Ocular manifestations in Proteus syndrome.

We report on the ocular manifestations of a Proteus syndrome patient. Several of the manifestations are due to severe maldevelopment and malfunction of the neuroretina including strabismus, nystagmus, high myopia, and retinal pigmentary abnormalities. In reviewing the literature, strabismus and epibulbar tumors were recorded most commonly. Some articles about presumed Proteus syndrome are spurious; these have not been included here. Also, because of anecdotal and nonsystematic study of the eye and because of the ascertainment bias inherent in literature reports, numbers of cases of each ocular manifestation have not been tabulated.

A novel PAX6 frameshift mutation in a kindred from Atlantic Canada with familial aniridia.

BACKGROUND: Many mutations in PAX6, a member of a family of genes essential for normal development, have been described. We carried out a study to identify the mutation in PAX6 responsible for aniridia, an autosomal dominant disorder, in a kindred from Atlantic Canada. METHODS: Polymerase chain reaction amplification of coding exons, single-strand conformation polymorphism analysis and DNA sequencing. RESULTS: A novel deletion of an adenosine residue at position 1030 (1030delA) was detected. INTERPRETATION: The mutation responsible for aniridia in this kindred is expected to cause a frameshift in the PAX6 coding sequence and truncation of the homeodomain, which is essential for the function of the pax6 protein.

Genotype/phenotype correlations in aniridia.

PURPOSE: To detect and characterize mutations in cases of familial and sporadic aniridia in Maritime Canada, and to look for indications of genotype/phenotype correlation within the cohort. METHODS: Twelve consecutive and unrelated patients (probands) who had total or nearly complete absence of irides, and four affected relatives, were recruited from Maritime Canada. Clinical data were obtained by chart review and electroretinogram testing. Mutations in the PAX6 gene were detected by single-strand conformation polymorphism and characterized by sequence analysis. RESULTS: Eleven different PAX6 mutations, 10 of which are novel, were found. The four patients with congenital cataracts all had mutations in the C-terminal proline-serine-threonine (PST)-rich domain of the PAX6 protein. Electroretinograms of nine of 11 patients displayed depressed scotopic maximum response b-wave amplitudes. The greatest decrease in b-wave amplitudes was seen in patients in whom the paired domain was disrupted by mutation. CONCLUSION: Some aspects of the phenotype of aniridia appear to correlate with the predicted effect of point mutations on the paired and PST domains of the PAX6 protein.

Effects of PAX6 mutations on retinal function: an electroretinographic study.

PURPOSE: To investigate the retinal function in aniridic patients with documented PAX6 mutations to determine the range of electroretinogram abnormalities in aniridic patients and to relate electroretinogram findings with specific PAX6 mutations. METHODS: Eleven patients with typical aniridia and fully characterized PAX6 mutations underwent electroretinography. RESULTS: In all 11 patients, electroretinogram recordings were abnormal, ranging from mild to severe. Rod-related and cone-related activities were equally affected. The amplitude of the oscillatory potentials was the most reduced, followed by the b-wave, then to a milder degree the a-wave. Mutations affecting the paired domain of the PAX6 protein had the biggest impact on the electroretinogram amplitudes. Implicit times were increased in a subgroup with mutations affecting only the homeodomain. CONCLUSION: Patients with aniridia have varying degree of retinal dysfunction, ranging from severely abnormal to almost normal. The paired domain appears to have more impact on retinal function than other regions of the PAX6 protein. It is unclear whether mutations affecting the homeodomain lead to alteration of the photoreceptor function.

Polymerase chain reaction-based risk assessment for Wilms tumor in sporadic aniridia.

PURPOSE: Sporadic cases of aniridia have a 30% risk for the development of Wilms tumor. Current guidelines for sporadic aniridia recommend screening by renal ultrasonography for the presence of tumors every 6 months until age 5 years. Deletions of chromosome 11p13 that affect both PAX6 (aniridia) and WT1 (Wilms tumor) loci are the basis for the association of these two uncommon disorders. We sought to develop a rapid polymerase chain reaction-based test that could rule out a chromosome 11p13 deletion covering the PAX6-WT1 region in sporadic aniridia. METHODS: Five patients with sporadic aniridia were recruited. Polymerase chain reaction-based genotyping was carried out for six highly informative marker loci across the PAX6-WT1 region to determine whether these patients had one or two haplotypes. The results were compared with those obtained from two cell lines with known deletions in the PAX6-WT1 region. RESULTS: All five patients were heterozygous at least at one of the four marker loci in the PAX6-WT1 region, indicating that there were no cases of gross chromosomal deletion. The cell lines showed hemizygosity in the four marker loci within the PAX6-WT1 region and in one of the two flanking marker loci. CONCLUSIONS: We have developed a rapid DNA test with an estimated sensitivity of 94.0% to 99.2%, using standard DNA diagnostic techniques and equipment, to rule out chromosomal deletion in sporadic aniridia. Patients in whom a chromosome 11p13 deletion has been ruled out do not require repeated renal imaging to screen for Wilms tumor.

The range and variability of ophthalmological parameters in normal children aged 4 1/2 to 5 1/2 years.

BACKGROUND: Some standards for childhood ophthalmological variables exist. However, for most parameters, the range of variation found in normal children remains poorly defined. METHODS: We have determined the range of normal function for a number of commonly measured ophthalmological variables in 162 children, classified normal by Gold Standard ophthalmological examination. This group is representative of almost 12,000 normal children aged 4 1/2 to 5 1/2 in Nova Scotia. RESULTS: In 56.8% of eyes the visual acuity was 6/4.5. The use of a chart with crowding bars was more discriminating between differences in higher levels of acuity and highlighted differences in acuity between the two eyes. Randot stereoacuity showed a uniform, non-Gaussian distribution of scores. Cycloplegic refractive errors were distributed about a modal value of between +0.5 and +1.0 diopter. Forty percent of eyes had no detectable astigmatism. Ninety-seven percent of subjects had no heterophoria. Fusional vergence data are presented. CONCLUSION: Our results document the complete normal range for selected ophthalmological parameters in normal preschoolers. The values obtained were in general better than expected.

Visual evoked potentials with crossed asymmetry in incomplete congenital stationary night blindness.

PURPOSE: To investigate a proposed postretinal defect in patients with the incomplete form of congenital stationary night blindness (CSNB2) and to compare visual evoked potential (VEP) results with those found in various forms of albinism. METHODS: Visual evoked potentials were performed in 10 patients with a diagnosis of CSNB2, 10 subjects with albinism, and 17 normal subjects. Visual evoked potentials were elicited monocularly with diffuse flash stimulation. Scalp electrodes were placed over each hemisphere and referred to the forehead. Interhemispheric bipolar recordings were derived, and the correlation coefficient (CC) was calculated for various segments of the interhemispheric responses. RESULTS: A crossed visual evoked potential asymmetry pattern could be demonstrated in 9 of 10 patients with CSNB2. All subjects with albinism and none of the normal subjects showed the crossed asymmetry pattern. Statistical comparison of the CC computed for various segments of the interhemispheric response shows that the pattern of inversion in CSNB2 is more prominent in the 25 to 100 msec range (median CC, -0.37) and in the 175 to 250 msec range (CC, -0.27). In subjects with albinism, all segments show a negative CC (range, -0.46 to -0.60). In normal subjects, all segments are positively correlated (range, 0.36 to 0.66). CONCLUSIONS: Crossed visual evoked potential asymmetry was found in patients with CSNB2; therefore, excessive decussation, as demonstrated by this testing procedure, should not be considered as pathognomonic for albinism.

The electroretinographic diagnosis of the incomplete form of congenital stationary night blindness.

Fifteen patients with the incomplete form of congenital stationary night blindness (iCSNB) were reviewed to better characterize their electroretinographic (ERG) findings in view of differential diagnosis with other retinal conditions also presenting with negative bright-flash ERG responses. In all 15 patients, in dark-adapted conditions, the bright-flash ERG response had a normal a-wave followed by a subnormal b-wave. Oscillatory potentials (OPs) observed on the ascending limb of the b-wave, although delayed in implicit time, were of large amplitude. The response to a long-wavelength stimulus showed cone-related components and some well-delineated OPs. On the other hand, the photopically elicited cone responses were strongly abnormal, with a subnormal a-wave followed by a barely recordable b-wave. No OPs could be elicited under photopic conditions. The cone related components and the OP characteristics clearly distinguish iCSNB from the complete form of CSNB and other retinal conditions presenting with minimal fundus abnormalities but with negative bright-flash ERG responses, such as found in Duchenne muscular dystrophy and Aland Island eye disease. The severely abnormal post-synaptic components in the photopic recordings contrast with the well-differentiated cone activity evoked in scotopic conditions. We propose a cone system that does not respond optimally under the normal operating range (photopic) but rather under mesopic or scotopic conditions. In spite of the severe cone-ERG deficits, visual acuity was only slightly reduced. We propose that the defect, which interferes marginally with the neuronal flow of information, lies in the structures responsible for the building of the b-wave.

Duchenne muscular dystrophy: negative scotopic bright-flash electroretinogram but not congenital stationary night blindness.

Patients with Duchenne muscular dystrophy (DMD) have recently been reported to have an abnormal scotopic electroretinogram (ERG) showing weak rod-related responses along with a negative configuration of the bright-flash response, which has been described as being similar to the one in congenital stationary night blindness (CSNB). We compared qualitatively and quantitatively the ERGs of 6 subjects with DMD, 10 subjects with the complete form of CSNB (cCSNB), 13 subjects with the incomplete form of CSNB (iCSNB) and 1 subject with complex glycerol kinase deficiency (CGKD). The rod-related activity and the bright-flash responses were abnormal and similar in all four groups. The cone-related activity, however, was within normal limits only in the DMD group; the b-wave was subnormal in CGKD, truncated in cCSNB and nearly absent in iCSNB. The electrophysiologic signature in DMD clearly distinguishes the retinal function of these patients from any other retinal condition so far described.

Duchenne muscular dystrophy: negative scotopic bright-flash electroretinogram and normal dark adaptation.

Recent reports indicate that most subjects with Duchenne muscular dystrophy (DMD) have a negative scotopic bright-flash electroretinogram (ERG). We performed dark adaptometry in seven patients with the DMD phenotype. Three patients had the negative bright-flash response combined with severely reduced rod-related activity; their mean psychophysical dark-adapted threshold was -5.5 +/- 0.3 (normally -5.4 +/- 0.3) cd.m-2. Two of the three patients were able to sit through the complete test: the profile of their dark adaptation curve was normal. The four other patients had a normal scotopic ERG, and their mean psychophysical dark-adapted threshold was -5.3 +/- 0.3 cd.m-2. One of the four was able to complete the entire procedure, and a normal profile was found. In patients with DMD the dark adaptation measurements are normal despite abnormalities in rod-related ERG activity.

Correlation between electroretinogram findings and molecular analysis in the Duchenne muscular dystrophy phenotype.

Fifteen consecutive patients with the Duchenne muscular dystrophy (DMD) phenotype were studied. Each patient was asked to undergo an ophthalmic examination, an electroretinogram (ERG), and to donate a blood sample for molecular diagnosis. All 15 patients had a normal ophthalmic examination. Electroretinography was successful in 14/15 patients. The ERG tracings were normal in seven patients, abnormal in seven, and unreliable in one. Blood for molecular analysis was obtained in 12/15 patients. In the seven patients with a normal ERG, five underwent molecular analysis, and in these five no deletion was detected in the dystrophin gene. In the seven patients with an abnormal ERG, six had molecular analysis available, and all six were found to have a deletion. These results suggest that patients with a classic DMD phenotype are genetically heterogeneous, and that this heterogeneity is reflected in the ERG.

Ocular findings in Cockayne syndrome.

The ocular findings in eight patients with Cockayne syndrome included enophthalmos, hyperopia, poor pupillary dilation, and retinal dystrophy in all patients. Four patients had strabismus. Two patients had cataracts. Three patients had nystagmus. Visual acuity was relatively well preserved in six patients, including a 25-year-old man with a visual acuity of 20/60 in each eye despite advanced retinal pigmentary changes. Failure of DNA and RNA synthesis to recover after ultraviolet light exposure as well as selective loss of repair of transcriptionally active DNA may account for the ocular abnormality in this progeric syndrome.

Negative predictive value of a population-based preschool vision screening program.

BACKGROUND: The Enhanced Vision Screening Program is a population-based vision screening program that has, at present, examined 59,782 children. Its main goal is to detect amblyopia, strabismus, and high refractive errors. An average of 11,910 4 1/2- to 5 1/2-year-old children are screened yearly. The current study determines the negative predictive value of the screening program: For a subject having passed the vision screening test, what is the probability of not having amblyopia, strabismus, or high refractive errors? METHODS: Of the 11,734 subjects who passed the vision screening, 200 were randomly chosen to undergo a strictly defined gold standard examination by an orthoptist and an ophthalmologist. RESULTS: Of the 200 randomly chosen subjects, 157 underwent the gold standard evaluation. The negative predictive value of the Enhanced Vision Screening Program was 97.6% for any potentially vision-threatening ocular condition. It was 98.7% if we considered only the visually significant ocular problems that the test was designed to detect. CONCLUSION: Because the negative predictive value of the Enhanced Vision Screening Program is not 100%, some children with amblyopia, strabismus, or refractive errors are missed. Occasionally, a rare, potentially vision-threatening condition may go undetected. Parents should be made aware of this when they receive the results of the vision screening.