Elsevier

The Lancet

Volume 349, Issue 9058, 12 April 1997, Pages 1059-1062
The Lancet

Articles
Prevalence of Pro250Arg mutation of fibroblast growth factor receptor 3 in coronal craniosynostosis

https://doi.org/10.1016/S0140-6736(96)09082-4Get rights and content

Summary

Background

The C749G (Pro250Arg) mutation in the gene for fibroblast growth factor receptor 3 (FGFR3) has been found in patients with various types of craniosynostosis. We aimed to find out the proportion of cases of apparently non-syndromic coronal craniosynostosis attributable to this mutation.

Methods

We studied 26 patients with coronal craniosynostosis but no syndromic diagnosis, who were referred to a supra-regional specialist centre. Genomic DNA was analysed by PCR and restriction-enzyme digestion to identify the C749G mutation in FGFR3. Family members of patients found to have the mutation were also tested.

Findings

Eight (31%) of the 26 probands were heterozygous for the C749G mutation. In two cases, the mutation showed autosomal dominant transmission with evidence of variable expressivity; the remaining six cases were sporadic. We demonstrated in six families that the mutation had arisen de novo from clinically unaffected parents.

Interpretation

The C749G mutation in FGFR3 is a frequent cause of apparently non-syndromic coronal craniosynostosis. Our finding will aid genetic counselling and prenatal diagnosis. The mutation rate at this nucleotide is one of the highest described in the human genome.

Introduction

Craniosynostosis, the premature fusion of one or more cranial sutures, is a common congenital defect, affecting at least one in 2500 livebirths.1, 2, 3, 4 More than 100 syndromes in which craniosynostosis is a feature have been described.5 The clinical identification of these syndromes has depended on the presence of extracranial abnormalities, most commonly in facial structures or limbs. However, during the past few years the molecular basis of several of these syndromes has been elucidated.6, 7, 8, 9, 10, 11, 12, 13, 14, 15 For these disorders, we can now classify patients by the molecular findings rather than by clinical findings alone.

For most cases of craniosynostosis, however, there is no clear syndromic label: either the craniosynostosis is an isolated finding, or there are minor anomalies of the hands and feet that do not fit any recognisable syndrome. Classification is by the pattern of involvement of the cranial sutures (ie, coronal, sagittal, metopic, or lambdoid). The extent to which these disorders are genetically determined or due to the maternal environment or other factors is uncertain. The higher sibling recurrence risk observed in non-syndromic coronal craniosynostosis2, 3, 16 and the likely inclusion of patients mildly affected with Saethre-Chotzen syndrome within this group,17 suggest that there is a greater genetic component to coronal than to sagittal synostosis. Elucidation of the genetic factors would shed light on the pathogenesis of craniosynostosis and aid genetic counselling.

We have investigated a cohort of patients with apparently non-syndromic coronal craniosynostosis, either unilateral (plagiocephaly) or bilateral (brachycephaly), for a mutation in the gene for fibroblast growth factor receptor 3 (FGFR3), which maps to the short arm of chromosome 4. This mutation (C749G; Pro250Arg) was initially identified in two families with a phenotype resembling Pfeiffer syndrome (craniosynostosis with broad big toes and thumbs), but was subsequently found in eight other patients with craniosynostosis and various other diagnostic labels.18 We report our findings in 26 unrelated patients with apparently non-syndromic coronal craniosynostosis.

Section snippets

Patients and methods

Patients were ascertained from referrals to the Oxford Craniofacial Unit. Two patients were referred from the Institute of Medical Genetics, Cardiff. Coronal craniosynostosis, unilateral or bilateral, was diagnosed on the basis of clinical examination, skull radiography, and computed tomography of the head. When possible, the abnormality was confirmed at operation. Patients with a recognised craniosynostosis syndrome were excluded. Saethre-Chotzen syndrome was excluded on the basis of typical

Results

The clinical features of the 26 unrelated patients ascertained for this study are summarised in the table. The coronal synostosis was bilateral in 18 cases, right-sided in four, and left-sided in four. Two patients had additional involvement of the sagittal suture, and one of the metopic suture. Minor hand and foot anomalies present in some patients included mild brachydactyly, mild cutaneous syndactyly of the toes, and broad or laterally deviated big toes. 17 patients had no obvious limb

Discussion

In our study, eight (31%) of 26 patients with apparently non-syndromic coronal craniosynostosis were heterozygous for a C749G point mutation in the FGFR3 gene. The 95% CI of this proportion suggests that this mutation accounts for between 14% and 52% of all cases. The frequency of this form of craniosynostosis at birth has been estimated as 0·8–1·0 in 10 000, with 61% sporadic cases.2, 3, 16 This estimate implies a mutation rate at this nucleotide of about 8×10−6 per haploid genome, which

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