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Eur J Ophthalmol 2012; 22 ( 5 ): 857-860

DOI: 10.5301/ejo.5000151

CASE REPORT

13q Deletion syndrome and retinoblastoma in identical dichorionic diamniotic monozygotic twins
Sonia De Francesco1, Paolo Galluzzi2, Alessandra Del Longo3, Elena Piozzi3, Alessandra Renieri4, Cristina Menicacci5, Francesca Mari4, Francis Munier6, Theodora Hadjistilianou1, Domenico Mastrangelo7
Retinoblastoma Referral Center, University of Siena, Siena - Italy NINT (NeuroImaging and NeuroInterventional) Unit, Azienda Ospedaliera Senese, Siena - Italy 3 Unit of Pediatric Ophthalmology, Niguarda Hospital, Milan - Italy 4 Unit of Medical Genetics, University of Siena, Siena - Italy 5 Department of Ophthalmology, University of Siena, Siena - Italy 6 Hopital Jules Gonin, Lausanne - Switzerland 7 Department of Biomedical Sciences, University of Siena, Siena - Italy
1 2
Unit of Pediatric Ophthalmology, Niguarda Hospital, Milan - Italy Retinoblastoma Referral Center, University of Siena, Siena - Italy Unit of Medical Genetics, University of Siena, Siena - Italy Unit of Pediatric Ophthalmology, Niguarda Hospital, Milan - Italy

PurPose. To report the case of identical dichorionic diamniotic female twins with unilateral retinoblastoma in 13q deletion syndrome. Methods. Clinical and ophthalmoscopic evaluation, combination of multiple ligation-dependent probe amplification, array–comparative genomic hybridization analyses, and magnetic resonance imaging were performed. results. Peculiar facial features, marked hypotonia, gastroesophageal reflux, interatrial septal defect with left to right shunt and light dilatation of right chambers, 5th finger hypoplasia, 3rd-5th toes clinodactyly, 2nd toe overlapped to 3rd toe, and cutis marmorata were found. Ophthalmoscopic evaluation revealed unilateral retinoblastoma in both girls. Magnetic resonance imaging detected corpus callosum hypoplasia in both twins. A 34.4-Mb deletion involving bands 13q13.2-q21.33 and including the RB1 gene was identified in both twins. The deletion was not present in the DNA of their parents and older brother. ConClusions. Dysmorphic features in children must be always suspicious of 13q deletion syndrome and a short ophthalmoscopic follow-up is necessary to detect the presence of a retinoblastoma. Key words. 13qdel syndrome, Corpus callosum hypoplasia, Monozygotic twins, Retinoblastoma
Accepted: March 1, 2012

INTRODUCTION
Retinoblastoma is the most common eye cancer in infancy (1). Between 5% and 10% of hereditary retinoblastoma can be related to chromosome deletions involving the RB1 locus in 13q14. The majority of these aberrations are interstitial deletions at chromosome band 13q14 with variable size. The extent of the deletions affecting the long arm of chromosome 13 may result in various developmental anomalies that constitute the 13q deletion syndrome, characterized by mental retardation, structural malformations, facial dysmorphism, and predisposition to develop retinoblastoma (approximately 80%) (2). Large deletions affect additional regions in the long arm of chromosome 13 and result in various development anomalies that constitute 13q deletion syndrome. The larger the deletion, the more severe the phenotypic syndrome. These children typically have a moderate to severe development delay, mental retardation, structural brain malformations, and dysmorphic features such as broad forehead (85%) 857

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and vitreous showed no significant findings in both twins. thus implying that they both derived from one fertilized oocyte (Available at: http://medical-dictionary. Foot anomalies such as clubfoot. twin 2 returned at age 9 months.(A) Twin 1: unilateral. Structural anomalies of the brain often underline these manifestations. had no evidence of retinoblastoma. multifocal retinoblastoma in the left eye. The right eye was normal. Both twins were conservatively treated. The karyotype of both babies was promptly performed. thin and arched upper lip. The family history was negative for retinoblastoma. prominent. seen at the same time. and bony synostosis of the metacarpals. dichorionic diamniotic twins are twins having 2 distinct chorions and developing in two separate amniotic cavities (Available at: http://medical-dictionary. large mouth.5 cm [10th– 25th centile]. the anterior segment. but neural tube defects and agenesis of corpus callosum also have been reported. a length of 42 cm (<[minus]2 SD). low-set ears. In both cases. they were monozygotic. lens.ISSN 1120-6721 . 40 cm [3rd–10th centile]).5 disk diameters in the inferonasal periphery. 5th finger hypoplasia. both twins had normal Apgar score (10 at 1 min858 © 2012 Wichtig Editore . At birth. Twin 2.com/twin). and cutis marmorata. Case report The case of unilateral retinoblastoma occurring in dichorionic diamniotic monozygotic twins is reported. the larger one of 10 × 10 disk diameters and the smaller one of 6 × 6 disk diameters in the posterior pole. They also showed marked hypotonia.13q Deletion syndrome in monozygotic twins Fig. On ophthalmoscopic examination. unifocal retinoblastoma (right eye). low-set ears (90%). Defects in the skeletal system include absent or hypoplastic thumbs. By definition. multifocal retinoblastoma (left eye). twin 2. 31. after a convulsive crisis. and syndactyly of the fourth and fifth toes also have been described. and thin upper lip. Indirect ophthalmoscopy of the left eye in twin 1 revealed 2 tumors. after a white reflex was noticed in her right eye. broad nasal bridge. Indirect ophthalmoscopy of the right eye in twin 2 revealed a single avascular balloon-like mass of 6.5 × 6. thefreedictionary. twin 1 was referred to our department under suspicion of unilateral. and peculiar facial features such as prominent eyebrows. low birthweight (twin 1. Neurologic abnormalities often are present in patients with 13q deletion syndrome (5). (B) Twin 2: unilateral. bulbous nasal tip. short great toe. 4). the condition resulting from abnormal midline prosencephalic development (6). The majority of patients display impaired mental functions and motor deficits. in the case reported herein. 1950 g [<[minus]1 SD]). By age 5 months. The pregnancy was natural. 2nd toe overlapped to 3rd.thefreedictionary. A B ute and 5 minutes). The left eye was unaffected (Fig. Holoprosencephaly and encephalocele are major malformations. gastroesophageal reflux. In spite of the recommendation for a monthly control. twin 2. 2040 g [<[minus]1 SD]. Twin 1 achieved complete remis- and nasal bridge. and cardiac and renal anomalies (3. brachyphalangia of the middle phalanx of the little finger (clinodactyly). 1). A unilateral unifocal retinoblastoma was detected. long philtrum (65%). Epilepsy may be present and usually takes the form of infantile spasms. 1 . 3rd–5th toes clinodactyly. B-mode ultrasonography documented solid masses compatible with retinoblastoma. com/monozygotic+twins). interatrial septal defect with left to right shunt and light dilatation of right chambers. large. brachycephaly (twin 1.

Amsterdam. The deletion was absent in parents and older brother.94 Mb (last oligonucleotide present and first deleted. Walker (10) described the case of discordant monozygotic twins. sion after 6 cycles of chemotherapy with carboplatin and etoposide.000 60-mer probes (Human Genome CGH Microarray 44B Kit.02 Mb in 13q21. USA). respectively). and anterior body and very thin posterior body. between DISCUSSION Approximately 5% and 10% of patients with retinoblastoma demonstrate a karyotypic visible deletion of the chromosomal region 13q14 (7-9). containing probes specific for all RB1 exons excluding exons 5. Genetic tests were performed after informed consent. 15.33 (last oligonucleotide deleted and first present. The proximal breakpoint was mapped in 13q13. Retinoblastoma rarely occurs in twins. retinoblastoma in twins with no evidence of 13q deletion syndrome has been described. However. genu. 2). and in most cases involving dizygotic twins. A case of an homologous retinoblastoma in identical twins developed from a single ovum was reported by Benedict (13). Spontaneous regression of retinoblastoma in 2 identical twins with positive family history was reported by Migdal (11).De Francesco et al Fig.ISSN 1120-6721 . California. respectively). whole genome array–comparative genomic hybridization (CGH) analysis was performed using commercially available oligonucleotide microarrays containing about 43. which they described 859 © 2012 Wichtig Editore . and 1 cycle of intra-arterial chemotherapy (3 injections of melphalan at intervals of 21 days). particularly thinning of rostrum. only one twin is affected. A B 34. T2-weighted axial and T1-weighted sagittal images of the brain showed diffuse hypoplasia of the corpus callosum. was performed to search for the RB1 deletion. Patients underwent a comprehensive clinical evaluation by geneticists. and 16 and for the near genes (ITM2B.(A) T2-weighted axial and (B) T1-weighted sagittal images of the brain showing diffuse hypoplastic corpus callosum. 10. Santa Clara. Twin 2 was treated with brachytherapy and regression type IV (atrophic chorioretinal scar) was achieved.2. with thinning of rostrum. Duncan and Maynard (14) reported a case of Italian twins affected by bilateral retinoblastoma. MRI detected hypoplasia of corpus callosum in both twins.4-Mb deletion of long arm of chromosome 13. Boniuk and Zimmerman (12) reported identical twins with unilateral retinoblastoma. the Netherlands). In order to define deletion size and breakpoints. Agilent Technologies. Further follow-up was characterized by severely delayed psychomotor development and marked hypotonia. while the distal breakpoint was located between 68. In 1950. genu. focal therapy (photocoagulation). DLEU1. tapering of the hypoplastic splenium is also appreciable (Fig. Multiple ligation-dependent probe amplification (MLPA) analysis using Kit P047 (MRC-Holland.88 and 69. A combination of MLPA and array-CGH analyses showed in both twins a 34. and CHCIL). 2 . and anterior body and very thin posterior body was visible. one with retinoblastoma and one with cleft palate.63 and 34.

Address for correspondence: Domenico Mastrangelo. Ophthalmic Paediatr Genet 1989. Mastrangelo D. de Graaf P. Speciale C. 22: 951-62. Mitter D. Woods WG. The case reported herein confirms that constitutional deletions of RB1 gene do not necessarily determine the bilateral disease phenotype. De Francesco S. The authors report no proprietary interest. this is the first report of dichorionic diamniotic identical monozygotic twins both affected by unilateral retinoblastoma and 13q deletion syndrome. Kenue RK. Rodjan F. Homologous retinoblastoma in identical twins. 93: 1129-31. et al. 2: 375-84. Constitutional karyotype in retinoblastoma. MD Department of Biomedical Sciences University of Siena Viale Bracci 53100 Siena. Retinoblastoma and the genetic theory of cancer: an old paradigm trying to survive to the evidence. Jotterand-Bellomo M. Br J Ophthalmol 1982. To our knowledge. Emanuel BS. J Hum Genet 2007. Brain abnormalities on MR imaging in patients with retinoblastoma. 27: 173-6. 12. Italy mastrangelo@unisi. J Med Genet 2007. 10. Mitra S. Pescucci C. 3. J Natl Cancer Inst 1989. 45: 52-9. 13. 66: 691-4. Epub 2009 Oct 27. 860 © 2012 Wichtig Editore . 9. Spontaneous regression of retinoblastoma.13q Deletion syndrome in monozygotic twins as a case of “identical tumors in identical twins. Retinoblastoma and the 13q deletion syndrome. 5. Br J Ophthalmol 2009. Genotype-phenotype correlations in patients with retinoblastoma and interstitial 13q deletions. Walker NF. 11. Am J Med Genet 1993. 13q Deletion and central nervous system anomalies: further insights from karyotype phenotype analyses of 14 patients. Kivelä T. et al. Rados A. Bunin GR. Scott RS. Hadjistilianou T. Ullmann R.ISSN 1120-6721 . Warburton D. Muradyan A. et al. Moore and Scott (16) reported a similar case. 31: 1385-9. Loré C. 6. Frequency of 13q abnormalities among 203 patients with retinoblastoma. The epidemiological challenge of the most frequent eye cancer: retinoblastoma. In 1929. 2. an issue of birth and death. 10: 129-50. Brown S. there is an evident discrepancy between expected and real incidence of bilateral retinoblastoma among patients affected by the 13q deletion syndrome. Moore RF. J Cancer Epidemiol 2009. Falls (15) described a case of monozygotic twins. 4. Preliminary definition of a “critical region” of chromosome 13 in q32: report of 14 cases with 13q deletions and review of the literature. Proc R Soc Med 1929. Am J Hum Genet 1950. 8. Clinical and pathological report of bilateral glioma retinae. Occurrence of glioma of retina and brain in collateral lines in same family. Pescia G. Int Ophthalmol Clin 1962. Migdal C. Discordant monozygotic twins with retinoblastoma and cleft palate. D Eur J Hum Genet 2011. Caselli R. 44: e60. 15. As a matter of fact. 133: 171-4.” In 1947. 19: 947-58. as previously reported by us elsewhere (17). 52: 535-42. Case report and review of literature. but the cases reported herein also have other relevant implications for a better understanding of the pathogenesis of retinoblastoma and genotype–phenotype correlations. AJNR Am J Neuroradiol 2010. 16. 2: 525-42. Hammond GD. J Am Med Assoc 1947. Munier F. 14. Rossi E. 38: 247-50. Gersen S. Arch Ophthal 1946. Supported by the AIGR/ONLUS Associazione Italiana Genitori Retinoblastoma. Moll AC. Retinoblastoma and mental retardation microdeletion syndrome: clinical characterization and molecular dissection using array CGH. 81: 370-4. Trans Am Ophthalmol Soc 1929. Inheritance of retinoblastoma: two families supplying evidence. et al. Ballarati L. 35(1): 1-12 Falls HF. Bonati MT. Meadows AT. and this feature deserves further indepth investigation. 17. Buckley JD. each with bilateral retinoblastoma. Anyane-Yeboa K.it REFERENCES 1. Ganesh A. et al. Spontaneous regression of retinoblastoma in identical twins. Boniuk M. Benedict WL. J Pediatr Ophthalmol Strabismus 2001. Zimmerman LE. 7.

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