Jackson-Weiss syndrome: identification of two novel FGFR2 missense mutations shared with Crouzon and Pfeiffer craniosynostotic disorders

Abstract

Jackson-Weiss syndrome is a rare skeletal disorder characterized by craniosynostosis associated with foot malformations. This condition is inherited as an autosomal dominant trait with complete penetrance and wide phenotypic heterogeneity. Mutations in the fibroblast growth factor receptor 2 (FGFR2) gene have been recently identified as causes of this syndrome and of at least four other craniosynostotic disorders, namely the Apert, Beare-Stevenson cutis gyrata, Crouzon and Pfeiffer syndromes. We report two novel FGFR2 missense mutations associated with phenotypes consistent with Jackson-Weiss syndrome. Both nucleotide changes predict a serine for cysteine-342 substitution in the second half of the third immunoglobulin-like domain. The replacement of Cys342 with arginine has previously been reported in one of the three Jackson-Weiss cases investigated. Interestingly, both Cys342Ser and Cys342Arg substitutions have been found to be associated with the Crouzon and Pfeiffer phenotypes; a phenotypic heterogeneity, Crouzon vs Jackson-Weiss clinical features, has been also observed for Gln289Pro and Ala344Gly amino-acid changes. This finding indicates the genetic homogeneity of the "heterogeneous" Jackson-Weiss phenotype and a common molecular basis for these apparently "clinically distinct" craniosynostotic disorders.

A Case of Beare-Stevenson Cutis gyrata Syndrome Confirmed by Mutation Analysis of the Fibroblast Growth Factor Receptor 2 Gene

“…Several genetic mutations result in premature closure of the cranial sutures. Mutations in the FGFR genes cause Crouzon’s, Pfeiffer, Apert, Jackson- Weiss and Beare-Stevenson cutis gyrata syndromes [6, 7, 8]. Amutation in the TWIST gene is responsible for Saethre-Chotzen syndrome [9, 10], while a mutation in the MSX2 gene causes Boston-type craniosynostosis [11].…”

Clinical findings in a patient withFGFR1 P252R mutation and comparison with the literature

“…Moreover, the presence of normal thumbs seemed to exclude Pfeiffer syndrome [Muenke et al, 1994]. Thus, it was anticipated that she would harbor an exon 9 FGFR2 missense mutation, as described in JWS [Jabs et al, 1994;Tartaglia et al, 1997]. Unexpectedly, analysis of her FGFR1 gene demonstrated the presence of a heterozygous C to G transversion, leading to a proline substitution for arginine at residue 252 (P252R) [Muenke et al, 1994].…”

“…The molecular basis of these overlapping findings were clarified by the identification of FGFR2 missense mutations located in the third Ig-like domain (IgIII) for JWS, Crouzon and Pfeiffer (FGFR2) syndromes , Rutland et al, 1995, Tartaglia et al, 1997, including the original JWS pedigree [Jabs et al, 1994]. Conversely, the wide spectrum of variability observed in the Pfeiffer phenotype seemed to have a molecular basis as FGFR1-Pfeiffer syndrome patients had less severe craniofacial derangement than FGFR2-Pfeiffer syndrome patients [Schell et al, 1995;Rutland et al, 1995;Gripp et al, 1998].…”

Visualizing the origins of selfish de novo mutations in individual seminiferous tubules of human testes

“…Fertilization of the egg by a mutant sperm leads to serious congenital disorders in the next generation, characterized by multiple malformations and, in some cases, a predisposition to malignancy. These disorders include Apert, Crouzon, and Pfeiffer syndromes [caused by FGF receptor 2 (FGFR2) mutations] (17)(18)(19)(20), achondroplasia and thanatophoric dysplasia (TD) [FGF receptor 3 (FGFR3)] (21-23), multiple endocrine neoplasia (RET) (24), Noonan syndrome [protein tyrosine phosphatase, non-receptor type 11 (PTPN11)] (25), and Costello syndrome [Harvey rat sarcoma viral oncogene homolog (HRAS)] (25). Consistent with the proposed clonal expansion mechanism, strong gain-offunction mutations of HRAS and FGFR3 have been identified in spermatocytic tumor (seminoma), a testicular tumor characteristically occurring in older men (16,26).…”