LEUKEMIA IN TWINS

(1)

(Received March 14; accepted for publication April 30, 1973.)

Supported in part by research grants CA-07357 and CA-03161, and institutional cancer training grant CA-08017, all from the National Cancer Institute, National Institutes of Health.

ADDRESS FOR REPRINTS: (J.M.F.) Texas Children’s Hospital, 6621 Fannin Street, Houston,

Texas 77025.

PEDIATRICS, Vol. 52, No. 6, December 1973

846

LEUKEMIA

IN TWINS

John M. Falletta, M.D., Kenneth

A. Starling, M.D.,

and Donald J. Fernbach, M.D.

From the Department of Pediatrics, Baylor College of Medicine, and the Research Hematology

Laboratory, Texas Children’s Hospital

ABSTRACT. A disorder for which identical twins are not completely concordant must be caused, at

least in part, by environmental factors. Acute

childhood leukemia is such a disorder, with con-cordance ratios as follows : approximately 1:5 for monozygotic twins, approximately 1:80 for dizygo-tic twins, and more than 1:500 for ordinary siblings.

Of all malignancies, only acute childhood leu-kemia carries such an extraordinar risk of twin

concordance. It is the only childhood malignancy

in which a large number of circulating malignant

cells are found. In most instances, twins with

concordant leukemia have their onset of illness within weeks or months of each other, suggesting a similar inciting event. Since placenta! cross-circulation is found commonly in monozygotic

twins and occasionally in dizygotic twins, cross-infusion of malignant cells has been postulated to account for the high twin concordance ratios. Leukemia in most twins might then represent only one occurrence of leukemia and not two.

This hypothesis, while consistent with most ob-servations, does not explain the pattern of disease in the twins described in this paper. Our proband became ill at nearly 6 years of age, and her twin’s illness occurred more than 6 years later. These twins probably remained at risk of concordant

disease because of postnatal factors affecting

pre-disposed siblings. Whether the predisposition was

due to genetic or to prenatal environmental factors

remains unknown. Pediatrics, 52:846, 1973,

LEU-KEMIA, TWINS.

The relative contribution of heredity and environment in the genesis of acute leu-kemia is unclear. But the issue may be

evaluated by studying the occurrence of

acute leukemia in twins. A high

concord-ance rate in monozygotic

(

MZ

)

twins

might suggest that inherited factors govern

the onset of the disease. However, the effect of a heritable factor cannot with cer-tainty be distinguished from the response

to an intra-uterine insult,’ unless

varia-tion between twin siblings in the type of leukemia or the age at disease onset is

noted. This variation must then be at-tributed to pre- or postnatal environmental factors.2 Twin studies in general do not

permit further definition of the timing or nature of such environmental factors, al-though the disease occurrence in a

particu-lar twin pair might suggest the timing of the leukemogenic event(s).

The following report describes a MZ twin

pair with acute leukemia. The proband was

nearly 6 years old when her diagnosis was

made, and her twin developed leukemia

6 years, 3 months later. The long interval

be-tween their illnesses suggests that separate

environmental insults led to their disease.

Although a prenatal origin of their disease

cannot be excluded, their ages suggest that

separate postnatal leukemogenic events

occurred.

Genetic and environmental interaction may also be evaluated by comparing the

occurrence of acute leukemia in dizygotic

(

DZ) twins versus ordinary siblings.2 DZ twins are as genetically dissimilar as are

ordinary siblings, but they have a common

prenatal environment.2’ 3 A major excess in

their leukemia concordance rate compared

with ordinary siblings would tend to reflect

environmental factors, probably prenatal in origin. As will be shown, DZ twins

(2)

847

of concordance compared with observed

rates for ordinary siblings.

CASE REPORTS

The second pregnancy of the 24-year-old mother was uneventful, except for intermittent,

spontane-ous vaginal bleeding during the first 6 weeks.

Obstetrical x-ray studies were not done. Spontane-ous labor of 6 hours’ duration occurred in Decem-ber 1959, after approximately 34 weeks’ gestation.

The interval between the delivery of the twins

was 8 minutes. A single placenta with two

um-bilical cords was delivered intact. A membrane which could be divided into two layers separated the two cords, leading the obstetrician to note that two amnions and one chorion were probably present; histologic confirmation was not obtained.

TWIN A: (TCH #251,308) weighed 1.87 kg at birth. Her neonatal period was uneventful and she was discharged from the hospital at 35 days of age weighing 2.56 kg. Her growth and

develop-ment proceeded normally. Immunization to

diptheria-pertussis-tetanus, polio, and smallpox

occurred without sequelae. She recovered from

rubeola, rubella, and varicella infections without

complication. She was identical to her sister in

physical appearance. At 5 years, 10 months of age she developed fever, pharyngitis, and epistaxis.

She was pale and her liver was palpable 4 cm

below the right costal margin. Lymph nodes and

spleen were not palpably enlarged. Peripheral

blood studies were as follows: hemoglobin, 5.6

gm/100 ml; hematocrit, 18%; leukocyte count,

1,500/cu mm with 47% segmented neutrophils and

53% lymphocytes; reticulocyte count, 0.3%; platelet

count, 36,000/cu mm. Smears from the bone

marrow aspirate were diagnostic of acute stem

cell leukemia. The red blood cell type was A Rh

(

D) negative. Therapy with 6-mercaptopurine and prednisone led to clinical and bone marrow re-mission. Subsequent therapy included methotrexate and cyclophosphamide. Her final hospitalization

occurred while in bone marrow relapse when she

developed persistent epistaxis, fever, and cellulitis

of the vulva. Pseudomonas aeruginosa grew from

a culture of her blood. She did not respond to

antibiotic therapy and died 5 days after admission, 28 months after diagnosis. Postmortem examination revealed widespread agranulocytic cellulitis of the perineal area, agranulocytic pneumonia, and diffuse infiltration of undifferentiated mononuclear cells in the liver, spleen, lymph nodes, kidneys, lungs, colon, and skin.

TWIN B: (TCH #339,990) weighed 1.85 kg

at birth. Spontaneous respiration was not estab-lished for 2 minutes. She then had tachypnea, grunting respiration, chest retractions, and a poor Moro reflex. She received intravenous fluids for 2 days, then was gavage fed for 4 days. Her

respira-tory function improved, and she subsequently tolerated oral feedings well. She was discharged from the hospital at 37 days of age weighing 2.50

kg. Her subsequent growth and development were

normal. Immunization to diptheria-pertussis-tetanus,

polio, rubeola, and smallpox occurred without

sequelae. She recovered from varicella and rubella

infections without complication. At 12 years, 1

month of age she became pale and febrile, bruised easily, and had a 1 x 1 cm right postauricular mass thought to be a lymph node. Her liver and spleen

were not palpably enlarged. Peripheral blood

studies were as follows: hemoglobin, 5.5 gm/100

ml; hematocrit, 15%; leukocyte count, 4,300/cu mm with 26% segmented neutrophils and 74%

lympho-cytes; reticulocyte count, 0.1%; platelet count,

3,000/cu mm. Smears from the bone marrow

aspirate were diagnostic of acute stem cell leukemia and were identical with the initial bone marrow

smears of her twin. The red blood cell type was

also A Rh (D ) negative. Initial therapy with yin-cristine and prednisone led to clinical and bone marrow remission. She received intrathecal pro-phylaxis using methotrexate, cytosine arabinoside, and hydrocortisone. Presently she remains in

din-ical and bone marrow remission, receiving

6-mercaptopurine as continuous maintenance with a

month of prednisone reinforcement every 3 months.

FAMILY HISTORY: The father (age 26 when

the twins were born ) has multiple sclerosis; his symptoms began in 1958. Male siblings born in 1958 and 1962 are normal. A paternal granduncle died with an unspecified malignancy. The family history is negative for other twinning, congenital

malformations, or blood disorders. The mother had

one spontaneous abortion in 1961.

DISCUSSION

Acute leukemia occurs in both members

of a twin set more frequently than does

any other malignancy. Twenty-seven

con-cordant twin pairs have been reported.

These include 21 pairs listed by Zuelzer

and Cox in their comprehensive review,’

five previously unreported pairs

ascer-tamed by Miller from a death certfficate survey,4 and the present pair. (The third and sixth twin sets from Miller’s Table I are identical in identifying features with cases previously reported.5’6

)

Fourteen

pairs were male and 12 were female, with

only 1 male-female set. This proportion

differs strikingly from the distribution of

twins in the general population, in which

about one third are male-female pairs.’ The

(3)

LEUKEMIA IN TWINS

the like-sex pairs were MZ. While zygosity

was often not clearly established, three pairs proven to be DZ have been reported.1

If one considers all other sets to be MZ, the

MZ to DZ ratio is 24:3 or 8:1.

All cases of concordant acute leukemia

in twins have occurred in At

least 14 of the 27 probands were under 1

year of age at diagnosis, in contrast to the peak incidence of childhood leukemia

which occurs in 3-year-old children.r The

leukemia risk for MZ twins (the pair taken

as a single unit) is the same or slightly below the overall leukemia risk for any child.8 However, once a MZ twin develops leukemia, the co-twin has an exceptionally

high risk (about 1 :5) of also developing

the In addition, the co-twin

usu-ally becomes ill within weeks or months of his twin.’ Lack of concordance in about

80% of MZ twins indicates that genetic fac-tors alone do not account for the excess

6 Pre- and postnatal environmental

factors must play an important role.

In some instances a MZ pair may have

leukemia even when a single pre- or post-natal insult would not likely account for their concordance. Our proband was nearly

6 years old when her illness began, and her

sister became ill more than 6 years later. Their common intra-uterine experience and

genetic identity may have predisposed to extra-uterine susceptibility. But a single

insult would not likely have led to their

disease because they became ill 75 months apart. Although their disease may have had

a prenatal origin, their ages suggest that

one and possibly both of them experienced

a signfficant postnatal leukemogenic insult.

This twin pair differs strikingly from the

other 23 presumably MZ concordant pairs.

None of the other co-twins became ill or

died more than 3 years after their twin;

only three were separated by more than 1

year.”4 Only one other proband became ill

at an older age (7 years ).1

The effect of genetic and environmental

factors in leukemogenesis may also be

evaluated by comparing leukemia

con-cordance in DZ twins and ordinary siblings.

DZ twins are as genetically dissimilar as are

ordinary 23 A major variation in

their rate of concordant leukemia,

com-pared to ordinary siblings, would tend to

reflect environmental factors. The following

calculations, based on a review of leukemia in twins and siblings, suggest that DZ twins

rank between MZ twins and ordinary siblings in concordance risk.

Since the reported ratio of MZ to DZ

concordant pairs is 8: 1, and DZ twinning

occurs about twice as often as MZ

twin-3 the differential risk of leukemia

concordance in the general twin population

(

MZ: DZ) is about 16: 1. The observed MZ

concordance risk is about 1 :5,’ giving a

DZ risk of about 1 :80

(

1/16 of the MZ risk

)

. Estimates of the concordance rate of

acute leukemia in ordinary siblings range

from a rate equal to the risk in the general pediatric population to nearly four times

that rate.9 The overall incidence of acute

leukemia in children is about 3.7 new

cases/100,000 children/year. About one in

2,000 children will develop acute leukemia

between birth and 15 years of age. Even

the maximum estimated sibling

concor-dance risk (nearly 1:500) is considerably

less than the risk of about 1 :80 suggested for DZ twins.

These calculations are based on all re-ports of concordant acute leukemia in twins. Our observed MZ:DZ ratio probably

represents a valid approximation of the

true concordance ratio, for it is doubtful

that any bias exists in the reporting of MZ

or DZ pairs. However, at least one pair presumed to be MZ4 was actually DZ.5 Since the zygosity of other presumed MZ

pairs is not definitely established, the

cal-culated DZ risk is a minimum estimate.

A common prenatal experience is the major feature distinguishing DZ twins from ordinary siblings. Intra-uterine exposure to leukemogens probably contributes to their

excess leukemia. However, twins also have

a similar postnatal environment. Unlike

ordinary siblings, DZ twins would likely be exposed to a particular postnatal leuke-mogen at the same age and at a similar

point in their immunologic development.

(4)

849

likelihood of the twins having a concordant

response to the postnatal leukemogen. Regardless of zygosity, leukemia occur-ring in both members of a twin pair ap-pears to be due in large part to their shared

prenatal environment. Clarkson and Boyse1#{176}

have suggested that the most important

prenatal factor leading to the shared

en-vironment is placental cross-circulation, which occurs commonly in MZ twins1’ and occasionally in DZ 1 Leukemia in

twins, MZ in particular, might then

repre-sent only one occurrence of leukemia and

not two, with infusion of malignant cells

from the affected twin to the unaffected

co-twin leading to the concordance. The brief

interval separating the onset of disease in many twin pairs would support. this view. Even more convincing. is the observation

that only acute leukemia of childhood

car-ries such an extraordinary risk of twin

con-cordance.

Other childhood malignancies,

particular-ly neuroblastoma, are thought to have a

pre-natal origin but do not have the high twin

concordance rate noted for acute leukemia.

These malignancies differ from leukemia in

part by the absence of large numbers of

circulating malignant cells, making cross-transfusion much less likely for tumor cells than for leukemic cells. While the cross-circulation hypothesis is attractive in ex-plaining many instances of twin leukemia, it does not account for those instances in

which the proband’s illness occurred later

in childhood. Such pairs, as illustrated by

our twins, remain at risk of concordant

disease probably because of postnatal

fac-tors affecting predisposed twins. Whether

the predisposition is genetic or is due to

factors in the prenatal environment remains

unknown.

SUMMARY

Twin girls, who probably were

monozy-gotic, both developed acute leukemia. The

proband’s illness began when she was nearly 6 years old, and her twin’s occurred 75 months later. This long interval suggests

that separate environmental insults were responsible for their disease.

Concordance ratios for acute childhood leukemia in twins and ordinary siblings illustrate a decreasing risk of leukemia

con-cordance with decreasing genetic and environmental similarity. The risk of

concordance for monozygotic twins is ap-proximately 1 :5, for dizygotic twins it is approximately 1 : 80, and for ordinary

sib-lings it is more than 1:500.

REFERENCES

1. Zuelzer, W. W., and Cox, D. E. : Genetic as-pects of leukemia. Semin. Hematol., 8:228, 1969.

2. Thompson, J. S., and Thompson, M. W.:

Genetics in Medicine, ed. 1. Philadelphia and London: W. B. Saunders, 1966, p. 233. 3. McKusick, V. : Human Genetics, ed. 2. In

Suskind, S. R., and Hartman, P. E., ed.:

Foundations of Modern Genetics Series.

Englewood iiffs, New Jersey: Prentice-Hall, Inc., 1969, p. 116.

4. Miller, R. W. :‘iDeaths from childhood leukemia and solid tumors among twins and other sibs in the United States. J. Nat. Cancer Inst., 46:203, 1971.

5. Sandberg, A. A., Cortner, J., Takagi, N.,

Moghadam, M. A., and Crosswhite, L. H.:

Differences in chromosome constitution of

twins with acute leukemia. New Engl. J.

Med., 275:809, 1963.

6. Pearson, E. A., Grello, F. W., and Cone,

T. E., Jr. : Leukemia in identical twins. New

Eng. J.Med. 268:1151, 1963.

7. Fernbach, D. J.: Natural history of acute

leukemia. In Sutow, W. W., Vietti, T. J.,

and Fernbach, D. J., ed. : Clinical Pediatric Oncology. St. Louis, Missouri: C. V. Mosby,

in press.

8. MacMahon, B., and Levy, M. A. : Prenatal origin of childhood leukemia. New Eng. J. Med., 270:1082, 1964.

9. Miller, R. W. : Persons with exceptionally high risk of leukemia. Cancer Res., 27:2420, 1967. 10. Clarkson, B. D., and Boyse, E. A. : Possible

explanation of the high concordance for

acute leukaemia in monozygotic twins. Lan-cet, 1:699, 1971.

11. Strong, S. J., and Corney, G.: The Placenta in

Twin Pregnancy, ed. 1. Oxford: Pergamon

Press, 1967, p. 65.

Acknowledgment

The authors wish to thank Drs. Clark W. Heath, Jr., Dennis O’Connor, and Henry Falk for their

help in developing the ideas presented in this

manuscript, and Drs. George A. Dawson and

(5)

1973;52;846

Pediatrics

John M. Falletta, Kenneth A. Starling and Donald J. Fernbach