A pedigree with CS was recruited for this study (Fig. 1a). The patient received a systemic evaluation, and we collected peripheral blood samples from the patient and his lineal relatives. This study adhered to the tenets of the Declaration of Helsinki. The ethics committee of The Second People’s Hospital of Yunnan province approved the protocol, and we obtained written informed consent from all the study participants. Genomic DNA was extracted from the peripheral blood. Polymerase chain reaction (PCR) for the target sequence of FGFR2 was performed, according to the methods described previously [4].
The proband was a 4-year-old boy. He fell accidentally, following which luxation of the bulbus oculi occurred immediately (Fig. 1d). The patient’s family brought him to our hospital for treatment. We observed that the patient’s left eyeball was clearly dislocated and accompanied by hypophasis of the left eye. The eye movements were restricted in all directions. External strabismus was also observed. The relative afferent pupillary defect (RAPD) was negative. Upon physical examination, the proband (III:2), his father (II:3, 28 years old), and his grandfather (I:1, 54 years old) had ocular proptosis, shallow orbits, and mid-face hypoplasia, but clinically normal hands and feet (Fig. 1d). The boy’s father and grandfather had normal vision, while displaying a ‘surprised look’. The best corrected visual acuity (BCVA) of individual III:2 (4 years old) was 0.5 for the right eye, and 0.1 for the luxated left eye. The visual acuity of the left eye was in a precarious condition due to severe exposure keratitis and traumatic dislocation of the eyeball. The orbital pressure in left orbit was higher than that in the right orbit. Computed tomography and magnetic resonance imaging did not reveal retrobulbar hematoma and revealed shallow orbits and ocular proptosis in patient III:2 (Fig. 1b, c). Therefore, mannitol (10 g, q8h, intravenous drip) was administered for symptomatic reduction of orbital pressure for 3 days. At the same time, tobramycin eye ointment (topical instillation, qn) and carbomer eye drops (topical instillation, q8h) were administered to the left eye for 3 days to protect it from exposure keratitis and obstinate conjunctivitis. After treatment, the dislocated bulbus oculi reverted back to the orbit and left eyelid could be closed. The BCVA of the left eye increased to 0.2 (Fig. 1d). The restriction in eye movement improved after treatment. However, mild restricted internal eye movement and mild external strabismus were observed. The patient was re-examined at our hospital 1 week after discharge. There was no obvious dislocation of the eyeball. The BCVA of left eye was maintained at 0.2. Subsequently, the patient was lost to follow-up.
Genetic assessments revealed a heterozygous missense mutation (c.1012G > C, p.G338R) in exon 10 of the human FGFR2, cosegregated with the disease phenotype in this family (Fig. 2a). This mutation resulted in the replacement of hydrophilic glycine with more hydrophilic arginine at codon 338 (p. Gly338Arg) at the immunoglobulin (Ig)-like domain 3. Moreover, the missense mutation is not found in normal individuals, including II:4, who was the proband’s mother.
To study the structure of the mutant FGFR2 protein, three-dimensional crystal structures of the wild-type and mutant FGFR2 (residues 1–520) were constructed based on the human FGFR2, with a sequence confidence of 100% and coverage of 59%. Structural modeling of the FGFR2 protein (Fig. 2c) demonstrated that G338R was located in the β-sheet, which is required for receptor binding [5]. The mutated area was found in a highly conserved segment of the FGFR2 protein in humans and other species (Fig. 2b). We considered the variation as ‘likely pathogenic’ according to the standards and guidelines from American College of Medical Genetics and Genomics (ACMG), and 4 bioinformatics tools (SIFT, Mutation Taster, Polyphen2, REVEL) [6].
