Crouzon syndrome, an autosomal dominant condition characterized by craniosynostosis, ocular proptosis and midface hypoplasia, is associated with mutations in fibroblast growth factor receptor 2 (FGFR2) (refs 1-3). For example, we have identified 10 different mutations in the FGFR2 extracellular immunoglobulin III (IgIII) domain in 50% (16/32) of our Crouzon syndrome patients. All mutations described so far for other craniosynostotic syndromes with associated limb anomalies--Jackson-Weiss, Pfeiffer, and Apert--also occur in the extracellular domain of FGFR2, as well as FGFR1 for Pfeiffer syndrome. In contrast, only FGFR3 mutations have been reported in dwarfing conditions--achondroplasia, thanatophoric dysplasia, and hypochondroplasia. For achondroplasia, greater than 99% of mutations occur in the FGFR3 transmembrane domain. We now report the unexpected observation of a FGFR3 transmembrane domain mutation, Ala391Glu, in three unrelated families with Crouzon syndrome and acanthosis nigricans, a specific skin disorder of hyperkeratosis and hyperpigmentation. The association of non-dwarfing and even non-skeletal conditions with FGFR3 mutations reveals the potential for a wide range of FGFR pleiotropic effects as well as locus heterogeneity in Crouzon syndrome. Our study underscores the biologic complexity of the FGFR gene family.

The noses of 34 attractive young North American Caucasian women were analyzed quantitatively, based on 19 nasal measurements (6 single and 7 paired linear measurements, 3 angles, and 3 inclinations) and 15 craniofacial measurements (10 linear measurements and 5 inclinations) taken directly from the face of the women. The relationship between the nasal measurements was studied in 16 proportion indices and the relationship between the nasal and the other craniofacial measurements in 13 interareal indices. The findings were also compared with those in 21 women with below-average faces. Two types of facial harmony disruption were identified: disharmony, a normal index with a visually apparent failure of proportionality, and disproportion, an index value outside of the normal range. The percentage of disharmonies and disproportions was significantly higher in the group of 21 women with below-average faces. The study revealed a wide variety of "ideal" noses. Only a small portion of the measurements (12%) and proportion indices (7%) were at the mean value. At least two-thirds of the interareal proportion indices were located in the mean +/- 1 standard deviation portion of the normal range. Only about one-fifth of the interareal indices were disharmonious and 2.8% disproportionate. The disproportions were more areal in the attractive faces and more interareal in the below-average faces. The greatest disproportion in the attractive face was the moderately short columella in relation to the tip protrusion and in the below-average face the long nasal bridge related to the upper-lip height. Disproportions were associated with combinations of normal and abnormal measurements, or with two normal measurements of unequal quality, which resulted in a slightly smaller disfigurement. Analysis of ethnic and racial differences showed the soft nose as the main feature of the most characteristic differences. The study revealed that the key to restoration of facial harmony is the renewal of the uniformity of proportion index qualities by elimination disharmonies and/or disproportionate relationships.

No abstract

No abstract