Successful Bone Marrow Transplantation for Treatment of Chronic Myeloid Leukemia from a Donor with Mosaic Klinefelter Syndrome

Abstract

2007;86:287-288. doi: 10.1532/IJH97.A20705© 2007 The Japanese Society of HematologyKlinefelter syndrome (KS) is the most commonly diag-nosed sex chromosome disorder in males, with an annualincidence of 1 in 600 to 1000 [1]. In the majority (80%) ofcases, the karyotype is 47,XXY in all body cells, whereas theremaining patients (20%) display a mosaic XY/XXY pat-tern. Rarely, multiple-line mosaics can also be found[2].Since the early 1960s, numerous reports have stated thatKS patients tend to have an increased risk of developinggerm cell tumors, breast cancers, and hematologic malignan-cies, especially acute leukemias [3-8].We present the first description of a case in which KS wasdiagnosed in a donor’s bone marrow used in bone marrowtransplantation (BMT) for treatment of a related chronicmyeloid leukemia (CML) patient.The patient and donor arenow revealing similar mosaic KS karyotypes. Interestingly,the patient is still in clinical, cytogenetic, and molecularremission at more than 10 years after BMT.The patient was a 16-year-old girl when first admitted to ahospital in February 1996 with a 2-month history of generalmalaise, fatigue, fever, and weight loss. She had pallor andhuge splenomegaly.The initial blood investigation showed ahemoglobin level of 7 g/dL, a white blood cell count of213,000/ L, and a platelet count of 678,000/ L.An examina-tion of bone marrow morphology showed CML in thechronic phase. A cytogenetic analysis detected the Philadel-phia chromosome in almost 100% of the 25 metaphases stud-ied. The patient was placed on therapy with hydroxyurea (2g daily) and interferon (4.5 million units 3 times a week).After 2 months, the patient achieved hematologic remission.The Philadelphia chromosome,however,was still detected in60% of the metaphases after 9 months of treatment.HLA typing of the patient’s siblings revealed a fullymatched 23-year-old brother. The patient underwent condi-tioning for BMT with busulfan (12 mg/kg) and cyclophos-phamide (200 mg/kg) divided over 4 days. For graft-versus-host disease prophylaxis, the patient received cyclosporin Aand methotrexate. BMT was performed on February 1997,almost a year after diagnosis.The patient recovered promptlyand was discharged on day 13 after transplantation. On day90, the patient developed a skin rash and diarrhea that waslabeled as graft-versus-host disease. She received Solu-Medrol (methylprednisolone sodium succinate) intra-venously for 3 days and was maintained on oral steroids for1 month, after which the skin rash and diarrhea subsided.The initial cytogenetic analyses of the patient’s marrowcells were performed 1,2,and 3 years later and showed no signof the Philadelphia chromosome; the analyses revealed afemale XX karyotype, contrary to the expected male kary-otype of her brother.This discrepancy was not resolved at thetime, but it was later shown to be a false diagnosis, becauseonly a few metaphases were analyzed by conventional cytoge-netics from the bone marrow and peripheral blood samples.Indeed, a recent and more thorough karyotyping of thepatient’s peripheral blood revealed that her karyotype wasactually 77% 46,XX and 23% 46,XX,dic(Y;22)(p11.2;p11.2)in the 100 metaphases analyzed. An examination of thedonor sample then revealed a similar karyotype: 83% 46,XXand 17% 46,XX,dic(Y;22)(p11.2;p11.2) in 100 metaphases.Such findings are consistent with mosaic KS. This diagnosiswas confirmed in the donor by other KS-specific clinicalsymptoms, including a history of male infertility and severeazoospermia.The presence of the Y centromere region was confirmedby a fluorescence in situ hybridization analysis using the CEPY (Vysis, Downers Grove, IL, USA) satellite (Yp11.1-q11.1) for both the patient and the donor. A polymerasechain reaction (PCR) analysis with Y-specific primers for theamelogenin region AMXY, a nonpolymorphic marker