ACTA OPHTHALMOLOGICA VOL. 4 6 1 9 6 8

Author

From the department of Ophthalmology Rigslzospitalet, Tagensvej, Copenhagen, Denmark

(Head: Prolessor B. Lawaetz, M. D . and H . H . Seedorff, M . D.)

Country 1 Year Frequency

RETINOBLASTOMA AMONG OFFSPRING OF ADULT SURVIVORS I N DENMARK

BY

Michael Nielsen and Ernst Goldschmidt

The most frequent intraocular tumor in children is the retinoblastoma. The incidence varies from 1 :34.000 liveborn children in Holland [Hemmes (1931)] to 1:19.000 in Denmark [Bech & Jensen (19Sl)J, Table I.

Retinoblastoma occur either familially or sporadically. Familial cases of retinoblastoma are believed to be transmitted by a dominant gene, [Griffith & Sorsby (1944), Franceschetti & Bischler (1946), Falls 8 Neel (1951), Vogel (1957), Tucher (1957), Manchester (1961), Hemmes (1964)]. The penetrance of this gene ranges from 80 O/O [Franceschetti & Bischler (1946)] to 95 O/O

[Falls & Neel (1951).] Although the etiology of sporadic cases of retinoblastoma is still undeter-

mined, several theories of causation have been proposed. These include:

Table 1. Frequency of retinoblastoma in various countries

Hemmes Weller Griffith & Sorsby Falls & Neel Vogel Macklin Bech & Jensen Reese

Holland Holland England Michigan, USA W. Germany USA Denmark USA

1931 1941 1944 1951 1954 1959

. 1961 1963

1 : 34.000 1 : 34.000 1 : 33.000 1 : 20.000 1 : 29.000 1 : 23.000 1 : 19.000 1 : 22.000

Received November 28th 1967.

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1. All sporadic cases are genetic mutations with the afflicted individual becom- ing a transmitter of the trait. [Franceschetti and Bischler (1946), Reese (1 963), Macklin (1 959)].

2 . Sporadic cases are caused by a recessive gene [Krause (1944)]. 3. Only some of the sporadic cases are caused by genetic mutations with the

remainder being phenocopies. [Hemmes (1931), Tucher (1957), Vogel (1957), Manchester (196l)l.

An analysis of the frequency of retinoblastoma among the offspring of survivors is necessary to determine which of the theories is most likely.

Hemmes (1931), Herm & Heath (1956), Bohringer (1956), Vogel (1957), Tucher (1957) and Macklin (1959) have located patients with sporadic retino- blastoma from hospital records. The children of these patients were classified as to whether they had a history of retinoblastoma. Since indentical criteria were used by the above mentioned investigators the results have been pooled in Table 11 where a total of 66 retinoblastoma patients and their 131 children are listed.

Similar investigations have been made by Badthe (1940) and Krause (1941) but these authors do not identify the source of their patients. The 17 cases described by Manchester (1961) were patients of local ophthalmologists. These reports have not been included in the bable.

Since the investigations listed in Table I1 indicate that relatively few sporadic retinoblastomas are caused by genetic mutations it seems likely that most should be classified as phenocopies. This limited number of cases reported has re- sulted in a considerable range of calculated empirical risk numbers making eugenic advise rather uncertain. The purpose of the present investigation is to analyze the occurrence of retinoblastoma among the offspring of adult sur- vivors of sporadic cases in Denmark and to compare the results with availcable data from other countries.

M A T E R I A L S A N D M E T H O D S

The present series includes all patients treated for retinoblastoma at the Municipal Hospital of Copenhagen and Rigshospitalet in the years 1910 to 1945. Sixty nine such patients were found from the hospital records, of which 13 with certainty died from retinoblastoma. Since information on date of birth and address in the older histories was often incomplete, only S O of the patients could be located. The hospital records showed that retinoblastoma had not occurred in any of the family members of the 30 patients. All cases were there- fore considered as sporadic retinoblastomas. Twelve of the patients were female and 18 male. They ranged in age from 22 to 57 years with a mean of 32 years.

A letter was sent to each of the 30 patients informing theni of the purpose

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Tabl

e II

. R

etin

obla

stom

a am

ong

offs

prin

g of

adu

lt s

urvi

vors

as

repo

rted

in

the

liter

atur

e

num

ber

of

adul

t R

-sur

vivo

rs w

l ch

ildre

n

fam

ilies

w/

fam

ilies

w’

tota

l nu

mbe

r to

tal

num

ber

tota

l nu

mbe

r of

af

fect

ed

child

ren

norm

al

affe

cted

of

ch

ildre

n O

f

offs

prin

g ch

ildre

n ch

ildre

n

Hem

mes

(19

31)

%

He

m &

Hea

th (

1956

) B

ohri

nger

(19

56)

Vog

el (

1957

) T

uche

r (1

957)

M

ackl

in (

1 959

)

4 4

0 9

9 0

7 6

1 13

12

1

9 7

2 17

15

2

36

35

1 73

71

2

8 6

2 17

15

2

2 2

0 2

2 0

tota

l 66

60

6

131

124

7

of the investigation and soliciting their cooperation in answering a question- naire containing information on matrimonial status and number, age and sex of their children. All patients were then contacted personally and histories of the familial occurrence of retinoblastoma obtained.

Number of families

RESULTS

Number of children in each of the fami-

lies concerned

Two of the patients refused to participate in the investigation. Each of the remaining 28 had a history of sporadic unilateral retinoblastoma. Fifteen of the patients had a total of 28 children. Twenty seven of the children were more than 3 years of age; one was 2 years old. None of the children had retinobla- stoma. The specific data are contained in Table 111, IV and V.

Table I l l . A survey of the results of the presont study:

Number of adult survivors (all sporadic and unilateral)

Number of patients with children .................................. 15

. . . . . . . . . . . . . .

Number of children more than 3 years old .......................... 27 Number of children less than 3 years old .......................... 1 (2 years) Number of affected children ........................................ 0

Table IV. Age distribution of the offspring

less than 5 years old 5 - 10 years old more than 10 years

10 7 11

1. 1 8 5

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The results suggest thiat sporadic cases of retinoblastoma are rarely caused by genetic mutations.

The maximal statistical risk for retinoblastoma in children of patients treated for sporadic unilateral retinoblastoma was calculated from the equation:

- P, = 1 - n I/0.01

where P, is probability and n is number of children. The P, was 0.15027 indi- cating that the empirical risk factor at the 990/0 level of probability does not exceed 15 O / O .

DISCUSS10 N A N D CONCLUSIONS

l'he result of this investigation accord with previous findings for groups selected on the basis of the same criteria. Combining the results of the present investiga- tion with the data listed in Table I1 shows that 81 patients who survived a sporadic retinoblastoma had a total of 159 children. Seven (4.40//0) had retin- oblastoma. The 99'0/0 confidence limits for this value is 1.2 to 10.30/0. The findings indicate that only about 10 O / O of the sporadic unilateral retinoblastorna cases are genetic mutations, the remaining being phenocopies. This is calcu- lated according to a degree of manifesbation of 80 to 90 O / O .

The empirical risk number is a parameter of most practical value. On the basis of the available data it seems justified to conclude that the chance of children of patients treated for sporadic unilateral retinoblastoma developing this tumor is less than 1O10/o. No cases of bilateral retinoblastomas were found in this series and Vogel (1957), was unable to suggest any definite risk number of children of sporadic bilateral retinoblastoma patients.

I t would be of great value if representative material on sporadic retino- blastoma from other countries were selected on the basis of uniform criteria and especially series of retinoblastoma among offspring of bilateral cases are of great interest. This would make a more precise calculation of the empiri- cal risk number feasible.

SUMAIARY

From Copenhagen hospital records 69 patients with sporadic unilateral retino- blastoma were located. 15 of the patients had a total of 28 children, none of the children had retinoblastoma. Combining the results with similar previous investigations showed that 81 patients had 159 children, 7 (4.4 ' 0 / 0 ) had retino- blastoma. The findings indicated that only about 10 o/o of sporadic unilateral retinoblastoma cases are genetic mutations, the remaining being phenocopies.

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Bcch, K . & 0. A. Jensen: Bilateral Retinoblastoma in Denmark. Acta Ophthal. 1961,

Bohringer, H . R.: Statistik, Klinik und Genetik der Schweizerischen Retinoblastomfalle.

Dolfzis, M . A.: Le Gliome de la Retine et les Pseudogliomes. Masson et Cie. Paris 1953. Falls, H . F. & /. V . Neel: Genetics of Retinoblastoma. Arch. Ophthal. 1951, 46:

Fruncheschetti, A. R- V . Bischler: Ketinoblastome et heredite. Arch. Klaus-Stift. Vererb.-

Gri f l i th , A. D. Rr A. Sorsby: The genetics of Retinoblastoma. Brit. J. Ophthal. 1944,

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