Dominantly acting, allelic mutations of the fibroblast growth factor receptor 2 
(FGFR2) gene have been described in five craniosynostosis syndromes. In Apert 
syndrome, characterised by syndactyly of the hands and feet, recurrent mutations 
of a serine-proline dipeptide (either Ser252Trp or Pro253Arg) in the linker 
between the IgII and IgIII extracellular immunoglobulin-like domains, have been 
documented in more than 160 unrelated individuals. We have identified three 
novel mutations of this dipeptide, associated with distinct phenotypes. A C-->T 
mutation that predicts a Ser252Leu substitution, ascertained in a boy with mild 
Crouzon syndrome (craniosynostosis with normal limbs) is also present in three 
clinically normal members of his family. A CG-->TT mutation that predicts a 
Ser252Phe substitution results in a phenotype consistent with Apert syndrome. 
Finally, a CGC-->TCT mutation that predicts a double amino acid substitution 
(Ser252Phe and Pro253Ser) causes a Pfeiffer syndrome variant with mild 
craniosynostosis, broad thumbs and big toes, fixed extension of several digits, 
and only minimal cutaneous syndactyly. The observation that the Ser252Phe 
mutation causes Apert syndrome, whereas the other single or double substitutions 
are associated with milder or normal phenotypes, highlights the exquisitely 
specific molecular pathogenesis of the limb and craniofacial abnormalities 
associated with Apert syndrome. Ser252Phe is the first noncanonical mutation to 
be identified in this disorder, its rarity being explained by the requirement 
for two residues of the serine codon to be mutated. The description of 
independent, complex nucleotide substitutions involving identical nucleotides is 
unprecedented, and we speculate that this may result from functional selection 
of FGFR mutations in sperm.