MATERIALS AND METHODS

Over a 2 year period (1999–2001) 22 patients with Cohen syndrome, referred from clinical geneticists throughout the United Kingdom, were assessed by the authors and their clinical phenotype characterised. A diagnosis of Cohen syndrome was based on the presence of the at least seven of the following typical clinical features as originally reported by Cohen et al,¹ and further delineated by Norio et al¹⁴:

• mental retardation

• microcephaly

• characteristic facial appearance (thick eyebrows and eyelashes, down slanting and wave-shaped palpebral fissures, prominent nose, short and upturned philtrum with an open mouthed expression revealing the upper central incisors)

• slim tapering extremities with relative truncal obesity

• hypotonia

• joint laxity

• neutropenia

• ophthalmic abnormalities.

The authors recorded a detailed ophthalmic history from the parents of all patients. During the study period, nine patients underwent formal assessment (visual acuity, visual field assessment, full clinical examination, funduscopy, electroretinography, and visual evoked potential testing). In addition, past ophthalmic notes were reviewed on 15 patients. Although undertaken in different centres, electroretinograms (ERGs) were performed with skin electrodes in all cases and the results were graded as normal, attenuated, or extinguished.

RESULTS

The study patients’ ranged in age from 3–53 years. The spectrum of ophthalmic abnormalities are summarised in Table 1. The age at onset of visual problems, as noted by parents, ranged from 6 months to 15 years, with a median age of 3 years; 18/22 (82%) parents recalled their child’s visual difficulties as starting before the age of 5 years.

All patients were myopic with refractive errors ranging from −0.25D to −18D. It was frequently of early onset. Myopia was documented before 5 years of age in 15/22 patients. Three patients had not undergone a formal ophthalmic assessment before their teenage years and so myopia was not detected until then. In four patients, the age at which refractive error was first present was not remembered by the parents nor documented in the past ophthalmic notes. Of the four myopic patients aged 5 years or less for whom refraction details were available, one had low myopia (<−3D), and three had high myopia (>−7D). In the five myopic patients aged between 5 and 10 years, three were high and two were moderate myopes. Finally, in the 10 patients aged over 10 years, eight had high myopia and two had moderate myopia.

In the majority of patients abnormal ocular findings were confined to the posterior segment. However, presenile posterior subcapsular cataracts were identified in the two oldest patients, aged over 40 years. One of these patients also had bilateral keratoconus and lens subluxation.

Retinal examination had been performed on all 22 study patients. Nine were children examined aged under the age of 10 years. Of these, five were noted to have isolated bull’s eye maculopathy while the remaining three had more generalised changes with diffuse retinal pigment disturbance and arteriolar attenuation (Fig 1A). One child, aged 4 years, had fundal changes in keeping with her high myopia but no evidence of a pigmentary retinopathy. Of the 13 adolescent and adult patients examined, 11 had widespread, severe retinopathy with classic bone spicule pigment deposition, optic pallor, and vessel attenuation. Two siblings had a normal retinal appearance except for early onset optic nerve pallor. A single patient had bilateral and visually insignificant retinal colobomata (Fig 1B).

• Download figure
• Open in new tab
• Download powerpoint

Figure 1

(A, B) Two patients, aged 4 and 19 years, with Cohen syndrome illustrating the characteristic facial appearance. Note the short philtrum, prominent incisors, and grimace-like appearance on smiling. (C) Bilateral incomplete inferior coloboma and pigmentary retinopathy in a young man with Cohen syndrome, (patient 17). (D) Pigmentary retinopathy typically seen in Cohen syndrome: note bone spicule changes in the lower retina.

Electrodiagnostic tests had been carried out on 19 of the study patients. Ten were children aged less than 10 years, of which nine, including two siblings, had markedly attenuated or extinguished responses. In the nine older patients tested, seven had extinguished ERGs, the remainder were severely attenuated.

Nyctalopia was recorded in 18/22 (82%) of patients. Many parents were unable to pinpoint a particular time when they became aware of symptoms of poor night vision in their child. However, in the 11 cases when an age of onset of nyctalopia was recalled, the median age was 5 years (range 2–20 years).

DISCUSSION

Our study of a large group of Cohen syndrome patients illustrates the range, progression, and severity of ophthalmic abnormalities typically associated with Cohen syndrome. Review of the literature reveals marked clinical heterogeneity among the reported patients and as a result the range and severity of associated ocular anomalies with Cohen syndrome is unclear. Microphthalmia, microcornea, colobomata, strabismus, and myopia have all been reported. In Finnish patients with Cohen syndrome, specific visual problems have been delineated and high myopia and chorioretinal dystrophy have been proposed as a hallmark of Cohen syndrome.^14,20 Kivitie-Kallio et al’s recent, long term follow up study in 22 Finnish patients,²⁰ described severe and progressive myopia with chorioretinal dystrophy and extinguished ERG results in all but the youngest patients. However, their retrospective data collection identified nyctalopia and symptoms of progressive visual field loss in most patients before the age of 7 years.²⁰

Our study patients are from a geographically diverse population in whom haplotype analysis does not suggest the presence of a common founder mutation (unpublished observations). Therefore, they represent a valuable patient resource for assessment of the variability of ophthalmic abnormalities found in Cohen syndrome, particularly when compared with the Finnish patient group.

Our results confirm that the visual problems are of early onset: 82% of our patients developed squint or refractive errors during the first 5 years of life. Myopia occurred in all of our study patients, was early in onset (under 5 years) and progressive: 63% of patients had high myopia. The severity of the myopia in our patients was comparable to that seen in other studies with a median refraction of −8 dioptres (range −0.25 to −18D).

Patients with Cohen syndrome develop a progressive pigmentary retinopathy.^14,17–20 In our study, this was identified in all our patients and was frequently early in onset. All of the study children aged under 5 years had evidence of a retinopathy. Symptoms of nyctalopia were reported from a median age of 5 years. The rate of progression of visual symptoms varied between individual patients, even within the same families. However, by the second decade nyctalopia, reduced visual acuity, and peripheral visual field loss secondary to retinal degeneration were evident in 85% of patients. The pattern of progression of the retinal dystrophy is comparable to that described by Kivitie-Kallio et al.²⁰

The majority of our study patients had severe visual handicap and 35% were registered as partially sighted or blind. This contrasts with the Finnish group of Cohen syndrome patients in which marked deterioration of visual function occurred over the age of 50 years but no patient was totally blind.²⁰

Analysis of the range of visual problems seen in this group of children and adults with Cohen syndrome highlights the important contribution ophthalmic abnormalities make to the condition, not only in terms of handicap and morbidity but also in confirming the diagnosis. Ophthalmologists should consider Cohen syndrome in a young, developmentally delayed child who presents with severe myopia and nyctalopia. Similarly, for paediatricians and clinical geneticists considering a diagnosis of Cohen syndrome, evidence of an early onset, and progressive myopia in association with a pigmentary retinopathy should be sought. Early identification of a visual impairment in a child with Cohen syndrome and referral to the appropriate agencies within a multidisciplinary team are of vital importance to the family.