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  • br Authorship br Conflict of interest br Acknowledgments


    Conflict of interest
    Acknowledgments The Leukemia & Lymphoma Society supported CRC with a Scholar in Clinical Research award (2400-13). This work was supported by the Gatorade Trust from the University of Florida Department of Medicine.
    Introduction Klinefelter syndrome (KS), first described in 1942, is characterized by male infertility, gynecomastia, and hypogonadism, and is associated with the sex chromosome abnormality 47,XXY [1]. Patients with KS are known to be at an increased risk for developing malignancy, including breast cancer, germ cell tumors, non-Hodgkin lymphomas, and lung cancer [2]. Nevertheless, no clear association between constitutional 47,XXY and acute leukemias has yet been established [3]. We here report on a case of a patient with constitutional 47,XXY and a diagnosis of acute myeloid leukemia (AML), followed by a review of the relevant literature.
    Case A 54-year-old male with a medical history of non-insulin dependent diabetes mellitus, hypertension, and gastroesophageal reflux, initially presented to his dentist with left-sided gum pain. Due to persistence of the pain, he was then evaluated by his primary care physician, who noted a marked leukocytosis. He was subsequently referred to the emergency room, where he was found to have a white blood cell count (WBC) of 33,500/mm3, of which 2% were blasts, a hematocrit of 22.2%, and a platelet count of 131,000/mm3. He also had renal insufficiency, with a creatinine of 1.74mg/dL, and there was concern for tumor lysis syndrome, with a uric order pyrilamine maleate of 10.1mg/dL. On examination, he was obese and appeared mildly uncomfortable. He was not hypoxic, and his heart and lung exam were benign. Gynecomastia was present. He had no family history of hematologic malignancy. He had one brother and one sister, both of whom were reported to be healthy. He lived with his wife and had no children. He previously worked in construction, but was currently not working. Given these abnormal laboratory results, a bone marrow biopsy and aspirate were performed. The biopsy was hypercellular (95% cellularity) and was replaced by sheets of blasts (Fig. 1A). On the aspirate smear, there were 76% monoblasts (Fig. 1B), confirmed by flow cytometric immunophenotyping. Bone marrow karyotype was abnormal, with all metaphases (20 of 20) containing an additional X chromosome as the sole aberration (Fig. 1C). Given that a 47, XY, +X abnormality would be unusual for AML, a monolayer culture of non-neoplastic bone marrow stromal cells was studied to obtain a constitutional karyotype. Although no metaphases were obtained from the monolayer culture, interphase FISH analysis revealed that all scored nuclei contained two copies of the X and one copy of the Y chromosome, confirming that this patient׳s constitutional karyotype was 47,XXY (Fig. 1D). Subsequent molecular genetic analysis revealed an NPM1 mutation at exon 12, but no FLT3 or CEBPA mutations. The final diagnosis was acute myeloid leukemia with mutated NPM1. A bone marrow biopsy subsequently confirmed complete remission 32 days after the start of induction therapy. Given the relatively favorable prognostic risk associated with an isolated NPM1 mutation, the patient has gone on to receive cycles of consolidation chemotherapy with high dose cytarabine. He remains in remission, now five months after his initial diagnosis.
    Discussion Cases of AML have been reported in patients with Klinefelter syndrome since the 1960s [4], and there has been an interest in investigating a potential association between a 47,XXY chromosomal abnormality and myeloid malignancies. Certain constitutional chromosomal abnormalities are known to be associated with malignancy. For example, children with trisomy 21 (Down syndrome) have a 10–20 fold higher risk of developing acute leukemia than other children [5]. Additional hematological malignancies have been reported in patients with other constitutional chromosomal abnormalities (Table 1).