Ineffective regulation of granulopoiesis masquerading as congenital leukemia in a Mongoloid child

T H E JOURNAL OF

PEDIATRICS j u LY

1963

Volume

63

Number

1

Ineffective regulation of gran ulopoiesis masquerading as congenital leukemia in a Mongoloid child A patient is described who presented soon after birth with the findings of Mongolism and acute granuloeytic leukemia. However, he recovered completely from this condition and at his death, at the age of 33/4 years, there was no evidence of leukemia. Leukocyte alkaline phosphatase was increased initially but subsequently became normal. On a review of the literature, only 1 case was found which closely resembled this one. The known disorders of the leukocytes and previously reported in vitro studies of leukocyte growth in Mongolism suggest that there is ineI]ective regulation of granulopoiesis in Mongolism, perhaps related to trisomy of chromosome 21. The case described here may represent an accentuation of this defect.

Jean D. Ross, M.D., William C. Moloney, M.D., and Jane F. Desforges, M.D. "~ BOSTON~

MASS.

T H E increased incidence of acute leukemia in Mongolism is now well established.:, 2 It is not generally recognized, however, that From the Tufts Hematology Service, Boston City Hospital, and Department of Pediatrics, Boston Floating Hospital. This work was performed under tenure of a National Institutes of Health postdoctoral fellowship (].D:R.) and was also supported in part by Grant No. A T (30-1) 1871 of the Atomic Energy Commission. ~Address, Tufts Hematology Laboratory, Boston City Hospital, Boston 18, Mass,

another form of blood disorder, which can be mistaken for acute leukemia, may occur in Mongoloid children. It is the purpose of this paper to present an infant with Mongolism who was initially thought to have congenital acute granulocytic leukemia but who recovered completely from the hematologic condition. Evidence from the literature will be presented to suggest that our patient's blood disorder may have been the result of an intracelIular defect in the regulation of

2 Ross, MoIoney, and Desforges

the production or m a t u r a t i o n of the leukocytes in Mongolism. METHODS

Unless otherwise specified, Iaboratory studies were performed by s t a n d a r d metho d s ? Platelets were e n u m e r a t e d by the direct technique with the use of phase contrast microscopy. 4 Polymorphonuclear leukocyte alkaline phosphatase was assayed histochemically by the cobalt-calcium m e t h o d of Gomori s a n d scored as described by Kaplow. 6 T h e n o r m a l score for this m e t h o d at the Tufts Hematology Laboratory is between 15 a n d 75. Quantitatively this enzyme was assayed by the biochemical technique of Valentine a n d Beck 7 with preparation a n d separation of the leukocytes as previously described, s Results were expressed as milligrams of phosphorus released per 101~ leukocytes i n 1 hour (mg. P/101~ w b c ) . T h e normM range of values by this m e t h o d is 15 to 35 mg. phosphorus per 101~white blood cells. CASE

REPORT

A white male infant was born on April 5, 1956, to a 24-year-old woman. Both of his parents and four older siblings, 6, 4, 3, and 2 years old, were living and well. There was no family history of Mongolism or blood dyserasias. Pregnancy and delivery were uneventful. His mother was group A, Rh positive, and her blood Hinton test was negative. At birth his weight was 7 pounds, 11 ounces, and he was noted to have the stigmas of Mongolism and a cardiac murmur. At the age of 2 days a mass was felt in the left upper quadrant, and the white Mood cell count was 25,000 per cubic millimeter with 42 per cent neutrophils, 54 per cent lymphocytes, 3 per cent monocytes, and 1 per cent eosinophils. His blood was group A, Rh positive, and the direct Coombs' test ,;vas negative. Bone marrow aspiration was unsuccessful. On admission to the Boston City Hospital on April 13, 1956, at the age of 8 days, he appeared to be well developed and in no distress. The rectal temperature was 99 ~ F., pulse 150, and weight 7 pounds. His features were typical of Mongolism and he was generally hypotonic. A mild scaly, crusted, reddish papular eruption was present over both cheeks. The lungs were

July 1963

clear. The heart was enlarged to the anterior axillary line at the fifth interspace on the left, and a Grade II blowing systolic murmur was heard maximally in the fourth interspace at the left sternal border. The liver was palpable 2 to 3 cm. below the right costal margin, and the spleen was felt 5 cm. below the left costal margin. The umbilical cord was still attached and showed no signs of infection. There was no jaundice, pallor, cyanosis, purpura, or lymphadenopathy. The hemoglobin concentration was 16.8 Gm. per 100 ml., and leukocytes numbered 29,800 per cubic millimeter with 32 per cent segmented neutrophils, 3 per cent band forms, 28 per cent myeloblasts, 29 per cent lymphocytes, and 4 per cent unclassified primitive cells. Platelets appeared normal on smear. Erythrocytes were normochromic with slight target cell formation, rare teardrop-shaped cells, anisocytosis, and poikilocytosis. Urinalysis was normal on several occasions. A culture of the facial rash grew out hemolytic Staphylococcus aureus, but blood cultures were negative and no pathogenic organisms grew from the throat culture. Blood nonprotein nitrogen was 19 mg. per cent. Cephalin floceulation was negative. An intravenous pyelogram revealed no evidence of renal malformation. A chest x-ray was normal except for a slightly enlarged cardiac shadow. Aspiration of tibial bone marrow on the second day and again on the fifth day of hospitalization revealed a marked increase in myeloblasts and promyelocytes, frequently occurring in nests and clumps (Fig. 1 and Table I). Erythroid precursors and megakaryocytes were diminished in numbers but were normal morphologically. The patient's course is depicted in Fig. 2. By the sixth hospital day the white blood cell count had risen to 37,400 per cubic millimeter, the platelet count was 58,000 per cubic millimeter, and there were 43.5 per cent promyetocytes and myeloblasts in the peripheral blood smear. It was felt that the patient had a case of acute or subacute congenital granulocytic leukemia, and 1 mg. of busulfan daily was administered. He continued to receive 1 to 2 mg. of this medication per day from the sixth to the sixteenth day and again from the twenty-third to the twentysixth day. The facial rash gradually subsided with local washing with pHisoHex and oral penicillin, and a furuncle of the right buttock healed rapidly after incision and drainage. The enlargement of the liver and spleen per-

Volume 63 Number 1

Granulopoiesis simulating leukemia in mongolism

sisted and the hemoglobin concentration and leukocyte count gradually decreased. On day 47 the hemoglobin concentration was 5.1 Gm. per 100 ml. and leukocytes 7,000 per cubic millimeter with 23 per cent rnyeloblasts. A transfusion of 75 c.c. of whole blood was administered. O n day 55 a biopsy of the tibial marrow was found to consist almost exclusively of young granulocytic precursors. On day 63 he developed staphylococcal pneumonia. The hemoglobin concentration was 5.6 Gm. per 100 ml. and the leukocytes were 3,900 per cubic millimeter with 12 per cent myeloblasts.

3

He responded rapidly to treatment with a transfusion of 75 c.c. of whole blood, erythromycin, and chloramphenicoI. Following this, the hepatosplenomegaly gradually decreased so that by mid-August, 1956, it had disappeared. The hemoglobin concentration and leukocyte count were stabilized at almost normal values and myeloblasts were no longer present in the blood smears. A bone marrow aspiration on Sept. 6, 1956, was entirely normal (Table I). The patient continued to do well and was discharged to a state school for the retarded at the age of 9 months.

Fig. 1. Bone marrow on April 13, 1956, at age 10 days (second day in B, Original magnification the hospital). A, Original magnification • xl,000, demonstrating morphology of the myeloblasts.

4

Ross, Moloney, and Desforges

July 1963

T a b l e I. B o n e m a r r o w d i f f e r e n t i a l c o u n t s in p e r c e n t

Cells Blasts Promyelocytes

Date (age) 4/14/1956 (9 days) I 9/6/1956 (5 months') [3/11/1959 (35 months) 57.2 2.0

3.2 2.0

1.8 2.2

5.2 3.8 13.2 8.6

14.0 6.2 26.8 5.8

13.6 13.6 53.0' 4.8

-0.2 0.4 1.2 14.6 1.8 ---

2.4 1.2 -2.6 21.6 2.6 -1.2

1.0 0.4 -1.4 5.0 1.4 0.4 0.4

-1.6 0.2 --

1.6

1.4

7.4 1.0 0'.4

7.4 1.6 O.6

Neutrophilic Myelocytes Metamyelocytes Band forms Segmented forms

Eosinophiliv Myelocytes Segmented forms BasophiIs Monoeytes Lymphocytes Reticulum cells Plasma cells Pronormoblasts

Normoblasts Basophilic Polychromatophilic Orthochromatic Megakaryocytes

At the age of 3 years, when seen by the authors, he appeared to be well except for his obvious mental retardation and the stigmas of Mongolism. There was moderate pectus excavatum and a Grade I V harsh systolic murmur was heard maximally at the fifth interspace along the left sternal border. The spleen was not palpable. The liver was felt 3 cm. below the right costal margin. Bilateral inguinal hernias were noted. There was no lymphadenopathy, no purpura, and no pallor. The hemoglobin concentration was 9.9 Gm. per 100 ml., platelets 196,000 per cubic millimeter, and teukocytes 8,200 per cubic miIIimeter, with 63.5 per cent segmented neutrophils, 1.5 per cent band forms, 27.5 per cent lymphocytes, 3 per cent eosinphils, and 0.5 per cent basophils. The erythrocytes were slightly hypochromic and microcytic. Bone marrow aspirated from the anterior iliac crest was of normal cellularity and the morphology was normal (Table I, Fig. 3). Except for a greenstick fracture of the right femur in April, 1959, he continued to do well. On Dec. 21, 1959, he awoke feeling well and was playing actively, but he suddenly became cyanotic and apneic and died. At autopsy he weighed 27 pounds and measured 52 cm. in length. The cause of death was found to be aspiration of stomach contents to-

gether with a right lower lobe aspiration pneumonia. Addkional findings were a patent ductus arteriosus proximal to the subclavian artery on the left, moderate right ventricular hypertrophy, and a small adrenal rest in the right kidney. There was moderate congestion of the sinusoids of the liver. Examination of the brain revealed findings typical of Mongolism. There was no leukemic infiltration of any of the organs including bone marrow, spleen, liver, lungs, or lymph nodes. RESULTS

OF STUDIES

OF

LEUKOCYTE ALKALINE PHOSPHATASE

T h e s e results a r e listed in T a b l e I I a n d are also d e p i c t e d in Fig. 2. I n i t i a l l y the leukocyte alkaline p h o s p h a t a s e activity, determ i n e d b i o c h e m i c a l l y , was 72 rag. P per 10 t~ w h i t e b l o o d cells, a distinct elevation, a n d on M a y 1, 1956, it was still increased. H i s t o c h e m i c a l studies c o n f i r m e d this finding. T h e e n z y m e a c t i v i t y rose to a m a x i m u m of 177 m g . P p e r 10 ~~ w h i t e b l o o d cells by J u n e 1, 1956, a n d t h e n d e c r e a s e d s o m e w h a t by A u g u s t 1, 1956. O n M a r c h 1I, I959, t h e leukocyte alkaline p h o s p h a t a s e was n o r m a l . S i m u l t a n e o u s d e t e r m i n a t i o n s of t h e e n z y m e

Volume 63 Number 1

Granulopoiesis simulating leukemia in mongolism

It has recently been demonstrated that the leukocyte alkaline phosphatase is elevated in Mongolism. ls-2~ Significantly, chronic granulocytlc leukemia is also associated with abnormalities both of the chromosomaI karyotype and of the leukocyte alkaline phosphatase. Valentine and Beck 7 and also Wiltshaw and Moloney s demonstrated that the leukocyte alkaline phosphatase i~ markedly diminished in chronic granulocytic leukemia. Moreover, in most cases of the latter disease there is an abnormally small chromosome present, the Ph z chromosome, in place of one of the small acrocentrics of Gro.up 2122. 2a-23 Baikie and Tough and their co-workers~2, 2a have postulated that the genes responsible for the regulation of leukopoiesis are located on chromosome 21 or 22. It is possible that these same chromosomes may contain a locus for regulation of the activity of leukocyte alkaline phosphatase.

by the histochemical technique revealed parallel changes. The increase in alkaline phosphatase activity did not correlate with the presence of an infection, which is known to cause an increase in the activity of the enzyme.* DISCUSSION It is we11 established that Mongolism is the result of trisomy of a small acrocentric chromosome of Group 21-22 (Denver classification). In most Mongoloids the total somatic chromosome number is 47. 9-a2 Occasional, cases have been reported with a so~ matic chromosome number of 46 and, in most of these, besides the trisomy of number 21, there is a translocation, usually between chromosomes 21 and 14 or 15za-~Gor between 21 and 22. ~4-t~ Unfortunately, chromosomal analysis was not available to us at the time we were following our patient.

5TAPHYLOCOOC.~L. =YODERMIA

FURLINGLE

PNEUMONIA

N BLOOD

BLOOD

r

r

BUSULFAN mgms/DAY HGB ISGRAMS/IOOml. I05X 103/mm3

50-

TOTAL 40WBC ~. = ABSOLUTE NO, 30MYELOBLASTS X. . . . .

X

20 [O-

;~

-

-x.

X~ ,

,

-

-

~

X'-X'--X- -X- ~

% MYELOBLASTS

502O

ill

II11,,,

,

_, - ~,, ~ ~ _

=.r

__.x--~ ....

,t-~

I,I

I 9 NORMAL

ON B L O O D

SMEAR

/ PLATELETS X 1041mm3 LEUKOCYTE ALKALINE PHOSPHATASE mgms P/IOI~

I0-

_J

5

f

200

I00-

I

I

5 AGE IN MONTHS

1959)

Fig. 2. Schematic outline of patient's clinical and laboratory course.

6 Ross, Moloney, and Des[orges

]uly 1963

Fig. 3. Bone marrow at age 3 years. (Original magnification x640.)

Krivit, 2~ in 1956, indicated that the incidence of acute leukemia is greater among Mongoloid children under the age of 4 years than in the general pediatric population of the same age. H e confirmed this impression by a review of the literature and from the results of a survey of patients seen at various hematologic centers in the United States? Our patient was incIuded in his survey. Carter 2s also found that leukemia is a relatively frequent cause of death in Mon-

golism, and the study by Stewart and her co-workers 2 of childhood malignancies in Great Britain indicated that the incidence of leukemia in Mongoloids is at least fifteen times that of the general British pediatric population. Twelve, or approximately one third, of the cases reviewed by Krivit ~ were classified as acute granulocytic leukemia. I t is possible, in view of the difficulty of making an exact morphologic diagnosis in acute leukemia,

Table II. Summary of values for polymorphonuclear leukocytes, alkaline phosphatase, and simultaneous blood counts Leukocyte alkaline phosphatase Biochemicalquantitative Histochemical (my. P/lOl~ (Kaplow score)

Total leukocytes

%

Date

~er ram, g

myeloblasts

5 / 1/1956

15,500

15

82

5/14/1956

6,000

--

100

388

6 / 1/1956

4,80.0,

43

177

-

8/ 1/1956 3/11/1959

8,200

-None

55 34

-51

15 to 35

15 to 75

Normal range

219.5

Comments Furuncle of buttock Hgb. 12.2 Gm./100 ml. Platelets 120,0'0'0 per mm. a Busulfan 5,/11-5/14/56 Spleen 5 cm. below left costal margin Hgb. 6.3 Gin./1001 ml. Marrow hypoeellular In good health No splenomegaly No thrombocytopenia Marrow normal

Volume 63 Number I

Granulopoiesis simulating leukemia in mongolism

that this proportion may be even greater than reported. It should be noted, moreover, that the frequency of acute granuloeytic leukemia is significantly higher in the leukemic Mongoloid population than in the general pediatric leukemic population. Under the age of 15 years acute lymphoblastic or stem cell leukemia predominates and acute granulocytic leukemia is reported variously as comprising 13.0 per cent 26 or 6.06 per cent 27 of the cases in childhood. It has also been observed that congenital leukemia is most frequently of the acute granulocytic varietyY s, 29 Several of the reported cases of this rare disorder have occurred in Mongoloids One of 4 patients with congenital leukemia described by Bernhard and associates 2a was a Mongoloid and 2 of Krivit's 5 cases of leukemia and Mongolism occurred in newborn infantsY 4 Other such cases were described by O'Connor a~ and Lee? 1 In Krivit's 1 later survey he further indicated the frequent association of the two disorders in the neonatal period. Other hematologic disorders have been noted in Mongoloid children. A case of erythroleukemia has been described by Eliachar and co-wc}r~ers, a2 and Rosenherg and Taylor 33 have also reported a case of myelofibrosis and myeloid metaplasia that occurred in a 23-month-old child with Mongolism. Abnormalities of the leukocytes are apparently characteristic of Mongolism. 34-39 Benda 34 indicated that there is a reduced number of lymphocytes in the blood of Mongoloids and that the polymorphonuclear leukocytes show an increased proportion of cells with unsegmented nuclei. Mittwoch, 3~ in 1957, demonstrated that the mean lobe count of polymorphonuclear leukocytes of Mongoloids was significantly less than that of non, Mongoloid controls and that this finding was not related to the total leukocyte count or to the presence of infection. In a later paper she 39 indicated that those hematologic changes which are dependent upon the age of the patient, such as the gradual decrease of the lymphocyte count, do not take place in Mongoloids. O u r patient presented initially with spleno-

7

megaly together with the blood findings characteristic of acute or subacute granulocytic leukemia and was thought to have congenital leukemia associated with Mongolism. It became apparent as time passed, however, that he was gradually recovering from the blood dyscrasia. Three years later he showed no residual hematologic disorder and the blood and bone marrow were normal except for a mild hypochromic anemia. At the time of his death at the age of 4 years there was still no recurrence of the abnormal blood findings. The original diagnosis of congenital leukemia is therefore extremely unlikely. The patient recovered completely from the disorder with minimal antileukernia therapy. Moreover, the agent selected, busulfan, has been shown to be generally ineffective in the treatment of acute or subacute granulocytie leukemia. 4~ Cures of leukemia have been described 41 but are extremely rare. Moreover, all such reports have been in the older literature, making the diagnosis somewhat suspect. The possibility remains that a prolonged spontaneous remission occurred. However, it is extremely unlikely that a remission of such long duration couId occur withou~ specific therapy and with completely normal findings both at follow-up and at autopsy. Thus, the exact nature of the hematologic problem in our patient remains obscure. Infection was minimal or absent throughout most of his course and would not ordinarily be sufficient to result in a leukemoid reaction, even in the neonatal period. Moreover, the presence of thrombocytopenia and the large number of myeloblasts in the peripheral blood is unusual in a leukemoid reaction, as is the predominance of blasts in the marrow. Bernhard 2s has stressed the importance of ruling out erythroblastosis fetalis and congenital syphilis before making the diagnosis of congenital leukemia. In our case, the maternal Hinton test for syphilis was negative and there was no evidence of blood group incompatibility between the mother and child. The possibility of myeloid metaplasia must be considered. Although an eIevated leuko-

8 Ross, Moloney, and Desforges

cyte alkaline phosphatase, myeloid immaturity, thrombocytopenia, and anemia in association with splenomegaly suggest this diagnosis, normoblastemia was minimal and the erythrocytes exhibited none of the typical morphologic changes. Moreover, the number of myeloblasts was greater than one expects in myeloid metaplasia. Myelofibrosis was not found on examination of the bone marrow biopsy. An increase of leukocyte alkaline phosphatase activity is a nonspecific abnormality. Not only is it found in myeloid metaplasia 7, 9, 4a but also in association with infection, s pregnancy, and the neonatal period. 4a Although this enzyme is said to exhibit increased activity in most Mongoloid children, ls-2~ in our patient it returned to normal levels after subsidence of the hematologic disorder. We have been able to find only one case in the literature that closely resembled ours. Schunk and Lehman ~4 described a newborn infant with the typical findings of Mongolism who developed jaundice at the age of 3 days and splenomegaly and petechiae at the age of 8 days. Blood counts revealed anemia, extreme leukocytosis, and predominance of monoblasts and promonocytes. T h e diagnosis was made of congenital monoblastic leukemia, but all the abnormal findings gradually disappeared, and at the age of 4 years the blood and bone marrow were entirely normal. Serologic evidence of Rh incompatibility was found at a later date in this patient's mother, and the authors questioned whether his blood abnormality could have been related to this finding. Two other recorded cases are pertinent. Schunk and Lehman described a second infant thought to have congenital leukemia associated with Mongolism. Although this b a b y at autopsy exhibited widespread infiltration of all organs with immature granulocytes, he too was found to have a positive direct Coombs' test. Thus his blood disorder, although in every respect resembling congenital acute monocytic leukemia, m a y conceivably have been secondary to erythroblastosis fetalis. An almost identical case was

July 1963

described by Kaufmann and Hess. 45 They reported upon an infant born with Mongolism and hydrops fetalis who exhibited some of the findings of congenital acute monocytic leukemia in the peripheral blood. At autopsy there was a massive infiltration of almost all organs with mononuclear cells. Immunologic studies on the mother, however, revealed the presence of anti-A hemolysins and the baby was therefore believed to have suffered from severe AO incompatibility rather than from congenital leukemia. The exact mechanism of such abnomnal blood reactions is unknown. K a u f m a n n and Hess questioned the existence of congenital leukemia45, 46 and suggested that a wide variety of "anaphylactoid responses" may in the newborn lead to reactions resembling congenital leukemia. The hematologic disorders described by them and by Schunk and Lehman, however, occurred in Mongoloid newborn infants. Thus, these reactions may be a feature of Mongolism rather than of the neonatal period. We wish to postulate that in Mongoloids there is ineffective regulation of the production or maturation of leukocytes, specifically the granulocytes. The abnormality could be termed "labile granulopoiesis" and would result in the usual findings in Mongoloids of a left shift and decreased lobulation of the polymorphonuclear leukocytes in the peripheral blood. If subjected to relatively minor stimuli, such as a mild blood group incompatibility resulting in no symptoms, or minimal ones, the blood of the child with Mongolism m a y respond excessively with a nonfatal disorder resembling acute granulocytic leukemia. This m a y have been the case in the patient described by Schunk and Lehman and, possibly, that of K a u f m a n n and Hess. Minor infection m a y cause a similar reaction and this was possibly what happened to our patient. Moreover, such an abnormality would conceivably make Mongoloid children more susceptible to the factor or factors which result in true leukemia. With regard to this concept, it is of interest to note that Tough and her co-workers =a have remarked on the relative ease with

Volume 63 Number 1

Granulopoiesis simulating leukemia in mongolism

which leukemic cells o b t a i n e d from M o n g o loids grow in vitro in comparison with the growth rate of cells from leukemic n o n - M o n goloid subjects. This observation was also m a d e on a child with leukemia a n d M o n golism who was studied by Ross a n d Atkins. 4r I t is possible, therefore, t h a t in M o n golism there m a y be a n intrinsic, intracellular defect in the regulation of white cell m u l tiplication a n d m a t u r a t i o n , perhaps related to trisomy of chromosome n u m b e r 21.

8.

9. 10.

I1.

SUMMARY A p a t i e n t is described who presented soon after birth with the findings of Mongolism a n d congenital acute granulocytic leukemia. After a t h r e e - m o n t h period the blood findings h a d cleared and never recurred. Careful review of the literature revealed only one very similar case. It is suggested that this syndrome is the result of intrinsic ineffective regulation of granulopoiesis in Mongolism.

We are indebted to Dr. Karl V. Quinn, Superintendent, Wrentham State School, Wrentham, Massachusetts, who made available the autopsy findings and the events of the patient's final illness.

12. 13.

14. 15.

16.

17. 18.

REFERENCES i. Krivit, W., and Good, R. A.: Simultaneous occurrence of mongolism and leukemia. Report of a nationwide survey, A. M. A. J. Dis. Child. 94: 289, 1957. 2. Stewart, A., Wcbb, J., and Hewitt, D.: A survey of childhood malignancies, Brit. M. J. 1: 1495, 1958. 3. Page, L. B., and Culver, P. J., Editors: A syllabus of laboratory examinations in clinical diagnosis, revised edition, Cambridge, Mass., 1960, Harvard University Press. 4. Brecher, G., Schneiderman, M., and Cronkite, E. P.: The reproducibility and constancy of the platelct count, Am. J. Clin. Path. 23: 15, 1953. 5. Gomori, G.: Microscopic histoehemistry. Principles and practice, Chicago, 1952, University of Chicago Press, p. 184. 6. Kaplow, L. S.: Histochemical procedure for localizing and evMuating leukocyte alkaline phosphatase activity in smears of blood and bone marrow, Blood 10: 1023, 1955. 7. Valentine, W. N., and Beck, W. S.: Bioehemi-

19. 20. 21. 22.

23.

24.

9

cal studies on leukocytes. I. Phosphatase activity in health, leukocytosis and riiyelocytic leucemia, J. Lab. & Clin. Med. 38: 39, 1951. Wiltshaw, E., and Moloney, W. C.: Histochemical and biochemical studies on leukocytc alkaline phosphatase activity, Blood I0:1120, 1955. Lejeunc, J., Gautier, M., and Turpin, R.: Les chromosomes humains en culture de tissus, Compt. rend. Acad. so. 248: 602, 1959. Lejeune, J., Turpin, R., and Gautier, M.: Le mongolisme. Premier example d'ab4rration autosom!que humaine, Ann. genet, l: 41, 1959. Lejeune, J., Gautier, M., and Turpin, R.: Etude des chromosomes somatiques de neuf enfants mongoliens, Compt. rend. Acad. sc. 248: 1721, 1959. B65k, J. A., Fraccaro, M., and Lindsten, J.: Cytogenetical observations in mongolism, Acta paediat. 48:'453, 1959. Polani, P. E., Briggs, J. H., Ford, C. E., Clarke, C. M., and Berg, J. M.: A mongol girl with 46 chromosomes, Lancet 1: 721, 1960. Penrose, L. S., Ellis, J. R., and Delhanty, J. D.: Chromosomal translocations in mongolism and in normal relatives, Lancet 2: 409, 1960. Carter, C. O., Hamerton, J. L., Polani, P. E., Gunalp, A., and Weller, S. D. V.: Claromosome translocation as a cause of familial mongolism, Lancet 2" 67B, 196.0. Breg, W. R., Miller, O. J., and Schmickel, R. D.: Chromosomal translocations in patients with mongolism and in their normal relatives, New England J. Med. 266: 845, 1962 Fraccaro, M., Kaijser, K., and Lindsten, J.: Chromosomal abnormalities in father and mongol child, Lancet 1: 724, 1960. Alter, A. A., Lee, S. L., Pourfar, M., and Dobkin, G.: Leukocyte alkaline phosphatase in mongolism; a possible chromosome marker, J. Clin. Invest. 41: 1341, 1962. Truhowitz, S., Kirkman, D., and Masek, B.: The leukocyte alkaline phosphatase in mongolism, Lancet 2: 486, I962. King, M. J., Gillis, E. M., and Baikie, A. G.: The polymorph alkaline phosphatase in mongolism, Lancet 2: 661, 1962. Nowell, P. C., and Hungerford, D. A.: A minute chromosome in human chronic granulocytic leukemia, Science 132: 1497, 1960. Baikie, A. G., Court Brown, W. M., Buckton, K. E., Harnden, D. G., Jacobs, P. A., and Tough, I. M.: A possible specific chromosome abnormality in human chronic myelo!d leukaemia, Nature 188:1165, 1960. Tough, I. M., Court Brown, W. M., Baikie, A. G., Buckton, K. E., Harnden, D. G., Jacobs, P. A., King, M. J., and McBride, J. A.: Cytogenetic studies in chronic myeioid leukaemia and acute leukaemia associated with mongolism, Lancet 1: 411, 1961. Krivit, W., and Good, R. A.: The simultaneous occurrence of leukemia and mongolism, A. M. A. J. Dis. Child. 91: 218, 1956.

1 0 Ross, Moloney, and Des[orges

25. Carter, C. O.: A life-table for mongols with the causes of death, J. Ment. Defic. Res. 2: 64, 1958. 26. Tivey, I4.: Prognosis for survival in the leukemias of childhood, Pediatrics 10: 48, 1952. 27. Pierce, M. I.: The acute leukemias of childhood, Pediat. Clin. North America 4: 497, 1957. 28. Bernhard, W. G., Gore, I., and Kilby, R. A.: Congenital leukemia, Blood 6: 990, 1951. 29. Pierce, M. I.: Leukemia in the newborn infant, J. P~DIAT. 54: 691, 1959. 30. O'Connor, R. E., McKey, R. W., and Smith, J.: Congenital leukemia, Am. J. Dis. Child. 88: 740, 1954. 31. Lee, C. L.: Congenital leukemia associated with mongolism, J. P~DIAT. 51: 303, 1957. 32. Eliachar, E., Ratel, J., and Polet, C.: Erythroleucomy~lose et mongolisme, Semaine h6p. Paris, 34: 247P, 1958. 33. Rosenberg, H. S., and Taylor, F. M.: The myeloproliferative syndrome in children, J. PEDIAT. 52: 407, 1958. 34. Benda, C. E.: Mongolism and cretinism, New York, 1946, Grune & Stratton, pp. 213-218. 35. Turpin, R., and Bernyer, G.: De l'influence de l'hfiredit~ sur la formule d'Arneth (cas particulier du mongolisme), Rev. h~mat. 2: 189, 1947. 36. Shapiro, A.: The differential leukocyte count in mongols, J. Ment. Sc. 95: 689, 1949. 37. Luers, T., and Luers, H.: Uber eine Segmen-

July 1963

38. 39. 40. 41. 42.

43. 44. 45.

46. 47.

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