Cancer Genetics and Cytogenetics 147 (2003) 75–77

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Short communication

A case of Down syndrome with acutelymphoblastic leukemia and isochromosome Xp

Jillian M. Bakera, Max J. Coppesa,b, Birgitte Rolandc,d,*aDepartment of Pediatrics, University of Calgary, Calgary, Alberta, CanadabDepartment of Oncology, University of Calgary, Calgary, Alberta, Canada

cDepartment of Pathology and Laboratory Medicine, University of Calgary, Alberta, CanadadDepartment of Medical Genetics, University of Calgary, Calgary, Alberta, Canada

Received 4 February 2003; received in revised form 11 April 2003; accepted 24 April 2003

Abstract A 3-year, 9-month-old girl with trisomy 21 was diagnosed with acute lymphoblastic leukemia(ALL). The karyotype of her leukemic cells at diagnosis—48,XX,�i(X)(p10),�21c—included anextra, structurally abnormal X chromosome as the sole acquired abnormality. While an extra Xchromosome is a common abnormality in childhood ALL, it is seldom the only acquired aberration.Furthermore, an additional X chromosome that is structurally abnormal is rare, and has notbeen reported previously as a solitary abnormality. Here we report a novel karyotype in childhoodALL and review the eight previously described cases of ALL with an extra X isochromosome asthe only acquired abnormality. � 2003 Elsevier Inc. All rights reserved.

1. Case report

A 3-year-9-month-old girl who has Down syndrome wasdiagnosed with L1, pre–B-cell acute lymphoblastic leukemia(ALL) in the French–American–British (FAB) classification.The patient presented with a white blood cell count of15.4 × 109/l and was CNS-negative, so she was classifiedas having standard-risk ALL, according to the Pediatric On-cology Group ALL classification. Karyotyping (Fig. 1) ofthe diagnostic bone marrow revealed 48,XX,�i(X)(p10),�21c[12]/47,XX,�21c[10]. In situ hybridization using acentromeric probe for the X chromosome (Vysis, Downer’sGrove, IL) showed three signals in 42% of interphase nuclei.In situ hybridization using a telomeric probe for Xp and Yp(Vysis) confirmed that the additional abnormal chromosomewas an isochromosome Xp (Fig. 2). The patient continueson therapy in continuous remission 18 months after initial di-agnosis.

2. Discussion

Numerical abnormalities of chromosome 21 are the mostfrequent acquired genetic aberrations in childhood ALL.

* Corresponding author. Department of Pathology and LaboratoryMedicine, University of Calgary, Alberta Children’s Hospital, 1820 Rich-mond Road Southwest, Calgary T2T 5C7, Alberta, Canada. Tel.: (403)943-2216; fax: (403) 229-2455.

E-mail address: birgitte.roland@CLS.ab.ca (B. Roland).

0165-4608/03/$ – see front matter � 2003 Elsevier Inc. All rights reserved.doi: 10.1016/S0165-4608(03)00197-3

In patients with low hyperdiploid childhood ALL (modalchromosome number between 47 and 50), an additional Xchromosome is found in 21–57% of patients [1,2] and is thesecond most common acquired numerical abnormality. Evenso, an extra X chromosome is uncommon as the sole acquiredabnormality. A search of the Mitelman database of chromo-some aberrations in cancer [3] revealed only eight othercases of an additional X chromosome as the sole acquiredabnormality in ALL [2,4–9]. Three additional cases of ALLwith an acquired extra X chromosome, all in patients withtrisomy 21, have been reported in the literature [2,6], butthese are questionable cases, because either the karyotypeswere uncertain or reinterpretation of the karyotype revealedadditional acquired abnormalities. Table 1 summarizes thepublished information for the eight cases, as well as that forour patient. The limited number of cases does not allowdrawing any conclusions. Moreover, the information avail-able for each case varies greatly, and is limited, since mostcases were reported as part of a larger series. Nevertheless,we note that all patients for whom the age was reported werechildren, with ages ranging from 2 years to 6.6 years (fortwo patients, the age was not specified). Five patients werefemale and four were male. The most intriguing observationis that seven of the nine patients had constitutional trisomy 21.

In an analysis of 76 patients with Down syndrome whodeveloped ALL, Pui et al. [6] noted that an extra X chromo-some is the most common acquired numerical anomaly in

J.M. Baker et al. / Cancer Genetics and Cytogenetics 147 (2003) 75–7776

Fig. 1. Representative bone marrow karyotype at diagnosis, showing constitutional �21 and acquired �i(Xp).

patients with trisomy 21, although additional chromosomes4, 14, 17, 18, and 21 also occur, similar to what is seen inother childhood ALL cases. Nonetheless, in only two of the64 cases for which these investigators were able to perform

Fig. 2. Partial bone marrow metaphase at diagnosis, showing hybridizationof the Xp/Yp telomeric probe to both ends of the abnormal chromosome,confirming that it is an isochromosome Xp.

cytogenetic analysis of the leukemic cells was an extra Xchromosome the sole acquired abnormality.

Our patient is unique in that the additional X chromo-some as the sole acquired aberration was structurally abnor-mal. In the Mitelman database, four cases of deleted Xchromosomes were found: two cases of �del(X) and twocases of del(X). In each case, however, the abnormal Xchromosome was one of many abnormalities in the leuke-mic cell line [1,10–12]. Of note, the two cases with del(X)also had an extra chromosome 21, but it is unclear whetherthe extra chromosome was constitutional [1,11]. Only oneother case of �i(Xp) in ALL is reported in the Mitelmandatabase, but not as a sole abnormality [13].

Traditionally, attempts to classify ALL into therapeuti-cally relevant risk categories have relied on clinical parame-ters such as age and white blood cell count at diagnosis.More recently, however, chromosomal changes have beenincorporated into risk classification [14]. Initially, hyperdip-loidy of 47 to 50 chromosomes was associated with anadverse outcome, but treatment with contemporary multi-agent chemotherapy has significantly improved survival,such that this group of patients is now considered to have anintermediate prognosis [15]. The very limited data availablefor the low hyperdiploid ALL patients who have an addi-tional X chromosome do not suggest that this abnormalityconfers a better or poorer outcome [15].

A gain of chromosome 21 in leukemic cells of patientswithout Down syndrome, even as the sole acquired genetic

J.M. Baker et al. / Cancer Genetics and Cytogenetics 147 (2003) 75–77 77

Table 1Patients with ALL and �X as the only acquired abnormality

Age at WBC at diagnosis Outcomea

Case no. Reference diagnosis (y) Sex Bone marrow karyotype ALL Type (×109/L) (publication year)

1 [2] 3 F 48,XX,�X,�21c[cp4]/47,XX,�21c[13] Common L1 (� 90% blasts) 52.7� (1999)2 [4] Child M 48,XY,�X,�21c — — —3 [5] 3.3 F 48,XX,�X,�21c[25]/47,XX,�21c[5] Pre-B — 25� (1997)4 [6] 2 M 48,XY,�X,�21c[17] Early pre-B 164 43� (1993)5 [6] 4.5 F 48,XX,�X,�21c[6]/47,XX,�21c[3] — 6 55� (1993)6 [7] 6.6 M 47,XY,�X/47,idem,add(11)(p15) Pre-B 50.5 —7 [8] 4.7 F 48,XX,�X,�21c 2.1 144� (1992)8 [9] Child M 47,XY,�X T-lineage — —9 Present case 3.7 F 48,XX,�i(X)(p10),�21c[12]/47,XX,�21c[10] Pre-B L1 15.4 (78% blasts) Alive on therapy

a Months survival from diagnosis.Abbreviations: F, female; M, male; WBC, white blood cell count.

abnormality, is associated with a good prognosis [15]. Thereare no such data for leukemias with an additional X chromo-some as a sole acquired numerical abnormality. In general,children with both Down syndrome and ALL tend to havean overall response to treatment similar to those with ALLwho have constitutionally normal karyotypes [16]. The clini-cal significance of our patient’s unique karyotype and theeight similar cases presented (six with constitutional trisomy21) remains unknown.

Acknowledgments

We thank Heidi Jamro for expert technical assistance andPatricia Cox for preparation of the manuscript.

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