ArticlesPrevalence of Pro250Arg mutation of fibroblast growth factor receptor 3 in coronal craniosynostosis
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
References (27)
- et al.
A mutation in the homeodomain of the human MSX2 gene in a family affected with autosomal dominant craniosynostosis
Cell
(1993) Recent human germ-line mutation: inferences from patients with hemophilia B
Trends Genet
(1995)- et al.
Craniosynostosis: I sagittal synostosis; its genetics and associated clinical findings in 214 patients who lacked involvement of the coronal suture(s)
Teratology
(1976) - et al.
Craniosynostosis: II coronal synostosis; its familial characteristics and associated clinical findings in 109 patients lacking bilateral polysyndactyly or syndactyly
Teratology
(1997) - et al.
Genetic study of nonsyndromic coronal craniosynostosis
Am J Med Genet
(1995) - et al.
Genetic study of scaphocephaly
Am J Med Genet
(1996) - et al.
The London dysmorphology database
(1996) - et al.
Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome
Nat Genet
(1994) - et al.
Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans
Nat Genet
(1995) - et al.
A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome
Nat Genet
(1994)
FRFR2 mutations in Pfeiffer syndrome
Nat Genet
Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes
Nat Genet
Jackson-Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2
Nat Genet
Cited by (116)
Multilocus inheritance and variable disease expressivity in rare disease
2021, Genomics of Rare Diseases: Understanding Disease Genetics Using Genomic ApproachesDiagnosis and Surgical Options for Craniosynostosis
2018, Principles of Neurological SurgeryClassification, Diagnosis, and Etiology of Craniofacial Deformities
2017, Maxillofacial Surgery, 3rd Edition: Volume 1-2Craniosynostosis
2013, Emery and Rimoin's Principles and Practice of Medical GeneticsDiagnosis and surgical options for craniosynostosis
2012, Principles of Neurological SurgeryCerebral cortex maldevelopment in syndromic craniosynostosis
2022, Developmental Medicine and Child Neurology