Variable expressivity and clinical heterogeneity can complicate the diagnosis and management of Pfeiffer syndrome

We report here a newborn female infant with striking features consistent with severe Pfeiffer syndrome (PS). Pfeiffer syndrome is a rare craniofacial disorder that has an autosomal dominant mode of inheritance (OMIM 101600). Our patient had unexpected differences between her clinical features and those predicted from her genetic tests. The following clinical features were noted: severe exophthalmos, syndactyly, upper extremity contractures, and relative macroglossia. A head computed tomography with three-dimensional reconstruction showed that she did not have craniosynostosis. Genetic tests included a normal 46,XX karyotype and a chromosomal microarray that revealed a copy number gain at 14q23.1 as well as a copy number loss at 16p13.2. FGFR2 sequencing revealed a c.870G>T transversion in exon 8, which is predicted to encode a Trp290Cys substitution.The clinical features of severe exophthalmos and other features typical of PS without craniosynostosis were most consistent with a diagnosis of PS type III. However, her Trp290Cys FGFR2 mutation is reported to be associated with PS type II that includes kleeblatschädel (or "cloverleaf") skull anomalies as a cardinal feature. Our patient's lack of craniosynostosis predicted from this mutation is a striking example of variable expressivity. Such discrepancies between the physical findings (phenotype) and the mutation identified (genotype) and the association of different findings with different mutations in the same gene (clinical heterogeneity) can present difficulties in case management. Clinicians should be guided by careful phenotyping rather than by genotypic predictions alone.