WHOSE CHROMOSOMES TO COUNT IN MONGOLISM?

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VERY PHYSICIAN who must make

dcci-sions in tile management of a child

with Down’s syndrome faces the problem

of whether or not chromosomal analyses

should be done and, if so, upon which

members of the family. Tile purpose of

such analyses is tile identification of those

individuals \ilO may be expected to have

an increased incidence of mongolism

among tileir offspring as a result of a

trans-location of a 21 chromosome, a 21

isochno-nlosome, mosaicism for 21-tnisomy, or

21-trisomy itself. However, the high cost

and difficulty of obtaining chromosomal

analyses require that their number be kept

to the minimum necessary, and that

ap-I)roPniate short cuts in the laboratory

meth-od also be applied whenever possible. The

following paragraphs will attempt to lay a

base for, and to outline, a logical and

pnac-tical approach to the chromosomal

screen-ing of relatives of patients with Down’s

syndrome.

Table I lists various parental

ahnormali-ties involving the 21 chromosome, together

with tile theoretical proportion of cases of

mongolism to total live births for each. In

considering this table, the reader should

keep in mind that it refers to an estimated 1

or 2% only of parents of patients with

Down’s syndrome. In an estimated 98-99 of

instances, both parents are chromosomaliy normal.

‘Illis work was supported in part b’ Grant No.

Health and Ilunlan Development, U.S. Public Health Service.

PEDIArrncs, Vol. 36, No. 4, October 1965

WHOSE

CHROMOSOMES

TO

COUNT

IN MONGOLISM?

R. James McKay, Jr., M.D.

Department of Pediatrics, Unicersity of Vermont College of Medicine, Burlington, Vermont

INTRODUCTORY NOTE: A discussion of some common problem of pediatrics

regularly appears as the last article preceding the “Experience and Reason” section. Usually contributed by a member of the Editorial Board, each of these short papers is intended to present his current practice in regard to diagnosis or therapy or both. The Editor will welcome suggestions for de-sirable to/)ics.

Although the observed proportion of

cases of mongolism to total live births

ap-proximates the theoretical ratio among the

infants of mothers with the phenotype

char-acteristic of Down’s syndrome, the

ob-served proportion is lower than the

theoreti-cal ratio among the children of parents with

a normal phenotype and a chromosomal

ab-normality predisposing to mongoloid

offspring. Reproduction has never been

ne-ported in a male patient with typical

char-actenistics of mongolism. Correspondingly,

the incidence of offspring with Down’s

syn-drome is much lower among phenotypically

normal male than among phenotypically

normal female carriers of a chromosomal

abnormality predisposing to mongolism.

These discrepancies between observed and

theoretical incidences of mongolism are

presumably due to the lethal effect on the

gamete, zygote, or fetus of having less than

the normal complement of 21 chromosomal

material, and to diminished viability of the

gamete, zygote, or fetus having more than

the normal complement of 21 chromosomal

material. In addition, it would appear that

sperm with any type of chromosomal

ab-normality may be at a competitive

disad-vantage with chromosomaily normal sperm.

Also bearing on the desirability of

ob-taming chromosomal analyses on patients

with mongolism and their blood relatives

are reports of (1) instances of association of

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TABLE I

Parental Cliromosoniol Abnormality Theoretical Proportion of Mongoloid to Total Live Births

21-trisorny (all types) 1/’2 (50%)

‘21/(13-15) translocation (normal phenotype) 1/3 (33%)

‘21/’21 translocation (normal phenotype) 1/1 (100%)

Isochromosome ‘21 (normal phenotype) 1/1 (100%)

‘21/’2’2 translocation (normal phenotype) 1/3 (33%)

(‘21-trisomy)-(normal) mosaic Varies with proportion of ‘21-tnisomic cells to normal

(normal or abnormal phenotype) celLs. (1/4 (‘25%) if one assumes a mosaic with equal

numbers of 21-trisomic and normal cells)

ARTICLES 621

abnormalities of number of the sex

chromo-somes with 21-tnisomy in the same

individ-ual, (2) a predisposition in certain families

to apparently related or unrelated

chromo-somal abnormalities, (3) the occurrence of

mosaicism for 21-tnisomy in women of

essentially normal appearance, (4) the

ap-peanance of translocation 21-tnisomy in the

child of chromosomally normal parents, (5)

the appearance of “regular” 21-tnisomy in

the child of a parent with translocation of

one of the small acrocentnic chromosomes.

It has been estimated that at least

nine-teen out of twenty cases of mongolism have

a chromosome count of 47 as opposed to

the normal number of 46. The extra

chro-mosome is a 21 chromosome, so that tile

males have 6 instead of 5, and the females

have 5 instead of 4 small acrocentnic

chro-mosomes, which are easily identifiable in

most satisfactorily spread cells in

meta-phase. Many, if not most, of these patients

have parents, particularly mothers, who are

35 years of age or olden. Unless one or both

also have Down’s syndrome, the parents of

a child with this type of 21-trisomy are

al-most invariably (in about 98% of cases)

chro-mosomally normal, as are the siblings and

other blood relatives.

A relatively small number of mongoloid

individuals have a normal total

chromo-some count of 46 but nevertheless carry the

genetic material of three 21 chromosomes.

Most of these people have the normal

num-ben of small acrocentnic chromosomes for

their sex, only 5 instead of 6 chromosomes

in the 13-15 group (large acrocentric

chro-mosomes) and an extra, large chromosome

representing a translocation of a 21

chromo-some to one of the 13-15 chromosomes. Most

reported cases of mongolism with 211(13-15)

translocation have had a phenotypically

normal parent who carried the translocation

chromosome and had a total count of 45

in-stead of the normal 46, with one less than

the normal number of small acrocentnic

chromosomes appropriate for their sex.

Much more rarely mongolism may occur

as a result of a 21/21 or a 21/22

transloca-tion, or as a result of the formation of a 21

isochnomosome, which, in effect, is similar

to a 21/21 translocation chromosome. In

such instances the mongoloid individual

again has 46 instead of the expected 47

chromosomes. However, in this case the

male has 4 instead of the normal number of

5, and the female has 3 instead of the

nor-mal number of 4 small acrocentnic

chromo-somes. Again, though perhaps more rarely,

there may be a parent who carries the

trans-location chromosome or the

isochnomo-some. Since all offspring of a parent with a

21/21 translocation chromosome or a 21

isochnomosome (the reciprocal pattern

being presumably lethal) will be

mongo-bid, chromosomal studies of antecedents on

relatives of phenotypically normal carriers

of such chromosomes are without point.

Unfortunately, it is currently a practical

im-possibility to distinguish between these

ab-nonmalities and a 21/22 translocation which

can be transmitted from one phenotypically

normal generation to another.

Since it is uncertain whether mosaic

mongolism (varying proportions of

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622 CHROMOSOMES IN MONGOLISM

result of non-disjunction after formation of a normal zygote, or as a result of anaphase lag during division of a trisomy-21 zygote, there is a remote possibility that a phenotypically normal parent may, in fact, be a mosaic. However, for practical purposes it is probably safe to assume that both parents are normal and that chromosomal analysis of relatives is not indicated, unless there are other instances of mongolism, re- peated spontaneous abortion, children with multiple congenital malformations, known chromosomal abnormalities, or abnormalities of sexual development in the family.

In general, therefore, it may be presumed that (1) mongoloid individuals with 47 chromosomes and one more than the normal number of small acrocentric chromosomes will have parents with normal chromosomes, (2) mongoloid individuals with 46 chromosomes and a normal complement of small acrocentric chromosomes have a 21 /(13-15) translocation, and one of the parents, usually the mother, is likely to be a carrier of the translocation, (3) mongoloid individuals with 46 chromosomes and one less than the normal complement of small acrocentric chromosomes have a 21/21 or 21/22 translocation, or a 21 isochromosome, (4) until both parents of a carrier of a translocation chromosome have been proven not also to carry the translocation, all siblings and progeny of the carrier must be considered to be at high risk for being carriers with a greatly increased incidence of mongolism among their offspring.

From the preceding, it is apparent that the only way of being sure that a given set of parents of a child with Down's syndrome do not have a transmittable chromosomal abnormality is to do chromosomal analyses on both parents. It is equally apparent that blood relatives with mental retardation, multiple congenital malformations, abnormalities of structure or function of sexual organs, or an increased incidence of spontaneous abortions, should have chromosomal analyses in order to rule out a familial predisposition to chromosomal abnormali-

tifying persons with mosaicism by single cultures of single tissues suggests that, ide- ally, apparently normal parents of mongoloid children, particularly if such parents are under 30 years of age, should have both leukocyte and tissui: cultures done.

A practical, but not foolproof, approach

to the screening of families of individuals with mongolism for the presence of heri- table translocations would appear on the basis of the enumerated data, to be the following listed in sequence:

1. Count the chromosomes of the mongoloid patient in 5-10 satisfactory cells in me- taphase from culture of peripheral blood leukocytes. If 47 chromosomes are present and there is one more than the normal complement of the easily identifiable small acrocentric chromosomes, both parents may be presumed to be chromosomally normal, a karyotype of a set of chromosomes need not be made (although at least one is desirable), and no chromosomal studies need be made of any relative.

2. If the mongoloid individual studied has other than 47 chromosomes, several idi- ograms (diagrams or photographs of a set of chromosomes) should be set up for detailed analysis.

3. If an apparent 21/(13-15) translocation is identified, the mother should be studied.

4. If the mother has a chromosome count of 46, in 5-10 satisfactory cells, and appears to have the normal complement of 4 small acrocentric chromosomes, the father should be studied. This order of procedure should be reversed if the father has a mongoloid or other blood relative with a known or possible chromosomal abnormality.

5. If both parents have a chromosome count of 46 with the normal complement of small acrocentric chromosomes, further studies are not necessary, though at least one idiogram of each is desirable in order to make certain that the karyotype is in- deed normal.

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ARTICLES 623

should be prepared for detailed analysis of the living direct ancestry.

7. If an apparent translocation or other chromosomal abnormality is found in either parent, both parents of the affected parent should be studied likewise. This process should be carried back as far as possible in the living direct ancestry.

8. All offspring of individuals identified as carrying a translocation chromosome, or as having another chromosomal abnormality, should have counts of the total ngmber of chromosomes and of the small acrocentric chromosomes in at least

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satisfactory cells, and detailed analysis should be done in any instance where these counts are other than normal.

In situations where obtaining chromosomal analyses is very difficult, a rule of thumb might be that they need not be done in instances where the child has typical Down's syndrome and the mother is 35 or more years old. Conversely, if any blood relatives are known to have mongolism or any other chromosomal abnormality, if there is a family history of increased incidence of miscarriages and/or progeny with multiple congenital malformations, or if the mother is under 30 years of age, appropriate chromosomal analyses should be done if at all possible. Contrary to popular current medical belief, the presence of mongolism or a known chromosomal abnormality among the blood relatives is probably a more urgent indication for chromosomal studies than is youth of the mother.

Finally, it should be emphasized that, while the screening method proposed here may be adequate for practical purposes, it will inevitably fail to identify a few indi-

viduals with a significantly increased risk of having offspring with mongolism or another chromosomal abnormality. Therefore, whenever the carrying out of two chromosomal analyses instead of one is not an impor- tant consideration, it would be best to begin with chromosomal analysis of the mother (Step 3 of the proposed method). Chromosomal analysis of the index patient should always be done first if the diagnosis of Down's syndrome is in question, and chromosomal analysis should begin with any parent who has blood relatives with mongolism, with a known or suspected chromosomal abnormality, with a high rate of spontaneous abortions, or with progeny with multiple congenital malformations, rather than with the index patient.

Acknowledgment

The author is indebted to Dr. Park S. Gerald of Children's Hospital Medical Center, Boston, for review of the manuscript and for suggestions for its improvement.

REFERENCES

1. Edwards, J. H., Dent. T., and Guli, E.: Spo- radic mongols with translocations. Lancet

2:902, 1963.

2. Hamerton, J. L.: Cytogenetics of mongolism.

In Chromosomes in Medicine, pp. 140-183; Hamerton, J. L., Ed. Little Club Clinics in

Developmental Medicine No. 5, National Spastics Society in association with Wm. Heinemann (Medical Books) Ltd.

3. Lejeune, J.: The 21 trisomy-current stage of chromosomal research. In Progress in Medi-

cal Genetics. Vol. 111, pp. 144-177. Stein- berg, A. G. and Bearn, A. G., Eds. New York: Grune and Stratton, 1964.

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1965;36;620

Pediatrics

R. James McKay, Jr.