondroplasia, the most common genetic form of dwarfism in humans. Little is known about the mechanism by which FGFR3 inhibits bone growth and how FGFR3 signaling interacts with other signaling pathways that regulate endochondral ossification. To understand these mechanisms, we targeted the expression of an activated FGFR3 to growth plate cartilage in mice using regulatory elements from the collagen II gene. As with humans carrying the achondroplasia mutation, the resulting transgenic mice are dwarfed, with axial, appendicular and craniofacial skeletal hypoplasia. We found that FGFR3 inhibited endochondral bone growth by markedly inhibiting chondrocyte proliferation and by slowing chondrocyte differentiation. Significantly, FGFR3 downregulated the Indian hedgehog (Ihh) signaling pathway and Bmp4 expression in both growth plate chondrocytes and in the perichondrium. Conversely, Bmp4 expression is upregulated in the perichondrium of Fgfr3−/− mice. These data support a model in which Fgfr3 is an upstream negative regulator of the hedgehog (Hh) signaling pathway. Additionally, Fgfr3 may coordinate the growth and differentiation of chondrocytes with the growth and differentiation of osteoprogenitor cells by simultaneously modulating Bmp4 and patched expression in both growth plate cartilage and in the perichondrium.

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