Molecular diagnosis of bilateral coronal synostosis

The authors performed a prospective study evaluating molecular diagnosis in patients with bilateral coronal synostosis. The patients were divided into two groups: (1) those clinically classified as having Apert, Crouzon, or P feiffer syndrome and (2) those clinically unclassified and labeled as havin g brachycephaly. Blood samples were drawn for genomic DNA analysis from 57 patients from 1995 to 1997. Polymerase chain reactions were performed using primers flanking exons in FGFR 1, 2, and 3. Each exon was screened for mut ations using single-strand confirmation polymorphism, and mutations were id entified by DNA sequencing. Mutations in FGFR2 or FGFR3 were found in all patients (n = 38) assigned a phenotypic (eponymous) diagnosis. All Apert syndrome patients (n = 13) carr ied one of the two known point mutations in exon 7 of FGFR2 (Ser252Trp and Pro253Arg). Twenty-five patients were diagnosed as having either CI Crouzon or Pfeiffer syndrome. Five patients with Crouzon syndrome of variable seve rity had mutations in exon 7 of FGFR2. Fifteen patients (12 with Crouzon, 3 with Pfeiffer) had a mutation in exon 9 of FGFR2, many of which involved l oss or gain of a cysteine residue. A wide phenotypic range was observed in patients with identical mutations, including those involving cysteine. Two patients labeled as having Crouzon syndrome had the Pro250Arg mutation in e xon 7 of FGFR3. All three patients with the crouzonoid phenotype and acanth osis nigricans had the same mutation in exon 10 of FGFR3 (Ala391Glu). This is a distinct disorder, characterized by jugular foraminal stenosis, Chiari I anomaly, and intracranial venous hypertension. Mutations were found in 14 of 19 clinically unclassifiable patients. Three mutations were in exon 9, and one was in the donor splice site of intron 9 on FGFR2. The most common mutation discovered in this group was Pro250Arg i n exon 7 of FGFR3. These patients (n = 10) had either bilateral or unilater al coronal synostosis, minimal midfacial hypoplasia with class I or class I I occlusion, and minor brachysyndactyly. No mutations in FGFR 1, 2, or 3 we re detected in five patients with nonspecific brachycephaly. In conclusion, a molecular diagnosis was possible in all patients (n = 38) given a phenotypic (eponymous) diagnosis. Different phenotypes observed wit h identical mutations probably resulted from modulation by their genetic ba ckground. A molecular diagnosis was made in 74 percent of the 19 unclassifi ed patients in this series; all mutations were in FGFR2 or FGFR3. Our data and those of other investigators suggest that we should begin integrating m olecular diagnosis with phenotypic diagnosis of craniosynostoses in studies of natural history and dysmorphology and in analyses of surgical results.