ELSEVIER

XYY Male and Hematologic Malignancy

Nobuo Oguma, Chiharu Shigeta, and Nanao Kamada

ABSTRACT: Two cases o f X Y Y male with refractory anemia with excess of blasts are reported, and pre- vious reported X Y Y males with hematologic malignancy are reviewed. Altogether 26 cases were col- lected for analysi:~: acute myeloid leukemia (10), acute lymphocytic leukemia (seven), acute leukemia (two), chronic myelocytic leukemia (three), myelodysplastic syndrome (three), and essential throm- bocythemia (one) The age at the time of diagnosis ranged in age from 7.5 to 81 years. In three o f s& X Y Y / X Y mosaici.~m cases, X Y Y clone was associated with malignancy. However, in two cases X Y Y clone was not inw3lved. The evidence presented here suggests that the event of an X Y Y male with hema- tologic malignancy is incidental rather than a genetic etiology.

INTRODUCTION

It is generally accepted that children with Down's syn- drome are at high risk for developing acute leukemia, especially acute megakaryocytic leukemia [1]. It would be of great interest to examine whether such specificity is observed in an XYY male. Questions regarding this con- genital condition began in 1967 [2].

This report describes two cases of XYY males with my- elodysplastic syndrome [MDS). Altogether, 26 cases of XYY male with hematologic malignancy were analyzed and the association between XYY male and hematologic malignancy is discussed.

CASE REPORTS

Case 1

A 61-year-old man employed as a lead worker presented with general fatigue. His height was 180 cm and weight 72 kg; he had no apparent behavioral disorders. When first seen in July 1993, his hemoglobin was 73 g/L, and white cell count (WBC) was 2.5 × 109/L with 22.5% segmented neutrophils, 14.5% monocytes, 2% eosinophils, and 61% lymphocytes. The platelet count was 54 × 109/L. Bone marrow showed trilineage dysplasia with 11.0% myelo-

From the Department of Cancer Cytogenetics, Division of Molecular Biology, Researc;1 Institute for Radiation Biology and Medicine, Hiroshima Unive;~sity, Hiroshima, Japan.

Address reprint requests to: Dr. Nobuo Oguma, Department of Cancer Cytogenetics, Division of Molecular Biology, Research Institute for Radiation, Biolggy and Medicine, Hiroshima Univer- sity, 1-2-3 KasumL Minami-ku, Hiroshima 734, Japan.

Received December 21, 5!995; accepted March 5, 1996.

blasts. MDS, subtype of refractory anemia with excess of blasts (RAEB), was diagnosed.

Case 2

An 86-year-old man was hospitalized because of exer- tional dyspnea. His height was 171 cm and weight 60 kg. He gave a history of neither relevant occupational back- ground nor apparent behavioral disorders. Upon presenta- tion in August 1994, the WBC was 1.4 × 1Og/L with 1% metamyelocyte, 1% basophils, 4% eosinophils, 14% neu- trophils, 77% lymphocytes, and 3% monocytes. Hemoglo- bin and platelets were 44 g/L and 33 x 109/L, respectively. Bone marrow showed hypercellular, trilineage dysplasia, and 8.2% myeloblasts consistent with RAEB.

CYTOGENETIC STUDIES

At diagnosis chromosome analysis was performed on bone marrow using short-term (24-h) culture without stimula- tion. Peripheral blood (PB) cells of patients cultured for 72 h with phytohemagglutinin were also studied. Chromosomes were analyzed using a trypsin-Giemsa banding technique and annotated according to The International System for Human Cytogenetic Nomenclature (ISCN 1991 [3]).

RESULTS

Bone marrow chromosome analysis of case 1 revealed the karyotype to be 46,XYY,-7{4]/47,XYY{lO}. The karyotype of PB cells was 47,XYY{200}/46,XY{27}. Thus, a constitu- tional 47,XYYc/46,XY mosaicism was established. On the other hand, in case 2 bone marrow chromosome analysis showed a 47,XYY{20} karyotype and the karyotype of PB cells revealed two clones: 47,XYYc{151/46,XY{5}. Thus,

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180 N. Oguma et al.

we established that this case was also a consti tutional 47,XYYc/46,XY mosaicism.

DISCUSSION

To date, no oncogene has been mapped on the Y chromo- some. However, some growth and differentiation genes such as CSF2RA (c~ subunit of the granulocyte and mac- rophage colony-stimulating factor receptor) on Yp11, 1L3RA (c~ subunit of the interleukin 3 receptor) on Ypl l , and GCY (growth control, Y chromosome influenced) at Yq11 might be related to the oncogenesis. Xiao et al. [4] sug- gested that "the Y chromosome may have a growth-promo- tion effect on the hematopoietic system," in the case of the lymphoproliferative disorder with extra Y chromosome.

A number of XYY males with hematologic malignancy have been reported in the literature, but whether they rep- resent an incidental event is not well defined. We re- viewed the previously reported cases inc luding ours (Table 1). So far, 26 cases were collected. The type of he- matologic mal ignancy is variable: 10 acute myeloid leuke- mia (AML), seven acute lymphocytic leukemia (ALL), two acute leukemia (AL), three chronic myelocytic leukemia (CML), three myelodysplastic syndrome (MDS), and one essential thrombocythemia (ET). This observation suggests

that there is no propensity for any specific type of hemato- logic malignancy.

Six mosaicism cases were found: one CML case with an XY clone (case 5), one of AML with an XYY clone (case 13), one AML with an XY clone (case 22), and two MDS with XYY clones (our cases) were observed. Unfortunately, in case 20 there was no description about the origin of del(5)(q12q21) in the original report. In our cases, the con- stitutional component of XYY clone was 88.1% in case 1 and that of the second case 75%. The proportion of the constitutional component in the mosaicism may be decisive as to which clone is involved in hematologic malignan- cies. Interestingly, in case 5 the consti tutional component of the XY clone involved was only 1%. Thus, the XYY clone does not necessarily favor the development of hema- tologic malignancies. Of the 26 cases in Table 1, the age of the patients ranged from 7.5 to 81 years. This fact argues against a genetic etiology.

Addit ional chromosome abnormalities were seen in eight of the 13 acute leukemias and MDS. Generally, mono- somy 7 is one of the nonrandom cytogenetic changes seen in acute leukemia with a normal consti tut ional karyotype. This change was observed in two AML cases and in one of MDS (our case). Future studies need to determine whether the hematologic mal ignancy in XYY is associated with

Table 1 Reported cases of hematologic mal ignancy developing in patients with an XYY male karyotype

Constitutional Case Age abnormality Diagnosis Karyotypic change Reference

1 41 47,XYY AML (M2) ? 2 2 15 47,XYY AL ? 5 3 ? 47,XYY ALL ? 6 4 ? 47,XYY ALL ? 6 5 7.5 47,XYY (99%) CML XY,t(9;22)(q34;q11) 7

/46,XY (1%) 6 ? 47,XYY AL ? 8 7 29 47,XYY CML t(9;22)(q34;q11) 9 8 38 47,XYY CML t(9;22;13)(q34;q11;q14} 10 9 28.9 47,XYY AML (M4) -7 11

10 32 47,XYY AML (M3) None 12 11 56 47,XYY AML (MS) del(11)(q23) 12 12 54 47,XYY AML ( M 4 ) t(1;3)(p36;q21) 13 13 18 47,XYY/46,XY AML ( M 4 ) XYY,inv(16)(p13q22)/ 14

14 69 47,XYY AML (M2) 15 17< 47,XYY ANLL 16 17< 47,XYY ALL 17 17< 47,XYY ET 18 16 47,XYY ALL (L2) 19 15 47,XYY ALL (L1} 20 74 47,XYY/46,XY MDS 21 16 47,XYY ALL 22 57 47,XYY/46,XY AML (M3) 23 29 47,XYY AML (M4) 24 11 47,XYY ALL 25 61 47,XYY (88.1%) RAEB

/46,XY (11.9%) 26 86 47,XYY (75%) RAEB

/46,XY (25%)

XYY,inv(16)(p13q22),+ 22 ? 15 ? 16 ? 16 ? 16 None 17 XY 18 XYY?XY?,del(5)(q12q32} 18 None 19 XY,15q+,17q-/XY,15q+,17q-,+mar 2O t(3;3)(q22;q26),- 7 21 None 22 XYY,- 7 Our case

None Our case

XYY Male and Hema to log i ca l M a l i g n a n c y 181

m o n o s o m y 7. The o ther c h r o m o s o m e abnormal i t i e s in Ta- ble 1 were also recur ren t ones. Thus , these f indings indi - cate that, a lbei t r ep resen ted by smal l size, the assoc ia t ion of XYY male and hema to log i c m a l i g n a n c y is for tu i tous in occu r r ence ra ther t han a genet ic etiology.

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