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Acute Myeloid Leukemia in a Patient with Thrombocytopenia with Absent Radii: a Case Report and Review of the Literature

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Acute Myeloid Leukemia in a Patient with Thrombocytopenia with Absent Radii: a Case Report and Review of the Literature Hematol Oncol Stem Cell Ther (2018) 11, 245– 247 Available at www.sciencedirect.com ScienceDirect journal homepage: www.elsevier.com/locate/hemonc CASE REPORT Acute myeloid leukemia in a patient with thrombocytopenia with absent radii: A case report and review of the literature Maximilian Jameson-Lee a, Katherine Chen a, Ellen Ritchie a, Tsiporah Shore a, Omar Al-Khattab b, Usama Gergis a,* a Weill Cornell Medical College, New York, NY, USA b New York Presbyterian Hospital, USA Received 9 June 2016; accepted 6 February 2017 Available online 24 February 2017 Abstract Thrombocytopenia with absent radii (TAR) syndrome is a rare congenital disorder characterized by low platelet counts of various severity, bilateral absent radii but thumbs are usually present. TAR syndrome is not generally associated with bone marrow failure or malignancy. Janus kinase-2, myeloproliferative leukemia protein, and calreticulin are not mutated in TAR patients. Only four cases of leukemia were reported in TAR patients in the literature: three acute myeloid leukemia (AML) and one acute lymphoblastic leukemia. Of the three cases of AML found in TAR patient, only one was reported in an adult. We report a case of myelodysplas- tic syndrome progressing to AML with calreticulin driver mutation in an adult male with TAR syndrome who was successfully treated with hematopoietic allogeneic stem cell transplanta- tion. Ó 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc- nd/4.0/). Case report A 47-year-old Caucasian man with thrombocytopenia with * Corresponding author. absent radii (TAR) syndrome developed myelodysplastic syn- E-mail address: [email protected] (U. Gergis). drome (MDS) after a life-long history of thrombocytopenia. http://dx.doi.org/10.1016/j.hemonc.2017.02.001 1658-3876/Ó 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 246 M. Jameson-Lee et al. He was born with thrombocytopenia and upper extremity Because the thrombocytopenia usually remits after age 2 phocomelia bilaterally without any cardiac or genitourinary years, management of TAR syndrome patients is largely sup- abnormalities. At age 16 years, thrombocytopenia became portive [6]. Hematopoietic stem cell transplant is not indi- more severe and trials of glucocorticosteroids and intra- cated, and there is only one case report of hematopoietic venous immunoglobulin did not achieve a sustained allogeneic stem cell transplantation in the literature [7]. response. At age 33 years, he developed splenomegaly and The genetics of TAR syndrome were first localized to a became platelet transfusion dependent with following submicroscopic deletion in region 1q21.1 that accounted splenectomy at age 36 years and stabilization of platelets for most cases of the syndrome [8]. The exact genetic around 20 Â 109/L. At age 45 years, during the work-up for lesion(s) were debated until next generation sequencing worsening anemia, a bone marrow biopsy showed a hyper- revealed that insufficient levels of RBM8A accounted for cellular marrow with dysplasia, 14% myeloid blasts and an 53 of the 55 cases that were explored [9]. Lesions in RBM8A abnormal karyotype with add (3p) and (12q) and calreticulin included deletion, single nucleotide polymorphisms in exo- (CALR) mutation. He was monitored without active treat- nic, intronic, and 50 and 30 untranslated regions, all resulting ment for one year when a bone marrow biopsy showed pro- in low levels of RBM8A transcript and its cognate protein gression to acute myeloid leukemia (AML) with myeloid Y14. Y14 is part of the exon-junction splicing complex, hyperplasia and 20% myeloid blasts. He received induction which is involved in mRNA localization, transport, and decay chemotherapy with decitabine priming followed by 3 days [10]. of idarubicin and 7 days of cytarabine (NCI 8854 trial). He Thrombopoietin (TPO) was discovered in 1994 as the required a second induction with 3 days of idarubicin and major regulator of megakaryocytopoiesis and thrombocy- 7 days of cytarabine to achieve a morphologic complete topoiesis. Levels of TPO in TAR patients are normal to remission, albeit with persistent cytogenetic and molecular slightly increased, raising the possibility of a megakary- abnormalities [add (3p) and (12q) and CALR mutation]. He ocytic resistance to TPO signaling. Later studies found that underwent a matched related donor allogeneic stem cell the combined defect in platelet production and function in transplant with fludarabine and melphalan conditioning, TAR syndrome had a staggered recovery through childhood, in vivo T cell depletion with alemtuzumab and post- with recovery of TPO signaling in adulthood [5]. transplant graft-versus-host disease with tacrolimus. The In addition to TPO, complex interactions between RNA- transplant course was complicated by legionella pneumonia binding proteins and binding sites on RBM8A have been pos- treated with 5 weeks of levofloxacin, respiratory failure tulated to act in a temporal and tissue specific manner. An requiring intubation, and altered mental status secondary RBM8A mutation seen in several TAR patients was shown to to oxcarbazepine toxicity. The post-transplant course was create a binding site for the translational repressor Evil; this complicated by poor oral intake and weight loss due to gas- led to decreased levels of RBM8A product, Y14. In Mus mus- trointestinal transplant graft-versus-host disease Center for culus, Evil is expressed transiently in developing limb buds, International Blood and Marrow Transplant Research grade 3 which may partly explain the skeletal abnormalities in that was treated with a Janus kinase inhibitor (INCB39110) humans [9]. in combination with glucocorticosteroids. At 19 month Four cases of leukemia were reported in TAR patients, 3 follow-up, the patient is off immunosuppression, and main- developed AML and 1 progressed to acute lymphoblastic leu- tains a complete remission status, transfusion indepen- kemia [2,11–13]. Additionally, rare cases of solid tumors dence and full donor chimerism. have been reported. However, without a denominator, the suggestion of correlation can only be hypothetical for the TAR review time being. The incidence of AML in US adults is around four per 100,000 [14]. Although the incidence of AML in TAR patients First reported in 1969 by Judith Hall, hypomegakaryocytic reported in the literature is higher, this may not be repre- thrombocytopenia combined with absent radii is a clinical sentative of the natural history of TAR patients without a diagnosis usually made at birth [1]. Platelet count in infancy denominator. In a seminal 2013 publication, the genetics is low, ranging from 10 Â 109/L to 100 Â 109/L, and the of de novo AML in 200 patients was dissected and nine func- bone marrow analysis reveals few megakaryocytes and both tional categories of genes were described, each of which radii are absent (unilateral loss in 2%). Other abnormalities were mutually exclusive for mutations in other categories of the skeletal, genitourinary, and cardiac systems are also [16]. Splicesome-complex genes were one of the nine cate- observed in TAR syndrome: about 23% of children have car- gories, and RBM8A encodes Y14 of the exon junction com- diac abnormalities, most commonly tetralogy of Fallot and plex, which is directly involved in the splicesome complex atrial septal defects; roughly the same percentage have and would therefore make it a possible driver of AML patho- genitourinary abnormalities including duplex ureter and genesis. Genomes of AML patients have on average only 13 horseshoe kidney [1–3]. Mortality in the first year of life is genes mutated; we postulate that, because RBM8A is related to massive bleeding, although most TAR patients involved in RNA splicing, mRNA maturation, and mRNA who survive childhood have a normal life span [3,4]. The transport, downregulation of its protein Y14 may modify presence of thumbs distinguishes TAR syndrome from Fan- other genes and transcripts involved in AML pathogenesis, coni anemia, in which thumbs are hypoplastic or absent. without RBM8A lesions themselves directly predisposing Thrombocytopenia resolves after childhood, although plate- patients to leukemia. For example, RBM8A has been shown let counts may remain below average through adulthood to physically interact with SRRM2 and RBMX, both of which [5]. Acute myeloid leukemia with TAR 247 were manually curated as splicesome-complex genes found [5] Fiedler J, Strauss G, Wannack M, Schwiebert S, Seidel K, to be significantly altered in AML [15–17]. While our patient Henning K, et al. Two patterns of thrombopoietin signaling has the classic clinical presentation of TAR, a germline suggest no coupling between platelet production and throm- exome sequencing did not find any germline variants in bopoietin reactivity in thrombocytopenia-absent radii syn- drome. Haematologica 2012;97:73–81. RBM8A. [6] Geddis AE. Congenital amegakaryocytic thombocytopenia and thrombocytopenia with absent radii. Hematol Oncol Clin North Summary Am 2009;23:321–31. [7] Brochstein JA, Shank B, Kernan NA, Terwilliger JW, O’Reilly RJ. Here we report the first case of MDS developing in a patient Marrow transplantation for thrombocytopenia-absent radii syndrome. J Pediatr 1992;121:587–9. with TAR. Additionally, the presence of a CALR driver muta- [8] Klopocki E, Schulze H, Strauss G, Ott CE, Hall J, Trotier F, tion is unique to our patient and the absence of RBM8A et al. Complex inheritance pattern resembling autosomal mutation in our patient, while reported before [9], is still recessive inheritance involving a microdeletion in thrombocy- extremely unusual. Allogeneic transplantation reversed topenia-absent radius syndrome. Am J Hum Genet the bone marrow failure and, at 18 month follow-up, the 2007;80:232–40. patient is transfusion independent, in complete morpho- [9] Albers CA, Paul DS, Schulze H, Freson K, Stephens JC, logic, cytogenetic, and molecular remission and fully donor Smethurst PA, et al.
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