Chromosomal instability in Marinesco‐Sjögren Syndrome associated with acute myeloblastic leukemia

To the Editor: We recently reported on a 6-year-old girl with Marinesco-Sjogren syndrome (MSS), a rare autosomal recessive disorder, associated with acute myeloblastic leukemia (AML) (1). We hypothesized that causative genes of MSS predisposed our patient to oncogenesis due to chromosomal instability, because we detected t(8;2 l),(q22;q22) translocation in bone marrow blasts of the patient, an event which frequently occurs in AML (2). We report here additional findings in this patient, whose bone marrow blast chromosomal aberrations became more complex after several sessions of chemotherapy, strongly suggesting chromosomal instability in this patient. The diagnosis of MSS was made on the basis of typical clinical manifestations including short stature, delayed motor skills with ataxia, cerebellar atrophy, progressive cataracts and mental retardation. Histological analysis of a femoral muscle biopsy specimen indicating myopathic changes, such as variations in muscle fiber size, the appearance of some necrotic fibers, the formation rimmed vacuoles and the presence of some regenerating fibers, supported the diagnosis of MSS (I ) . The patient's karyotype was 46,XX. When she was 6 years old, she was diagnosed with AML (M2) associated with the t(8;21),(q22;q22) translocation. Following an initial treatment of the patient with anticancer agents, myeloblasts could no longer be detected in her peripheral blood and bone marrow. However, 8 months after this initial treatment, myeloblasts were again detected in her peripheral blood and her serum lactate dehydrogenase level was elevated to more than 10000 IUjl despite intensive chemotherapy. Analysis of a sample of bone marrow cells of the patient revealed that pathological myeloblasts accounted for 90% of her bone marrow cells, confirming the recurrence of AML. Two major chromosomal aberrations were identified in these cells. Among the 18 bone marrow cells subjected to G-banding analysis 8 months after the initial treatment, 8 of them were karyotyped as 45,idem,t( l;l)(p34;p36) and 7 of them were karyotyped as 45,idem,t(6; 12)(p21;q24), inv(9)(p22;q22). Neither of these karyotypes are typically found in AML. Two of the remaining three cells were karyoptyped as 45,X,-X, der(8)t(8;16)(~21;q22)t(8;21)(q22;q22), der( 16)t(8; 16)(p21 ;q22), der(21)t(8;21)(q22;q22) and 45,idem, de1(2)(p21), add( 15)(q22), add(19)(q13) (data not shown). A normal female karyotype, 46,XX, was found in only one of the 18 cells analyzed. We were surprised to find that bone marrow cell chromosomal abberations became more complex 8 months after relapse. The following abberations were noted. Ten of the 20 cells analyzed had the 45,X,X,t( 1; l)(p34;~36),der(8)t(8; 16)(p21 ;q22)t(8;2 l)(q22; q22),der(l6)t(8;16)(~21;q22), add(l7)(pl l), der(21) t(8;21)(q22;q22) karyotype. Five of the cells were karyotyped as 46,X,-X,1 , 2 3 , add( 5)(pl5), der( 8) t(8; 16) (p21; q22) t (8; 21) (q22; q22), der( 10) t ( 1 ; 10) ( p l?;q2?), 12, add( 1 3)( p 1 ?), der( 1 6) add( 1 6) (p 1 ?) t (8; 16)(p2 1; q22), 17, add (1 9)(pl3), der(2 1) t (8; 2 1) (q22; (q22;q22), + 6mar. Four of the cells were karyotyped as 45,idem, inv(2)(p23;q2 l),t(5: 1 O)(p 15;q22) and the remaining one had the 45,idem,t(3;6)(plO;qlO), + 17,-add( 17) karyotype. It seemed like the more anticancer agents she received, the more complex her chromosomal abberations became. Unfortunately, bone marrow myeloblasts did not disappear from her peripheral blood and bone marrow despite repetitive chemotherapy, and she died 17 months after the initial diagnosis of AML. The fact that the chromosomal aberrations in her bone marrow blasts became more complex during the chemotherapy and the fact that the AML recurred, suggested that her chromosomes were more unstable than expected and that the chromosomal abberations found in her bone marrow blasts were strongly associated with the reccurrence of AML. The gene products of her abnormal chromosomes must have some promoting effects on abnormal cell proliferation, an event which is likely to be associated with leukemic changes of the bone marrow cells.