Detection of segmentary heterochromia in foetuses irradiated in utero

Observations of mothers, irradiated on the pelvis or the abdomen during pregnancy were systematically searched for in the files of a large maternity hospital. For each case, the mode of irradiation and the date of application, were recorded. The period from 1946 to 1954 was covered. The irradiated children are now between 8 and 18 years old, a fact which simplifies all the investigations concerning pigmentation.

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Control cases

For each indexed case the closest file of a non-irradiated mother of the same class-age and same parity was selected as a control. (Some of these were subsequently found to have been irradiated at another hospital or for another pregnancy.)

Examination at home was performed for the indexed cases and the control cases, as well as for their parents and siblings. The actual total of the two enquiries, subjected to a small increase after definite completion, was 1,101 for children irradiated in utero, out of a grand total of 8,193 persons examined.

The absence of statistical differences between control cases, their sibs, the sibs of the index cases, and even the parents of both categories, with regard to some pigment characteristics, allows us to use these subsamples as pooled data.

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Analysis of data

For the actual analysis three characteristics have been selected, out of the ninety recorded for each individual.

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1. Segmentary heterochromia of the iris

A segment, delineated by the pupilla, two radii and the corresponding peripheral arc of the iris, is found to be uniformly in tone colour different from the rest of the iris. This unilateral trait looking like a "slice of cake" can be detected very safely and was known by the parents in most instances. All cases reported by our visiting students, have been controlled secondarily by an ophthalmologist. Many combinations of colours have been found, dark on blue, or white on dark.

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2. Dark lock in fair-haired children

In three instances (all three irradiated) a lock, the size of 1 to 2 cm on the skin, was dark in contrast with the rest of the blond hairs of the neck. The skin ifself did not show any abnormal pigmentation at the site of implantation of the dark lock.

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3. White forelock

This very characteristic dominant trait was used as a control for the infernal consistency of our data. Being related to one gene mutation, and being already well spread throughout the population, such a characteristic should not be influenced by X-raying the foetus, at least with the very low doses received.

Table I. Total number of persons examined in the two enquiries
	Total	Heterochromia of iris	Dark look	White forelock
Irradiated in utero	1,101	15	3	3
Controls (control cases, sibs, and parents)	7,092	11	0	24
Total	8,193	26	3	27

Table I shows:

(i) No relafionship between irradiation in utero and frequency of the white forelock. This expected negative finding is in favour of no selection in the irradiated group.

(ii) The dark look is much more common in the irradiated than among the unirradiated.

(iii) The frequency of heterochromia of the iris is much greater among irradiated than among non-irradiated ?2 is 36 for one degree of freedom (after Yates' correction).

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4. Time of irradiation

The time distribution of irradiation among the heterochromic children is strikingly different from that of the general irradiated population.

Table II shows a highly significant cluster of heterochromia for an irradiation age of 4 to 6-9 months in utero. This does suggest the existence of a sensitive period, a fact largely established in embryology.

TABLE II. The age of the foetus at the time of the irradiation in utero. The distribution among children of the second enquiry is very comparable to that of the first
Fi rst enquiry				Second enquiry
Month of irradiation in utero	Heterochromia of iris	Dark lock	Total of irradiated children	Heterochromia of iris	Dark lock	Total of irradiated children
0-0.9
1-1.9
2-2.9			9
3-3.9			8
4-4.9	2		14	1	1	not yet
5-5.9	2		32	4	1	tabulated
6-6.9	3	1	81	2
7-7.9	1		123
8-8.9			243
ante-partum			41
Unknown
exactiy			16
	8	1	567	7	2	534

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5. Dose of irradiation

Due to the mode of ascertainment, all radiological procedures are known precisely, at least with the accuracy of the transcription. The calculation of a mean dose is thus possible, with a general restriction concerning its precision.

From the actual data we can conclude that the mean probable dose received by the whole sample is of the order of 2 to 3 r. The mean dose received by the children showing heterochromia is also of the order of 2 to 3r.

The main interest of these findings is, in our opinion, to show that even small doses of radiation have a somatic effect, which can be detected if induced at a sensitive period of embryonic development.

The study of the frequency of cancers and leukaemias is in progress, as well as the statistical screening of the 87 other physical particularities recorded.

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Discussion

Mole: I would just like to ask a few questions about details. I understand that the children were all irradiated in utero, you have the records because they were irradiated in hospital, and from the hospital records you were able to deduce the dose. There are two questions here. What about other kinds of radiation exposure? I'm told that in France, pregnant women are fluoroscoped under the National Health legislation, as presumably happens with all the mothers; I don't know at what period in pregnancy. Secondly, you have lumped all the irradiated people together under one dose. Is it possible to get any kind of a dose reponse?

Lejeune: Well, I can answer the two questions. Every child has a personal file and every examination is recorded there as exactly as possible. The chest fluoroscopy of the mother is effectively systematic but is probably not relevant in this respect. First the dose to the foetus is likely to be small and randomly spread among the whole sample of mothers.

Rotblat: You said the average dose is 2 r.

Lejeune: Yes, of this order.

Rotblat: Obviously there must be some spread. Do you know what the actual doses were in the cases which you mentioned?

Lejeune: Yes, in three cases, one had two pictures, the other had five and the other had a urography-which means six. So one has received around two roentgens, and two of them around five. The differences are not much greater than that. We do not have in such a sample a relationship between the number of roentgens and the somatic effects.

Drasil: Have you calculated how many cells must be changed or damaged in order to obtain this changed segment of the iris?

Lejeune: I do not have any idea because of the possiblity of a different selection value for the mutant cells, but it is possible that the number is very small because a primary cell can have a big progeny.

Russel: I think that in this case calculation could be made in the same way as was made in the case of white segments of Drosophila eyes that had been irradiated as young or embryos. I'm thinking of course of just what you said, what portion this segment forms of the total and suppose it forms in the average one-tenth of the total it would mean that there were on the average 10 cells there.

Zeleny: Do you find any differences in the site of the segment and are they related to the time of exposure?

Lejeune: Yes, we did, and it was one of the best hopes we had that the earlier the irradiation the bigger should be the segment. And the only thing I can tell you is that the earliest foetus-around 3 months old when it was irradiated in utero had quite a large segment of one eye and that the smallest one was irradiated at 7 months, but inbetween the relation is linear. I am sorry, but there are variations. But then of course this was expected.

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Reference

LEJEUNE, J., TURPIN, R,, RETHORE, M.-O., and MAYER, M. (1960). Rev. , franç. Etudes Clin. Biol. 5, 982.