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, arraycomparative 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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13q Deletion syndrome in monozygotic twins

Fig. 1 - (A) Twin 1: unilateral, multifocal retinoblastoma (left eye). (B) Twin 2: unilateral, unifocal retinoblastoma (right eye).

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ute and 5 minutes), low birthweight (twin 1, 2040 g [<[minus]1 SD]; twin 2, 1950 g [<[minus]1 SD]), a length of 42 cm (<[minus]2 SD), brachycephaly (twin 1, 31.5 cm [10th 25th centile]; twin 2, 40 cm [3rd10th centile]), and peculiar facial features such as prominent eyebrows, broad nasal bridge, large, prominent, low-set ears, bulbous nasal tip, large mouth, and thin upper lip. They also showed marked hypotonia, gastroesophageal reflux, interatrial septal defect with left to right shunt and light dilatation of right chambers, 5th finger hypoplasia, 3rd5th toes clinodactyly, 2nd toe overlapped to 3rd, and cutis marmorata. By age 5 months, after a convulsive crisis, twin 1 was referred to our department under suspicion of unilateral, multifocal retinoblastoma in the left eye. Twin 2, seen at the same time, had no evidence of retinoblastoma. The karyotype of both babies was promptly performed. In spite of the recommendation for a monthly control, twin 2 returned at age 9 months, after a white reflex was noticed in her right eye. A unilateral unifocal retinoblastoma was detected. On ophthalmoscopic examination, the anterior segment, lens, and vitreous showed no significant findings in both twins. Indirect ophthalmoscopy of the left eye in twin 1 revealed 2 tumors; the larger one of 10 10 disk diameters and the smaller one of 6 6 disk diameters in the posterior pole. The right eye was normal. Indirect ophthalmoscopy of the right eye in twin 2 revealed a single avascular balloon-like mass of 6.5 6.5 disk diameters in the inferonasal periphery. The left eye was unaffected (Fig. 1). In both cases, B-mode ultrasonography documented solid masses compatible with retinoblastoma. Both twins were conservatively treated. Twin 1 achieved complete remis-

and nasal bridge, thin and arched upper lip, long philtrum (65%), low-set ears (90%), and cardiac and renal anomalies (3, 4). Neurologic abnormalities often are present in patients with 13q deletion syndrome (5). The majority of patients display impaired mental functions and motor deficits. Epilepsy may be present and usually takes the form of infantile spasms. Structural anomalies of the brain often underline these manifestations. Holoprosencephaly and encephalocele are major malformations, but neural tube defects and agenesis of corpus callosum also have been reported, the condition resulting from abnormal midline prosencephalic development (6). Defects in the skeletal system include absent or hypoplastic thumbs, brachyphalangia of the middle phalanx of the little finger (clinodactyly), and bony synostosis of the metacarpals. Foot anomalies such as clubfoot, short great toe, and syndactyly of the fourth and fifth toes also have been described.

Case report
The case of unilateral retinoblastoma occurring in dichorionic diamniotic monozygotic twins is reported. By definition, dichorionic diamniotic twins are twins having 2 distinct chorions and developing in two separate amniotic cavities (Available at: http://medical-dictionary.thefreedictionary. com/monozygotic+twins); in the case reported herein, they were monozygotic, thus implying that they both derived from one fertilized oocyte (Available at: http://medical-dictionary. thefreedictionary.com/twin). The family history was negative for retinoblastoma. The pregnancy was natural. At birth, both twins had normal Apgar score (10 at 1 min858

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De Francesco et al

Fig. 2 - (A) T2-weighted axial and (B) T1-weighted sagittal images of the brain showing diffuse hypoplastic corpus callosum, with thinning of rostrum, genu, and anterior body and very thin posterior body.

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34.63 and 34.94 Mb (last oligonucleotide present and first deleted, respectively), while the distal breakpoint was located between 68.88 and 69.02 Mb in 13q21.33 (last oligonucleotide deleted and first present, respectively). The deletion was absent in parents and older brother. Further follow-up was characterized by severely delayed psychomotor development and marked hypotonia.

sion after 6 cycles of chemotherapy with carboplatin and etoposide, focal therapy (photocoagulation), and 1 cycle of intra-arterial chemotherapy (3 injections of melphalan at intervals of 21 days). Twin 2 was treated with brachytherapy and regression type IV (atrophic chorioretinal scar) was achieved. MRI detected hypoplasia of corpus callosum in both twins. T2-weighted axial and T1-weighted sagittal images of the brain showed diffuse hypoplasia of the corpus callosum; particularly thinning of rostrum, genu, and anterior body and very thin posterior body was visible; tapering of the hypoplastic splenium is also appreciable (Fig. 2). Patients underwent a comprehensive clinical evaluation by geneticists. Genetic tests were performed after informed consent. Multiple ligation-dependent probe amplification (MLPA) analysis using Kit P047 (MRC-Holland, Amsterdam, the Netherlands), containing probes specific for all RB1 exons excluding exons 5, 10, 15, and 16 and for the near genes (ITM2B, DLEU1, and CHCIL), was performed to search for the RB1 deletion. In order to define deletion size and breakpoints, whole genome arraycomparative genomic hybridization (CGH) analysis was performed using commercially available oligonucleotide microarrays containing about 43,000 60-mer probes (Human Genome CGH Microarray 44B Kit, Agilent Technologies, Santa Clara, California, USA). A combination of MLPA and array-CGH analyses showed in both twins a 34.4-Mb deletion of long arm of chromosome 13. The proximal breakpoint was mapped in 13q13.2, between

DISCUSSION
Approximately 5% and 10% of patients with retinoblastoma demonstrate a karyotypic visible deletion of the chromosomal region 13q14 (7-9). Retinoblastoma rarely occurs in twins, and in most cases involving dizygotic twins, only one twin is affected. However, retinoblastoma in twins with no evidence of 13q deletion syndrome has been described. In 1950, Walker (10) described the case of discordant monozygotic twins, one with retinoblastoma and one with cleft palate. Spontaneous regression of retinoblastoma in 2 identical twins with positive family history was reported by Migdal (11). Boniuk and Zimmerman (12) reported identical twins with unilateral retinoblastoma. A case of an homologous retinoblastoma in identical twins developed from a single ovum was reported by Benedict (13). Duncan and Maynard (14) reported a case of Italian twins affected by bilateral retinoblastoma, which they described 859

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13q Deletion syndrome in monozygotic twins

as a case of identical tumors in identical twins. In 1947, Falls (15) described a case of monozygotic twins, each with bilateral retinoblastoma. In 1929, Moore and Scott (16) reported a similar case. To our knowledge, this is the first report of dichorionic diamniotic identical monozygotic twins both affected by unilateral retinoblastoma and 13q deletion syndrome, but the cases reported herein also have other relevant implications for a better understanding of the pathogenesis of retinoblastoma and genotypephenotype correlations. As a matter of fact, as previously reported by us elsewhere (17), there is an evident discrepancy between expected and real incidence of bilateral retinoblastoma among patients affected by the 13q deletion syndrome. The case

reported herein confirms that constitutional deletions of RB1 gene do not necessarily determine the bilateral disease phenotype, and this feature deserves further indepth investigation.
Supported by the AIGR/ONLUS Associazione Italiana Genitori Retinoblastoma. The authors report no proprietary interest. Address for correspondence: Domenico Mastrangelo, MD Department of Biomedical Sciences University of Siena Viale Bracci 53100 Siena, Italy mastrangelo@unisi.it

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