Pediatr Blood Cancer 2005;44:85–91

BRIEF REPORTTetrasomy 21 Transient Leukemia With a GATA1 Mutation in

a Phenotypically Normal Trisomy 21 Mosaic Infant:Case Report and Review of the Literature

Claudio Sandoval, MD,1* Sharon R. Pine, PhD,1 Qianxu Guo, MD,1 Sudha Sastry, BS,2

Julian Stewart, MD, PhD,1 David Kronn, MD,1 and Somasundaram Jayabose, MD1

INTRODUCTION

Transient leukemia is typically diagnosed in infantswith constitutional trisomy 21 (OMIM 190685). Thisdisorder of abnormal, monoclonal (by methylation pat-terns of the hypoxanthine phosphoribosyl transferase orphosphoglycerate kinase genes) myelopoiesis undergoesspontaneous resolution [1]. However, approximately 20%of these infants develop acute leukemia by 18 to 24monthsof age [2]. The exact molecular basis for transientleukemia remains elusive, but most certainly involvesgenes on chromosome 21. Recently, acquiredmutations inGATA, preventing synthesis of full-length GATA, wereidentified in and limited to constitutional trisomy 21 acutemegakaryoblastic leukemia (AMKL), as well as constitu-tional and mosaic trisomy 21 transient leukemia [3–8],which suggests that GATA1 plays a critical initial role intrisomy 21 megakaryoblastic leukemogenesis.

Transient leukemia in infants without constitutionaltrisomy 21 resembles that in constitutional trisomy 21infants with the common characteristics of leukocytosis,organomegaly, and spontaneous resolution [9–34]. Cyto-genetic features of blast cells in transient leukemia in non-constitutional trisomy 21 infants include: trisomy 21,isochromosome 21q, and tetrasomy 21. Indeed, some ofthese infants are trisomy 21 mosaics.

In the current work we describe a phenotypicallynormal female infantwith tetrasomy21 transient leukemiawith a GATA1 mutation. Low levels of trisomy 21 mos-aicism within the hematopoietic tissue were detected24 months after diagnosis and trisomy 21 mosaicism andthe GATA1 mutation were no longer detected 30 monthsafter diagnosis. We review the literature of transientleukemia in non-constitutional trisomy 21.

CASE REPORT

A 2.5-kg female infant born at 35-weeks gestation wastransferred to our center from a community hospitalbecause of anemia, hyperleukocytosis, and pericardialeffusion. The gestation was reported as normal. At our

Infants with constitutional trisomy 21 are atincreased risk of developing transient and acutemegakaryoblastic leukemia (AMKL). Mutationsin GATA1 have been identified in trisomy 21patients with AMKL, and this lesion is thought tobe an initial event by virtue of its presenceduring transient leukemia. Transient leukemia isalso observed in phenotypically normal infantsalbeit much less commonly so. Almost all theseinfants are mosaic for trisomy 21, and the clini-cal course of transient leukemia recapitulatesthat observed in constitutional trisomy 21. Wereport a phenotypically normal infant with tetra-somy 21 transient leukemia, GATA1 mutationwithin exon 2, and trisomy 21 mosaicism re-stricted to the hematopoietic tissue. Two years

after diagnosis, low levels of trisomy 21 per-sisted in the peripheral blood, which resolved2.5 years after diagnosis. The GATA1 mutationwas not detected at last follow-up. The literaturereview identified 32 phenotypically normalinfants with transient leukemia. Ninety-one per-cent (29 of 32) were observed and three re-ceived chemotherapy at diagnosis of transientleukemia. Nineteen percent (6 of 32) developedacute leukemia, and four continued in remission(two died). Transient leukemia in trisomy 21mosaicism recapitulates the condition observedin constitutional trisomy 21 at the biological andclinical levels. Infants should be followed for thedevelopment of acute leukemia. Pediatr BloodCancer 2005;44:85–91. � 2004 Wiley-Liss, Inc.

Key words: GATA1; tetrasomy 21; transient leukemia; trisomy 21 mosaicism

——————1Department of Pediatrics, New York Medical College, Valhalla,

New York

2Genzyme Genetics, Yonkers, New York

Grant sponsor: Children’s Cancer Fund.

*Correspondence to: Claudio Sandoval, Department of Pediatrics,

New York Medical College, Munger Pavilion Room 110, Valhalla,

New York 10595. E-mail: claudio_sandoval@nymc.edu

Received 19 March 2004; Accepted 6 July 2004

� 2004 Wiley-Liss, Inc.DOI 10.1002/pbc.20161

institution, the physical examination showed a phenoty-pically normal female infant in no respiratory distress.The liver and spleen descended to the iliac crests. Anerythematous, papular rash was present on the face, trunk,and extremities. The white cell count was 58.9� 103/mlwith 53% blasts, the hemoglobin was 7.4 g/dl, and theplatelet count was 157,000/ml. The chest radiographshowed an enlarged cardiac silhouette and left-lower lobeatelectasis. A large pericardial effusion was confirmedby echocardiography and was evacuated. Bone marrowaspirate and skin biopsy were performed. A diagnosisof transient leukemia was confirmed when the rash andorganomegaly spontaneously resolved, and the bloodcounts normalized by 8 weeks of age. At 2.5 years of agethe physical examination and blood counts remainednormal.

MATERIALS AND METHODS

A review of the literature was conducted by a PubMedsearch for the following terms:Downmosaicism, transientleukemia, and transient myeloproliferative disorder.Standard cytogenetics and flowcytometrywere performedon peripheral blood, bone marrow, and pericardial fluid;and cytogenetic analysis was performed on skin fibro-blasts at diagnosis. Peripheral blood was examined bystandard cytogenetics and fluorescent in situ hybridization(FISH) 1, 3, 4, 24, and 30 months after diagnosis. Molec-ular analysis for clonal IgH, TCRd, and TCRg generearrangements were performed on DNA from peripheralblood and pericardial fluid obtained at diagnosis, asdescribed [35]. DNA samples (250 ng) were screened formutations in exon 2 of GATA1 by SSCP analysis. PCRconditions were 35 cycles of 948C for 10 sec, 608C for10 sec, and 688C for 60 sec, using primers GT2F 50AAAGGA GGG AAG AGG AGC AG 30 and GT2R 50 GACCTA GCC AAG GAT CTC CA 30. PCR products werepurified by SSCP analysis using MDE Gel Solution(CambrexBioScienceRockland, Inc., Rockland,ME) andthen directly sequenced as described [35]. DNA fromperipheral blood taken 2.5 years after diagnosis wasamplified by mutation-specific real-time PCR [36], usingprimers mutGT2F 50 CTCCACACCAGAATCGGGTT30 and GT2bR 50 TGG AGG AAG CTG CTG CAT C 30.

RESULTS

Table I shows the clinical features and outcomes of non-constitutional trisomy 21 and transient leukemia cases, inchronological order (including the present case).

Morphologic evaluation of the peripheral blood, bonemarrow, and pericardial fluid showed similar appearingblasts (Fig. 1). Flow cytometry showed that the blastsexpressed CD7, CD34, CD33, CD13, CD42a, CD 117,and HLA-DR consistent with either acute myelogenousleukemia (AML) or transient leukemia. Molecular analy-

sis showed no evidence of clonal IgH, TCRd, or TCRggene rearrangements. Cytogenetics of peripheral blood,bone marrow, and pericardial fluid showed 48,XX,þ21,-þ21, and that of skin showed 47,XX,þmar[3]/46,XX[47].The marker chromosome was further characterized byFISH using chromosome 21- and chromosome 13-specificDNA probes. The FISH assay showed two copies each ofchromosomes 13 and 21 in 100% of the 150 interphasenuclei analyzed. At 2 years of age, standard cytogeneticsof blood showed only normal metaphases; however, 7.8%of 500 interphase nuclei showed three signals for chromo-some 21, consistent with trisomy 21mosaicism (>3.5%ofnuclei with three signals considered positive, P¼ 0.001).At 2.5 years of age, standard cytogenetics and FISHshowed only normal metaphases.

A deletion of two nucleotides (202 del AG) wasdetected in exon 2 ofGATA1 from the peripheral blood andpericardial fluid, causing a disruption of the reading frameofGATA1 after Gly31, and resulting in the introduction ofa premature stop codon within the N-terminal activationdomain (Fig. 2). SSCP analysis of the peripheral blooddrawn 2.5 years later, revealed only wild type GATA1sequence. Mutation-specific real-time PCR analysis con-firmed the absence of the mutation (sensitivity 1� 10�4)(Fig. 2).

RESULTS OF LITERATURE REVIEW

Thirty-two infants with non-constitutional trisomy 21transient leukemiawere identified (Table I). The 12 femaleand 20male infantsmostly presented at birth (n¼ 19)witha range of 0 to 27 days. The most common presentingphysical examination findings were hepatomegaly with orwithout splenomegaly and rash. The median white-cellcount was 56,500� 103/ml (range, 8,600–924,000), themedian hemoglobin was 13.9 g/dl (range, 8.7–21.6), andthe median platelet count was 123,000/ml (range, 23,000–700,000). Twenty-four infants expressed trisomy 21 in theblasts (one each also expressed trisomyY; trisomy 18; andYqs and del(13)(q13q31)), three expressed isochromo-some 21q, and one each expressed pentasomy 21,tetrasomy 21, and translocation (21;21). Two expressedonly normal metaphases, but these patients were notfurther analyzed by more sensitive techniques. After theresolution of transient leukemia, trisomy 21 mosaicismwas detected in 12 infants (eight in blood, three in bloodand skin, and one in skin) and isochromosome 21(q10) inone. In 13 infants mosaicism was not present and in six itwas not tested for. Twenty-six infants had completeresolution of transient leukemia. Six (19%) developedAML, a median of 18.5 months (range, 12–34 months)after diagnosis of transient leukemia. Two of these sixinfants weremosaic for trisomy 21 in either blood or bloodand skin, two did not have mosaicism detected, and twowere not analyzed for mosaicism after the resolution of

86 Sandoval et al.

TABLEI.

Literature

Review

ofNon-C

onstitutionalTrisomy21TransientLeukem

ia

Gender

Age

Presentation

WBC/

Blasts(%

)Hem

oglobin

Platelets

Cytogenetics

Mosaicism

(þ21)a

Treatment

Outcome

Reference

Male

5days

Purpura

14,600/18

15.3

NP

49,XY,þ

21,þ

21,þ

21

Notpresent

Vincristine,

Prednisone

Resolution

Van

den

Berg

Male

3days

Hepatosplenomegaly,rash

136,000/70

15.9

242,000

47,XY,þ

21

Bloodandskin

Observation

Resolution

Brodeur

Male

NB

NP

42,000/58

NP

NP

46,XY,�

21,þ

i(21q)

Bloodandskin

Observation

Resolution

Heaton

Fem

ale

NB

Norm

alexam

ination

46,000/13

18

36,000

47,XX,þ

21

Blood

Observation

Resolution

Weinberg

Male

NB

Hepatomegaly,rash,epicanthal

folds

80,000/63

15.7

155,000

47,XY,þ

21

Blood

Observation

Resolution

Seibel

Male

NB

Pallor

22,900/23

13.7

96,000

47,XY,þ

21

Notpresent

Observation

Resolution

Siebel

Fem

ale

15days

Facialsw

elling

25,000/45

12.7

71,000

47,XY,þ

21

Notpresent

Observation

Resolution

Hanna

Fem

ale

NB

Hepatosplenomegaly,rash

394,000/50

NP

NP

46,XX

Notperform

edObservation

Resolution

Lam

pkin

Fem

ale

NB

Hepatosplenomegaly,rash

384,000/73

9.5

130,000

47,XX,þ

21

Blood

Observation

Resolution

Jones

Male

NB

Petechialrash

82,400/34

18.1

40,000

46,XY,�

21,t(21;21)

Blood

Observation

Resolution

Jones

Male

7days

Hepatomegaly,cyanosis

14,000/20

15.8

NP

47,XY,þ

21

Notpresent

Observation

Resolution

Kalousek

Fem

ale

7days

Hepatosplenomegaly

168,000/79

NP

NP

48,XX,þ

21,þ

21

Notperform

edPrednisone,

mercaptopurine

Resolution

Takeda

Fem

ale

2days

Hepatosplenomegaly

17,000/24

17

107,000

47,XX,þ

21

Notpresent

Observation

Resolution

Faed

Male

NB

Hepatosplenomegaly,

maculopapularrash

66,000/53

9.4

295,000

47,XY,þ

21

Notpresent

Observation

Resolution

Ridgway

Male

NB

Hepatosplenomegaly

924,000/45

8.7

92,000

47,XY,þ

21

Notpresent

Observation

Resolution

Ridgway

Male

NB

Hepatosplenomegaly,rash

131,000/83

9.6

241,000

47,XY,þ

21

Notperform

edObservation

Resolution

Jiang

Complexb

Doxorubicin,

cytarabine

AMLdeath

Fem

ale

NB

Norm

alexam

ination

8,600/8

10.5

69,000

46,XX

Notperform

edObservation

Resolution

Lam

Male

14days

Hepatosplenomegaly,rash

15,000/28

9.1

23,000

48,XY,þ

Y,þ

21

Notpresent

Observation

Resolution

Homans

Fem

ale

NB

Hepatomegaly,facial

features

oftrisomy21

210,000/80

14.3

184,000

47,XX,þ

21

Notperform

edObservation

Resolution

Homans

Complexc

AMLdeath

Male

2days

Hepatosplenomegaly

60,000/49

12.8

42,000

47,XY,þ

21

Blood

Observation

Resolution

Brissette

Daunomycin,

cytarabine

AMLremission

Male

NB

Rash

84,900/50

18

462,000

47,XY,þ

21

Skin

Observation

Resolution

Bhatt

Male

NB

Hepatosplenomegaly

31,900/31

11.2

441,000

47,XY,þ

21

Bloodandskin

Cytarabine,

dexam

ethasone

Resolution

Doyle

Chem

otherapy

AMLremission

Fem

ale

27days

Hepatosplenomegaly,abnorm

al

facies

anddigits

43,000/36

12.2

477,000

47,XX,þ

21

Blood

Observation

Resolution

Zubizarreta

Male

20days

Hepatosplenomegaly,jaundice,

edem

a,abnorm

aldigits,

pericardialeffusion

89,000/78

14.1

208,000

47,XY,þ

21

Blood

Observation

Resolution

Zubizarreta

Fem

ale

NB

Hepatosplenomegaly,rash

33,000/48

19.1

175,000

48,XX,þ

18,þ

21

Notpresent

Observation

Resolution

Kem

pski

(Continued)

Tetrasomy 21 Transient Leukemia With a GATA1 Mutation 87

transient leukemia. In four infants the leukemia remittedafter chemotherapy and two infants died. Three infantswith AML had complex karyotypes during leukemiaevaluation.

DISCUSSION

Our case demonstrates three salient features of non-constitutional trisomy 21 transient leukemia. First, it mustbe differentiated from acute leukemia, so that those neo-nates with transient leukemia are not subjected to chemo-therapy. Second, the clinical course and biologic featuresresemble constitutional trisomy 21 transient leukemiaand may be managed accordingly. Third, aneuploidy ofchromosome 21 must be looked for, in the hematopoietictissue and skin, to determine the degree of trisomy/tetrasomy 21 mosaicism so that genetic counseling can beprovided.

Differentiating acute leukemia from transient leukemiamay place the treating oncologist in a diagnostic quag-mire. These conditions share many common features

Fig. 1. Representative smears from our patient. A: Blasts in the

peripheral blood and (B) blasts in the pericardial fluid (Wright-Giemsa

stain).

TABLEI.

(Continued

)

Gender

Age

Presentation

WBC/

Blasts(%

)Hem

oglobin

Platelets

Cytogenetics

Mosaicism

(þ21)a

Treatment

Outcome

Reference

Fem

ale

7days

Maculopapularrash,extrem

ity

swelling

29,300/15

10

158,000

47,XX,þ

21

Notpresent

Observation

Resolution

Richards

Complexd

Mitoxanthrone,

cytarabine,

etoposide

AMLremission

Male

6days

Hepatosplenomegaly,rash

53,000/64

21.6

39,000

47,XY,þ

21

Notpresent

Observation

Resolution

Richards

Male

NB

Hepatomegaly

120,800/33

NP

NP

46,XY,i(21)(q10)

Notpresent

Observation

Resolution

Worth

Male

NB

Petechealrash

NP/29

NP

36,000

47,XYqs,þ21,del(13)(q13;q13)

Notpresent

Observation

Resolution

Polski

Chem

otherapy

AML

Male

NB

Norm

al21,000/21

15.8

46,000

47,þ

21

Notpresent

Observation

Resolution

Slayton

Male

NB

Hepatosplenomegaly,edem

a154,000/54

12.4

123,000

46,XY,i(21)(q10)

Blood

Observation

Resolution

Wu

Fem

ale

5days

Hepatomegaly,rash

64,000/62

NP

700,000

47,XX,þ

21

Notperform

edObservation

Resolution

Wolfe

Fem

ale

NB

Hepatosplenomegaly,rash,

pericardialeffusion

58,900/53

7.4

157,000

48,XX,þ

21,þ

21

Blood

Observation

Resolution

Presentcase

aMosaicism

detectedafterresolutionoftransientleukem

ia.

b41,X,�

Y,�

4,�

9,�

13,�

17,�

20,þ

21,der(5)t(5;17)(q11;p11),der(7)t(7;?)(p11;?),der(11)t(4;11)(q12;q25),der(12)t(X

;12)(q11;p13),der(13)t(?;13)(?;p12),der(15)t(4;15)(q13;q26).

c47,XX,þ

21/47,XX,þ

21,4qþmar/48,XX,þ

21,þ

8,t(1;4)(q25;q31).

d47,XX,der(10)t(1;10)(q32.3;q26)ins(10;?)(q26;?)x2,þ

21.

88 Sandoval et al.

including leukocytosis, presence of peripheral blood andbone marrow blasts, organomegaly, and skin lesions [37].In the scenario of an ill appearing or clinically deteriorat-ing infant, anti-leukemia therapy may need to be com-menced before an unequivocal diagnosis is made. Readilyavailable diagnostic clues for acute leukemia could be dueto the presence of central nervous system leukemia andlineage specific immunophenotype. Indeed, in a reviewof perinatal leukemia 38% of infants with leukemia hadcentral nervous system disease compared to only 2% of

perinatal constitutional 21 transient leukemia. The blastsin transient leukemia lack definitive identifying featuresand co-express CD 36 (myeloid differentiation), CD 34(stem cell), CD 7 (T-cell), may express megakaryocytic(CD 61) and other myeloid (CD 13, CD 33) antigens, anddo not express Tdt, B-cell antigens, and other T-cellantigens [38]. Moreover, identification of chromosome 21aneuploidy by FISH analysis on interphase nuclei canprovide results within 24 to 48 hr and support a diagnosisof transient leukemia.

Fig. 2. GATA1mutation in tetrasomy 21 transient leukemia patient.A: SSCP analysis ofGATA1 from normal bonemarrow negative control (NC)

and patient peripheral blood (PB) and pericardial fluid (PF) at diagnosis. Arrow indicates mutated GATA1, (B) sequence analysis of GATA1 at

diagnosis reveals a frameshift mutation after Gly 31 resulting in a premature stop codon and (C)GATA1mutation-specific real-time PCR analysis of

serial dilutions of the diagnosis bone marrow DNA (10�2–10�4), NC, and PB taken 2.5 years after diagnosis.

Tetrasomy 21 Transient Leukemia With a GATA1 Mutation 89

We concur with Zipursky et al. that transient leukemiaoccurs exclusively in the presence of trisomy21 or trisomy21 mosaicism [2]. Indeed, the disease, treatment, andoutcome are similar in both phenotypes. In our literaturereview, 29 of 32 cases were managed with observationalone. Three infants received chemotherapy because ofincreasing blast counts, the need for repeated blood pro-duct transfusions, and/or clinical deterioration. Notably,46% of infants analyzed (12 of 26) were detected asbeing trisomy 21 mosaics after the resolution of tran-sient leukemia. In the remaining cases, mosaicism eitherdid not exist or resolved prior to testing. The clinicalconsequences of persistent trisomy 21 mosaicism are notyet known; however, the finding of identical GATA1mutations during transient leukemia and AMKL inpatients with constitutional trisomy 21 [5] are intriguingand calls for careful clinical scrutiny for the emergenceof AMKL.

Tetrasomy 21, as a sole cytogenetic abnormality, wasdetected in five cases of non-lymphoblastic leukemia(three with acute myeloid leukemia [39–41] and one eachwith erythroleukemia [42] and megakaryoblastic leuke-mia [43]). Each of these patients was constitutionallynormal. In one of these cases, a biallelic point mutationin the runt domain of AML1 was identified [39]. In an ad-ditional case of erythroleukemia (48,XX,del(13)(q12;q14),del(14)(q22;q32),þ21,þ21) the authors showed that themalignant tetrasomy 21 clone developed from an ancestralmarrow clone with trisomy 21 of meiotic origin [44]. Thisevidence buttresses the contention that patients withtransient leukemia should undergo surveillance for thedevelopment of acute leukemia.

GATA1 serves essential functions in the orderlydifferentiation of erythroid and megakaryocytic progeni-tors [45]. In mice with genetically altered GATA1,megakaryocytes proliferate excessively and thrombocy-topenia develops [46]. GATA1mutations in constitutionaltrisomy 21 infants with transient leukemia and AMKLare the result of small deletions or insertions, which alterthe reading frame of GATA1 and introduce a prematurestop codon in the gene sequence encoding the amino-terminal activation domain. Indeed, GATA1 mutationsarise early in the timeline of leukemogenesis, and AMKLmay arise from occultGATA1 positive clones. In our case,we identified a deletion of AG at position 202 within exon2 of GATA1 at diagnosis of transient leukemia (this samemutation was identified in patient one reported by Rainiset al. [7]). This mutation was not identified by SSCPand mutation-specific real-time PCR at last follow-up,2.5 years after diagnosis of transient leukemia. Becausethe patient-specificGATA1mutation disappeared after theresolution of transient leukemia and the patient did notdevelopAMKL, this suggests thatGATA1mutations couldbe exploited to monitor minimal residual disease anddisease progression. Additional patients would need to be

monitored to confirm the usefulness of GATA1 mutationsin predicting development of AMKL.

In summary, clinical, immunophenotypic, karyotypic/FISH, and molecular data can assist oncologists indiagnosing non-constitutional trisomy 21 transient leuke-mia. Once diagnosed, this condition can be managedconservatively, reserving chemotherapy for clinicallydeteriorating infants. The natural history and biology ofthis condition resembles that detected in infants withconstitutional trisomy 21.

ACKNOWLEDGMENT

S.R.P and Q.G are supported by the Children’s CancerFund. The authors thank ChangHong Yin, MD for helpwith the real-time PCR.

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