Extra X Chromosome in Mosaic Klinefelter Syndrome Is Associated with a Hematologic Malignancy

Klinefelter syndrome (KS), with an incidence of 1 in 600 male newborns, is the most common type of X chromosome aneuploidy. Individuals with KS are characterized by tall stature, decreased secondary sexual characteristics, small testicles, gynecomastia, and infertility. About 80% of patients have the karyotype 47,XXY [1]. An extra X chromosome as a sole acquired abnormality has also been reported in patients with several hematologic malignancies such as acute lymphoblastic leukemia [2], AML [3, 4], and chronic neutrophilic leukemia [5]. It has been suggested that an extra X chromosome has high oncogenic potential, predisposing the carriers to leukemia. In practice, it is sometimes difficult to distinguish whether the extra X chromosome is constitutional or acquired in a patient with hematologic malignancy. Here, we describe a mosaic KS patient who was diagnosed with primary myelofibrosis, which progressed to AML. Because of the obscure clinical phenotype, we originally reported his sex chromosome aneuploidy as an acquired anomaly secondary to his hematologic malignancy. A 62-yr-old man presented with pancytopenia with sustained fatigue, poor general condition, and excessive weight loss (10 kg in 2 months). His complete blood count revealed the followings: hemoglobin, 7.4 g/dL; leukocyte count, 3.45×10/L (absolute neutrophil count, 0.93×10/L); and platelets, 42×10/L. In addition, analysis of the peripheral blood revealed 3% myeloblasts and leukoerythroblastic features. The patient had mild splenomegaly on the abdominal computed tomography scan. For further evaluation, the patient underwent bone marrow aspiration and biopsy, and the results suggested primary myelofibrosis (PMF), fibrotic stage, with diffuse bone marrow fibrosis that was evident on Masson-trichrome and reticulin staining. The estimated cellularity of the bone marrow section was 100%. JAK2 V617F mutation analysis was negative. Conventional cytogenetic evaluation of the peripheral blood lymphocyte culture using conventional G-banding revealed 2 cell lines, 47,XXY and 46,XY, with the dominant karyotype being 47,XXY (Fig. 1). Clinical investigation revealed normal-sized testes, masculine pubic and axillary hair, no gynecomastia, average height (174 cm) and weight (75 kg), and a normal serum testosterone level (0.75 μIU/mL; cut-off level, 0.35–5.5 μIU/mL). The patient was married and fathered a child, inconsistent with KS. Therefore, we reported the karyotype of 47,XY,+X[14]/46,XY[2] as an acquired anomaly rather than a constitutional abnormality. Two months later, the blasts in the patient’s blood increased up to 47%, and marrow examination revealed a packed marrow with myeloperoxidase (MPO)positive blasts and diffuse fibrosis, as observed before. Flow cytometric immunophenotyping revealed blasts positive for CD33, CD117, CD11c, CD64, CD56, and MPO. These findings were consistent with a diagnosis of AML with monocytic differentiation. At the time of AML transformation, the chromosome analysis still showed the 47,XXY karyotype in all 23 metaphase cells analyzed. After induction chemotherapy, the patient achieved complete remission; however, the karyotype abnormality did not