Ophthalmic Genetics, Early Online, 1–3, 2014 ! Informa Healthcare USA, Inc. ISSN: 1381-6810 print / 1744-5094 online DOI: 10.3109/13816810.2014.921315
C ASE REPORT
Hereditary Diffuse Infiltrating Retinoblastoma Katharina J. E. Schedler1, Peter G. Traine1, Dietmar R. Lohmann2, Christos Haritoglou3, Klaus A. Metz4, and Eduardo B. Rodrigues5
Ophthalmic Genet Downloaded from informahealthcare.com by Korea University on 12/25/14 For personal use only.
1
Department of Ophthalmology, Clinic Pallas, Olten, Switzerland, 2Institute of Human Genetics, Faculty of Medicine, University Duisburg-Essen, Essen, Germany, 3Department of Ophthalmology, Ludwig Maximilians University, Munich, Germany, 4Institute of Pathology and Neuropathology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany, and 5Department of Ophthalmology, Vision Institute – IPEPO, Federal University of Sa˜o Paulo, Sa˜o Paulo, Brazil
ABSTRACT Retinoblastoma is one of the most common childhood cancers. The diffuse infiltrating retinoblastoma is a rare subtype of this neoplasm. The majority of cases of diffuse infiltrating retinoblastoma are unilateral and occur sporadically. Herein we report on a family with three children affected by retinoblastoma, among them one girl with diffuse infiltrating retinoblastoma. This girl was diagnosed at the age of 8 years with a unilateral diffuse infiltrating retinoblastoma. By contrast, the two brothers became clinically apparent in the first 2 years of life with bilateral retinoblastoma. The parents were clinically unremarkable. Genetic analysis of RB1 gene was performed. The girl with diffuse infiltrating RB was found to be heterozygous for an oncogenic mutation in the RB1 gene that was also carried by both brothers and the father of the family. These results show that diffuse infiltrating retinoblastoma can develop on the background of a hereditary predisposition to retinoblastoma. Keywords: Genetics, retina, retinoblastoma
INTRODUCTION
retinoblastoma and has a diffuse growth pattern infiltrating the retina.3 Single tumor cells may enter into the vitreous and the anterior chamber, mimicking uveitis without presenting a macroscopic tumor mass. The tumor grows slowly and the mean age of patients at diagnosis is about 4 years.3 The diffuse infiltrating retinoblastoma is described to occur sporadically.3 Herein we report on a family, wherein all three children were affected by retinoblastoma. The girl presented with a unilateral diffuse infiltrating retinoblastoma, the two brothers with bilateral retinoblastoma. Genetic analysis of the RB1 gene identified a mutation in the RB1 gene in all three children and the father. This finding allows the conclusion that diffuse infiltrating retinoblastoma can occur on the background of a heritable predisposition to retinoblastoma.
Retinoblastoma is one of the most common childhood cancers. Approximately 60% of cases occur secondary to non-hereditary somatic mutations. These patients develop predominantly unilateral, solitary tumors. The remaining 40% of cases result from heritable, germline mutations (10% have a positive family history of retinoblastoma, while 30% are new-onset germline mutations without a pre-existing family history).1 The heritable form of retinoblastoma usually presents as a multifocal tumor that most frequently occurs bilaterally, at a mean age of 1.2 years.2 The diffuse infiltrating retinoblastoma is a rare subtype of retinoblastoma. It accounts for about 2% of
Received 9 December 2013; revised 23 March 2014; accepted 11 April 2014; published online 3 June 2014 Correspondence: Katharina Schedler, Aarepark 5c, 5000 Aarau, Switzerland. Tel: +41 767709237. Fax: +49 7082413835. E-mail: [email protected]
1
2
K. J. E. Schedler et al.
Ophthalmic Genet Downloaded from informahealthcare.com by Korea University on 12/25/14 For personal use only.
CASE REPORT An 8-year-old Caucasian girl presented with 6 days history of conjunctival redness and a small whitish discoloration of the iris in the right eye. She reported unilateral reduction in vision and denied pain. The previous medical and ophthalmic history was unremarkable. In both brothers, bilateral retinoblastoma was diagnosed in the first few months of life. In the right eye, the corrected visual acuity was 20/80, and the intraocular pressure was 20 mmHg. The left eye was unremarkable. The right eye showed moderate injection, corneal edema, and a pseudohypopyon of 2 mm (Figure 1, upper panel). There was flare and cells (2+) in the anterior chamber and heterochromia of the iris. Gonioscopy showed a white-colored thickening on the iris root and the trabecular meshwork. The presence of corneal edema and dense vitreous inflammation made clinical examination of the posterior segment difficult. Ultrasonography showed vitreous seeds as hyperecogenic peaks but there was no evidence of retinal calcifications (Figure 1, lower panel). Computed tomography of the orbit and the skull, and a chest X-ray, to exclude other reasons for uveitis like tuberculosis or sarcoidosis, did not show
FIGURE 1. Upper panel: Anterior segment photo of the right eye showing a mixed injection and a pseudohypopyon of about 2 mm. Lower panel: Ultrasonography showing intravitreous hyperecogenic peaks, but no retinal calcifications.
abnormal findings. The requested MRI of the orbit and skull showed only a slight thickening of the retina, but no evidence of a tumoral mass. With increased clinical deterioration, i.e. visual decline and progressive inflammation, 1 month after the initial presentation, a suspected retinoblastoma was treated with systemic chemotherapy with vincristine, etoposide, and carboplatin (6 cycles), followed by enucleation. Compatible with a diffuse infiltrative retinoblastoma, histological findings showed a small focal retinal infiltration and an invasion of poorly differentiated cells (grade 3) with large basophilic nuclei and scanty cytoplasm in the ciliary body accounting for the involvement of the anterior chamber. There was no choroidal infiltration and no infiltration of the optic nerve. Compatible with an undifferentiated retinoblastoma, there were no Flexner-Wintersteiner and no Homer-Wright rosettes found (Figure 2). Histopathological stage was pT1, pNx. A mutational analysis of the RB1 gene of the children and their non-phenotypic parents was performed using PCR and sequencing analysis of the promoter, exons 2 to 27 and flanking intron regions,
FIGURE 2. Histopathology of the right eye. Upper panel: Diffuse thickening of the retina by tumor cells. Lower panel: Tumor cells in the ciliary body, in the posterior part of the iris and in the anterior chamber. Ophthalmic Genetics
Ophthalmic Genet Downloaded from informahealthcare.com by Korea University on 12/25/14 For personal use only.
Hereditary Diffuse Infiltrating Retinoblastoma
3
comparing sequencing data with a reference (L11910). The father and all three children were found to be heterozygous for the RB1 gene mutation NM_000321.2: c.1050-3_1050-1delinsAA. This mutation disrupts the normal splice acceptor site of intron 10 and, most likely, results in skipping of exon 11,5 which causes a frameshift and premature termination. In all probability it is the cause of heritable predisposition to retinoblastoma in this family. It appears that the father is a heterozygous carrier of the mutation with incomplete penetrance. However, we cannot exclude that he has mutational mosaicism although we did not note a distortion of the mutant to normal signal ratio in sequence analysis on DNA from blood of the father.
melanoma, and leiomyosarcoma should be offered to all patients with germline mutation.
DISCUSSION
DECLARATION OF INTEREST
Diffuse infiltrating retinoblastoma is characterized by its specific growth pattern with a relatively flat infiltration of the retina and tumoral cells spreading to the vitreous and anterior structures of the eye. It has mostly been described to occur sporadically. There are only two case reports that hypothesize a hereditary component.6,7 Our patient with diffuse infiltrating retinoblastoma, her brothers with bilateral retinoblastoma and their parents underwent genetic testing. In all children and the father we identified the same oncogenic RB1 gene mutation, that in all likelihood causes heritable predisposition for retinoblastoma in this family. Therefore one can assume that diffuse infiltrating retinoblastoma can be heritable. The reason for the specific growth pattern of the subtype of retinoblastoma remains unclear and further scientific investigations seem appropriate. Several hypotheses have already been discussed that include variation in the immune response against tumor antigens;6 mutation of a heterotopic precursor cell in the anterior chamber;8 or we include a new theory of certain mutation of the tumoral adhesive molecules that provoke the specific growth pattern. Genetic testing should be offered to patients with diffuse infiltrating retinoblastoma. Genetic counseling and further examinations for associated neoplasms such as osteosarcoma, cutaneous
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
!
2014 Informa Healthcare USA, Inc.
ACKNOWLEDGEMENTS Several pictures were acquired with the help of the Department of Pathology, UFSC, Florianopolis, Brazil. The collection and dispatch was supported by Dra. Maria Elizabeth Menezes and Dra. Ana Latorre from DNAnalise Laboratory, Florianopolis, Brazil. Genetic testing was performed by the Eye Cancer Genetics Group at the University of Duisburg-Essen, Germany. We thank Mrs Birgit Ansperger-Rescher for expert technical assistance.
REFERENCES 1. Melamud A, Palekar R, Singh A. Retinoblastoma. Am Fam Physician 2006;73:1039–1044. 2. Woo KI, Harbour JW. Review of 676 second primary tumors in patients with retinoblastoma: association between age at onset and tumor type. Arch Ophthalmol 2010;128:865–870. 3. Shields CL, Ghassemi F, Tuncer S, et al. Clinical spectrum of diffuse infiltrating retinoblastoma in 34 consecutive eyes. Ophthalmology 2008;115:2253–2258. 4. Materin MA, Shields CL, Shields JA, Eagle Jr RC. Diffuse infiltrating retinoblastoma simulating uveitis in a 7-year-old boy. Arch Ophthalmol 2000;118:442. 5. Zhang K, Nowak I, Rushlow D, et al. Patterns of missplicing caused by RB1 gene mutations in patients with retinoblastoma and association with phenotypic expression. Human Mutation 2008;29:475–484. 6. Kao LY. Diffuse infiltrating retinoblastoma: an inherited case. Retina 2000;20:217–219. 7. Crosby MB, Hubbard GB, Gallie BL, Grossniklaus HE. Anterior diffuse retinoblastoma: mutational analysis and immunofluorescence staining. Arch Pathol Lab Med 2009; 133:1215–1218. 8. Herwig MC, Hubbard GB, Wells JR, Grossniklaus HE. Diffuse anterior retinoblastoma. Ophthalmologe 2011;108: 969–972.
C ASE REPORT
Hereditary Diffuse Infiltrating Retinoblastoma Katharina J. E. Schedler1, Peter G. Traine1, Dietmar R. Lohmann2, Christos Haritoglou3, Klaus A. Metz4, and Eduardo B. Rodrigues5
Ophthalmic Genet Downloaded from informahealthcare.com by Korea University on 12/25/14 For personal use only.
1
Department of Ophthalmology, Clinic Pallas, Olten, Switzerland, 2Institute of Human Genetics, Faculty of Medicine, University Duisburg-Essen, Essen, Germany, 3Department of Ophthalmology, Ludwig Maximilians University, Munich, Germany, 4Institute of Pathology and Neuropathology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany, and 5Department of Ophthalmology, Vision Institute – IPEPO, Federal University of Sa˜o Paulo, Sa˜o Paulo, Brazil
ABSTRACT Retinoblastoma is one of the most common childhood cancers. The diffuse infiltrating retinoblastoma is a rare subtype of this neoplasm. The majority of cases of diffuse infiltrating retinoblastoma are unilateral and occur sporadically. Herein we report on a family with three children affected by retinoblastoma, among them one girl with diffuse infiltrating retinoblastoma. This girl was diagnosed at the age of 8 years with a unilateral diffuse infiltrating retinoblastoma. By contrast, the two brothers became clinically apparent in the first 2 years of life with bilateral retinoblastoma. The parents were clinically unremarkable. Genetic analysis of RB1 gene was performed. The girl with diffuse infiltrating RB was found to be heterozygous for an oncogenic mutation in the RB1 gene that was also carried by both brothers and the father of the family. These results show that diffuse infiltrating retinoblastoma can develop on the background of a hereditary predisposition to retinoblastoma. Keywords: Genetics, retina, retinoblastoma
INTRODUCTION
retinoblastoma and has a diffuse growth pattern infiltrating the retina.3 Single tumor cells may enter into the vitreous and the anterior chamber, mimicking uveitis without presenting a macroscopic tumor mass. The tumor grows slowly and the mean age of patients at diagnosis is about 4 years.3 The diffuse infiltrating retinoblastoma is described to occur sporadically.3 Herein we report on a family, wherein all three children were affected by retinoblastoma. The girl presented with a unilateral diffuse infiltrating retinoblastoma, the two brothers with bilateral retinoblastoma. Genetic analysis of the RB1 gene identified a mutation in the RB1 gene in all three children and the father. This finding allows the conclusion that diffuse infiltrating retinoblastoma can occur on the background of a heritable predisposition to retinoblastoma.
Retinoblastoma is one of the most common childhood cancers. Approximately 60% of cases occur secondary to non-hereditary somatic mutations. These patients develop predominantly unilateral, solitary tumors. The remaining 40% of cases result from heritable, germline mutations (10% have a positive family history of retinoblastoma, while 30% are new-onset germline mutations without a pre-existing family history).1 The heritable form of retinoblastoma usually presents as a multifocal tumor that most frequently occurs bilaterally, at a mean age of 1.2 years.2 The diffuse infiltrating retinoblastoma is a rare subtype of retinoblastoma. It accounts for about 2% of
Received 9 December 2013; revised 23 March 2014; accepted 11 April 2014; published online 3 June 2014 Correspondence: Katharina Schedler, Aarepark 5c, 5000 Aarau, Switzerland. Tel: +41 767709237. Fax: +49 7082413835. E-mail: [email protected]
1
2
K. J. E. Schedler et al.
Ophthalmic Genet Downloaded from informahealthcare.com by Korea University on 12/25/14 For personal use only.
CASE REPORT An 8-year-old Caucasian girl presented with 6 days history of conjunctival redness and a small whitish discoloration of the iris in the right eye. She reported unilateral reduction in vision and denied pain. The previous medical and ophthalmic history was unremarkable. In both brothers, bilateral retinoblastoma was diagnosed in the first few months of life. In the right eye, the corrected visual acuity was 20/80, and the intraocular pressure was 20 mmHg. The left eye was unremarkable. The right eye showed moderate injection, corneal edema, and a pseudohypopyon of 2 mm (Figure 1, upper panel). There was flare and cells (2+) in the anterior chamber and heterochromia of the iris. Gonioscopy showed a white-colored thickening on the iris root and the trabecular meshwork. The presence of corneal edema and dense vitreous inflammation made clinical examination of the posterior segment difficult. Ultrasonography showed vitreous seeds as hyperecogenic peaks but there was no evidence of retinal calcifications (Figure 1, lower panel). Computed tomography of the orbit and the skull, and a chest X-ray, to exclude other reasons for uveitis like tuberculosis or sarcoidosis, did not show
FIGURE 1. Upper panel: Anterior segment photo of the right eye showing a mixed injection and a pseudohypopyon of about 2 mm. Lower panel: Ultrasonography showing intravitreous hyperecogenic peaks, but no retinal calcifications.
abnormal findings. The requested MRI of the orbit and skull showed only a slight thickening of the retina, but no evidence of a tumoral mass. With increased clinical deterioration, i.e. visual decline and progressive inflammation, 1 month after the initial presentation, a suspected retinoblastoma was treated with systemic chemotherapy with vincristine, etoposide, and carboplatin (6 cycles), followed by enucleation. Compatible with a diffuse infiltrative retinoblastoma, histological findings showed a small focal retinal infiltration and an invasion of poorly differentiated cells (grade 3) with large basophilic nuclei and scanty cytoplasm in the ciliary body accounting for the involvement of the anterior chamber. There was no choroidal infiltration and no infiltration of the optic nerve. Compatible with an undifferentiated retinoblastoma, there were no Flexner-Wintersteiner and no Homer-Wright rosettes found (Figure 2). Histopathological stage was pT1, pNx. A mutational analysis of the RB1 gene of the children and their non-phenotypic parents was performed using PCR and sequencing analysis of the promoter, exons 2 to 27 and flanking intron regions,
FIGURE 2. Histopathology of the right eye. Upper panel: Diffuse thickening of the retina by tumor cells. Lower panel: Tumor cells in the ciliary body, in the posterior part of the iris and in the anterior chamber. Ophthalmic Genetics
Ophthalmic Genet Downloaded from informahealthcare.com by Korea University on 12/25/14 For personal use only.
Hereditary Diffuse Infiltrating Retinoblastoma
3
comparing sequencing data with a reference (L11910). The father and all three children were found to be heterozygous for the RB1 gene mutation NM_000321.2: c.1050-3_1050-1delinsAA. This mutation disrupts the normal splice acceptor site of intron 10 and, most likely, results in skipping of exon 11,5 which causes a frameshift and premature termination. In all probability it is the cause of heritable predisposition to retinoblastoma in this family. It appears that the father is a heterozygous carrier of the mutation with incomplete penetrance. However, we cannot exclude that he has mutational mosaicism although we did not note a distortion of the mutant to normal signal ratio in sequence analysis on DNA from blood of the father.
melanoma, and leiomyosarcoma should be offered to all patients with germline mutation.
DISCUSSION
DECLARATION OF INTEREST
Diffuse infiltrating retinoblastoma is characterized by its specific growth pattern with a relatively flat infiltration of the retina and tumoral cells spreading to the vitreous and anterior structures of the eye. It has mostly been described to occur sporadically. There are only two case reports that hypothesize a hereditary component.6,7 Our patient with diffuse infiltrating retinoblastoma, her brothers with bilateral retinoblastoma and their parents underwent genetic testing. In all children and the father we identified the same oncogenic RB1 gene mutation, that in all likelihood causes heritable predisposition for retinoblastoma in this family. Therefore one can assume that diffuse infiltrating retinoblastoma can be heritable. The reason for the specific growth pattern of the subtype of retinoblastoma remains unclear and further scientific investigations seem appropriate. Several hypotheses have already been discussed that include variation in the immune response against tumor antigens;6 mutation of a heterotopic precursor cell in the anterior chamber;8 or we include a new theory of certain mutation of the tumoral adhesive molecules that provoke the specific growth pattern. Genetic testing should be offered to patients with diffuse infiltrating retinoblastoma. Genetic counseling and further examinations for associated neoplasms such as osteosarcoma, cutaneous
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
!
2014 Informa Healthcare USA, Inc.
ACKNOWLEDGEMENTS Several pictures were acquired with the help of the Department of Pathology, UFSC, Florianopolis, Brazil. The collection and dispatch was supported by Dra. Maria Elizabeth Menezes and Dra. Ana Latorre from DNAnalise Laboratory, Florianopolis, Brazil. Genetic testing was performed by the Eye Cancer Genetics Group at the University of Duisburg-Essen, Germany. We thank Mrs Birgit Ansperger-Rescher for expert technical assistance.
REFERENCES 1. Melamud A, Palekar R, Singh A. Retinoblastoma. Am Fam Physician 2006;73:1039–1044. 2. Woo KI, Harbour JW. Review of 676 second primary tumors in patients with retinoblastoma: association between age at onset and tumor type. Arch Ophthalmol 2010;128:865–870. 3. Shields CL, Ghassemi F, Tuncer S, et al. Clinical spectrum of diffuse infiltrating retinoblastoma in 34 consecutive eyes. Ophthalmology 2008;115:2253–2258. 4. Materin MA, Shields CL, Shields JA, Eagle Jr RC. Diffuse infiltrating retinoblastoma simulating uveitis in a 7-year-old boy. Arch Ophthalmol 2000;118:442. 5. Zhang K, Nowak I, Rushlow D, et al. Patterns of missplicing caused by RB1 gene mutations in patients with retinoblastoma and association with phenotypic expression. Human Mutation 2008;29:475–484. 6. Kao LY. Diffuse infiltrating retinoblastoma: an inherited case. Retina 2000;20:217–219. 7. Crosby MB, Hubbard GB, Gallie BL, Grossniklaus HE. Anterior diffuse retinoblastoma: mutational analysis and immunofluorescence staining. Arch Pathol Lab Med 2009; 133:1215–1218. 8. Herwig MC, Hubbard GB, Wells JR, Grossniklaus HE. Diffuse anterior retinoblastoma. Ophthalmologe 2011;108: 969–972.
