Paternal origin of FGFR2 mutations in sporadic cases of Crouzon syndrome and Pfeiffer syndrome

Crouzon syndrome and Pfeiffer syndrome are both autosomal dominant craniosy nostotic disorders that can be caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. To determine the parental origin of these FGFR2 mutations, the amplification refractory mutation system (ARMS) was us ed, ARMS IS PCR primers were developed to recognize polymorphisms that coul d distinguish maternal and paternal alleles, A total of 4,374 bases between introns IIIa and 11 of the FGFR2 gene were sequenced and were assayed by h eteroduplex analysis, to identify polymorphisms. Two polymorphisms (1333TA/ TATA and 2710 C/T) were found and were used with two previously described p olymorphisms, to screen a total of 41 families, Twenty-two of these familie s were shown to be informative (11 for Crouzon syndrome and 11 for Pfeiffer syndrome), Eleven different mutations in the 22 families mere detected by either restriction digest or allele-specific oligonucleotide hybridization of ARMS PCR products. We molecularly proved the origin of these different m utations to be paternal for all informative cases analyzed (P = 2.4 x 10(-7 ); 95% confidence limits 87%-100%). Advanced paternal age was noted for the fathers of patients with Crouzon syndrome or Pfeiffer syndrome, compared w ith the fathers of control individuals (34.50 +/- 7.65 years vs. 30.45 +/- 1.28 years, P < .01), Our data on advanced paternal age corroborates and ex tends previous clinical evidence based on statistical analyses as well as a dditional reports of advanced paternal age associated with paternal origin of three sporadic mutations causing Apert syndrome (FGFR2) and achondroplas ia (FGFR3). Our results suggest that older men either have accumulated or a re more susceptible to a variety of germline mutations.