Cancer Genetics and Cytogenetics 164 (2006) 152–154

Short communication

Isochromosome 7q in Down syndrome

K.F. Wong*, S.C. Lam, Jennifer N.S. LeungDepartment of Pathology, Queen Elizabeth Hospital, 30 Gascoigne Road, Kowloon, Hong Kong SAR, China

Received 16 May 2005; received in revised form 19 July 2005; accepted 20 July 2005

Abstract Isochromosome 7q is not an uncommon chromosomal abnormality. It has been reported in associ-ation with Shwachman–Diamond syndrome, Wilms tumor, and hepatosplenic T-cell lymphoma. Inother hematolymphoid malignancies, it occurs almost invariably as a secondary change. A notableexample is its association with t(4;11)(q21;q23) in acute lymphoblastic leukemia. It has rarely beendescribed in myelodysplastic syndrome and acute myeloid leukemia. We report the occurrence ofi(7q) as the primary abnormality in a 2-year-old boy with Down syndrome and minimally differen-tiated acute myeloid leukemia. � 2006 Elsevier Inc. All rights reserved.

1. Introduction

Chromosome 7 rearrangement is not infrequently seen inchildren with myeloid disorders, and often signifies a poorresponse to conventional chemotherapy and a fatal outcome[1]. In children with Down syndrome, however, chromo-some 7 abnormalities appear not to carry the same prognos-tic significance as for other children [1,2]. The chromosome7 rearrangements are mostly monosomy 7 or deleted 7q;isochromosome 7q is uncommon [3]. As an isolated occur-rence, isochromosome 7q has been reported in only twochildren with Down syndrome and acute myeloid leukemia(AML) [4,5]. We report a case of minimally differentiatedAML in association with Down syndrome and withi(7)(q10) as the primary abnormality. Serial cytogeneticanalyses showed rapid clonal evolution to a very complexkaryotype after the emergence of i(7q).

2. Case report

A 1-month-old boy with Down syndrome was found tohave anemia and leukocytosis. Clinical examinationshowed hepatosplenomegaly. Peripheral blood counts were:hemoglobin 10.2 g/dL, platelets 242 � 109/L, and leuko-cytes 32.8 � 109/L with 27% neutrophils, 33% lympho-cytes, 4% monocytes, 26% eosinophils, 1% basophils, 1%metamyelocytes, 2% myelocytes, and 6% blast cells. Theblast cells were shown to express CD33 but not CD61.

* Corresponding author. Fax: 1852-29586790.

E-mail address: kfwong@ha.org.hk (K.F. Wong).

0165-4608/06/$ – see front matter � 2006 Elsevier Inc. All rights reserved.

doi:10.1016/j.cancergencyto.2005.07.014

Bone marrow aspiration resulted in a blood tap with nomarrow particles. Cytogenetic analysis performed by over-night fluorodeoxyuridine-synchronized culture of the mar-row blood showed the constitutional trisomy 21 with noadditional chromosomal abnormality. Both the anemiaand leukocytosis subsided spontaneously after 3 weeks.Bone marrow aspiration was repeated and showed an activemarrow with no increase in blast cells.

At the age of 14 months, the patient developed thrombo-cytopenia (platelets 80 � 109/L). Bone marrow aspirationshowed a normocellular marrow with increased megakar-yocytes, active and normoblastic erythropoiesis, and nor-mal granulopoiesis. Some megakaryocytes were smallwith hypolobulated nuclei. Blast cells were not increased.

The thrombocytopenia continued to worsen and blastcells began to appear in the peripheral blood after 6 months.Peripheral blood counts were: hemoglobin 13.5 g/dL,platelets 50 � 109/L, and leukocytes 9.7 � 109/L with20% neutrophils, 63% lymphocytes, 8% monocytes, 1%eosinophils, and 8% blast cells. Bone marrow aspira-tion again resulted in a blood tap without any marrow parti-cles. Cytogenetic analysis of the marrow blood showed theconstitutional trisomy 21 alone. The platelet count fell to4 � 109/L within 3 months, and there were 11% blastcells in the peripheral blood. Bone marrow aspirationagain resulted in a blood tap but trephine biopsy showed adense infiltrate of blast cells. Immunohistochemical studyshowed that the blast cells were negative for CD31 andmyeloperoxidase. Cytogenetic analysis at this time showed47,XY,i(7)(q10),121c[11]/47,XY,121c[5] (Fig. 1).

Bone marrow aspiration was repeated after 3 weeks forfurther immunophenotypic study, and the blast cells wereshown to express CD13, CD33, and CD117 but not CD3,

153K.F. Wong et al. / Cancer Genetics and Cytogenetics 164 (2006) 152–154

Fig. 1. Complete karyotype showing the i(7)(q10) and trisomy 21, with a random loss of chromosome 20. G-banding with trypsin–Giemsa.

CD10, CD19, CD61, and myeloperoxidase. The diagnosiswas made of acute myeloid leukemia, minimally differen-tiated, according to the WHO classification [6]. Cytogenet-ic analysis showed a complex karyotype with numerousstructural changes in addition to the i(7q): 47,XY,11,der(1;8)(q10;q10),i(7)(q10),add(11)(q25),del(16)(q12.1),add(18)(p11.2),121c[17]/94,idem�2[2]/47,XY,121c[2] (Fig. 2).The patient was treated with daunorubicin, etoposide, cy-tarabine, and methotrexate.

3. Discussion

At least 10% of infants with Down syndrome developtransient abnormal myelopoiesis (TAM) [7], a clonal

megakaryoblastic proliferative disorder characterized byrelative preservation of blood counts, disproportionatelyhigh circulating blast count, and megakaryoblastic natureof the circulating blasts. Furthermore, 20–30% of infantswith Down syndrome and TAM develop acute megakaryo-blastic leukemia within 3 years [8]. In fact, the risk of acuteleukemia in Down syndrome is 10-20 fold higher than thatof the general age-matched population, with AML beingmore frequently seen [7]. We report the case of a boy withDown syndrome who developed minimally differentiatedAML with an unusual clinical course. The AML was pre-ceded by a transient period of anemia and leukocytosis, fol-lowed by progressive and severe thrombocytopenia withfew circulating myeloblasts, unlike TAM. The development

Fig. 2. Complete karyotype showing 47,XY,11,der(1;8)(q10;q10),i(7)(q10),add(11)(q25),del(16)(q12.1),add(18)(p11.2),121c. G-banding with

trypsin–Giemsa.

154 K.F. Wong et al. / Cancer Genetics and Cytogenetics 164 (2006) 152–154

of AML was accompanied by the emergence of an isolatedi(7)(q10), but serial cytogenetic analyses showed rapidclonal evolution to a complex karyotype with multiple ad-ditional structural changes and a tetraploid subclone.

Isochromosome 7q is not an uncommon chromosomalabnormality in human malignancies [3]. It is associatedwith hepatosplenic T-cell lymphoma [9] and with Wilmstumor [10]. It is also a common secondary chromosomalchange in hematolymphoid malignancies [11], particularlyacute lymphoblastic leukemia, in which case it is often as-sociated with t(4;11)(q21;q23) [12]. It is also found inShwachman–Diamond syndrome (an autosomal recessivedisorder with exocrine pancreatic dysfunction, recurrent in-fection, and bone marrow failure), even in the absence ofaccompanying hematolymphoid disorders [13]. In myelo-dysplastic syndrome (MDS) and AML, however, i(7)(q10)is rare and mostly occurs in the setting of complex chromo-somal changes [3]. In fact, Andersen and Pedersen-Bjergaard [14] failed to find a single example of i(7)(q10)among O 400 cases of de novo and secondary MDS/AML, despite a high incidence of chromosome breakagesat the centromeres.

In children with Down syndrome and AML, an isolatedoccurrence of i(7)(q10) has been described in only two pa-tients (one with acute monoblastic leukemia and the otherwith acute myeloid leukemia with maturation) [4,5]. Ithas been speculated that the i(7)(q10) is due to misdivisionof the centromere of chromosome 7 with resulting partialmonosomy 7p and trisomy 7q, and that the leukemogeniceffect is probably due to dosage effect rather than locus-specific disruption. It has, however, been shown that theShwachman–Bodian–Diamond syndrome (SBDS ) gene islocated at the pericentromeric region of chromosome 7[15]. Whether the SBDS gene is affected by the i(7)(q10)and whether it has any relevance to leukemogenesis hasyet to be determined. It has also been suggested that, inhepatosplenic T-cell lymphoma, the i(7)(q10) might benefitthe outgrowth of malignant clones because of its accumula-tion in cases with features of cytologic progression [9].Notably, the development of AML coincides with theappearance of i(7)(q10), and cytogenetic evolution rapidlyensued in our patient. Further study is therefore requiredto determine the importance of i(7)(q10) in the pathogene-sis and progression of human malignancies.

References

[1] Luna-Fineman S, Shannon KM, Lange BJ. Childhood monosomy 7:

epidemiology, biology, and mechanistic implications. Blood 1995;85:

1985–99.

[2] Kobayashi K, Usami I, Kubota M, Nishio T, Kakazu N. Chromo-

some 7 abnormalities in acute megakaryoblastic leukemia associ-

ated with Down syndrome. Cancer Genet Cytogenet 2005;158:

184–7.

[3] Mitelman F, Johansson B, Mertens F, editors. Mitelman database of

chromosome aberrations in cancer [Internet]. Updated May 2005.

Available from http://cgap.nci.nih.gov/Chromosomes/Mitelman.

[4] Creutzig U, Ritter J, Vormoor J, Ludwig WD, Niemeyer C,

Reinisch I, Stollmann-Gibbels B, Zimmermann M, Harbott J. Myelo-

dysplasia and acute myelogenous leukemia in Down’s syndrome:

a report of 40 children of the AML-BFM Study Group. Leukemia

1996;10:1677–86.

[5] Pui CH, Raimondi SC, Murphy SB, Ribeiro RC, Kalwinsky DK,

Dahl GV, Crist WM, Williams DL. An analysis of leukemic cell chro-

mosomal features in infants. Blood 1987;69:1289–93.

[6] Brunning RD, Matutes E, Flandrin G, Vardiman J, Bennett J, Head D,

Harris NL. Acute myeloid leukaemia not otherwise categorised. In:

Jaffe ES, Harris NL, Stein H, Vardiman JW, editors. Pathology and

genetics of tumours of haematopoietic and lymphoid tissues. World

Health Organization classification of tumors. Lyon: IARC Press;

2001. pp. 91–105.

[7] Gurbuxani S, Vyas P, Crispino JD. Recent insights into the mecha-

nisms of myeloid leukemogenesis in Down syndrome. Blood 2004;

103:399–406.

[8] Zipursky A, Poon A, Doyle J. Leukemia in Down syndrome: a review.

Pediatr Hematol Oncol 1992;9:139–49.

[9] Wlodarska I, Martin-Garcia N, Achten R, De Wolf-Peeters C,

Pauwels P, Tulliez M, de Mascarel A, Briere J, Patey M,

Hagemeijer A, Gaulard P. Fluorescence in situ hybridization study

of chromosome 7 aberrations in hepatosplenic T-cell lymphoma: iso-

chromosome 7q as a common abnormality accumulating in forms

with features of cytologic progression. Genes Chromosomes Cancer

2002;33:243–51.

[10] Rubin BP, Pins MR, Nielsen GP, Rosen S, Hsi BL, Fletcher JA,

Renshaw AA. Isochromosome 7q in adult Wilms’ tumors: diagnos-

tic and pathogenetic implications. Am J Surg Pathol 2000;24:

1663–9.

[11] Johansson B, Mertens F, Mitelman F. Secondary chromosomal abnor-

malities in acute leukemias. Leukemia 1994;8:953–62.

[12] Schoch C, Rieder H, Freund M, Hoelzer D, Riehm H, Fonatsch C.

Twenty-three cases of acute lymphoblastic leukemia with transloca-

tion t(4;11)(q21;q23): the implication of additional chromosomal

aberrations. Ann Hematol 1995;70:195–201.

[13] Maserati E, Minelli A, Olivieri C, Bonvini L, Marchi A, Bozzola M,

Danesino C, Scappaticci S, Pasquali F. Isochromosome (7)(q10) in

Shwachman syndrome without MDS/AML and role of chromosome

7 anomalies in myeloproliferative disorders. Cancer Genet Cytogenet

2000;121:167–71.

[14] Andersen MK, Pedersen-Bjergaard J. Increased frequency of di-

centric chromosomes in therapy-related MDS and AML com-

pared to de novo disease is significantly related to previous

treatment with alkylating agents and suggests a specific suscep-

tibility to chromosome breakage at the centromere. Leukemia

2000;14:105–11.

[15] Goobie S, Popovic M, Morrison J, Ellis L, Ginzberg H, Boocock GR,

Ehtesham N, Betard C, Brewer CG, Roslin NM, Hudson TJ,

Morgan K, Fujiwara TM, Durie PR, Rommens JM. Shwachman–

Diamond syndrome with exocrine pancreatic dysfunction and bone

marrow failure maps to the centromeric region of chromosome 7.

Am J Hum Genet 2001;68:1048–54.