INSTRUCTIVE CASE Bilateral exophthalmos: Report of a case and review of a fibroblast growth factor receptor 2 mutation associated with non-penetrant Crouzon syndrome Fabiola Quintero-Rivera 1 and Julian A Martinez-Agosto 2,3 1 Department of Pathology and Laboratory Medicine, and Departments of 2 Human Genetics and 3 Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California, United States Abstract: The differential diagnosis of exophthalmos requires careful examination to identify potentially serious aetiologies. We present the case of a child with exophthalmos in whom genetic analysis identified a mutation in the fibroblast growth factor receptor 2 associated with Crouzon syndrome. The variable presentation should remind paediatricians to consider mutations in fibroblast growth factor receptor 2 among the aetiologies of exophthalmos. Key words: Crouzon; exophthalmos; FGFR2; non-penetrance; ocular proptosis. Introduction Crouzon syndrome is one of the eight disorders comprising the fibroblast growth factor receptor (FGFR)-related craniosynostosis spectrum. It is characterised by cranial synostosis, hypertelorism, exophthalmos, external strabismus, parrot-beaked nose, short upper lip, hypoplastic maxilla and a relative mandibular prog- nathism 1 (MIM: 123500). Crouzon represents approximately 4.8% of cases of craniosynostosis at birth, 2 with a prevalence estimated to be 16.5 per million births. Mutations in the FGFR2 gene inherited in an autosomal dominant manner are seen in almost 90% of the cases. 3,4 Affected individuals have a 50% chance of passing the disease-causing mutation to their children. Advanced paternal age is frequently cited for the fathers of patients with Crouzon syndrome. 5 A novel missense A362S mutation in FGFR2 has been previously reported in two ‘clinically normal’ patients, suggesting the possibility of non-penetrance. 6,7 Here, we present a third report that expands the spectrum of phenotypic variability associated with this mutation. Patient Presentation A Filipino boy was born at 38 weeks via normal spontaneous vaginal delivery to a 40-year-old mother and a 40-year-old father. There was no known maternal exposure to medications or teratogens during the pregnancy. Prenatal testing and ultra- sound were normal. Birthweight was 7 lbs, 1 oz, and birth length was 19 in. with a normal head circumference. Develop- ment proceeded normally: he smiled at 2 months, held his head up at 4 months, sat at 7 months, crawled by 10 months, pulled to stand and was babbling by 11 months. The patient was referred to the Genetics Clinic by the paedia- trician at 12 months of age because of significant proptosis since birth. Because of the possibility of exophthalmos, thyroid studies were performed, and these were normal. An ophthal- mological evaluation revealed normal findings other than the proptotic eyes. Because of a concern for Crouzon syndrome, skull X-rays were taken as part of the workup, which were normal. Synostosis of sutures at the base of the skull could not be visualised on skull X-rays. Cranial three-dimensional recon- structed computed tomography scan was not pursued. Physical examination showed a weight of 9.9 kg (40th percentile), a height of 76 cm (50th percentile) and a head circumference of 46 cm (40th percentile). He had significant exophthalmos with very proptotic eyes, as well as midface hypoplasia with shallow eye orbits. Cranial sutures appeared to be normal. His nasal bridge was depressed with a normal nasal tip, columella and alae. Ears measured 5.8 cm bilaterally (97th percentile). He had a prominent lower lip with some prognathism (Fig. 1). Inter- nipple distance was 11.5 cm (75th percentile), with a chest that Key Points 1 Evaluate for genetic aetiologies in paediatric patients with ocular proptosis. 2 Mild mutations in fibroblast growth factor receptor 2 are associated with isolated bilateral proptosis without craniosynostosis. 3 Patients with isolated ocular proptosis should be evaluated for genetic etiologies even in the presence of familial ethnic traits. Correspondence: Dr. Julian A Martinez-Agosto, Department of Human Genetics, 695 Charles Young Dr. South, Gonda Center 4554, Los Angeles, CA 90095, USA. Fax: +310-794-5446; email: julianmartinez@mednet. ucla.edu Contributions: All authors have reviewed and revised the final manuscript, and agreed to its submission. Accepted for publication 28 June 2009. doi:10.1111/j.1440-1754.2009.01692.x Journal of Paediatrics and Child Health 46 (2010) 693–695 © 2010 The Authors Journal of Paediatrics and Child Health © 2010 Paediatrics and Child Health Division (Royal Australasian College of Physicians) 693