Although acquired mutations in the GATA1 gene have been reported for Down syndrome-related acute megakaryoblastic leukemia (DS-AMKL) in Caucasians, this is the first report of a Korean Down syndrome patient with AMKL carrying a novel mutation of the GATA1 gene. A 3-yr-old Korean girl with Down syndrome was admitted to our hospital complaining of pallor and fever. The findings of a peripheral blood smear and bone marrow study were compatible with the presence of AMKL. A chromosome study showed 48,XX,-7,+21c,+21,+r[3]/47,XX,+21c[17]. Following GATA1 gene mutation analysis, a novel mutation, c.145dupG (p.Ala49GlyfsX18), was identified in the N-terminal activation domain of the GATA1 gene. This mutation caused a premature termination at codon 67 and expression of an abnormal GATA-1 protein with a defective N-terminal activation domain, and the absence of full-length GATA-1 protein. This case demonstrates that a leukemogenic mechanism for DS-AMKL is contributed by a unique collaboration between overexpressed genes from trisomy 21 and an acquired GATA1 mutation previously seen in Caucasians and now in a Korean patient.
Base Sequence ; Child, Preschool ; Chromosomes, Human, Pair 21 ; Down Syndrome/complications/diagnosis/*genetics ; Female ; GATA1 Transcription Factor/*genetics ; Humans ; Karyotyping ; Korea ; Leukemia, Megakaryoblastic, Acute/diagnosis/etiology/*genetics ; *Mutation ; Phenotype ; Trisomy

No abstract available.
*Aneuploidy ; Bone Marrow/pathology ; Chromosomes, Human, Pair 21 ; Down Syndrome/*complications ; Female ; Humans ; Hyperplasia/pathology ; In Situ Hybridization, Fluorescence ; Infant ; Isochromosomes/*genetics ; Karyotype ; Leukemia, Megakaryoblastic, Acute/complications/*diagnosis ; Megakaryocytes/pathology

INTRODUCTIONInfants with Down syndrome (DS) are at higher risk of hearing loss (HL). Normal hearing at one year of age plays an important part in language development. An audit was conducted to determine the impact of the newborn hearing screening program on the incidence, type and timing of diagnosis of HL during first year of life.

MATERIALS AND METHODSInfants with DS were scheduled for Universal Newborn Hearing Screening (UNHS) within 4 weeks of life. If they passed, they had a high-risk screen at 3 to 6 months. They were referred to the otolaryngology department if they did not pass the UNHS or the high-risk screen. Information was obtained from the computerised data tracking system and case notes. Infants born from April 2002 to January 2005 and referred to the DS clinic of our hospital were analysed.

RESULTSThirty-seven (82.2%) of 45 infants underwent UNHS, of which 12 (32.4%) infants did not pass. Of remaining 33 infants, 27 had high-risk screen done of which 14 (51.8%) did not pass. Twenty-eight infants were referred to the ear, nose, throat (ENT) clinic: 12 from UNHS, 14 from high-risk screens and 2 from the DS clinic. Eleven (39.2%) defaulted follow-up. Fourteen (82.3%) of 17 infants who attended the ENT Clinic had HL. Twelve (85.7%) were conductive, and 2 (14.2%) mixed. Nine (64.2%) had mild-moderate HL and 3 (21%) had severe HL. The mean age of diagnosis was 6.6 ± 3.3 months. All were treated medically, plus surgically if indicated. By 12 months of age, the hearing had normalised in 4 (28.6%) infants and remained the same in 3 (21.4%). Five (35.7%) defaulted follow-up. Thirty-five out of 45 (77.8%) underwent complete hearing screen in the first year of life (UNHS & High-risk screen). Six out of 45 (13.3%) had incomplete screening. Fourteen out of 41 (34.1%) had HL of varying degrees. Four out of 45 (8.8%) did not have any audiological assessment in first year of life.

CONCLUSIONThe incidence of HL in the first year of life was high (34.1%). Eighty-five percent were conductive with 64.2% in mild-moderate range. One third of infants hearing normalized after treatment, one third remained unaltered and one third of infants did not attend follow-up. An aggressive approach involving early screening after birth and continued surveillance and early referral to appropriate agencies are essential for establishing timely diagnosis and treatment. Measures to reduce the high default rate during long-term follow-up are needed. Parent education and integrated multidisciplinary follow-up clinic may be useful.

Down Syndrome ; complications ; Early Diagnosis ; Female ; Hearing Loss ; diagnosis ; epidemiology ; etiology ; physiopathology ; Hearing Tests ; Humans ; Infant ; Male ; Mass Screening ; Medical Audit ; Population Surveillance ; methods ; Severity of Illness Index ; Singapore ; epidemiology ; Trisomy ; genetics