American Journal of Medical Genetics 138A:278–281 (2005) Clinical Report Novel Phenotype of Craniosynostosis and Ocular Anterior Chamber Dysgenesis With a Fibroblast Growth Factor Receptor 2 Mutation Emma McCann, 1 * Stephen B. Kaye, 2 William Newman, 3 Gail Norbury, 4 Graeme C.M. Black, 5,6 and Ian H. Ellis 1 1 Department of Clinical Genetics, Royal Liverpool Children’s Hospital, Eaton Rd, Liverpool, United Kingdom 2 St. Paul’s Eye Unit, 8Z Link, Royal Liverpool University Hospital, Prescot Street, Liverpool, United Kingdom 3 Department of Paediatric Ophthalmology, Royal Liverpool Children’s Hospital, Eaton Rd, Liverpool, United Kingdom 4 Regional Molecular Genetics Laboratory, Level 5, Camelia Botnar Laboratories, Great Ormond Street Hospital for Children, London, United Kingdom 5 Academic Unit of Medical Genetics and Regional Genetic Service, St. Mary’s Hospital, Manchester, United Kingdom 6 Manchester Royal Eye Hospital, Central Manchester and Manchester Children’s University Hospitals NHS Trust, Oxford Road, Manchester, United Kingdom Fibroblast growth factor receptor 2 (FGFR2) mutations are associated with syndromic and non-syndromic craniosynostoses. More recently it has been recognized that FGFR2 may have a role in the development of the anterior chamber of the eye following the finding of a specific FGFR2 mutation (p.Ser351Cys, c.1231 C ! G) with an- terior chamber dysgenesis. Affected patients had a severe craniofacial phenotype and clinical course. A child with a different FGFR2 muta- tion (p.Ala344Ala, c1032 G ! A heterozygote), pre- mature fusion of the sagittal suture, and an Axenfeld–Rieger anomaly but otherwise normal clinical course is reported. The case provides further evidence that FGFR2 has a role in anterior chamber embryogenesis. ß 2005 Wiley-Liss, Inc. KEY WORDS: FGFR2; craniosynostosis; scapho- cephaly; anterior chamber dys- genesis; Axenfeld–Rieger INTRODUCTION Fibroblast growth factor receptor 2 (FGFR2) is a member of the high affinity, tyrosine kinase protein family that binds fibroblast growth factors. Mutations in this gene are associated with craniosynostosis syndromes including Crouzon, Pfeiffer, Apert, and Jackson–Weiss [Jabs et al., 1994; Reardon et al., 1994; Lajeunie et al., 1995]. Unclassifiable craniosynostosis has also been observed with FGFR2 mutations [Steinberger et al., 1996]. Axenfeld–Rieger malformation refers to a collection of ocular findings including anomalies of the anterior chamber angle and aqueous drainage structures that are associated with a high risk of glaucoma as well as iris hypoplasia, corectopia, and posterior embryotoxon. It may be associated with extraocular developmental abnormalities of the umbi- licus, dentition, heart, or limbs. A number of genes are implicated in the development of the Axenfeld–Rieger anom- aly and are reviewed by Lines et al. [2002]. Okajima et al. [1999] previously reported on three cases with anterior chamber dysgenesis, craniosynostosis, and with a FGFR2 mutation. A further case is presented with different anterior chamber findings, sagittal suture craniosynostosis, and in whom a FGFR2 mutation was detected. CLINICAL REPORT A boy, the second child of unrelated parents, was found to have a right-sided cataract at 3 weeks of age that required surgical extraction at 5 weeks of age. Additional anterior seg- ment developmental abnormalities suggestive of Axenfeld– Rieger anomaly were also present including right-sided microcornea, bilateral posterior embryotoxon, and bilateral iris hypoplasia with corectopia. At the time of diagnosis, and subsequently intraocular pressures were normal. Posterior segment examination also revealed no abnormalities. There were no umbilical, teeth, limb or heart abnormalities. Scaphocephaly was detected at 6 months of age (Fig. 1a,b) and a skull X-ray confirmed premature fusion of the sagittal suture. Magnetic resonance imaging of his brain revealed an Arnold–Chiari malformation with prolapse of the cerebel- lar tonsils 5 mm below the level of the foramen magnum. Surgical correction of his craniosynostosis was necessary because of concerns about raised intracranial pressure. There were no other dysmorphic features and development was age appropriate. At 6 years of age, the patient remains under regular ophthalmology and craniofacial follow-up; there are no new problems and no learning difficulties. The patient’s karyotype is normal. Ophthalmologic examination of the mother revealed mild iris hypoplasia and bilateral embryotoxon. She also has mild exophthalmus but no craniosynostosis. The patient’s father and older sibling have no abnormal eye findings on clinical examination. The maternal grandmother was reported by the family to have developed glaucoma around 55 years of age. MUTATION ANALYSIS AG ! A base change at c.1032 in exon 10 of the FGFR2 gene was detected by Aci 1 restriction enzyme digestion of amplified *Correspondence to: Emma McCann, Royal Liverpool Chil- dren’s Hospital, Eaton Rd., Liverpool, L12 2AP, United Kingdom. E-mail: emma.mccann@rlc.nhs.uk Received 5 May 2005; Accepted 27 June 2005 DOI 10.1002/ajmg.a.30944 ß 2005 Wiley-Liss, Inc.