FGFR2 mutation associated with clinical manifestations consistent with Antley-Bixler syndrome

Abstract

The Antley-Bixler syndrome (ABS) is a rare syndrome with synostosis of cranial sutures and elbow joints as minimal diagnostic criteria. The inheritance has been suggested to be autosomal recessive based on two families with sib recurrence with both sexes being affected, and two cases born to consanguineous parents. We report the first case of ABS associated with an apparent dominant de novo mutation in the fibroblast growth factor receptor 2 (FGFR2) gene. The patient was found to be heterozygous for a C-->G transversion at nucleotide 1064, which predicts a Ser351Cys amino acid substitution in the IgIII domain of FGFR2. Apart from the craniosynostosis and elbow ankylosis, our patient also presented with severe spinal dysraphism, the first report of such a finding in association with ABS. This suggests that FGFR2 is expressed as early as the fourth week of embryogenesis when somite formation occurs. We propose that the Antley-Bixler syndrome is an autosomal dominant condition with possible gonadal mosaicism. Alternatively, there may be two types of ABS: an autosomal dominant form and an autosomal recessive form. In light of our findings, FGFR mutations should be looked for in other craniosynostosis patients with elbow synostosis.

Fibroblast growth factors, their receptors and signaling.

“…There is a wealth of data supporting the existence of activating point mutations of FGFRs, but such mutations have only been found in developmental defects such as skeletal dysplasias (Webster et al 1996) and craniosynostotic syndromes (Mangasarian et al 1997, Chun et al 1998, Gripp et al 1998. In these cases, point mutations may occur in the extracellular, transmembrane or kinase domains and all such mutations result in ligand-independent activation of the FGFRs (Neilson & Friesel 1996).…”

Malformation syndromes caused by disorders of cholesterol synthesis

“…Many patients demonstrate defects in steroidogenesis and disturbances of sexual development. However, ABS is genetically heterogeneous; a subset of patients with an ABS phenotype without ambiguous genitalia have heterozygous, autosomal dominant gain-of-function mutations in fi broblast growth receptor 2 ( FGFR2 ) ( 309,310 ). This group can be considered part of the FGFR -related craniosynostosis syndromes and will not be discussed further.…”

Loss of fibroblast growth factor receptor 2 ligand-binding specificity in Apert syndrome

“…Dwarfing chondrodysplasia syndromes, including hypochondroplasia, achondroplasia, and thanatophoric dysplasia, result from missense mutations in FGFR3 and primarily affect bones undergoing endochondral ossification. Craniosynostosis syndromes, which include Apert syndrome (AS) (5), Crouzon syndrome (CS) (6,7), CS with Acanthosis Nigricans (CSAN) (8), coronal craniosynostosis (CC) (9), Pfeiffer syndrome (PS) (10), Jackson-Weiss syndrome (JWS) (11), AntleyBixler syndrome (12), and Beare-Stevenson cutis gyrata (13), share phenotypes that include premature closure of some cranial sutures but have distinct facial features, limb abnormalities, and, in some cases, central nervous system malformations (1,3,4,14). With the exception of PS, CC, and CSAN, most craniosynostosis syndromes result from missense mutations in FGFR2.…”