Familial scaphocephaly syndrome caused by a novel mutation in the FGFR2 tyrosine kinase domain.

C raniosynostosis, the premature fusion of one or more sutures of the skull, is a common craniofacial anomaly, with an estimated incidence of 1/2000 to 1/3000 births. 2 Characteristic deformities of skull shape occur as a result of different patterns of sutural fusion, while compensatory skull expansion occurs at unaffected sutures to accommodate the growing brain. Premature fusion of the sagittal suture, for example, results in anterior to posterior elongation of the skull known as scaphocephaly. Sagittal synostosis is the most common type of craniosynostosis, occurring in 40–58% of cases reported in large neurosurgical surveys, and shows a male predominance. Most of the cases in these reports are ‘‘non-syndromic’’ instances of sagittal synostosis, while familial cases represent 2–9% of the total. Mental retardation is uncommon in isolated sagittal synostosis, but is more common in cases with associated malformations. Over 90 syndromic forms of craniosynostosis have been described. Apert, Crouzon, Pfeiffer, Muenke, and Saethre–Chotzen syndromes are the most common of these, being classified according to the clinical involvement of the cranium, face, hands and feet, and other organs. In these syndromes, brachycephaly or acrocephaly resulting from coronal synostosis is the predominant cranial deformity, and this is variably associated with mid-face hypoplasia, broad toes, syndactyly, and intellectual deficits. Sagittal synostosis is seen almost exclusively in combination with coronal synostosis, while macrocephaly in the absence of craniosynostosis occurs infrequently. Familial scaphocephaly syndromes, which include Berant syndrome, ‘‘Philadelphia’’ type craniosynostosis, and Jones craniosynostosis, are rare and their molecular aetiology remains unknown. Mutations in five genes have been shown to cause various craniosynostosis syndromes. These are the transcription factor genes TWIST (Saethre–Chotzen syndrome, MIM 101400) and MSX2 (Boston-type craniosynostosis, MIM 604757), and three fibroblast growth factor receptor genes, FGFR1, FGFR2, and FGFR3 (Pfeiffer syndrome, MIM 101600; Apert syndrome MIM 101200; Crouzon syndrome, MIM 123500; Jackson–Weiss syndrome, MIM 123500). Mutations in TWIST, FGFR2, and FGFR3 also cause isolated nonsyndromic coronal synostosis; however, mutations resulting in isolated sagittal suture synostosis and scaphocephaly have yet to be identified. The FGFR mutations have been located predominantly in hotspots in these genes in the more than 800 patients where mutations have been characterised. 9 Only one FGFR1 mutation, P252R, has been identified and it results in a mild Pfeiffer syndrome variant. In contrast, FGFR2 mutations are a common cause of several craniosynostosis syndromes: Pfeiffer, Apert, Crouzon, Jackson–Weiss, and Beare–Stevenson (MIM 123790). 11 The FGFR2 mutations are non-randomly distributed throughout the gene, concentrated in exons 8 and 10. Two mutations, S252W and P253R, are relatively common and invariably cause Apert syndrome. 11 In FGFR3, the A391E mutation causes Crouzon syndrome with acanthosis nigricans and the P250R mutation causes Muenke syndrome (MIM 602849). Mutations in FGFR3 also cause thanatophoric dysplasia (MIM 187600). Although craniosynostosis is a feature of this disorder, it is more commonly considered a severe generalised skeletal dysplasia. 12 FGFR3 mutations also result in a range of other chondrodysplasias including achrondroplasia and hypochondroplasia, emphasising the central role that FGF signalling plays in skeletal development. The wide range of limb abnormalities that occurs in the craniosynostosis syndromes indicates that the pathways of cranial bone growth and limb morphogenesis share some critical components. Characterisation of the genes involved in these syndromes is providing important information about the regulatory pathways of craniofacial and skeletal development. We report the clinical and molecular findings in a three generation family showing autosomal dominant inheritance of a novel craniosynostosis syndrome (fig 1). Thirty family members were examined and the clinical findings are detailed in table 1. The appearances of the 11 affected individuals are shown in fig 2. The study was approved by the Royal Children’s Hospital ethics in human research committee, and informed consent was obtained from participating family members. All the subjects shown in fig 2, or their legal guardians, gave written consent for their images to be reproduced in this paper. Macrocephaly was defined as an occipito-frontal circumference greater than the 98th centile Key points