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12-year-old girl experiences progressive vision loss and nyctalopia
The retina had a ‘moth-eaten’ appearance with scattered peripheral bone spicule pigmentation and foveal granularity.
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A 12-year-old girl was referred to the New England Eye Center by an outside ophthalmologist for evaluation of decreased vision in both eyes.
She was first noticed to have decreased vision at age 4 years, when her teachers noted she was unable to see the blackboard at school. Starting 1 year before presentation, she reported worsening nyctalopia. She was seen by an ophthalmologist who initially recommended refractive correction. Of note, 6 months before presentation she immigrated to the United States from Brazil. She continued to experience worsening vision at that time and was re-evaluated. She was noted to have retinal changes bilaterally and referred for further work-up.
Examination
The patient’s best corrected visual acuity was 20/50 in the right eye and 20/60 in the left eye. She had no afferent pupillary defect or anisocoria. She identified 1 out of 16 Ishihara color plates with the right eye and 0 out of 16 with the left eye. Extraocular motility and IOPs were normal. Her anterior segment exam was unremarkable. Fundus examination revealed the retina had a “moth-eaten” appearance with scattered peripheral bone spicule pigmentation and foveal granularity (Figure 1).
Review of systems was negative for any prolonged illnesses or history of trauma. The patient’s grandmother had poor vision of unknown etiology. On physical examination, she was noted to have six toes on each foot.
Figure 1. Color fundus photographs showing foveal granularity in the right eye (a) and left eye (b). There was a "moth-eaten" appearance and bone spicule changes in the periphery in the right eye (c) and left eye (d). Enhanced depth imaging OCT showing attenuation of the inner segment/outer segment junction in the right eye (e) and left eye (f).
Images: Klein K, Reichel E
Figure 2. Full-field ERG in both eyes showing diminished scotopic a- and b-wave amplitudes, diminished bright-flash rod-cone response and a preserved photopic flicker waveform.
Enhanced depth imaging optical coherence tomography demonstrated an attenuated ellipsoid zone in the fovea of both eyes (Figure 1). The optic nerves were normal. Full-field ERG (ffERG) testing showed severely decreased amplitudes of the scotopic and bright-flash rod-cone response in both eyes. There was relative preservation of the photopic flicker and S-cone response amplitudes (Figure 2).
What is your diagnosis?
Progressive vision loss, nyctalopia
Bardet-Biedl syndrome, or BBS, first described in 1920, is an autosomal recessive multisystem disease that is characterized by rod-cone dystrophy, polydactyly, obesity, mental retardation, hypogonadism and renal abnormalities. BBS is similar to Laurence-Moon syndrome except that BBS is associated with polydactyly and lacks spastic paraparesis and muscle weakness. The highest prevalence of BBS is in the Middle East, with a rate of one in 13,500, but the rate is only one in 100,000 in North America.
Discussion
BBS is clinically and genetically heterogeneous, and at least 15 genetic loci (BBS1 to BBS15) have been mapped in this disease. The most common allele of the most common form of BBS is the BBS1 genotype.
Retinal degeneration has been reported to have more than 90% penetrance and is a common manifestation of BBS. Retinal degeneration typically begins in early childhood, with progressive decline in vision into adolescence. In one study of 109 patients with BBS, the mean age at which parents first noted night blindness in their children was 8.5 years and the mean age at which patients were registered blind was 15.5 years. In comparison to typical retinitis pigmentosa, BBS has an earlier onset and more rapid progression. Funduscopic findings include a bull’s-eye macula, bone spicules in the mid-peripheral retina, vessel narrowing and pigment clumping. Additional ocular findings include posterior subcapsular cataract, astigmatism, strabismus, color blindness, macular edema and optic atrophy. Children may present with myopia or strabismus before retinal changes become evident. Typical ffERG findings are similar to this case with diminished amplitudes in the scotopic and bright-flash rod-cone waveforms, consistent with rod-cone dystrophy. The photopic flicker may be unaffected or minimally diminished.
Daniels et al analyzed the fundus and ffERG findings in 37 patients from 31 families with BBS mutations and found that patients with mutations in the BBS1 gene had a milder ocular phenotype than those with other BBS mutations, with better visual acuities and less diminished ffERG amplitudes.
Presenting symptoms can vary, even within families with the same mutation, ranging from asymptomatic to severe visual acuity loss or visual field deficits, independent of age. Likewise, ERG findings vary from reduced to undetectable. Three of four patients with ERG abnormalities in a study of 10 patients with the BBS1 mutation showed a “negative” ERG waveform with greater reduction in b-wave amplitude than a-wave amplitude, indicating greater inner retinal dysfunction than outer retinal dysfunction. Azari et al hypothesized that the negative ERG waveform represented a stage in the evolution of the disease, rather than a primary disease feature. OCT imaging can also vary and be nonspecific, although it may show thinning and attenuation of the ellipsoid zone.
Mutations in BBS2, BBS3 and BBS4 are common in the Bedouin population in Israel and have been found to be associated with more severe and earlier-onset pigmentary retinopathy. High myopia has been associated with BBS4 patients. A severe ocular phenotype has been described for the BBS6 mutation, most prevalent in Newfoundland, Canada. Likewise, patients with BBS8 and BBS9 mutations have been found to have severe vision loss with severely reduced ERG recordings.
The pathogenesis of retinal dystrophy in BBS is not known, but the BBS gene products have been found to be associated with cell trafficking proteins in the basal body of cilia. Photoreceptors, being modified ciliated cells, are also implicated, and histopathological studies suggest a primary degeneration of photoreceptors with a secondary involvement of other retinal layers, the retinal pigment epithelium and retinal vasculature. Unlike the other BBS gene products that form the structure of the complex localized to the cilium body, the BBS1 gene product is believed to be an adapter protein for the complex, which may be why BBS1 mutations lead to milder manifestations of the syndrome. It is also possible that the milder phenotype in BBS1 is related to the type of mutation typically found in this gene, namely a missense mutation, resulting in a dysfunctional protein, rather than a nonsense, deletion or frameshift mutation more commonly found in other BBS mutations, resulting in truncated or completely absent gene products.
Renal failure is the main cause of morbidity and mortality in BBS patients, caused by chronic glomerulonephritis, cystic tubular disease and lower urinary tract malformations. In one study, by Hjortshøj et al, parents of patients with BBS were found to have a 17-fold increased risk of developing renal cell carcinoma in comparison to the general population. Because of these associations, renal ultrasound should be performed in all suspected cases of BBS.
Conclusion
This 12-year-old girl was diagnosed with BBS and will be observed with yearly examinations. She is scheduled for further work-up with a geneticist and a renal ultrasound.
References:
Azari AA, et al. Invest Ophthalmol Vis Sci. 2006;doi:10.1167/iovs.06-0517.Beales PL, et al. J Med Genet. 1997;doi:10.1136/jmg.34.2.92.
Beales PL, et al. J Med Genet. 1999;doi:10.1136/jmg.36.6.437.
Bek T, et al. Br J Ophthalmol. 1995;doi:10.1136/bjo.79.1.76.
Daniels AB, et al. Arch Ophthalmol. 2012;doi:10.1001/archophthalmol.2012.89.
Héon E, et al. Am J Med Genet A. 2005;doi:10.1002/ajmg.a.30466.
Hjortshøj TD, et al. Am J Med Genet A. 2007;doi:10.1002/ajmg.a.31805.
For more information:
Kendra Klein, MD, and Elias Reichel, MD, can be reached at New England Eye Center, Tufts University School of Medicine, 750 Washington St., Box 450, Boston, MA 02111; 617-636-4219; website: www.neec.com.Edited by Gregory D. Lee, MD, and Nora W. Muakkassa, MD. They can be reached at New England Eye Center, Tufts University School of Medicine, 750 Washington St., Box 450, Boston, MA 02111; 617-636-4219; website: www.neec.com.