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Treacher Collins syndrome (TCS) results from defects in a nucleolar trafficking protein (Treacle) coded for by the TCOF1 gene.1 The purpose of this report is, firstly, to describe an isolated male with TCS associated with macular degeneration who also had a novel TCOF1 gene mutation and, secondly, to evaluate this mutation in a well characterised cohort of 95 patients with age related macular degeneration (AMD).
A 44 year old man presented with a 1 month history of metamorphopsia. He had minimal dysmorphic features but was noted to have an antimongoloid slant of the palpebral fissures with mild flattening of the midface. Sensorineural deafness had been diagnosed from childhood but the external ears were normal in appearance. Best corrected visual acuity was 6/9 (−2.25 DS) right eye and 6/24 (−1.50 DS) left eye. Ocular examination revealed bilateral posterior embryotoxon with adhesions between iris and Schwalbe’s line, and iris hypoplasia. No eyelid colobomata were present. Posterior segment examination (fig 1) revealed atrophic macular degeneration in both eyes and a choroidal neovascular membrane (CNV) in the left eye confirmed on fluorescein angiography. No drusen were seen in either eye. Mutation screening of TCOF1 gene was instigated because his facial appearance and deafness suggested possible TCS. A mutation was identified in exon 13 (2055 del AG), which is predicted to create a premature stop codon. In view of this unique genotype and phenotype we wished to evaluate whether this mutation in the TCOF1 gene was commonly associated with macular degeneration. Ninety five white patients with AMD were therefore screened for the 2055 del AG mutation by denaturing high performance liquid chromatography (dHPLC),2 using the DNA from our patient with TCS as a positive control (fig 2). The spectrum of AMD in this cohort was AREDS grade I (21 patients); AREDS grade II (20 patients); AREDS grade III (19 patients) and AREDS grade IV (35 patients).3 No abnormal chromatograms were detected in any of these patients.
Ophthalmological features in TCS may be extensive, but rarely involve intraocular structures. Common features include astigmatism, defective inferior lateral angle of the orbit, caudal displacement of the superolateral orbit, coloboma of the lateral part of the lower lid, pseudocoloboma of the eyelids, lateral canthal dystopia, nasolacrimal obstruction, orbital and limbal dermoids, and microphthalmos.4 Hansen et al5 have observed bilateral iris, choroid, and optic nerve colobomata. Cataracts, lacrimal duct atresia, pupillary ectopia, distichiasis, and uveal colobomas have been reported less frequently. A solitary case with aniridia, sclerocornea, and retinal maldevelopment has also been reported.6 We believe this is the first report of atrophic macular degeneration and CNV demonstrated in a patient with a proved molecular diagnosis of TCS.
Disease expressivity is highly variable in TCS, ranging from the clinically undetectable to death in the perinatal period.6 The late clinical presentation in our case may be explained by the mild phenotype in the spectrum of TCS. The TCS Collaborative Group7 first identified different mutations in the TCOF1 gene in each of five unrelated families with TCS. All of the mutations were predicted to result in a premature stop codon leading to premature termination of the protein product. Since then over 100 disease causing mutations have been reported8 throughout the TCOF1 gene in patients with TCS, which represented a detection rate of 60%. Our patient has a 2055 del AG mutation in exon 13 of the TCOF1 gene which has not been previously reported. We speculated that there may be a causal relation between the mutation and the macular degeneration seen in our patient with TCS.
The specific role of TCOF1 in the molecular pathogenesis of TCS remains elusive, but mechanisms such as abnormal neural crest cell migration and abnormal cell death seem important.9TCOF1 is expressed in the human eye and apoptotic regression has been described in organs such as ears and kidneys in animal models of TCS.10 Therefore, it seemed possible that this TCOF1 mutation may also trigger cellular apoptosis resulting in atrophic macular degeneration. However, we tested for the presence of this mutation in 95 patients with AMD but did not identify any mutation carriers in this cohort.
We acknowledge that it is possible that this macular finding is incidental to TCS and the TCOF1 mutation. The early age of onset of macular degeneration in this patient is also atypical for AMD. We also note that the macular degeneration seen in this patient is more severe than would be expected with his low degree of myopia. It is therefore possible that patients with TCS may have an increased risk of developing macular degeneration.
In summary, we describe a new clinical phenotype in a patient with molecularly proved TCS and a novel TCOF1 mutation. Although most cases of TCS present early in life, ophthalmologists need to review adults with TCS to see if macular degeneration is more widespread than reported. This mutation, however, does not appear to be implicated in AMD.