History of present illness
A 12-year-old White female child presented around age 7 years with blurred vision, which could not be corrected with glasses, and mild visual distortion (metamorphopsia) of more recent onset. The remainder of the past and present medical history was unremarkable. She denied floaters, photopsias, photophobia, or nyctalopia.
Ocular examination findings
Visual acuity with correction was 20/25 in the right eye and 20/30 in the left eye. Intraocular pressure was normal. External and anterior segment examinations were unremarkable. Dilated fundus examination showed coin-shaped, egg yolk–like, yellowish elevated lesions in the center of the macula in both eyes ( Fig. 1.1 ). The remainder of the fundus examination was normal, without evidence of any satellite lesions, flecks, atrophy, retinal pigment epithelium (RPE) mottling, or other fundus changes.
Imaging
Spectral domain optical coherence tomography (SD-OCT) showed dome-shaped hyperreflective lesions under the fovea of each eye ( Fig. 1.2 ), with moderate fragmentation of the ellipsoid zone (EZ) but overall intact external limiting membrane (ELM). No intraretinal or subretinal fluid was seen. Fundus autofluorescence (FAF) imaging showed discrete round hyperautofluorescent lesions in both eyes at the foveal level ( Fig. 1.3 ). In the right eye, the lesion showed partial fragmentation superiorly of the hyperautofluorescence. In the left eye, the hyperautofluorescent lesion was more compact and discrete but exhibited a focal hypofluorescent foveal spot (target-like appearance).
Questions to ask
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Does the patient have a family history of ocular conditions or consanguinity? This patient’s 43-year-old mother reported a positive history of possible Best disease on her side of the family, with multiple reportedly affected individuals of both sexes and across three generations, but the mother also reported having a previously normal eye examination herself and reported having been told she was unaffected with the condition.
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Yes
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Has the patient been diagnosed with any cancer to this date, particularly with a melanoma or a teratoma? Although at this young age the possibility of a paraneoplastic acquired vitelliform maculopathy is very low, it cannot be 100% excluded. In young female patients a paraneoplastic retinopathy has been reported in conjunction with teratomas expressing, in those cases, retinal tissues that triggered the autoimmune reaction against the retina. Thus if this patient had a history of cancer or a teratoma, it would be important to exclude that the patient’s cancer tissue did not exhibit RPE tissue within it (or other RPE-like antigens, particularly bestrophin) and that she did not exhibit antibestrophin autoantibodies, which are present in patients with vitelliform paraneoplastic phenotypes and are usually associated with the same functional findings (see later) as in genetically determined vitelliform phenotypes.
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No
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Assessment
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This is a 12-year-old girl with no past ocular, medical, or surgical history to indicate or suggest an underlying teratoma or a malignancy, with a family history positive for possible Best disease on the maternal side but with a reportedly normal and unaffected mother. The patient demonstrates bilateral dome-shaped subfoveal macular vitelliform lesions on both SD-OCT and FAF.
Differential diagnosis
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Autosomal dominant Best disease
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Autosomal recessive bestrophinopathy (ARB)
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Autosomal dominant macular pattern dystrophy (MPD) expressing a vitelliform phenotype
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Paraneoplastic acquired vitelliform maculopathy
Working diagnosis
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Best disease
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This condition is typically inherited in autosomal dominant fashion, and variable disease expression among family members with Best disease has been reported, although autosomal recessive variants (ARBs) of the disease are possible and can present with early-onset vitelliform lesions like the ones seen in our index case. Because the mother was reportedly unaffected, presently an autosomal recessive inheritance pattern cannot be excluded. Also, because MPDs can present with a macular vitelliform phenotype, especially the ones linked to the PRPH2 (peripherin/RDS) gene, , and family members presenting with a mild MPD phenotype can be asymptomatic well into their 60s, , presently it cannot be excluded that the mother of the index case may appear unaffected because she has not expressed the phenotype yet. The differential can be addressed clinically by functional testing with an electrooculogram (EOG), which would be expected to be pathological (Arden ratio <1.5) in either Best disease or patients with ARB but not in patients with MPD or in the parents of a patient with ARB.
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Multimodal testing and results
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Fundus photos
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As mentioned earlier, dilated fundus examination showed coin-shaped, egg yolk–like, yellowish elevated lesions in the center of the macula in both eyes ( Fig. 1.1 ).
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This presentation is equally common in bona fide dominant Best disease, ARBs, and MPDs expressing a vitelliform phenotype. , In the latter, neovascular exudative complications responsive to anti–vascular endothelial growth factor (VEGF) injections are common, but they can be seen also in patients with early-onset ARB. Patients with dominant Best disease are not immune from this possible complication, but these frank exudative complications are far less common.
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SD-OCT
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As illustrated earlier, dome-shaped hyperreflective lesions were seen under the fovea of each eye ( Fig. 1.2 ), with moderate EZ fragmentation but an overall intact ELM, and no intra- or subretinal fluid.
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This imaging modality is critical in establishing the clinical impression of the elevated subfoveal lesions, showing whether fluid is present, and ascertaining the state of the EZ and the ELM, but it does not permit a differential diagnosis.
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EOG
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An EOG was obtained on the index case, but the patient was unreliable during the test, which requires tracking a moving light target correctly and repeatedly to measure the ocular standing potential (i.e., the steady flow of electricity being released by the eyes) and comparing reliably the lowest such potential in the dark (the “dark trough” [DT]) and the highest such potential once lights are turned on (the “light peak” [LP]). The mathematical rapport between the two values (LP/DT) is known as the Arden ratio .
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The unreliability of the EOG test in the index case yielded an Arden ratio greater than 3.0, which per se would have ruled out the diagnosis of either Best disease or an ARB but was potentially misleading. Thus to overcome the uncertainly in this case, we extended the investigation to the asymptomatic 43-year-old mother, who had visual acuity of 20/20 in both eyes and exhibited a minimal SD-OCT phenotype ( Fig. 1.4 ) insufficient to support outright the diagnosis of dominant Best disease, as it would have been suggested by the positive history on her side of the family. However, she was able to perform an EOG correctly, and her Arden ratio was less than 1.0 ( Fig. 1.5 ), which is diagnostic for a generalized RPE compromise and the diagnosis of either Best disease or an ARB. Because the positive family history of Best disease was present on her side, this outcome supported the working diagnosis of Best disease and an autosomal dominant inheritance pattern as the top diagnosis on the differential.
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