Genotypic and phenotypic analyses of Korean patients with syndromic craniosynostosis.

To the Editor : Craniosynostosis, the premature fusion of one or more cranial sutures, is a common malformation occurring in approximately 1 in 2500 live births (1), and ocular hypertelorism, proptosis, beaking of the nose and midface hypoplasia are the common facial features of the craniosynostosis (2, 3). The syndromic craniosynostosis is the hereditary form of craniosynostosis, which is associated with extracranial phenotypes such as limb, cardiac, central nervous system and tracheal malformations (2). Syndromic craniosynostosis has been reported to be associated with mutations of several genes including FGFR1, FGFR2, FGFR3, FBN1, TWIST, and MSX2 genes (1, 2). Among these identified mutations, mutations in the genes of fibroblast growth factor receptors (FGFRs), particularly FGFR2, are most common and have been implicated in syndromic craniosynostosis (4–8). The molecular mechanisms and genotype–phenotype correlations of FGFR2 mutations have been shown to be very diverse (6–8). In this study, we carried out phenotype analysis of unrelated 12 Korean patients with syndromic craniosynostosis and characterized the patients as five syndromes according to the clinical features (2, 3); Pfeiffer syndrome (PS), Crouzon syndrome (CS), Apert syndrome (AS), Beare– Stevenson cutis gyrata syndrome (BSS), and Muenke syndrome (MS). Clinical and radiographic features of the patients are summarized in Table 1 and Figure 1. All the patients had exhibited characteristic features, including fused suture, ocular proptosis and abnormal head shape from their early infancy. Brachycephaly was the most common skull deformity, and facial morphology was very diverse. Proptosis coexisted with small midface in 11 of 12 patients. Syndactyly and broad digit were found in all of the patients with PS and severe webbing with syndactyly in the second, third and fourth digits were found in the patient with AS1. All patients with CS showed the typical craniofacial characteristics of CS such as abnormal head shape, small midface, proptosis and fused sutures. Vertebral anomalies were found in the patient with BSS1. Patient with MS1 showed mild midfacial hypoplasia with coronal suture fusion, severe sensorineural hearing loss and strabismus. Congenital severe hydrocephalus was detected in four patients (AS1, PS2, CS6 and BSS1) on their fetal ultrasonogram (US). We also carried out a molecular study of mutation of three FGFR genes using polymerase chain reaction (PCR)-direct sequencing of the hot spot region for FGFR1, FGFR2 and FGFR3 genes (1, 4, 7). Eleven missense mutations of FGFR2 gene and one missense mutation of FGFR3 gene were detected in 12 patients (Table 2). As previously described (7, 9–12), mutations occurred preferentially in the exon 10 of FGFR2, encoding the third immunoglobulin (Ig) loop of the receptor, and these mutations were found in most of the patients with CS (5/6) and one patient with PS. Two mutations (S252W and P253R) (7, 13, 14) in the exon 8 of FGFR2 encoding the linker domain between the IgII and IgIII were detected in patients with PS1 and AS1, respectively. The S252W mutation was reported previously to be related not only to AS but also to PS (14). Patient with PS1 carrying the S252W mutation is characterized as PS according to his clinical features including the cloverleaf skull, proptosis, broad thumbs, and great toes that are distinguished from AS (Fig. 1a,b). Mutations (L641R and Y375C) in the tyrosine kinase domain 2 (TK2) and juxtamembrane-extracellular region (7, 15) were detected in each patient with PS and BSS, respectively. Common mutation P250R (16) in the FGFR3 gene was detected in a patient with MS. A genotype–phenotype correlation analysis suggests that genetic and phenotypic heterogeneity exists in FGFR2 mutations. Few of the genotype–phenotype correlations were absolute; that is, there was significant variability with given mutation as reported previously (5, 7). Some