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Show Photo and Video Essay Section Editors: Melissa W. Ko, MD Dean M. Cestari, MD Peter Quiros, MD Atypical Ocular Coloboma in Tuberous Sclerosis-2: Report of Two Novel Cases Giacomo M. Bacci, MD, PhD, Silvio Polizzi, MD, Francesco Mari, MD, PhD, Valerio Conti, PhD, Roberto Caputo, MD, Renzo Guerrini, MD, FRCP FIG. 1. Patients ophthalmological features. A. Case 1. Anterior segment photography of the left eye showing a large, atypical coloboma. The lens was surgically removed because of a cataract and subluxation, and the image shows the postoperative aphakic appearance. B. Case 1. Fundus image of the left eye showing a large area of retinal abnormality with a V-shaped appearance pointing toward the optic nerve head. C. Case 2. Anterior segment photography of the right eye showing an atypical iris coloboma and notching of the lens at the superior equator. D. Case 2. Fundus image of the right eye revealing an area of V-shaped retinal dystrophy extending toward the anterior coloboma. E. Graphic representation of the TSC2 gene structure in which the mutations identified in Case 1 (c.3131G.A), Case 2 (c.3099+1G.A), and in the patient described by Hocking et al (c.5026C.T) are reported at the nucleotide level. F. TSC2 protein representation showing its functional domains and the position of the missense mutation identified by Hocking et al (3), indicated by the red square. G, H. Predicted TSC2 proteins encoded by mutant mRNAs in Case 1 (G) and Case 2 (H). In both cases, if translated, mutant TSC2 protein is expected to lose 4 of its 7 functional domains (TAD1, GAP, TAD2, and CaM). TSC, tuberous sclerosis complex. CaM, calcium-modulated protein calmodulin; GAP, GTPase activating protein. Pediatric Ophthalmology Unit (GMB, SP, RC), Children’s Hospital A. Meyer-University of Florence, Florence, Italy; and Pediatric Neurology (FM, VC, RG), Neurogenetics and Neurobiology Unit and Laboratories, Children’s Hospital A. Meyer-University of Florence, 50139 Florence, Italy. The authors report no conflicts of interest. Address correspondence to Giacomo M. Bacci, MD, PhD, Pediatric Ophthalmology Unit, Children’s Hospital A. Meyer-University of Florence, Viale Pieraccini 24, Florence 50139, Italy; E-mail: giacomo. bacci@meyer.it Bacci et al: J Neuro-Ophthalmol 2021; 41: e363-e365 Abstract: Tuberous sclerosis complex (TSC) is an autosomal dominant multisystemic disorder caused by mutations in either TSC1 or TSC2 genes and is characterized by hamartomas in multiple organs. The most frequent and bestknown ocular manifestation in TSC is the retinal hamartoma. Less frequent ocular manifestations include punched out areas of retinal depigmentation, eyelid angiofibromas, uveal colobomas, papilledema, and sector iris depigmentation. In this article, we report 2 patients carrying known pathogenic variants in the TSC2 gene who exhibited an e363 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Photo and Video Essay atypical, unilateral, iris coloboma associated with localized areas of retinal dysembryogenesis. Journal of Neuro-Ophthalmology 2021;41:e363–365 doi: 10.1097/WNO.0000000000001099 © 2020 by North American Neuro-Ophthalmology Society A 5-year-old boy was referred to the Pediatric Ophthalmology Unit of the Meyer Children’s Hospital for ophthalmic baseline evaluation in tuberous sclerosis complex (TSC). In the right eye, the anterior segment was unremarkable, whereas fundus examination revealed a parafoveal retinal hamartoma. Spectral-domain optical coherence tomography (SD-OCT) showed the hamartoma with distortion of the foveal profile. In the left eye , anterior segment examination revealed an atypical temporal coloboma of the iris, a lens subluxation due to severe loss of one-third zonular support extending for the entire sector area of iris coloboma (Fig. 1A), and a clinically significant opacity of the lens. Fundus examination showed a striking appearance of a V-shaped area of apparent retinal dysplasia, in direct continuity with the iris coloboma (Fig. 1B). OCT scan of colobomatous area demonstrated lack of retinal tissue. Sanger sequencing performed in blood DNA revealed a known, heterozygous, pathogenic variant (c.3131+1G.A) (1) of the TSC2 gene. A two-year-old girl was referred to the Pediatric Ophthalmology Unit of the Meyer Children’s Hospital for ophthalmic baseline evaluation in TSC. In the right eye, anterior segment examination showed a superior iris coloboma and notching of the lens at the superior equator (Fig. 1C). Fundus examination revealed an area of a “Vshaped” abnormal retina that extended anteriorly toward the iris coloboma (Fig. 1D). SD-OCT demonstrated an interruption of the normal inner retina and ellipsoid zone at the margin of the retinal anomaly, with focal alterations of the retinal pigment epithelium within the dystrophic area. Examination of the left eye was unremarkable. Sanger sequencing performed in blood DNA revealed a known, heterozygous, pathogenic variant (c.3099C.G:p.Tyr1033Ter) (2) of the TSC2 gene. Ocular coloboma is defined as “typical” if it occurs in the inferonasal quadrant and “atypical” if it occurs elsewhere. To date, only a few articles have reported uveal coloboma in patients with TSC (3–6). For most of the reported patients, phenotypic description is not detailed enough to conclude whether the coloboma was typical or atypical. In the series reported by Williams and Taylor (6), one of the 100 patients presented with atypical coloboma involving nasal lens and iris. More recently, Hocking et al (3) described a patient with unilateral, superior iris coloboma carrying the p.Arg1676Trp TSC2 mutation. The accepted pathogenesis of typical coloboma is related to a defective closure of choroidal fissure, but this e364 pathophysiological mechanism cannot explain atypical forms. Studying eye development in animal models, Hocking et al identified a transient division of the dorsal eye which they named superior ocular sulcus (SOS) and demonstrated that failure of its closure due to Bmp or Tbx2b signaling defects may contribute to the development of superior coloboma (3). By inactivating TSC1 and TSC2 in the Drosophila ovary, Sun et al demonstrated that, by simultaneously controlling Bmp-dependent and Bmpindependent differentiation pathways, these genes play a role in maintaining germline stem cells (GSCs) and that their disruption leads to precocious GSCs differentiation (7). Therefore, we can hypothesize that bone morphogenetic protein (BMP) pathway dysregulation and precocious GSCs differentiation in the SOS might be related to the development of atypical coloboma in patients carrying TSC2 mutations. The hypothesis of a role of BMP pathway dysregulation in atypical coloboma development is supported by the recent identification of a new bone morphogenetic protein receptor type 1B (Bmpr1b) mouse mutant line in which a mutation causing the skipping of Bmpr1b exon 10 resulted in optic disc coloboma, gliosis in the optic nerve head and ventral retina, defective optic nerve axons, and irregular retinal vessels due to loss of Bmp signaling (8). Thus, mutations in BMP pathway genes could be an underestimated cause of atypical coloboma, and the screening of these genes should be considered in patients with this condition. The c.3099C.G and c.3131+1G.A variants are predicted to introduce premature stop codons between CCD2 and TAD1 protein domains (Figs. 1G, H). The truncated proteins, if translated, are expected to lose 4 of the 7 tuberin’s functional domains (TAD1, GTPase activating protein TAD2, and CaM). Interestingly, the p.Arg1676Trp TSC2 mutation associated with atypical coloboma (3) maps 2 amino acids away from one of these domains (GTPase activating protein domain, Fig. 1). However, the very small number of patients with atypical coloboma and TSC2 mutations identified so far and the different type of mutations identified in the 3 patients (missense in Hocking and coworker’s report and stop and frameshift in our patients) makes identifying possible genotype/phenotype correlations too difficult at present. Both variants we identified in our patients had already been described in 2 patients with TSC (1,2), neither exhibiting atypical coloboma. Phenotype variability associated with the same mutation is known to occur in patients with TSC because it has been reported in different mutationpositive individuals belonging to the same family and even in monozygotic twins (9). Considering the patients we described and the 2 additional patients with atypical coloboma reported, we hypothesize that atypical coloboma might be a phenotypic feature of TSC; although given the extremely limited number of patients in whom this association has been identified, further observations are needed to clarify whether this ocular anomaly is somehow related to specific mutations affecting the TSC2 gene. Bacci et al: J Neuro-Ophthalmol 2021; 41: e363-e365 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Photo and Video Essay STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: B. Giacomo and P. Silvio; b. Acquisition of data: P. Silvio, M. Francesco, and B. Giacomo; c. Analysis and interpretation of data: C. Valerio, P. Silvio, M. Francesco, and B. Giacomo. Category 2: a. Drafting the manuscript: B. Giacomo, C. Valerio, M. Francesco, and P. Silvio; b. Revising it for intellectual content: G. Renzo and C. Roberto. Category 3: a. Final approval of the completed manuscript: B. Giacomo, C. Valerio, P. Silvio, M. Francesco, C. Roberto, and G. Renzo. REFERENCES 1. Ali M, Girimaji SC, Markandaya M, Shukla AK, Sacchidanand S, Kumar A. Mutation and polymorphism analysis of TSC1 and TSC2 genes in Indian patients with tuberous sclerosis complex. Acta Neurol Scand. 2005;111:54–63. 2. Nellist M, Brouwer RWW, Kockx CEM, van Veghel-Plandsoen M, Withagen-Hermans C, Prins-Bakker L, Hoogeveen-Westerveld M, Mrsic A, van den Berg MMP, Koopmans AE, de Wit MC, Jansen FE, Maat-Kievit AJA, van den Ouweland A, Halley D, de Klein A, van IJcken WFJ. Targeted next generation sequencing reveals previously unidentified TSC1 and TSC2 mutations. BMC Med Genet. 2015;16:1–11. Bacci et al: J Neuro-Ophthalmol 2021; 41: e363-e365 3. Hocking JC, Famulski JK, Yoon KH, Widen SA, Bernstein CS, Koch S, Weiss O, Agarwala S, Inbal A, Lehmann OJ, Waskiewicz AJ, Andrew J. 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