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Purpose: Craniosynostoses are premature ossifications of cranial sutures. They occur isolated and syndromic. Syndromic craniosynostoses are mainly associated with mutations of the Fibroblast Growth Factor Receptors (FGFR) 1 - 3. This paper gives an overview of the etiology and pathophysiology of isolated and syndromic craniosynostoses and discusses the molecular genetic results in 21 index cases (19 seemingly isolated craniosynostoses, 2 cases with a clinical diagnosis of Crouzon's syndrome)., Method: Mutation analysis in exons of the FGFR 1 - 3 known to be preferentially affected in craniosynostoses was performed on DNA samples from peripheral blood and bone specimen excised at the time of surgery to correct the craniosynostosis., Results: In a girl with seemingly isolated plagiocephaly we identified a P250L (749C-->T) mutation in FGFR3. Her mother showed minor signs of craniosynostosis when the family was re-evaluated. She was shown to carry the same mutation. In two patients with suspected Crouzon's syndrome 2 different mutations were detected at the same nucleotide (1025G-->A or C) and confirmed the clinical diagnosis. No mutation was found in 18/19 seemingly isolated craniosynostosis cases., Conclusion: In contrast to syndromic forms isolated craniosynostoses are rarely associated with mutations in FGFR. The affection of further family members is a strong indication of involvement of FGFR mutations. Because of variable expressivity, parents should be examined carefully in isolated craniosynostoses to identify minor signs.

Background: The FGFR3-associated coronal synostosis syndrome (Muenke craniosynostosis) is caused by a point mutation (C749G) on the FGFR3 gene resulting in a Pro250Arg substitution., Methods: To characterize this malformation, the neuro- and viscerocranium were analyzed by axial CT scans of the skull and cephalometric radiographs of up to 13 affected children before and in part after fronto-orbital advancement., Results: Preoperative analysis of the intracranial volume of four patients showed a mean decrease of 3.6%, indicating a compensatory growth pattern of the skull in cases of coronal synostosis. The typical brachycephaly could be verified by the significant shortening of the skull length of 13.2% on average and by the significant reduction of the anterior cranial base length of maximal 5.9% on average. The anterior part of the skull was characterized by a significant mean increase of the intercoronal distance of 8.6%, which indicates a compensatory transversal growth in this malformation. The widened bilateral interorbital and anterior interorbital distances were increased by 7.3 or 9.0%, respectively, confirming a hypertelorism typical for this syndrome. The "frontal bossing" frequently found in brachycephaly was characterized by the preoperatively increased sagittal extension of the forehead (about 112.9% above the norm) and by the increased height of the frontal prominence (about 47.8% above the norm). Following surgery, both variables defining the morphology of the forehead were reduced and appeared to be constant throughout the follow-up. Hypoplasia of the midface described by Muenke et al. (1997) was confirmed in the present study only by the significant reduction of the sagittal length of the maxillary base, which was decreased by 6.8%., Conclusion: In accordance with the current literature, the skull configuration described for Muenke craniosynostosis shows similarities with the Saethre-Chotzen syndrome.

Background: Cherubism is a rare fibro-osseous disorder that almost exclusively affects the maxilla and mandible., Case Report: We report on three affected males in three generations in family A, and ten affected patients in family B. The youngest affected relative in family A also had craniosynostosis. His father and grandfather had cherubism and clubbed fingers., Results and Discussion: Cherubism was mapped to region 4p16.3. Because of the associated craniosynostosis, we excluded the FGFR3 gene as a candidate gene for cherubism. The inheritance pattern is autosomal dominant with variable expression. The penetrance is 100% in males and 50-70% in females. We found incomplete penetrance in males, which does not conform with all publications.

Transient expression by hair cells, increasing levels of FGF-1 mRNA in neonatal rat spiral ganglion neurons and strong expression in adulthood, make FGF-1 a candidate to be associated with development and maintenance of the mammalian spiral ganglion. To test this hypothesis, dissociated spiral ganglion cells from 5 day old rats were cultured in the presence of FGF-1 at 100 ng/ml plus heparan sulfate proteoglycans (HSPG) at 500 ng/ml for 72 hours. Spiral ganglion cells incubated with FGF-1/HSPG achieved an average neurite length of 323 microns while control cells gained an average neurite length of 203 microns. The results of this study are consistent with our previous findings in whole spiral ganglion explants (3) where FGF-1 incubation significantly stimulated neurite outgrowth at about the same range. However, stimulation of neurite outgrowth in dissociated spiral ganglion cells suggests that FGF-1 directly binds to FGF receptors on the surface of spiral ganglion neurons and/or neurites instead of acting via intermediate cells such as glia. Since FGF receptor mRNA was found to be expressed only at very low levels in neonatal spiral ganglion neurons (7) it is possible that the receptors are highly localized, perhaps to neurite growth cones. Alternatively, an unknown FGF receptor or splice variant may be expressed in these cells. Adequate FGF-1 application to the human inner ear may stimulate spiral ganglion cell survival and neurite extension after hair cell loss in patients suitable for cochlear implant treatment. By creating a closer contact between spiral ganglion cells and the electrode, FGF-1 might also improve the efficacy of cochlear implants.

In the present study, the expression of a acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor-1 were analyzed in 60 pancreatic cancer samples using Northern blot analysis, immunoblotting, in situ hybridization and immunohistochemical techniques. aFGF, bFGF and FGFR-1 were present in 63%, 55% and 52% of the tumor samples, respectively. Twenty-seven of the 60 pancreatic cancer tissue samples exhibited coexpression of aFGF and bFGF. In contrast, 14 of the tumor samples did not show immunoreactivity for aFGF or bFGF in the tumor cells. The expression of aFGF in the tumor cells had no influence on the postoperative survival period, whereas patients whose tumors were positive for bFGF and/or FGF-receptor-1 had significantly shorter postoperative survival periods. Our results suggest that bFGF and FGFR-1 may play a role in the growth behavior of pancreatic cancer and may contribute to tumor aggressiveness.