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. 2024 Mar 11;12(3):e2414. doi: 10.1002/mgg3.2414

Retinoblastoma and polydactyly in a child with 46, XY, 15pstk+ karyotype—A case report and literature review

Xiaohuan Pi 1, Qiming Zhang 1, Xinghua Wang 2, Fagang Jiang 2,✉
PMCID: PMC10926652  PMID: 38465842

Abstract

Background

Retinoblastoma (Rb) is the most common intraocular malignancy in childhood, originating from primitive retinal stem cells or cone precursor cells. It can be triggered by mutations of the RB1 gene or amplification of the MYCN gene. Rb may rarely present with polydactyly.

Methods

We conducted karyotype analysis, copy number variation sequencing, and whole‐genome sequencing on the infant proband and his family. The clinical course and laboratory results of the proband's infant were documented and collected. We also reviewed the relevant literature.

Results

A 68‐day‐old boy presented with preaxial polydactyly and corneal edema. His intraocular pressure (IOP) was 40/19 mmHg, and color Doppler imaging revealed vitreous solid mass‐occupying lesions with calcification in the right eye. Ocular CT showed flaky high‐density and calcification in the right eye. This was classified as an International Retinoblastoma Staging System group E retinoblastoma with an indication for enucleation. Enucleation and orbital implantation were performed on the child's right eye. Karyotype analysis revealed an abnormal 46, XY, 15pstk+ karyotype, and the mother exhibited diploidy of the short arm of chromosome 15. The Alx‐4 development factor, 13q deletion syndrome, and the PAPA2 gene have been reported as potential mechanisms for Rb combined with polydactyly.

Conclusion

We report the case of a baby boy with Rb and polydactyly exhibiting a 46, XY, 15pstk+ Karyotype. We discuss potential genetic factors related to both Rb and polydactyly. Furthermore, there is a need for further exploration into the impact of chromosomal polymorphisms in Rb with polydactyly.

Keywords: abnormal karyotype, case report, polydactyly, retinoblastoma

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1. INTRODUCTION

Retinoblastoma (Rb) is a congenital malignant neoplasm of the retina, always fatal if left untreated. The incidence of retinoblastoma is one in every 16,000 to 18,000 live births (Rushlow et al., 2013). Leukocoria is the most common initial sign of retinoblastoma, followed by proptosis, swelling, and strabismus (Abramson et al., 1998; Bowman et al., 2008; Goddard et al., 1999; Menon et al., 2009). Retinoblastoma can be initiated by mutations in the RB1 gene (OMIM:180200), the first‐described tumor‐suppressor gene (Abramson et al., 2003; Comings, 1973; Friend et al., 1986; Knudson Jr., 1971), and can also be triggered by the MYCN gene (OMIM:164840) amplification (Dimaras & Corson, 2019). Polydactylism refers to the occurrence of redundant digits, toes, or any complex duplication of digital parts. The incidence rate is estimated at 1.6–10.7/1000 in general populations, 0.3–3.6/1000 in live births, and males are often affected twice as often as females (Umair et al., 2018). Rb may rarely present with polydactyly. Here, we report a 68‐day‐old baby with retinoblastoma and polydactyly and review the relevant literature.

2. CASE PRESENTATION

A 68‐day‐old baby boy was referred to our hospital on 5 December 2019, due to corneal edema persisting for 11 days in his right eye. The baby was full‐term with no family history. Ocular examination revealed cornea edema (Figure 1a) with a relatively shallow anterior chamber. Intraocular pressure was 40 mmHg in his right eye and 19 mmHg in his left eye. Systemic examination was normal, except for preaxial polydactyly in the left hand (Figure 1a). Color Doppler flow imaging showed a solid vitreous mass of 17.3 × 18.1 mm with calcification in his right eye, accompanied by incomplete lens dislocation and local retinal detachment (Figure 1b). Computed tomography (CT) revealed a flake high‐density mass with calcification in the right eye, approximately 1.7 × 1.2 cm in cross‐section (Figure 1c). The child was diagnosed with intraocular tumor (suspicious retinoblastoma, International Retinoblastoma Staging System group E), secondary glaucoma in the right eye, and preaxial polydactyly in the left hand.

FIGURE 1.

FIGURE 1

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Right eye appearance (5 December 2019) and preaxial polydactyly in the baby's left hand (a). Color Doppler flow imaging (5 December 2019) showed continuous blood flow between the tumor and the central artery and vein of the retina (b). CT scan (5 December 2019) revealed a flake high‐density shadow with calcification in the right eye (c). The tumor cells exhibited highly proliferated (20 December 2019), displaying abundant mitosis and necrosis (HE, ×200) (d). Positive immunohistochemical staining (20 December 2019) with Syn (×200) (e). Ki‐67 (20 December 2019) showed a low proliferation index (×200) (f). Post‐operative appearance (10 March 2021) photo (g). MRI (10 March 2021) showed an orbital implant on the T1‐weighted image (h) and a thin ocular prosthesis on the T2‐weighted image (i).

The right eye enucleation and orbital implantation were performed. Pathology confirmed retinoblastoma with prominent necrosis. The tumor cells were predominantly composed of a large basophilic nucleus and small cytoplasm (Figure 1d), expressing synaptophysin (Syn) (Figure 1e) and CD56, and partially defined neuron‐specific enolase (NSE) and chromogranin A (CgA). Conversely, they did not express pan‐cytokeratin (PCK), S‐100, CD99, and glial fibrillary acidic protein (GFAP) and had a low Ki‐67 index (Figure 1f).

Over the 2‐year follow‐up, the child remained generally healthy with no noticeable changes in the left eye. Magnetic resonance imaging (MRI) revealed an orbital implant on the T1‐weighted image (T1WI) and a thin ocular prosthesis on the T2‐weighted image (T2WI). The right optic nerve was absent on both T1WI and T2WI (Figure 1g,h). During this follow‐up, with the family's consent, we conducted related genetic testing, including karyotype analysis, copy number variation sequencing (CNV‐seq), and whole exome sequencing (WES).

3. METHODS

This study was conducted according to the Declaration of Helsinki, meeting all requirements for a retrospective study in humans. Clinical data, images, and peripheral blood samples were collected after obtaining informed consent, as approved by the Institutional Research Ethics Committee.

3.1. Karyotype analysis

The G‐banding technique was employed for karyotype analysis using peripheral blood samples from the child and his parents. Twenty metaphase cells were analyzed, revealing that the child had a 46, XY, 15pstk+ karyotype, where the short arm of chromosome 15 increased in the length with the stalk (Figure 2a). The association of this chromosomal polymorphism with clinical symptoms remain unclear. The mother's karyotype was all 46, XX, 15pss, indicating a normal variant with a double satellite stalk on chromosome 15 (Figure 2b). Whether this was associated with clinical symptoms was also unknown. The analysis indicated that his father had a normal 46, XY karyotype (Figure 2c), and no abnormal chromosomal clones were found within the scope of the technique.

FIGURE 2.

FIGURE 2

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The karyotype of the child's mother, with the red arrow indicating the presence of a double satellite stalk on chromosome 15 (a). The karyotype of the child, with the red arrow indicating the short arm of chromosome 15 increases with the length of the stalk (b). The karyotype of the child's father, with the red arrow indicating no observed abnormal chromosome clone (c). Whole‐genome test results (d). Chromosome coverage depth distribution map for the sample (e).

3.2. Copy number variation sequencing

CNV‐seq, a chromosomal disease detection method based on high‐throughput sequencing (HTS) technology, analyzed the child's peripheral blood sample. The assay covered 23 pairs of chromosomal aneuploidies and genomic copy number variations over 100Kb simultaneously (Figure 2d). Variant detection was performed using the HTS platform, and the test concluded that no CNV variants were related to the clinical phenotype of the subject.

3.3. Whole exome sequencing

The coverage depth of each chromosome site was counted, and the coverage depth distribution map of the reference genome was generated (Figure 2e ). Detection of single nucleotide variant (SNV) and small fragment insertion and deletion (small InDel) was primarily utilized by the GATK software toolkit (McKenna et al., 2010). ANNOVAR software was used for SNV and small InDel annotation (Chang & Wang, 2012; Wang et al., 2010; Yang & Wang, 2015). The average clean bases of one sample were 14.35 Gb, with a Q30 reaching 92.61%. The alignment efficiency with the reference genome (UCSC hg19) was approximately 99.75%, and the average depth of the target region was around 158.86×. The results were compared with the reference RB1 genomic sequence (GenBank: L11910.1). No potentially clinically significant variants (including SNVs and InDels) associated with the patient's clinical phenotype were detected between the sample and the reference genome.

4. DISCUSSION

The median age at the diagnosis of Rb is 23.5 months (Fabian et al., 2020). Rb may be associated with multiple malformations, including mental retardation, developmental delay, facial phenotype, and polydactyly (Baud et al., 1999; Bojinova et al., 2001; Caselli et al., 2007). Rb cells are primarily undifferentiated neuroblasts that can originate from any nuclear layer of the retina. The tumor cells in the baby express Syn and CD56, and partially defined NSE and CgA. Syn, NSE, and CgA are markers of neuroendocrine tumors, while CD56 is a neural cell adhesion molecule mainly distributed in neuroectodermal cells. S‐100, a marker of melanoma, can be used to identify malignant melanoma. Ki67 serves as a biological marker of cell proliferation in various tumors, with high ki67 levels usually associated with rapid tumor proliferation.

The etiology of Rb is complex, involving genetic, birth, and socioeconomic factors, among others. It can be initiated by the RB1 gene mutations or the MYCN gene amplification. Regarding polydactyly, the classical theory suggests that disruption of the necrosis of the ectoderm and preaxial mesoderm during the eighth week before embryo development is the cause of radial polydactylism (Cabrera González et al., 2013). A loss of 13q14 or 13q32 segments has been frequently detected in patients with Rb, possibly associated with the molecular mechanism of this disease occurrence (Lansink et al., 2005).

In examining the pathogenic mechanism of Rb combined with polydactyly, several factors merit consideration. Firstly, the Alx‐4 development factor is noteworthy. Mutations in the Alx‐4 gene in mice have been associated with various abnormalities, including preaxial polydactyly (Qu et al., 1997). Previous studies have shown that proteins encoded by the RB gene family can form a complex with Alx‐4, leading to manifestations of retinoblastoma and polydactyly. Therefore, it is conceivable that the child may harbor mutations in the Alx‐4 gene (Hudson et al., 1998; Tsinopoulos et al., 2001). Secondly, the 13q deletion syndrome has been linked to retinoblastoma and digit deformities (Comings, 1973). Reports indicate that the 13q14 deletion segments vary in size and may be accompanied by diverse systemic abnormalities (Privitera et al., 2021). Previous research has demonstrated that hand and foot abnormalities are associated with the loss of chromosome segment 13q32 (Knudson Jr., 1971).

The third factor is the PAPA2 gene, with its locus associated with polydactyly. The PAPA2 locus is situated at 13q21‐q32, close to the RB gene locus 13q14.1‐q14.2. Further investigation is required to explore this potential link (Mishra et al., 2013). While retinoblastoma is highly curable, it remains fatal if left untreated. The initial symptoms of retinoblastoma are diverse, emphasizing the need for rigorous screening. Additionally, further exploration is essential to elucidate the exact relationship between retinoblastoma and polydactyly.

Karyotypes play a pivotal role in identifying translocations, inversions, and aneuploidy in the genome, commonly employed to examine abnormalities (Jain et al., 2018; Miga, 2015). The child's karyotype shows an increase in the length of the satellite stalk on the short arm of chromosome 15, while the mother's karyotype consistently exhibits double satellite stalks on the arm of chromosome 15. Chromosome 15 belongs to the submetacentric acrocentric chromosome (SAAC) in humans, encompassing the satellite heterochromatin, the satellite stalk, and the satellite. The satellite stalk contains multiple copies of rRNA‐encoding genes, and because the cell's nucleolus is formed by the aggregation of rRNA, it is sometimes referred to as the “nucleolar organizing region” (NOR) (Antonarakis, 2022). The silver‐stained nucleolar organizing region (AgNOR) is used to study cell proliferation in various types of tumors (Awasthi et al., 2023; Gupta et al., 2018). The child's increase in the length of the satellite stalk on the short arm of chromosome 15 may be related to cell proliferation in RB. Centromeric satellite DNA arrays exhibit considerable variation among populations, yet limited genomic tools have been available to study the full extent of this sequence variation.

This knowledge gap concerning a small part of the human genome may directly contribute to cancer and other diseases (Black & Giunta, 2018; Enukashvily et al., 2007; Ferreira et al., 2015). The degree of variation at this site has been demonstrated at the cytogenetic level, with rearrangements and/or repeat expansions implicated in cancer and infertility (Atkin & Brito‐Babapulle, 1981; Berger et al., 1985; Sahin et al., 2008). Considering the in vitro cytogenetic observation of “satellite association” and the possibility of similar occurrences in meiosis in vivo, making chromosomes prone to abnormal segregation, some propose that individuals with a “double NOR” on the SAAC may have an increased risk of giving birth to children with Down syndrome (Green et al., 1989). However, some results suggest that the risk does not increase (Serra & Bova, 1990). Since the complete, gap‐free sequence of the short arm of SAAC remains unknown, and the sequence of SAAC shows a wide variation in the CNV repetitive elements, the full extent of which is currently unclear. The increase in the length of the satellite stalk on the short arm of chromosome 15 and the double satellite stalk on the short arm of chromosome 15 in relation to retinoblastoma (Rb) and polydactyly warrants further investigation. Recently, next‐generation sequencing (NGS) has emerged as an alternative method for detecting the CNV (Dong et al., 2017; Liang et al., 2014; Xie & Tammi, 2009). Sequence‐based karyotyping, CNV‐seq, and WES strategies have gained widespread approval. Simultaneously, CNV‐seq and WES allow comprehensive detection of congenital disabilities involving CNVs and variants. Although both tests yielded negative results in our reported patient sample, a dual diagnosis approach enhances diagnostic yield. Detecting germline mutations in retinoblastoma patients is crucial, as they may be susceptible to second non‐ocular malignancies later in life. Fortunately, the genetic test on the reported child's peripheral blood was negative for germline mutations, significantly reducing the child's chances of developing a second tumor, as well as the likelihood of his siblings developing the same disease. Nevertheless, the child still requires regular follow‐up and attention to orbital development.

In 2001, a parallel study from Greece reported an 11‐month‐old child with retinoblastoma complicated by polydactyly (Tsinopoulos et al., 2001). The child lacked a family history of the condition. with polydactyly surgically addressed at the age of 4 months. The IOP was measured at 25 mmHg. This case fell within the Reese–Ellsworth group 5 retinoblastoma classification, indicating the necessity of enucleation. The pathology report from the enucleated globe revealed an invasion of the choroidal and ciliary body. Subsequent treatment involved chemotherapy. Unfortunately, this case was not subjected to DNA sequencing analysis. In 2013, a study from India reported on an 8‐year‐old boy with retinoblastoma and postaxial polydactyly (Mishra et al., 2013). Similarly, the boy had no family history, experiencing vision loss in his left eye. with an IOP of 26 mmHg. Classified as International Retinoblastoma Classification (IRC) group C, the patient underwent enucleation of the left eye, followed by orbital prosthesis implantation. Histopathology examination confirmed retinoblastoma with IRC group C grade.

Interestingly, commonalities emerged among these three cases, including male gender, absence of a family history, elevated IOP, and an absence of other complications (Table 1). Additionally, relevant literature suggests potential associations between retinoblastoma and polydactyly, prompting further exploration of contributing factors.

TABLE 1.

Clinical characteristics of three retinoblastoma patients with polydactyly.

No Author Sex Age Affected eye IOP (mmHg) Affected hand Family history Presentation Classification (RE/IRC) Treatment
1 Tsinopoulos et al. (2001) Male 11 months Left 25 Not mentioned No Whitish spots RE group 5 Enucleated, subsequent chemotherapy
2 Mishra et al. (2013) Male 8 years Left 26 Left No Loss of vision IRC group C Enucleated, prosthesis implanted
3 This report Male 68 days Right 40 Left No Cornea edema IRC group E Enucleated, prosthesis implanted
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Abbreviations: IRC, International Classification of Retinoblastoma; RE, Reese–Ellsworth classification for intraocular tumors.

Approximately 15% of unilateral retinoblastoma cases exhibit detectable the RB1 gene mutation in the blood, signifying a heritable mutation (Dimaras & Corson, 2019). For the remaining patients, the RB1 gene mutation is typically identified in their tumor tissues, necessitating a comprehensive assessment to ascertain whether the mutation is of germline or somatic origin. Notably. in 2013, it was reported that 1.4% of unilateral retinoblastomas lacking the RB1 gene mutation display MYCN gene amplification, termed MYCN retinoblastoma (Rushlow et al., 2013). However, the recognition of MYCN retinoblastoma requires enucleation, and MYCN amplification can be detected through techniques such as fluorescence in situ hybridization.

In summary, we observed the overexpression of satellite transcripts in both the infant and the mother. Nevertheless, the potential association between chromosomal polymorphism and retinoblastoma with preaxial polydactyly remains unclear, warranting further investigation in future studies.

AUTHOR CONTRIBUTIONS

X.P., X.W., and F.J. designed and wrote the manuscript. Z.M. reviewed the references, provided ideas, and compiled the tables. All authors contributed to the article and approved the submitted version of the manuscript.

FUNDING INFORMATION

This work was supported by the National Natural Science Foundation of China (No. 81900912). Their support had no effect on data collection, interpretation, and writing of the manuscript.

CONFLICT OF INTEREST STATEMENT

The authors declare that the data supporting the findings of this study are available in this article.

ETHICS STATEMENT

The study was approved by the Ethics Committee of Union Hospital, Huazhong University of Science and Technology, China, and conducted according to the principles of the Declaration of Helsinki.

PATIENT CONSENT

Written informed consent was obtained from the baby's parents, for the publication of any potentially identifiable images or data included in this article.

PERMISSION TO REPRODUCE MATERIAL FROM EXTERNAL SOURCES

Not applicable.

CLINICAL TRIAL REGISTRATION

Not applicable.

ACKNOWLEDGMENTS

The authors would like to thank the teachers of the Department of Pathology and the Department of Ultrasound Medicine of the Union Hospital Affiliated with Tongji Medical College of Huazhong University of Science and Technology for their help, and the team of Professor Zhu Hongwen of the Second Affiliated Hospital of Lanzhou University for providing us with genetic support.

Pi, X. , Zhang, Q. , Wang, X. , & Jiang, F. (2024). Retinoblastoma and polydactyly in a child with 46, XY, 15pstk+ karyotype—A case report and literature review. Molecular Genetics & Genomic Medicine, 12, e2414. 10.1002/mgg3.2414

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available in the supplementary material of this article.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data that support the findings of this study are available in the supplementary material of this article.

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