After the first 13q deletion syndrome case was described in 1963, approximately 180 cases associated with partial or complete deletion of the long arm (q) of chromosome 13 have been reported in medical literature. The various clinical features of this rare syndrome have been established and include moderate to severe mental retardation, growth delay, facial dysmorphic features, limb defects, digestive anomalies, deafness, and various other malformations of the brain, kidney, heart, or eye. Retinoblastoma is the most concerning ocular finding associated with the 13q deletion syndrome.1
The deletion of the RB1 tumor suppressor gene (RB1) located at 13q14 is rare with whole-germline monoallelic deletion of RB1 accounting for 6% of the RB1 mutational spectrum.2 Only a few patients with the RB1 deletion, with additional iris and anterior segment ocular findings, have been presented in previous studies.3 However, these iris and anterior segment findings serve as key features that can potentially identify patients with RB1 deletions. We herein report the case of one patient who was referred to our clinic for evaluation of bilateral iris heterochromia, and was subsequently found have iris hypoplasia, mimicking heterochromia, and bilateral retinoblastoma, in the setting of 13q deletion syndrome.
A 10-month-old female infant with developmental delay and failure to thrive was diagnosed as having 13q and 16p deletions. Specifically, Oligo-SNP microarray revealed a 39 Mb loss affecting the 13q14.2-q31.1 region, which includes loss of RB1, and a 949 kb loss of 16p12.2.
The child was subsequently referred to our institution for the evaluation of bilateral iris heterochromia. She was also noted to have leukocoria. The patient has a sibling with albinism but no other family history of genetic disease, eye disease, or other systemic diseases. Due to the leukocoria and 13q deletion, the patient underwent an examination under anesthesia for diagnosis and staging. Examination of the anterior segment revealed sectoral iris hypoplasia superiorly in the right eye and diffuse iris hypoplasia with Brushfield spots in the left eye without the presence of neovascularization. This iris hypoplasia had created the appearance of heterochromia. The remainder of the anterior segment examination, including intraocular pressures, was within normal limits for both eyes. Dilated fundus examination of the right eye demonstrated a cohesive, creamy white endophytic mass in the temporal macula along the inferotemporal arcade with a minimal cuff of fluid and associated spherical vitreous seeds at the base of the tumor. The macula and optic nerve were free of tumor. There were no other peripheral tumors noted. The examination results were consistent with International Intraocular Retinoblastoma Classification (IICR) Group C Retinoblastoma.4 In the left eye, there was a creamy white endophytic mass with prominent intratumoral vasculature centered at the 5-o'clock position along the inferior arcade. The edge entered the macular region; however, the fovea was spared. There were diffuse large spherical vitreous seeds overlying the macula, adjacent to the optic disc and inferiorly. There was a small cuff of subretinal fluid at the base of the tumor but the majority of the retina was attached. The examination results were consistent with IICR Group D Retinoblastoma.4
Fluorescein angiography did not demonstrate evidence of subclinical neovascularization of the iris; however, prominent stromal vessels were seen in areas of iris hypoplasia with early hyperfluorescence (Figure 1). Posteriorly, the tumors showed early filling with late hyperfluorescence consistent with retinoblastoma. Optical coherence tomography of the macula was performed and revealed intact foveas in both eyes and scattered preretinal dust and spheres in the macula of the right eye. Gadolinium enhance magnetic resonance imaging revealed bilateral enhancing intraocular masses, hypointense to the vitreous on T2 imaging, consistent with retinoblastoma, without involvement of the optic nerve or central nervous system.
(A) Sectoral superior iris hypoplasia in the right eye. (B) Diffuse iris hypoplasia with Brushfield spots on the left eye. Fluorescein angiographic images of the (C) right and (D) left iris in early phase demonstrating the early hyperfluorescence of the iris vasculature in the area of hypoplasia. (E) IICR Group C Retinoblastoma in the right eye. (F) IICR Group D Retinoblastoma in the left eye.
The decision was made to treat the patient with reduced-dose three-drug systemic chemotherapy with local consolidation via the previously published protocol for infants 6 months and younger.5 This was due to the fact that patients with 13q retinoblastoma have a higher incidence of treatment-induced neutropenia than those without the deletion, requiring dose reductions in chemotherapy.2 Despite this increased toxicity and adjustments made to treatment protocol, the response to therapy and overall survival rates are not different for patients with 13q retinoblastoma compared with other patients with retinoblastoma.6 Our patient will undergo examination under anesthesia every 4 weeks during chemoreduction with local consolidation to monitor for appropriate tumor regression and surveillance for new tumors to prevent progression of disease.
The first case to describe the ocular findings of bilateral iris stromal atrophy in a patient with chromosome 13q deletion syndrome (q21, q31) was presented in 2007.3 In the medical literature to date, only a few patients have been described with the combination of 13q deletion, bilateral retinoblastoma, and iris hypoplasia (which often masquerades as heterochromia).7 The pathophysiology of iris hypoplasia observed in case of 13q deletion remains a topic of continued research and debate.
The pursuit to identify the genetic etiology of anterior segment disorders associated with 13q deletion has revealed multiple genetic loci. A proband with Axenfeld–Rieger anomaly, global delay, dysmorphic features, and retinoblastoma was found to have deletion of 13q12;q22 including RB1 at 13q14.8 The 13q deletions were reported in two previous cases of Rieger syndrome, and chromosome analysis revealed a deletion of the long arm of chromosome 13: 13q14,q31 and 13q12,q22. The authors suggested that a gene for this disorder may be located in the segment spanning 13q14 to 13q22.9
A possible target is the Endothelin Receptor B (EDNRB) gene, located at 13q22.3, which appears to have a role in the development of melanocytes from primitive neural crest cells such as those in the iris stroma, ciliary body, and choroidal melanocytes. The receptor interacts with proteins called endothelins to regulate several critical biological processes, including the production of melanocytes, the development and function of blood vessels, the production of certain hormones, and the stimulation of cell growth and division.10 Deletions, especially in the proximal section of the long arm of chromosome 13, are linked to EDNRB inactivation and may cause hypopigmentation of the iris due to damaged melanocyte migration. However, the clinical phenotypes of these genetic deletions exhibit wide variability, and iris changes may not always be present. Furthermore, other genes such as DACH1 and SPRY2 may somehow influence the pathogenesis of such ocular defects.11
We have reported the case of a 10-month-old infant who was referred to our clinic for bilateral iris heterochromia and subsequently found to have bilateral iris hypoplasia and bilateral retinoblastoma. Children diagnosed as having retinoblastoma associated with 13q deletion present similarly to any child with a germline deletion of the RB1 gene and thus more often have bilateral disease and are diagnosed at a younger age.5 It is imperative that pediatric ophthalmologists recognize bilateral iris hypoplasia as a potential phenotypic finding in patients with 13q syndrome and recommend the appropriate systemic work-up, along with a dilated examination, to evaluate for retinoblastoma. In this case, the genetic evaluation had already been completed before referral. Additionally, dilated screening eye examinations for retinoblastoma are indicated during the first 3 years in life in patients with known or suspected 13q deletion for early diagnosis and optimal therapy.
- Lohmann DR, Gallie BL. Retinoblastoma: revisiting the model prototype of inherited cancer. Am J Med Genet C Semin Med Genet. 2004;129C:23–28. doi:10.1002/ajmg.c.30024 [CrossRef]
- Brennan RC, Qaddoumi I, Billups CA, Kaluzny T, Furman WL, Wilson MW. Patients with retinoblastoma and chromosome 13q deletions have increased chemotherapy-related toxicities. Pediatr Blood Cancer. 2016;63:1954–1958. doi:10.1002/pbc.26138 [CrossRef]
- Kutzbach B, Mendelsohn N, Rath P, Summers CG. Sectoral iris heterochromia and retinal pigment variation in 13q-syndrome. J AAPOS. 2007;11:513–515. doi:10.1016/j.jaapos.2007.04.012 [CrossRef]
- Shields CL, Mashayekhi A, Au AK, et al. The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology. 2006;113:2276–2280. doi:10.1016/j.ophtha.2006.06.018 [CrossRef]
- Berry JL, Jubran R, Kim JW, et al. Long-term outcomes of Group D eyes in bilateral retinoblastoma patients treated with chemoreduction and low-dose IMRT salvage. Pediatr Blood Cancer. 2013;60:688–693. Erratum in: Pediatr Blood Cancer. 2014;61:1147. doi:10.1002/pbc.24303 [CrossRef]
- Mitter D, Ullmann R, Muradyan A, et al. Genotype–phenotype correlations in patients with retinoblastoma and interstitial 13q deletions. Eur J Hum Genet. 2011;19:947–958. doi:10.1038/ejhg.2011.58 [CrossRef]
- Golde KT, Westerfeld CB, Mukai S. Ocular findings in patients with retinoblastoma and the 13q deletion syndrome. Invest Ophthalmol Vis Sci. 2009;50:4107–4107.
- Reis LM, Semina EV. Genetics of anterior segment dysgenesis disorders. Curr Opin Ophthalmol. 2011;22:314–324. doi:10.1097/ICU.0b013e328349412b [CrossRef]
- Stathacopoulos RA, Bateman JB, Sparkes RS, Hepler RS. The Rieger syndrome and a chromosome 13 deletion. J Pediatr Ophthalmol Strabismus. 1987;24:198–203.
- Rennie IG. Don't it make my blue eyes brown: heterochromia and other abnormalities of the iris. Eye (Lond). 2012;26:29–50. doi:10.1038/eye.2011.228 [CrossRef]
- Córdova-Fletes C, Rivera H, Garza-Villarreal EA, et al. A del (13) (q21. 32q31. 2) dn refined to 21.9 Mb in a female toddler with irides heterochromia and hypopigmentation: appraisal of interstitial mid-13q deletions. Clin Dysmorphol. 2017;26:33–37. doi:10.1097/MCD.0000000000000159 [CrossRef]