Table 1.

RB1 mutation inheritance pattern	Age difference between parents		p value	Odds ratio (95% CI)
RB1 mutation inheritance pattern	<10 years (n = 194), N (%)	≥10 years (n = 53), N (%)	p value	Odds ratio (95% CI)
De novo germline (n = 69)	48 (25)	21 (40)	0.0387	0.501 (0.2676–0.9329)
Sporadic (n = 155)	128 (66)	27 (51)	0.0545	1.868 (1.025–3.39)
Familial (n = 23)	18 (9)	5 (9)	>0.9999	0.9818 (0.3459–2.52)
Heritable RB (n = 92)	66 (34)	26 (49)	0.0545	0.5355 (0.295–0.9754)

Table 1. Age difference of parents with mutational inheritance pattern.

N Frequency, % Percentage.

Table 2.

	RB1 mutation inheritance pattern				p value
	De novo germline (n = 69)	Sporadic (n = 155)	Familial (n = 23)	Heritable RB (n = 92)	De novo germline vs. sporadic	Sporadic vs. familial	De novo germline vs. familial	Sporadic vs. heritable RB
Mean parental age ± SD	28.8 ± 5.7	28 ± 5.4	28.7 ± 6.7	28.8 ± 5.9	0.1112	0.8	0.8957	0.2641
Mean paternal age ± SD	32.2 ± 4.8	30.9 ± 4.8	31 ± 7.1	31.9 ± 5.4	0.0286	0.963	0.4383	0.0682
Mean maternal age ± SD	25.3 ± 4.2	25.0 ± 4.3	26.3 ± 5.5	25.6 ± 4.5	0.5931	0.0006	0.4525	0.336

Table 2. Mean age of parents with mutational inheritance pattern.

SD Standard deviation, RB retinoblastoma, Age is in months.

Table 3.

RB1mutation Inheritance	<10-year age difference				≥10-year age difference
	≤25		26–30		31–35		>35		≤25		26–30		31–35		>35
	p value	OR (CI)	p value	OR (CI)	p value	OR (CI)	p value	OR (CI)	p value	OR (CI)	p value	OR (CI)	p value	OR (CI)	p value	OR (CI)
De novo germline vs. sporadic	0.2275	0.4684 (0.1665–1.315)	0.0301	0.4776 (0.254–0.9345)	0.2574	1.487 (0.797–2.803)	>0.9999	0.9592 (0.3581–2.447)	–	–	>0.9999	1.129 (0.3018–4.279)	0.1944	1.902 (0.7176–5.276)	0.0875	2.219 (0.8749–5.379)
Sporadic vs. familial	>0.9999	1.38 (0.3344–6.36)	0.2402	2.094 (0.7328–5.363)	0.6022	1.597 (0.5513–4.547)	0.0084	0.227 (0.081990.6018)	–	–	0.276	0.4228 (0.097032.182)	– >0.9999	1.517 (0.2306–17.19)	0.6768	0.8021 (0.1993–3.839)
De novo germline vs. familial	0.6375	0.6462 (0.1426–3.604)	>0.9999	1 (0.3459–2.782)	0.1902	2.375 (0.7197–6.995)	0.016	0.2177 (0.066520.7248)	–	–	0.5957	0.4773 (0.093232.855)	0.4414	2.885 (0.4579–33.35)	0.7234	1.78 (0.4125–8.615)
Sporadic vs. heritable RB	0.2667	1.883 (0.7432–4.763)	0.0157	2.094 (1.148–3.823)	0.5521	0.8094 (0.4647–1.451)	0.2913	0.6034 (0.2782–1.34)	–	–	0.5441	0.7007 (0.1993–2.088)	0.4593	0.636 (0.2421–1.534)	0.1728	0.5093 (0.2246–1.182)
*RB1* mutation Inheritance			<10-year age difference							≥10-year age difference
			36–40				>40			36–40				>40
			p value		OR (CI)		p value		OR (CI)		p value		OR (CI)		p value	OR (CI)
De novo germline vs. sporadic			0.7800		1.133 (0.4174–3.2)		>0.9999		0.5551 (0.04477–3.452)		0.0966		2.41(0.8522-6.774)		>0.9999	1.242 (0.216–6.201)
Sporadic vs. familial			0.0288		0.2483 (0.0762–0.7268)		0.1735		0.2781 (0.06224–1.549)		>0.9999		1.197 (0.1626–13.85)		0.4279	0.4342 (0.06277–5.876)
De novo germline vs. familial			0.1137		0.2813 (0.07873–1.021)		0.1531		0.1544 (0.01054–1.413)		0.4414		2.885 (0.4579–33.35)		>0.9999	0.6567 (0.074–9.914)
Sporadic vs. heritable RB			0.2348		0.5655 (0.2221–1.444)		0.7137		0.7859 (0.2073–3.179)		0.1966		0.5019 (0.1876–1.267)		0.6736	0.5855 (0.1347–2.556)

Table 3. Mutation inheritance pattern with paternal age adjusted to age difference between parents.

The values in bold highlight the increasing or decreasing trend of Odd’s Ratio across the different categories.

OR odds ratio, CI confidence interval, RB retinoblastoma.

Table 4.

RB1mutation Inheritance	<10-year age difference				≥10-year age difference
	≤20		21–25		26–30		>30		≤20		21–25		26–30		>30
	p value	OR (CI)	p value	OR (CI)	p value	OR (CI)	p value	OR (CI)	p value	OR (CI)	p value	OR (CI)	p value	OR (CI)	p value	OR (CI)
De novo germline vs. sporadic	0.3534	0.3908 (0.08471–1.686)	0.7649	0.892 (0.502–1.588)	0.3281	0.7008 (0.3656–1.343)	>0.9999	1.054 (0.4117–2.743)	0.5208	1.652 (0.5736–4.954)	0.3578	1.582 (0.6729–3.648)	0.0262	4.825 (1.26–17.91)	>0.9999	0 (0–4.861)
Sporadic vs. familial	>0.9999	1.681 (0.2648–18.9)	0.1667	2.153 (0.754–5.511)	0.8093	0.906 (0.3442–2.311)	0.0348	0.3036 (0.1013–0.9142)	0.1233	0.3153 (0.0759–1.204)	>0.9999	2.357 (0.4048–25.97)	0.4279	0.4342 (0.06277–5.876)	>0.9999	Infinity (0.0678–infinity)
De novo germline vs. familial	>0.9999	0.6567 (0.074–9.914)	0.3059	1.92 (0.6402–5.159)	0.4085	0.6349 (0.2301–1.679)	0.1666	0.4065 (0.117–1.327)	0.4076	0.5208 (0.1198–2.121)	0.28	3.729 (0.5481–42.22)	0.6754	2.095 (0.3023–25.04)	–	–
Sporadic vs. heritable RB	0.2633	2.266 (0.6713–7.748)	0.4088	1.299 (0.7638–2.199)	0.4616	1.261 (0.7124–2.264)	0.4085	0.7143 (0.3332–1.641)	0.1597	0.4339 (0.156–1.438)	0.6688	0.789 (0.3593–1.717)	0.0425	0.2397 (0.06638–0.8956)	0.5306	Infinity (0.2746–infinity)

Table 4. Mutation inheritance pattern with maternal age adjusted to age difference between parents.

The values in bold highlight the increasing or decreasing trend of Odd’s Ratio across the different categories.
OR odds ratio, CI confidence interval, RB retinoblastoma.

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CME

Parental Age and Retinoblastoma – A Retrospective Study of Demographic Data and Genetic Analysis

Authors: Meghana Tanwar, DNB, FRCS; Sekaran Balaji, BSc, MSc; Ayyasamy Vanniarajan, MSc, PhD; Usha Kim, DO, DNB; Gunja Chowdhury, DO, DNB
CME Released: 11/19/2021
THIS ACTIVITY HAS EXPIRED FOR CREDIT
Valid for credit through: 11/19/2022, 11:59 PM EST

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Target Audience and Goal Statement

This activity is intended for ophthalmologists, pediatricians, neurologists, geneticists, and other clinicians caring for patients with or at risk for retinoblastoma.

The goal of this activity is to describe the associations between parental age gap, maternal age, and paternal age and risk for retinoblastoma development in offspring, based on a retrospective study in India of 247 patients with retinoblastoma diagnosed between March 2013 and December 2019 at a single tertiary eye care center.

Upon completion of this activity, participants will:

Assess the proportion of sporadic vs heritable retinoblastoma and the association between parental age gap and risk for retinoblastoma development in offspring, based on a retrospective study in India
Evaluate the associations between maternal age and paternal age with risk for retinoblastoma development in offspring, based on a retrospective study in India
Determine the clinical implications of the associations between parental age gap, maternal age, and paternal age and risk for retinoblastoma development in offspring, based on a retrospective study in India

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Faculty

Meghana Tanwar, DNB, FRCS

Aravind Eye Hospital & PG Institute of Ophthalmology, Madurai

Disclosures

Disclosure: Meghana Tanwar, DNB, FRCS, disclosed has no relevant financial relationships.

Sekaran Balaji, BSc, MSc

Department of Molecular Genetics, Aravind Medical Research Foundation, Madurai

Disclosures

Disclosure: Sekaran Balaji, BSc, MSc, disclosed has no relevant financial relationships.

Ayyasamy Vanniarajan, MSc, PhD

Department of Molecular Genetics, Aravind Medical Research Foundation, Madurai

Disclosures

Disclosure: Ayyasamy Vanniarajan, MSc, PhD, disclosed has no relevant financial relationships.

Usha Kim, DO, DNB

Aravind Eye Hospital & PG Institute of Ophthalmology, Madurai

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Disclosure: Usha Kim, DO, DNB, disclosed has no relevant financial relationships.

Gunja Chowdhury, DO, DNB

Aravind Eye Hospital & PG Institute of Ophthalmology, Madurai

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Disclosure: Gunja Chowdhury, DO, DNB, disclosed has no relevant financial relationships.

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Laurie Barclay, MD

Freelance writer and reviewer
Medscape, LLC

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Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

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Sobha Sivaprasad, MD

Editor, Eye

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Disclosure: Sobha Sivaprasad, MD, has disclosed the following relevant financial relationships:
Served as an advisor or consultant for: Allergan, Inc.; Apellis; Bayer AG; Boehringer Ingelheim Pharmaceuticals, Inc.; Heidelberg Pharma GmbH; Novartis Pharmaceuticals Corporation; Oculis; Optos; Oxurion; Roche
Served as a speaker or a member of a speakers bureau for: Allergan, Inc.; Bayer AG; Novartis Pharmaceuticals Corporation; Optos
Received grants for clinical research from: Allergan, Inc.; Bayer AG; Boehringer Ingelheim Pharmaceuticals, Inc.; Novartis Pharmaceuticals Corporation; Optos

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Stephanie Corder, ND, RN, CHCP

Associate Director, Accreditation and Compliance
Medscape, LLC

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From Eye

CME

Parental Age and Retinoblastoma – A Retrospective Study of Demographic Data and Genetic Analysis

Authors: Meghana Tanwar, DNB, FRCS; Sekaran Balaji, BSc, MSc; Ayyasamy Vanniarajan, MSc, PhD; Usha Kim, DO, DNB; Gunja Chowdhury, DO, DNBFaculty and Disclosures

THIS ACTIVITY HAS EXPIRED FOR CREDIT

CME Released: 11/19/2021

Valid for credit through: 11/19/2022, 11:59 PM EST

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Introduction

Retinoblastoma (RB), the most common paediatric intraocular malignancy, has been reported to occur 1 in 15,000–20,000 live births ^[1]. It usually occurs in children before the age of 2 years ^[2]. The tumour arises as a result of mutation affecting both alleles of RB1 gene at chromosome 13q14. Depending on the pattern of inheritance, two types of RBs have been defined: Heritable and Sporadic RB. Heritable RB is caused by germline mutation (first hit) that occurs pre-zygotically and mostly present as bilateral disease, while in sporadic cases, both the mutations (first and second hit) are somatic and occur post-zygotically ^[3].

About 90% of cases, carrying a germline mutation in RB1 gene, have been known to develop RB during their early childhood ^[4], ^[5]. The germline mutation can either be inherited as in familial RB or occur de novo. Familial RB has an autosomal dominant inheritance with one of the parents affected ⁶. When it occurs de novo, phenotype is seen only in child but not in parents. It is well known that the number of new mutations in germ cells increases with age ^[7] and that advanced paternal age is associated with a number of congenital syndromes, including a number of cancers like RB ^[8]- ^[10]. It has also been observed that a paternal transmission will occur in populations in which older men frequently marry much younger women. However, an increasing maternal contribution is to be expected when women conceive at 35 years of age or older ^[11]. We conducted this study to determine the association of paternal age, maternal age and difference in parental age with an increased risk of RB in offspring. To date this is the first study that has been conducted in the Indian population looking specifically at the age difference between parents and its possible impact in RB.

Page 1 of 5

Methods

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Introduction
Methods
Results
Discussion
Summary

References

References

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The educational activity presented above may involve simulated, case-based scenarios. The patients depicted in these scenarios are fictitious and no association with any actual patient, whether living or deceased, is intended or should be inferred. The material presented here does not necessarily reflect the views of Medscape, LLC, or any individuals or commercial entities that support companies that support educational programming on medscape.org. These materials may include discussion of therapeutic products that have not been approved by the US Food and Drug Administration, off-label uses of approved products, or data that were presented in abstract form. These data should be considered preliminary until published in a peer-reviewed journal. Readers should verify all information and data before treating patients or employing any therapies described in this or any educational activity. A qualified healthcare professional should be consulted before using any therapeutic product discussed herein.

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Table 1.

Table 2.

Table 3.

Table 4.

References

Faculty and Disclosures

Faculty

Meghana Tanwar, DNB, FRCS

Sekaran Balaji, BSc, MSc

Ayyasamy Vanniarajan, MSc, PhD

Usha Kim, DO, DNB

Gunja Chowdhury, DO, DNB

CME Author

Laurie Barclay, MD

Editor

Sobha Sivaprasad, MD

CME Reviewer

Stephanie Corder, ND, RN, CHCP

CME

Parental Age and Retinoblastoma – A Retrospective Study of Demographic Data and Genetic Analysis

Target Audience and Goal Statement

Disclosures

Faculty

Meghana Tanwar, DNB, FRCS

Sekaran Balaji, BSc, MSc

Ayyasamy Vanniarajan, MSc, PhD

Usha Kim, DO, DNB

Gunja Chowdhury, DO, DNB

CME Author

Laurie Barclay, MD

Editor

Sobha Sivaprasad, MD

CME Reviewer

Stephanie Corder, ND, RN, CHCP

Accreditation Statements

For Physicians

Instructions for Participation and Credit

Parental Age and Retinoblastoma – A Retrospective Study of Demographic Data and Genetic Analysis

Introduction

Table of Contents