Abstract
Purpose
To describe the finding of circularly grouped hypomelanotic spots in the central macula of a patient with syndromic characteristics.
Methods
Case report of a patient with albinotic spots grouped within the macula, café au lait spots, and left-sided hemihypertrophy.
Results
A 15-year-old boy presented with hypomelanotic spots which were hyperautofluorescent on fundus autofluorescence imaging with no disruption of the retinal laminae or photoreceptor inner and outer segment (IS/OS) junction on spectral domain optical coherence tomography. His developmental history included hemihypertrophy, café au lait spots over his axilla and extremities, and surgically corrected left-sided cryptorchidism. Other ocular history included resolved convergence insufficiency and red–green color blindness.
Conclusions
It is essential to recognize that circularly grouped hypomelanotic spots are a benign condition. The location and arrangement of the hypomelanotic spots were atypical for congenital grouped albinotic spots of the retinal pigment epithelium (CGAS) as they were grouped within the macula in addition to a more characteristic linear “bear track” formation in the periphery. To the authors’ knowledge, this is the first report of CGAS present in a patient with hemihypertrophy, café au lait spots, and cryptorchidism and may represent a novel syndromic association.
Keywords: Gass albinotic spots, Hemihypertrophy, Café au lait
Introduction
Congenital grouped albinotic spots of the retinal pigment epithelium (CGAS) or “polar bear tracks” are characterized by flat, distinct, placoid lesions arranged in linear tracks on the retina. Lesions are generally larger and more frequent in the peripheral retina. This retinal finding is considered benign and incidental for the majority of cases. There are only two reports of CGAS in the context of low vision, either from choroidal neovascularization or a wide atrophic macular lesion [1, 2]. Fundus autofluorescence (FAF) and spectral domain optical coherence tomography (SD-OCT) findings were previously described as primarily hypoautofluorescent spots, with disruption of the inner and outer segment (IS/OS) junction [3]. Here, we report the finding of a circularly grouped pattern of CGAS in the macula of a patient with hemihypertrophy, café au lait spots, and cryptorchidism. We describe the appearance of the lesions using multimodal imaging, SD-OCT, FAF, optical coherence tomography angiography (OCTA), in addition to full-field electroretinogram (ffERG) recordings.
Case report
A 15-year-old boy presented to the Edward S. Harkness Eye Institute by optometrist referral for retinal evaluation of a mottled appearance of the macula. Previous ocular history included eye therapy for convergence insufficiency and red–green colorblindness. He denied poor night vision or a family history of retinal dystrophy or colorblindness. He had a history of an undescended left testicle at birth. He did not regularly take any medications. Evaluation by a pediatric geneticist at the age of 3 years revealed hemihypertrophy with an enlarged left chest, abdomen, and thigh compared to the right side. He did not have any facial hemihypertrophy. He was also found to have café au lait spots on the left axilla and legs bilaterally. Serial abdominal ultrasounds at the time did not reveal congenital renal disease.
His uncorrected visual acuity was 20/25 in both eyes. Confrontational visual fields were full. Slit lamp exam of the anterior segments and vitreous cavity was unremarkable. Intraocular pressure was within normal limits in both eyes. ffERG performed according to the guidelines of the International Society for Clinical Electrical Physiology and Vision (ISCEV) showed adequate rod and cone function (Fig. 1, Table 1) [4, 5]. Fundoscopy of both eyes showed hypomelanotic spots arranged in a central grouped pattern in the foveal and perifoveal regions (Fig. 2a, b). The pale spots were of relatively equal size and the largest lesions were twice the diameter of the retinal veins. These spots were hyperautofluorescent centrally on FAF (Fig. 2c), and of variable intensity in linear formations peripherally in both eyes (Fig. 2d). SD-OCT revealed preservation of retinal layers and IS/OS junction bilaterally (Fig. 3). Optical coherence tomography angiography (OCTA) did not reveal any vascular abnormalities in the superficial and deep angioplex layers (Supplemental Fig. 1).
Fig. 1.
Full-field electroretinogram of the patient’s right and left eye compared to a normal control
Table 1.
Scotopic and photopic full-field electroretinogram measurements
| ffERG parameters | OD | OS | Normal |
|---|---|---|---|
|
| |||
| Scotopic B-Wave amplitude (μV) | 195.8 | 257 | 266.1 ± 170.2 |
| Scotopic B-Wave implicit time (ms) | 74 | 75 | 90.36 ± 22.93 |
| Maximum A Wave amplitude (μV) | − 214.3 | − 284 | − 175.1 ± 146.7 |
| Maximum B-Wave amplitude (μV) | 312.6 | 379.8 | 335 ± 273.2 |
| Transient photopic B-Wave amplitude (μV) | 101.7 | 114.7 | 178.8 ± 116.9 |
| 30 Hz flicker peak amplitude (μV) | 94.57 | 90.95 | 131 ± 82 |
| 30 Hz flicker implicit time (ms) | 25 | 25 | 24.17 ± 4.33 |
Fig. 2.
Congenital gass albinotic spots of the retinal pigment epithelium. a, b Color fundus photography revealing spots bilaterally in the central macula. c, d Autofluorescence imaging of the spots in the central macula and periphery. OCT of the right (e) and left (f) eye
Fig. 3.
Optical coherence tomography of the right eye with an IR fundus image showing a representative cut approximating the congenital gass albinotic spots within a dense scan
Discussion
While no genetic basis for CGAS has been defined, a report of four family members with the finding suggests that there is a hereditary component or that a familial form exists [6]. Syndromic associations with CGAS have previously been described in a syndrome of microcephaly and hyperreflexia [1]. Hypomelanotic retinal spots have also been described in a patient with a microcephaly syndrome caused by Zika virus [7]. There is no description in the literature of hemihypertrophy associated with CGAS; however, pitting of the optic disc has been identified in a patient with facial hemihypertrophy [8]. The relationship between the hypomelanotic spots on the retina and systemic findings in our case is unclear.
Original reports of CGAS tended to describe lesions as white, sparing the macula, and monocular [9]. To our knowledge, this is the second report describing the spots to be bilateral and located in the macula [6]. Other associated findings with CGAS included yellow spots, particularly in the posterior pole. Previous FAF studies have described the spots as having variable autofluorescence with the majority showing hypoautofluorescence [3]. The hyperautofluorescent spots in this case may be the result of impaired RPE lipofuscin metabolism in the focal albinotic areas causing hyperautofluorescent accumulations. Previous OCT findings have described disruption in signal from the hyperreflective layer corresponding to the photoreceptor IS/OS junction [3, 6]. This case did not have similar disruption, and this patient did not have any visual complaints suggesting damage to photoreceptors, in congruence with no generalized retinal dysfunction detected on ffERG.
While neurofibromatosis type 1 (NF1) is the most common syndrome seen in patients with multiple café au lait spots, distinctive freckling patterns can also be seen in other disorders involving the RAS-MAPK pathway, including Legius, Noonan, and Costello syndromes [10]. The clinical diagnosis of NF1 is based on the National Institutes of Health diagnostic criteria including six or more café au lait spots, neurofibromas, axillary/inguinal freckling, Lisch nodules, optic glioma, osseous lesions, and a first-degree relative affected. This patient presented with six café au lait spots in the absence of other clinical criteria or family members with neurofibromatosis. Genetic testing results are currently unavailable for this patient. Legius syndrome presents with similar café au lait spots but differs from neurofibromatosis 1 in that there is negative genetic testing for the NF1 gene in the presence of mutations in the SPRED1 gene. Choroidal nodules, consisting of proliferating Schwann cells arranged concentrically around an axon, have been documented as another manifestation of NF1 and Legius syndrome and can be identified by direct ophthalmoscopy as well as near infrared imaging [11]. This patient did not have any evidence of choroidal nodules on exam or imaging (Figs. 2, 3). Hemihypertrophy of the face due to facial plexiform or diffuse neurofibromas has been associated with NF1. This patient did not present with discrete nodules as the cause of facial hemihypertrophy, rather a more syndromic appearing global facial asymmetry [12]. Definitive testing for neurofibromatosis with incomplete penetrance in this patient is still pending; however, this remains the first report of albinotic spots of the RPE present in a patient with café au lait spots and hemihypertrophy.
Supplementary Material
Acknowledgements
Jonas Children’s Vision Care, and Bernard & Shirlee Brown Glaucoma Laboratory are supported by the National Institute of Health [5P30EY019007, R01EY018213, R01EY024698, R01EY026682, R21AG050437], National Cancer Institute Core [5P30CA013696], the Research to Prevent Blindness (RPB) Physician-Scientist Award, unrestricted funds from RPB, New York, NY, USA. E.C.W is supported by the Sarnoff Cardiovascular Research Fellowship. J.D.S is supported by the RPB Medical Student Eye Research Fellowship. S.H.T is a member of the RD-CURE Consortium and is supported by the Tistou and Charlotte Kerstan Foundation, the Schneeweiss Stem Cell Fund, New York State [C029572], the Foundation Fighting Blindness New York Regional Research Center Grant [CNY05-0705-0312], the Crowley Family Fund, and the Gebroe Family Foundation.
Footnotes
Compliance with ethical standards
Statement of human rights All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Statement of the welfare of animals This article does not contain any studies with animals performed by any of the authors.
Informed consent The data presented in this study, including images and genetic testing results, are not identifiable to individual patients. For this type of study, formal consent is not required.
Conflict of interest All authors certify that they have no affiliations with or involvement in any organization or entity with a financial interest (such as honoraria; educational grants; participation in speaker’s bureaus; membership, employment, consultancies, stock ownership or other equity interest; and expert testimony or patent-licensing arrangements) or non-financial interest (such as personal or professional relationship, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.
Contributor Information
Eugenia C. White, Department of Ophthalmology, Columbia University, New York, NY, USA Louisiana State University Health Sciences Center, Shreveport, LA, USA.
Jesse D. Sengillo, Department of Ophthalmology, Columbia University, New York, NY, USA State University of New York Downstate Medical Center, New York, NY, USA.
Galaxy Y. Cho, Department of Ophthalmology, Columbia University, New York, NY, USA
Mathieu F. Bakhoum, Department of Ophthalmology, Columbia University, New York, NY, USA Department of Ophthalmology, Nassau University Medical Center, East Meadow, NY, USA.
Stephen H. Tsang, Jonas Children’s Vision Care, and Bernard & Shirlee Brown Glaucoma Laboratory, New York, NY, USA; Department of Ophthalmology, Columbia University, New York, NY, USA.
References
- 1.Parke JT, Riccardi VM, Lewis RA, Ferrell RE (1984) Asyndrome of microcephaly and retinal pigmentary abnormalities without mental retardation in a family with coincidental autosomal dominant hyperreflexia. Am J Med Genet 17(3):585–594. 10.1002/ajmg.1320170306 [DOI] [PubMed] [Google Scholar]
- 2.Battaglia Parodi M, Iacono P (2004) Indocyanine green angiography pattern of congenital grouped albinotic retinal pigment epithelial spots. Semin Ophthalmol 19(3–4):114–116. 10.1080/08820530490882670 [DOI] [PubMed] [Google Scholar]
- 3.Kim DY, Hwang JC, Moore AT, Bird AC, Tsang SH (2010) Fundus autofluorescence and optical coherence tomography of congenital grouped albinotic spots. Retina 30(8): 1217–1222. 10.1097/IAE.0b013e3181cea5a5 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.McCulloch DL, Marmor MF, Brigell MG et al. (2015) ISCEV Standard for full-field clinical electroretinography (2015 update). Doc Ophthalmol 130(1):1–12. 10.1007/s10633-014-9473-7 [DOI] [PubMed] [Google Scholar]
- 5.McCulloch DL, Marmor MF, Brigell MG et al. (2015) Erratum to: ISCEV Standard for full-field clinical electroretinography (2015 update). Doc Ophthalmol 131(1): 81–83. 10.1007/s10633-015-9504-z [DOI] [PubMed] [Google Scholar]
- 6.Arana LA, Sato M, Arana J (2010) Familial congenital grouped albinotic retinal pigment epithelial spots. Arch Ophthalmol 128(10):1362–1364. 10.1001/archophthalmol.2010.242 [DOI] [PubMed] [Google Scholar]
- 7.de Miranda HA, Costa MC, Frazão MAM, Simão N, Franchischini S, Moshfeghi DM (2016) Expanded Spectrum of congenital ocular findings in microcephaly with presumed Zika infection. Ophthalmology 123(8):1788–1794. 10.1016/j.ophtha.2016.05.001 [DOI] [PubMed] [Google Scholar]
- 8.Rochels R, Knieper P, Wunderlich M (1980) Hemihypertrophia faciei und Papillenanomalien. Klin Monbl Augenheilkd. 176(5):813–815. 10.1055/s-20081057559 [DOI] [PubMed] [Google Scholar]
- 9.Gass JDM (1989) Focal congenital anomalies of the retinal pigment epithelium. Eye 3(1):1–18. 10.1038/eye.1989.2 [DOI] [PubMed] [Google Scholar]
- 10.Tucci A, Saletti V, Menni F et al. (2017) The absence that makes the difference: choroidal abnormalities in Legius syndrome. J Hum Genet 62:1001–1004. 10.1038/jhg.2017.78 [DOI] [PubMed] [Google Scholar]
- 11.Viola F, Villani E, Natacci F et al. (2012) Choroidal abnormalities detected by near-infrared reflectance imaging as a new diagnostic criterion for neurofibromatosis 1. Ophthalmology 119(2):369–375. 10.1016/j.ophtha.2011.07.046 [DOI] [PubMed] [Google Scholar]
- 12.Hivelin M, Wolkenstein P, Lepage C, Valeyrie-Allanore L, Meningaud JP, Lantieri L (2010) Facial aesthetic unit remodeling procedure for neurofibromatosis type 1 hemifacial hypertrophy: report on 33 consecutive adult patients. Plast Reconstr Surg 125(4):1197–1207. 10.1097/PRS.0b013e3181d180e9 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.