We thank Dr. Gripp, Dr. Zackai, and Dr. Cohen, Jr. for their communication [Gripp et al., 2003]. We agree that a complete physical examination and review of the medical and family history by the medical geneticist are the first and most important steps in evaluating a patient. Based on these findings, the most appropriate molecular test should then be ordered.
We are a referral center for craniosynostosis testing and therefore, receive specimens for testing from many genetics centers. Three of the four patients with the FGFR3 P250R mutation had been referred for Saethre-Chotzen syndrome testing before the Muenke syndrome was described in 1997 [Muenke et al., 1997]. The fourth patient was referred very shortly after. Furthermore, although all the patients described in the publication of Chun et al. [2002] were assessed by clinical geneticists, clinical overlap of the Muenke syndrome with the Saethre-Chotzen syndrome made it a challenge for those geneticists less experienced with the craniosynostosis syndromes. Since then, many more patients with craniosynostosis have been diagnosed by mutational analysis and more clinical information has become available. Now with the clinical phenotypes more firmly established, clinical geneticists are better equipped to distinguish patients with Saethre-Chotzen syndrome from those with Muenke syndrome. To this end, we are in agreement with Dr. Gripp, Dr. Zackai, and Dr. Cohen Jr that sequencing of TWIST should be the first molecular test performed for a patient with Saethre-Chotzen syndrome, and that if this is negative, testing for the FGFR3 P250R mutation be done. Indeed, the testing algorithm for Saethre-Chotzen syndrome had already been modified since our publication, which is reflected in a paper [Chun et al., 2003] that describes a stepwise molecular diagnostic approach to syndromic craniosynostosis testing.