A Novel GATA-1 Mutation in a Neonate with Transient Abnormal Myelopoiesis without Down Syndrome
Keywords:
myeloproliferative disorder, Down syndrome, GATA-1 geneAbstract
Transient abnormal myelopoiesis (TAM) is a rare disorder usually diagnosed in newborns with Down syndrome, less frequently in mosaic trisomy 21 and only sporadically in phenotypically normal infants. In addition to the association with trisomy 21, TAM is also associated with mutations in the GATA-1 gene. We report a case of TAM with a novel mutation in the GATA-1 gene. A newborn boy was found to have leukocytosis (52.9 x 109/l) with 50% myeloid blast forms. Fluorescence in situ hybridization (FISH) on peripheral blood showed trisomy 21 limited to the blast forms. Further cytogenetic studies revealed that he did not have constitutional trisomy 21 or mosaic trisomy 21. Sequencing studies performed on DNA isolated from a peripheral blood sample containing blast forms showed a frameshift mutation in the GATA-1 gene (c.148_149dup CC) implying premature termination. A diagnosis of transient myeloproliferative disorder spectrum was made. The patient was treated with a short course of cytarabine with resolution of leukocytosis and a blast count of less than 0.5% at one month of age. Follow-up at 2 years after diagnosis showed normal peripheral blood counts and sustained molecular remission with normal karyotype.
References
Miyauchi J. Unique myeloid leukemias in young children with Down syndrome: cell origin, association with hematopoietic microenvironment and leukemogenesis. In Dey S, ed. Prenatal Diagnosis and Screening for Down syndrome. InTech; 2011:107-128.
Carpenter E, Valverde-Garduno V, Sternberg A, et al. GATA-1 mutation and trisomy 21 are required only in haematopoietic cells for development of transient myeloproliferative disorder. Brit J Haematol. 2005; 128: 548–551.
Richards M, Welch J, Watmore A, Readett D, Vora AJ. Trisomy 21 associated transient neonatal myeloproliferation in the abscence of Down’s syndrome. Arch Dis Child Fetal Neonatal Ed. 1998; 79:F215- F217.
Tsai MH, Hou JW, Yang CP, et al. Transient myeloproliferative disorder and GATA1 mutation in neonates with and without Down syndrome. Indian J Pediatr. 2011; 78: 826-832.
Taub JW, Mundschau G, Ge Y, et al. Prenatal origin of GATA1 mutations may be an initiating step in the development of megakaryocytic leukemia in Down syndrome. Blood. 2004; 104: 1588- 1589.
Ahmed M, Sternberg A, Hall G, et al. Natural history of GATA1 mutations in Down syndrome. Blood. 2004; 103(7): 2480-2489.
Birger Y, Goldberg L, Chlon T, et al. Perturbation of fetal hematopoiesis in a mouse model of Down syndrome’s transient myeloproliferative disorder. Blood. 2013; 122: 988-998.
Ciovacco W, Raskind W, Kacena M. Human phenotypes associated with GATA-1 mutations. Gene. 2008; 427: 1-6.
Gamis A, Smith F. Transient myeloproliferative disorder in children with Down syndrome: clarity to this enigmatic disorder. Brit J Haematol. 2012; 159: 277–287.
Gamis A, Alonzo T, Gerbing R, et al. Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the children’s oncology group study A2971. Blood. 2011; 118:6752–6759.
