Article Text
Abstract
Aim To evaluate ophthalmological findings in children with Silver–Russell syndrome (SRS).
Methods An ophthalmological evaluation including visual acuity (VA), refraction, strabismus, near point of convergence (NPC), slit-lamp examination, ophthalmoscopy, axial length measurements and full-field electroretinogram was performed on 18 children with SRS (8 girls, 10 boys; mean age 11.6 years). Fundus photographs were taken for digital image analysis. Data were compared with data on an age- and gender-matched reference group (ref) of school children (n=99).
Results Seventeen out of 18 children with SRS had ophthalmological abnormalities. Best corrected VA of the best eye was <0.1 log of the minimal angle of resolution in 11 children (ref n=98) (p<0.0001), and 11 children had refractive errors (ref n=33) (p=0.05). Anisometropia (≥1 dioptre) was noted in three of the children (ref n=3) (p=0.046). Subnormal stereo acuity and NPC were found in 2/16 (ref=0) (p=0.02). The total axial length in both eyes was shorter compared with that in controls (p<0.006 and p<0.001). Small optic discs were found in 3/16, large cup in 3/16 and increased tortuosity of retinal vessels in 4/13 children with SRS.
Conclusion Children with SRS, who are severely intrauterine growth retarded, show significant ophthalmological abnormalities. Based on the present findings, ophthalmological examination is recommended in children with SRS.
- Visual function
- ocular findings
- Silver–Russell syndrome (SRS)
- prenatal programming
- intrauterine growth-retarded (IUGR)
- optic nerve
- vision
- optics and refraction
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- Visual function
- ocular findings
- Silver–Russell syndrome (SRS)
- prenatal programming
- intrauterine growth-retarded (IUGR)
- optic nerve
- vision
- optics and refraction
Introduction
Silver–Russell syndrome (SRS) is a rare syndrome characterised by prenatal and postnatal growth retardation, a triangular face, micrognathia, lateral asymmetry and clinodactylia (figure 1A).1 So far, little is known about the cause of the disease, although several genetic abnormalities have been described involving chromosomes 1, 7, 8, 11, 15, 17 and 18.2 3 Today we know that a large proportion of children with SRS have either hypomethylation at the imprinting control region of chromosome 11p15 (30–65%) with a more severe phenotype4 or maternal uniparental disomy of chromosome 7 (5–10%) with a milder phenotype.4 5 The candidate genes are those imprinted in the regions of chromosomes 7 and 11, such as insulin-like growth factor 2 (IGF-2), IGF-2 receptor (IGF-2R), and growth factor receptor-bound protein 10 (Grb 10).
Different ophthalmological findings, such as ptosis, epicanthal folds, hypertelorism, long eyelashes, eyebrows meeting in the midline, protruding eyeballs, microphthalmia, strabismus, blue sclera, absence of the lacrimal duct, microcornea, heterochromia, myopia, subnormal visual acuity (VA), cataract, asymmetry and central excavation of the optic discs, pigmentary retinopathy, retinal detachment, decreased full-field electroretinogram (ERG) potential and congenital glaucoma, have previously been described in separate case reports in patients with SRS.6–8
However, to our knowledge, no detailed ophthalmological investigation in a larger number of patients with SRS has previously been reported. Therefore, the purpose of this study was prospectively to evaluate visual function and ocular findings in patients with SRS, a group born extremely small for gestational age (SGA).
Materials and methods
Patients
Eighteen children and adolescents (8 girls, 10 boys; mean age 11.6 years, range 3.4–18.1 years) fulfilling all criteria for the diagnosis of SRS were referred from across Sweden and examined by a national multidisciplinary team at the Queen Silvia Children's Hospital, Gothenburg, Sweden. Table 1 shows auxological data at birth and the proportion of preterm births in the children with SRS. Birth weight and birth length were converted into standard deviation scores (SDSs) based on Swedish reference values.9 The mean birth weight SDS was –3.1 (range −1.2 to −4.5) and the mean birth length SDS was −3.2 (range 0 to −5.6); all of these children were SGA by birth weight, birth length or both. At the time of the investigation, 16 of the 18 children had been treated with growth hormone (GH) for a mean period of 6.6 years (range 2–14 years).
Reference group
Ophthalmological data were compared with data for an age- and sex-matched reference group (ref) of Swedish school children (n=99, 54 girls and 45 boys, mean age 11.5 years (range 7.4–15.9 years)) tested under conditions identical to those of the study cohort.10 Auxological data at birth are presented in table 1. Another 99 healthy Swedish children and adolescents (56 boys, 43 girls) aged between 3 and 19 (mean age 10.1 years) and born at term constituted a reference group for evaluation of ocular fundus morphology.11
Methods
A detailed ophthalmological evaluation was performed, including the following.
Determination of best corrected VA (BCVA) for near and distant fixation
BCVA was tested with a linear KM-Boks chart.12 For children who could not read the KM-Boks chart, we used the HOTV chart. Distance VA was tested monocularly at a distance of 3 m and near vision was tested binocularly at a distance of 0.33 m.
Refraction under cycloplegia
Refraction tests were performed with an autorefractor (Topcon A6 300; Topcon, Tokyo, Japan) after a single instillation of a mixture of cyclopentolate (0.85%) and phenylephrine (1.5%). Significant refractive errors were defined as the spherical equivalent (SE) of ≥0.5 dioptre (D) for myopia or ≥2.0 D for hyperopia. Astigmatism was assessed at a level of ≥0.75 D SE, and anisometropia at ≥1.0 D SE.
Investigation of strabismus and ocular motility
Heterotropia, defined as intermittent or constant, near (0.33 m) or at distance (3 m), was diagnosed with cover–uncover tests. Heterophoria was diagnosed with alternate cover tests, and deviations were quantified using alternate prism cover tests. Exophoria was defined as values below the 5th percentile in the control group (negative values), and esophoria as values above the 95th percentile (positive values). Thus, the cut-off values defining significant heterophoria were between less than −2 and >0 prism dioptres (pD) for distance and between less than −10 and >0 pD for near vision. Motility was assessed with a penlight and described in terms of overfunctioning or underfunctioning.
Testing of stereo acuity
Stereo acuity was tested with the TNO random dot stereo test, the Lang I stereo card or the Titmus test, as appropriate. Subnormal stereo acuity was defined as >60 s (60'') of arc.
Near point of convergence (NPC)
NPC, in centimetres, was measured three times with a Royal Air Force ruler and the mean value of the measurements was recorded.
Fixation recordings
The simultaneous horizontal and vertical positions of the right and left eye were recorded using the Orbit infrared (IR) system (IOTA, Timrå, Sweden). In this IR device, pulsed IR light, emitted inside a pair of goggles, is reflected against the ocular surface and detected by eight detectors. Eye position signals are conducted via a sound card to a computer, where they are recorded. The investigation is described in detail elsewhere.13
Assessment of ocular dimensions
The medial intercanthal distance (ICD) and right and left palpebral fissure lengths (PFLs), in millimetrres, were measured with a ruler. Total axial length (TAL) was measured by ultrasound biometry (Paxis, version 2.01; BIOVISION, Clermont-Ferrand, France).
Examination of the anterior segment, media and ocular fundus
Examination of the anterior segment of the eye was performed with a slit-lamp, and the ocular fundus was examined by indirect ophthalmoscopy.
Electroretinogram
A full-field ERG of one eye was recorded using a bipolar contact lens in a Nicolet Analysis System (Nicolet Biomedical Instruments, Madison, Wisconsin, USA) as described elsewhere,14 according to International Society for Clinical Electrophysiology of Vision standards.15 In some cases, skin electrode ERGs were registered. This involved placing a silver–silver chloride electrode just below the central lower lid margin. A single flash, using a red filter, with a Grass flashlight stimulus of supramaximal intensity (<100 μs, ∼0.5 J) was projected at a distance of ∼20 cm to the child's eye.
Photography of the ocular fundus for quantitative digital image analysis
Ocular fundus photographs taken in cycloplegia were analysed with a specially designed computer-assisted digital mapping system16 in regard to the optic disc area (ODA), optic cup area, neuroretinal rim area, tortuosity of veins and arteries, and number of branching points.
Statistical analysis
Means, SDs, medians and ranges were calculated for descriptive purposes. For a comparison between two groups, Mann–Whitney U test was used for ordered and continuous variables; for dichotomous variables, Fisher exact test was used. Test results were considered to be significant at values of p<0.05. The reference group for this study was selected individually by minimising the maximal t values over the variables age and sex between the group of children with SRS and a reference group of 143 healthy, Swedish school-aged children.10
Results
Altogether, 17/18 children with SRS had ophthalmological abnormalities. Table 2 summarises the ophthalmological findings in each of the 18 children and youths with SRS.
VA, refraction, strabismus, ocular motility, stereo acuity and NPC
Table 3 shows BCVA at distance (better eye), near VA (binocular), refractive errors, heterotropia, significant heterophoria, ocular motility, stereo acuity and NPC in the two groups.
In total, 11/18 children with SRS had refractive errors (ref 33/99) (p=0.05). The median SE in the study cohort was +0.56 (range −4.25 to +6.25) for right eyes and +0.31 (range −4.25 to +6.125) for left eyes. No statistical difference between right and left eyes was found regarding VA, refraction in SE or astigmatism in the children with SRS.
Fixation
No significant difference between the eyes or between the children with SRS and the controls was found regarding fixation in primary position—that is, fixation time, and number of intruding saccades, drifts or blinks recorded by the Orbit IR system.
Ocular dimensions
The mean and SDs of ICD, PFL and TAL of right and left eyes for the children with SRS as well as for the reference group are shown in table 4. No significant difference between right and left eyes was found regarding PFL and TAL in the children with SRS. An ICD of ≥5–10 mm ≥ PFL was recorded in 7/15 children (ref 10/99) (p=0.002).
Examination of the anterior segment, media and ocular fundus
Abnormal growth of the eyebrows was recognised in four children with SRS, and four had long, full prominent lashes bilaterally. Epicanthal folds and unilateral ptosis were seen in one child (table 2).
Electroretinogram
An ERG was performed in 16 children with SRS, in 11 of whom skin-electrode ERG was performed, while 5 underwent full-field ERG. The retinal conditions showed normal activity in all children.
Digital image analysis
Ocular fundus photographs of 16 children were analysed with regard to the ODA, cup area and neuroretinal rim area. Tortuosity of veins and arteries and number of branching points were analysed in 13 children.
Optic disc morphology
Of 16 children, 3 had an ODA and 3 had a neuroretinal rim area that was smaller than the 5th percentile for the controls (<1.82 and <1.52 mm2, respectively) (table 2; figure 1B). Three children had a cup area larger than the 95th percentile for the controls (>0.79 mm2) (table 2). There was no significant difference in optic disc, cup or rim area between the two groups. However, there was a tendency towards larger cups in children with SRS (median 0.56; range 0.0–1.20) than in controls (median 0.34; range 0.0–1.61) (p=0.056). No significant difference between right and left eyes regarding optic disc, cup or rim area was found.
Retinal vessel morphology
Two out of 13 children with SRS had an increased tortuosity of arteries (ITA), and four children had an increased tortuosity of veins (ITV) above the 95th percentile for the controls (>1.17 and >1.09, respectively) (table 2; figure 1C). Five children with SRS had a decreased number of central vascular branching points below the 5th percentile for the controls (<21) (see figure 1C). However, no significant difference was found in ITA, ITV or number of branching points between the two groups.
Discussion
The children and adolescents with SRS in this prospective study showed a high number of visual and ocular abnormalities, such as subnormal VA, refractive errors, anisometropia, subnormal stereo acuity and subnormal NPC, as well as short eyes compared with controls. In addition, ptosis, epicanthal folds, long eyelashes, eyebrows meeting in the midline, hypertelorism, small optic discs, large cup, and increased tortuosity of retinal vessels were seen in some of the children.
Children with SRS commonly show a lateral facial and/or skeletal asymmetry. In an interesting case report presented by Siegel et al in 1998, an asymmetry of the optic discs was demonstrated in a child with SRS.7 A 0.6 mm difference between the optic discs was measured biomicroscopically using a 78 D-ruled indirect lens. Two of the children in our study (cases 8 and 17) also showed a difference of optic disc size (0.88 mm), as measured by the digital analysing system used in this study (table 2). However, for the group as a whole, no significant difference between the sizes of the right and left optic discs could be found. On the other hand, we found that anisometropia (≥1.0 D SE), reflecting an asymmetric disorder, was more common in children with SRS than in controls (tables 2 and 3). This finding has not previously been reported in children with SRS. In addition, three children (cases no. 3, 5 and 8) have an astigmatism with ≥1.0 D difference between the eyes (table 2). Knowledge of an asymmetry of refraction is important for the development of the child's visual function and for preventing anisometric amblyopia.
GH and IGF-1 are involved in ocular growth by influencing the synthesis of the extracellular matrix of the sclera and by inducing angiogenesis.17 An association between optic nerve hypoplasia and reduced retinal vascularisation, as well as a mean hyperopic defect related to shorter axial length and an increased central corneal thickness, is documented in individuals with GH deficiency.17–19
At the time of this investigation, 16 children with SRS were being treated with GH, three of whom had small optic discs as measured by the digital analysis system. Interestingly, despite being treated with GH, these children still had significantly shorter TALs than the controls. Overall, however, their emmetropisation seemed to process normally. Parentin and Perissutti hypothesised, in their study on the effect of GH treatment on refraction, that correct and well-timed substitutive GH treatment could permit normal emmetropisation.20 It can only be speculated whether the change in refraction is related to the GH-induced somatic growth per se, or whether it is a direct effect of GH and/or IGF-1. Further studies are needed regarding the effects of GH replacement treatment on the development of the visual and ocular system.
Abnormal optic nerve and retinal vascular morphology—that is, reduced rim area and decreased number of central branching points—have previously been reported in young adults who were intrauterine growth-retarded (IUGR) infants.21 22 In the present study, 3/16 children had a reduced rim area and 5/13 children had a decreased number of branching points. A decrease in the neuroretinal rim area reflects either a decrease in the number of axons or a reduction in axonal volume in the optic disc. The underlying mechanisms and the importance of the decreased number of central branching points are not known.
It is known that humans who have been undernourished during gestation become less healthy later in life.23 Several studies have shown that prenatal exposure to famine is associated with cardiovascular risk factors and coronary heart disease, brain abnormalities, affective disorders and antisocial behaviour.24 25 Children with SRS are a heterogeneous group with different genetic backgrounds.2 Though they exhibit different severity, they all share the same general phenotype and have all had both in utero and postnatal growth retardation. Whether it is the genetic background or the fetal milieu per se which has an adverse impact in these children is not known. Children with SRS are found to have impaired growth early in gestation, and this would probably affect several organs, including the brain and the eyes. Besides the ophthalmological impact, as described here, we hypothesise that perception and brain function may also be impaired. It is therefore of great interest to evaluate further the visual perception and other cognitive functions of children with SRS.
Conclusion
On the basis of our findings, we recommend that an ophthalmological examination be performed in children born with severe IUGR, and especially in children with SRS, to optimise the visual and ocular development of these children.
Acknowledgments
Our study results have been presented in part at the 11th Nordic Paediatric Ophthalmology Congress held in Uppsala, Sweden, in September 2003 and at the ARVO annual meeting held in Fort Lauderdale, FL, USA, in April 2004. The authors would like to thank Birgitta Melander, Jonna Johansson, and Eva Rudholm for their technical assistance. We would also like to thank Professor Kerstin Albertsson-Wikland, Birgit Lidwall and the staff at Endocrine Ward 335, who took care of the children with SRS. Emma Jaensson and Per Ekman of the Statistiska Konsultgruppen, Gothenburg, Sweden, are gratefully acknowledged for their help with the statistical analyses.
References
Footnotes
Funding This study was supported by the Gothenburg Medical Society, the W & M Lundgrens Vetenskapsfond II, the Sven Jerring Foundation, the Swedish Research Society (grant #10863 and grant 522-2005-7238), and Research and Development of Region Västra Götaland (grant 2002–2004).
Competing interests None.
Patient consent Obtained.
Ethics approval This study was conducted with the approval of the Ethical Committee at the Medical Faculty, Sahlgrenska Academy at the University of Gothenburg, Sweden.
Provenance and peer review Not commissioned; externally peer reviewed.