Sequence Analysis of Fibroblast Growth Factor Receptor 2 (FGFR2) in Japanese Patients with Craniosynostosis

Abstract

Recently, mutations of the fibroblast growth factor receptor ( FGFR ) genes have been detected in syndromic craniosynostosis. We examined nucleotide sequences of FGFR2 in Japanese craniosynostosis patients (Crouzon syndrome: 9 cases; Apert syndrome: 6 cases; scaphocephaly: 3 cases as non-syndromic patients) by polymerase chain reaction (PCR) followed by direct sequencing methods. The results demonstrated FGFR2 heterozygous mutations at codons 252, 290 of exon 7, and at codon 342, 354 of exon 9 in Crouzon syndromes. In Apert syndrome patients, Ser252Trp and Pro253Arg were detected in five and one patients, respectively. No mutation was detected in one case of Crouzon, all cases of scaphocephaly and healthy individuals. Thus far sequence analysis of FGFR2 in syndromic craniosynostosis has been reported in many white patients, whereas in Japanese only several cases have been studied. The current study with 18 patients confirmed that a similar series of mutations occur in Japanese patients as in white patients regardless of ethnicity and environment. The frequency of the mutation was 82% (9/11 cases) in Japanese Crouzon patients. The ratio of S252W:P253R was 5 : 1 in Japanese Apert patients. Moreover, in Japanese Apert patients, complication rate of cleft palate was 60% for mutation of Ser252Trp and 0 of 2 patients for Pro253Arg, with their syndactyly score being 4.90 and 5.50, respectively.

Genetic considerations in nonsyndromic midline craniosynostoses: a study of twins and their families

“…20 To date no such mutations have been identified in midline craniosynostoses. 21,25 Conclusions This is the first genetic study of craniosynostosis in which data from a cohort of twin pairs are examined. Our data are compatible with a multifactorial casuality, supporting both an environmental and genetic origin.…”

“…20 No FGFR mutations, however, are found in nonsyndromic midline craniosynostoses. 21,25 Other putative causes of synostosis are environmental, such as intrauterine or perinatal factors. Graham, et al, 6,7 have suggested that intrauterine head constraint might be a cause of sagittal synostosis.…”

Gain-of-function amino acid substitutions drive positive selection of FGFR2 mutations in human spermatogonia

“…(ii) Average mutation levels are positively correlated with donor age, and mirror epidemiological observations of paternal age for Apert syndrome births. (iii) Surprisingly, levels of the 755CϾT transition (encoding Ser252Leu), which is usually clinically silent in the heterozygous state but occasionally causes Crouzon syndrome (26,27), are also elevated (but overall, are Ϸ1.7-fold lower than 755CϾG) and also positively correlate with donor age. Levels of the third possible substitution, 755CϾA (encoding a stop codon) are not increased.…”

A Case of Pfeiffer Syndrome

“…However, it is rarer in Asian population: only several cases were reported in Japan (10, 11) and no reports as yet in Korea. Cohen (12) in 1993 classified this syndrome into 3 clinical subtypes and suggested that these subtypes might not be classified as separate entities, even though these classifications have important diagnostic and prognostic implications.…”