|Year : 2016 | Volume
| Issue : 1 | Page : 29-34
Visual acuity, fundus changes, and electroretinographic findings in Egyptian children with Bardet-Biedl syndrome
Dina El-Fayoumi1, Rasha Helmy2, Marwa Nabhan2, Nevien Soliman2
1 Department of Ophthalmology, Faculty of Medicine, Cairo University, Cairo, Egypt
2 Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo, Egypt
|Date of Submission||30-Sep-2015|
|Date of Acceptance||01-Dec-2015|
|Date of Web Publication||16-Mar-2016|
10 El-Fawakeh Street, Mohandeseen, Giza 12311
Source of Support: None, Conflict of Interest: None
The aim of the present study was to assess visual acuity, measure the degree of visual impairment, and examine fundus changes in Egyptian children with Bardet-Biedl syndrome (BBS), and to correlate these findings with the results of flash electroretinography (ERG).
Materials and methods
A cross-sectional study was conducted on infants and children with BBS. Diagnosis was carried out by a specialized pediatrician. Full ophthalmological examination, including slit-lamp examination, refraction, and indirect ophthalmoscopy, was carried out. Best-corrected visual acuity was measured and full-field flash ERG was performed.
This study included 20 patients with BBS. The median age was 9 years (ranged from 1 day to 18 years). The mean age of onset of symptoms in the whole group was 6.5 ± 4.3 years. Visual impairment, defined as a best-corrected visual acuity in the better seeing eye of 20/60 (6/18) or less, was present in 11 patients (55% of the cases), and night blindness as a symptom was present in nine patients (45%); pigmentary retinopathy was clinically detected in 35% of the patients and retinal dystrophy as an ERG finding was detected in 60% of the patients.
Visual impairment in BBS is mainly caused by rod-cone dystrophy, which is one of the major criterion of diagnosis, which manifests with age. Before the age of 6, children rarely present with ocular manifestations, and usually have normal fundus examination; on the other hand, retinitis pigmentosa-like picture is usually seen in children older than 6. However, the electrophysiological changes may precede the fundus changes.
Keywords: Bardet-Biedl, children, electroretinography, retinal dystrophy, visual impairment
|How to cite this article:|
El-Fayoumi D, Helmy R, Nabhan M, Soliman N. Visual acuity, fundus changes, and electroretinographic findings in Egyptian children with Bardet-Biedl syndrome. Delta J Ophthalmol 2016;17:29-34
|How to cite this URL:|
El-Fayoumi D, Helmy R, Nabhan M, Soliman N. Visual acuity, fundus changes, and electroretinographic findings in Egyptian children with Bardet-Biedl syndrome. Delta J Ophthalmol [serial online] 2016 [cited 2018 Oct 15];17:29-34. Available from: http://www.djo.eg.net/text.asp?2016/17/1/29/178769
The study was conducted in the Cairo University Center of Pediatric Nephrology and Transplantation.
| Introduction|| |
Bardet-Biedl syndrome (BBS) is a significant genetic cause of chronic and end-stage renal failure in children. Despite being a relatively rare recessive disorder, BBS has come to prominence during the past few years because of the understanding of the underlying pathogenesis of primary cilia dysfunction . Its incidence is estimated to be one in 100 000 individuals in European populations but is higher in consanguineous populations (e.g. North Africa and in Middle East) or geographically isolated areas .
Rod-cone dystrophy in the form of retinitis pigmentosa (RP)-like fundus picture represents one of the six primary clinical features of BBS. Occurring in over 90% of patients with BBS, RP often begins in childhood and frequently in the context of the other BBS features such as postaxial polydactyly and renal disease. Although a spectrum of RP can occur, bone spicule formation with atrophic changes may be the only predominating feature. Early in the disease, maculopathy with or without peripheral retinal degeneration can be observed and can range from a diffuse maculopathy to a bull's eye pattern. Vascular attenuation often accompanies macular changes. By the second to third decade of life, legal blindness affects about 75% of the affected individuals. Moderate to severe visual field loss may occur and has been reported to occur at an annual loss rate of up to 3° per year during adolescence. Often accompanying electroretinographic (ERG) findings are severely reduced or extinguished responses with the pattern being described as rod-cone in some and cone-rod in others. Other ocular findings described in BBS include strabismus, cataracts, astigmatism, and iris and chorioretinal coloboma . The aim of the present study was to carry out a full visual assessment in children with BBS and to determine the degree of visual impairment in these children and its relation to their fundus changes, ERG findings, and to their intelligence quotient (IQ).
| Materials and methods|| |
The study protocol was approved by the Cairo University Hospital Research Committee. The study and data collection conformed to all local laws and were compliant with the principles of the Declaration of Helsinki. In total, 20 Egyptian children, diagnosed phenotypically with BBS, were chosen from the Cairo University Center of Pediatric Nephrology and Transplantation (CPNT) during the period from December 2012 to December 2013 (12 months). These children presented to CPNT as having kidney problems, where they were clinically assessed and diagnosed phenotypically as having BBS. The clinical diagnosis of BBS was based on the presence of at least four primary features or three primary and two secondary features. According to a study by Beales and colleagues, these primary criteria included learning difficulties, RP, postaxial polydactyly, obesity, male hypogonadism, and renal anomalies. Secondary features included speech delay, strabismus, cataracts, brachydactyly, nephrogenic diabetes insipidus, ataxia/poor coordination, congenital heart disease, left ventricular hypertrophy, situs inversus, anosmia, and hepatic fibrosis .
These children underwent full ophthalmological examination by a single experienced pediatric ophthalmologist (D.E.). Using the slit-lamp examination, dilated indirect ophthalmoscopy and refraction were carried out. Best-corrected visual acuity (BCVA) was measured in each eye using a retro-illuminated Early Treatment Diabetic Retinopathy Study Chart (ETDRS) built with tumble 'E' optotypes presented at a distance of 4 m. Pattern of fixation described as central, steady, and maintained fixation was used for children younger than 4 years. Ocular motility was assessed using cover/uncover and alternate cover testing for distance and near vision testing, with and without glasses, with emphasis on the diagnosis of strabismus and nystagmus.
Full-field flash ERG was carried out in the Neurophysiology Department in Kasr Al-Ainy Hospital, Cairo University. A minimum pupil diameter of 6 mm was obtained after administering a drop of tropicamide 1% with a drop of phenylephrine 10%. Flash ERG examination was carried out using surface electrodes under photopic conditions, flicker stimulation, and after 20 min of dark adaptation.
Data were tabulated and subjected to computer-assisted analysis using Microsoft Excel version 6.0 and the Statistical Package for Social Science (SPSS) version 15.0 (Chicago, Illinois). Frequency and percentage distributions, mean, SD, and range of numerical data were used to describe variables. comparison and determining differences between means using the Student t-test; determining differences between means for statistical significance. Correlations between numerical data, correlation coefficients (r-values) obtained were tested for significance using the t-test and were compared using the χ2 -test. Non-numerical data were compared using the χ2 -test. Charts were prepared using Microsoft Excel.
| Results|| |
The current study included 20 patients diagnosed phenotypically with BBS. They belonged to 16 unrelated families. The study comprised 10 males (50%) and 10 females (50%). Fifteen patients (75%) had consanguineous parents. The ages ranged from 1 day to 18 years, with a mean of 109.3 ± 66.8 months. The mean weight was 34.8 ± 23 kg, the mean BMI was 25 ± 9 kg/m 2 , and the mean height was 110 ± 25 cm. Patients 1 and 2 were brothers, patients 13 and 14 were sisters, and patients 10 and 11, and 12 and 16 were brothers and sisters.
Dysmorphic features [Figure 1] were found in 14 patients (70%) and hypogonadism was found in five male patients (25%). Polyuria and polydypsia were documented in 13 patients (65%). Hypertension was present in three patients (15%). Eleven patients (55%) presented with end-stage kidney disease at the time of initial diagnosis. Polydactyly was present in 10 patients (50%), whereas polysyndactyly in seven patients (35%). Four cases had a history of sibling's death (20%). The cause of death was unknown in two of them (10%); one died of renal cyst (5%) and the other of repiratory distress and polydactyly (5%). A history of similar conditions was present in 11 patients (55%).
|Figure 1: Clinical presentations and diagnostic criteria of Bardet– Biedl syndrome (BBS); (a) morbid obesity in case no. 5, (b) brachycephaly and depressed nasal bridge in patient no. 2, (c) polysyndactyly in the right hand of case no. 2, (d) polysyndactyly in both feet in case no. 17, (e) short broad hand in case no. 15.|
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Regarding the pattern of clinical presentation, the mean age of onset of symptoms for the whole group was 6.5 ± 4.3 years. As for the ophthalmological manifestations, visual impairment in the form of BCVA in the better seeing eye of 20/60 (6/18) or worse was documented in 11 patients (55%), whereas night blindness as a complaint of the child or their parents was present in nine patients (45%). Slit-lamp examination revealed six children (30%) with deep anterior chamber, whereas one (5%) had an additional bilateral posterior polar cataract. Dilated fundus examination of those children revealed RP-like picture with periperal pigmentation in seven patients (35%), attenuated vesseles in 14 patients (70%), hypopigmented fundus in two patients (10%), tigroid fundus in two patients (10%), myopic fundus in four patients (20%), pale optic disc in seven patients (35%), maculopathy in two patients (10%) [Figure 2], and chorioretinal coloboma in one eye of one patient (5%). Completely normal fundus was found in five cases (25%). The total number was greater than the number of the cases, as every case might have had more than one fundus finding. We reported one case of bilateral severe clinical microphthalmos, which was diagnosed clinically at birth but could not be investigated as the infant died shortly after birth from severe renal malformation [Figure 3].
|Figure 2: (a) Colored fundus image of peripheral hyperpigmentation 'retinitis pigmentosa (RP) like' fundus in patient no. 16. (b) Pale optic disc, attenuated vesseles, and retinitis pigmentosa of case no. 16. (c, d) Colored fundus image of bilateral hyperemic swollen optic discs of case no. 4. (e) Pale optic disc, attenuated vesseles, maculopathy, and hypopigmented fundus of case no. 10. (f) Pale optic disc, attenated vesseles, maculopathy, and tigroid fundus in case no. 14.|
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|Figure 3: (a, b) Neonate showing flat ocular contour in severe microphthalmos; (c, d) polydactyly in the hands and in the feet.|
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The BCVA in the better seeing eye varied from counting fingers at 50 cm (logMAR 2.1) in one patient (5%) to 2/60 (logMAR 1.52) in one patient (5%), 3/60 (logMAR 1.3) in two patients (10%), 4/60 (logMAR 1.22) in one patient (5%), 6/60 (logMAR 1.0) in six patients (30%), and 6/12 (logMAR 0.3) in four patients (20%). One patient (5%) who was 1 month old at the time of examination had bilateral central maintained steady fixation. Visual acuity was very difficult to assess in three patients (15%) because of their young age and extremely low IQ. One child (5%) was born with bilateral severe microphthalmos.
The cycloplegic refraction of these children ranged from a spherical equivelent refraction of −14.0 to +5.0 D, with a mean of −3.9 ± 5.6 D. ERG findings were abnormal in 12 patients (60%) and varied from bilateral defects in both rods and cones in nine patients (45%) to bilteral defects in rods only in two patients (10%), and one patient (5%) had absent flash ERG. Normal ERG findings were found in five patients (25%). Two patients missed the follow-up, and thus ERG was not carried out for them; there was one infant with clinical microphthalmia. The relationship between the age of these patients and the ERG findings is shown in [Table 1].
|Table 1: The relationship between the age of the children and electroretinographic findings|
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Because the mean age of appearance of symptoms was 6.5 years, the study group was divided into two subgroups: those who started to symptomatize before the age of 6 and those after the age of 6. No statistically significant difference was found between the two groups regarding different forms of clinical presentations, and no visual symptoms were noted before the age of 6. Uremia was a common finding in the present study group as 15 children presented with uremia, six of them below the age of 6 and nine children older than 6 years.
When we divided the study group according to the current age at the time of the study and compared both groups regarding various clinical manifestations and the presence of RP and ERG findings, there was a statistically significant difference between the two groups regarding night blindness only, as none of the patients reported night blindness as a symptom before the age of 6.Those nine paients who reported nightblindness were older than 6 years (P = 0.014). Three children had diminution of vision and were below 6 years of age and the other eight children who had visual impairment were older than 6 years, but there was no statistically significant difference between the two groups (P = 0.061).
When we described the fundus changes in terms of the age of the patients, none of the childern who were less than 6 years showed any pigmentary changes, whereas the seven patients who showed pigmentary changes were older than 6 years. There was no satistically significant difference between the two groups regarding pigmentary retinopathy (P = 0.051).
On dividing the study group according to the presence or absence of RP and comparing both groups regarding ERG findings, there was no statistically significant difference between the two groups [Table 2].
|Table 2: Comparison between both groups regarding electroretinographic findings|
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The nonocular manifestations that were detected in the present study included.
The nonocular manifestations detected in the present study included the following: IQ of the study group varied from 55 to 85% with a mean of 72.6 ± 8.5%, with five patients (25%) with extremely low IQ (below 69%), eight patients (40%) with borderline IQ (70-79%), and five patients (25%) with low average IQ (80-89%); renal involvement in the form of juvenile nephronophthisis was present in eight patients (40%), renal dysplasia in seven patients (35%), and renal dysplasia with cysts in four patients (20%). Duplex kidney was found in one patient (5%).
| Discussion|| |
BBS is a significant genetic cause of chronic and end-stage renal failure in children. Despite being a relatively rare recessive condition, BBS has come to prominence during the past few years owing to revelations of primary cilia dysfunction underlying pathogenesis .
Renal and retinal involvement in BBS are the two major manifestations with major clinical and prognostic implications influencing both survival as well as quality of life of BBS patients. The diagnosis of BBS is often made in late childhood when patients present with recently diagnosed renal failure occurring in the context of visual impairment and a history of hyperphagia and obesity .
In the current work, we focused on studying the spectrum of renal and ocular manifestations in patients with BBS for better clinical phenotyping of the disease in children and because those are the two major manifestations affecting the life quality and survival of patients. Children with renal and/or retinal involvement will eventually reach end-stage renal disease and/or severe visual impairment.
The present study included 20 Egyptian children with BBS belonging to 16 families, 75% of them products of consanguineous marriages. This high percentage can be explained by the high prevalence of consanguineous marriages in Egypt, which is close to 35.3%, especially among first cousins (86%) according to a study by Shawky et al. . When comparing this with the study conducted by Beales et al. (1999) , in which only 8% of the studied patients were found to have consanguineous parents, it seemed that the difference in the incidence of consanguineous marriages between different populations was the cause of this discrepancy .
The cases comprised 10 males (50%) and 10 females (50%), in contrast to the study done by Berezovsky et al. , in which male predominance was found, with a male-to-female ratio of 15 : 8. These results are also inconsistent with previously reported findings in both adults and pediatric BBS patients ,. However, other studies have reported a slight female predominance . These discrepancies could be explained by the low incidence of this recessive condition, with studies on a limited number of participants.
In the present study, 55% of the cases (11 patients) were defined as having low vision with BCVA in the better seeing eye of 20/60 (6/18) or worse, and 45% suffered night blindness, whereas a study by Berezovsky et al.  reported night blindness in 95.6% and visual impairment in 82.6% of the 23 patients with the BBS phenotype, with ages ranging from 6 to 36 years.
Other reports , have shown decreased vision in the first decade of life, as was found in the present sample. Good BCVA in the better-seeing eye (20/40) was found in only four patients (20%) in the current study. These results are similar to the results reported in a group of 10 BBS patients, with four patients showing good visual acuity . Visual impairment - defined as a visual acuity of 6/18 or worse in the better seeing eye - was reported for 11 patients in the present study; all of them were considered legally blind, having a visual acuity of 20/200 or worse in their better seing eye. In the study by Berezovsky et al.  legal blindness was present in two (8.7%) patients only. Follow-up and longitudinal data from these patients should be collected to detect the visual acuity loss rate (in lines/year).
In the present study, high ametropias were found in 25% of the participants, with all of these cases demonstrating high myopia (SE³-6.0 D), which is slightly similar to that found in a study by Berezovsky et al. , as they reported high ametropias in 26% of the participants, but it varied between 17.3% with high myopia and 8.6% with hyperopia (SE³6.0 D).
Regarding fundus examination, attenuated vessels were found in 70% of the studied cases, pale optic disc in 35%, and pigmentary changes in 35% of our cases. In a study by Berezovsky et al. , attenuated vessels were seen in 67% of the cases, disc pallor in 42.8%, and pigmentary changes in 23.8%.
ERG examination showed retinal dystrophy in 60% of the studied cases, which varied from defects in both rods and cones in 45%, defects in rods only in 10%, and abscent flash ERG in 5% of the studied cases, whereas in a study by Berezovsky et al.  retinal dystrophy was found in all patients; all of them showed defects in both rods and cones. This variation may be attributed to different age group used in that study, as in the present study only pediatric age group was included while retinal dystrophy becomes evident with age. In addition, all patients included in the study by Berezovsky et al.  were referred to the Electrophysiology of Vision Laboratory at the Department of Ophthalmology.
Obesity is one of the major criteria of BBS and was found in 45% of the patients in the present study (above 95th centile), whereas 20% were found to be overweight (85th-95th centile). According to a study by Putoux et al. , birth weight is usually within the normal range, although there is an evidence of skewed distributions toward the upper centiles. One-third of those with a normal birth weight develop obesity by the age of 1 year . Whereas in a study by Beales et al. , 72% were overweight and 52% were obese. This is higher than that found in the present study because of the different age group of their studied patients whose ages ranged from 2 to 60 years.
Dysmorphic features were found in 70% of the participants. This was in contrast to a study conducted by Moore et al. , in which dysmorphic features were found in 56% of the patients. The most frequent dysmorphic feature in the present study was depressed nasal bridge (57%). Other less frequent features included brachycephaly, hypertolerism, low set ears, and short broad hands. The most frequent feature in the study by Moore et al.  was brachycephaly. Their study included 46 patients from 26 families, with an age range of 1.5-67.9 years and a median of 44 years . Polydactyly and polysyndactyly were found in 85% of our cases as compared with 69% of the cases in a study by Beales et al.  and 63% in a study by Moore et al. .
As regards other clinical manifestations, hypertension was documented in only 15% of our study patients, which was lower than that reported in a study by Moore et al. (2005) , as 67% of their studied patients were hypertensive. On the other hand, Ucar et al. (1997)  did not report hypertension in their studied patients.
The renal phenotype for the patients in the current study included a broad spectrum of renal dysplasia (± a cyst) or nephronophthesis. Renal cysts were detected in almost 50% of the patients. In a study by Moore et al. , renal cysts were present in 50% of the studied cases.
Notably, the current study reported the pattern of clinical presentation of BBS to our center with special emphasis on both the renal and retinal involvement. Accordingly, one of the limitations of this study was that it did not describe the clinical presentation of BBS in the general population, but rather focused on BBS patients with renal involvement as a cardinal feature presenting to the major national pediatric nephrology referral center.
| Conclusion|| |
BBS in children usually starts to symptomatize around the age of 6; visual symptoms, visual impairment, and fundus changes are rare before the age of 6. Most developing countries lack the access to modern molecular diagnostic techniques, and therefore there is a need for a detailed phenotypic description to reach a precise clinical diagnosis . Therefore, the present study tried to reach a better phenotypical diagnosis. It is recommend that these molecular diagnostic techniques should be available and feasible to all patients with genetic ocular diseases in developing countries.
D.E. was involved in the conception and design, analysis and interpretation, writing of the article, critical revision of the article, data collection, and provision of patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]