GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity.
Haploinsufficiency of the hematopoietic transcription factor GATA2 underlies monocytopenia and mycobacterial infections; dendritic cell, monocyte, B, and natural killer (NK) lymphoid deficiency; familial myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML); and Emberger syndrome (primary lymphedema with MDS). A comprehensive examination of the clinical features of GATA2 deficiency is currently lacking. We reviewed the medical records of 57 patients with GATA2 deficiency evaluated at the National Institutes of Health from January 1, 1992, to March 1, 2013, and categorized mutations as missense, null, or regulatory to identify genotype-phenotype associations. We identified a broad spectrum of disease: hematologic (MDS 84%, AML 14%, chronic myelomonocytic leukemia 8%), infectious (severe viral 70%, disseminated mycobacterial 53%, and invasive fungal infections 16%), pulmonary (diffusion 79% and ventilatory defects 63%, pulmonary alveolar proteinosis 18%, pulmonary arterial hypertension 9%), dermatologic (warts 53%, panniculitis 30%), neoplastic (human papillomavirus+ tumors 35%, Epstein-Barr virus+ tumors 4%), vascular/lymphatic (venous thrombosis 25%, lymphedema 11%), sensorineural hearing loss 76%, miscarriage 33%, and hypothyroidism 14%. Viral infections and lymphedema were more common in individuals with null mutations (P = .038 and P = .006, respectively). Monocytopenia, B, NK, and CD4 lymphocytopenia correlated with the presence of disease (P < .001). GATA2 deficiency unites susceptibility to MDS/AML, immunodeficiency, pulmonary disease, and vascular/lymphatic dysfunction. Early genetic diagnosis is critical to direct clinical management, preventive care, and family screening.
Laboratory of Clinical Infectious Diseases, and.
Michael A
MA
Spinner
Lauren A
LA
Sanchez
Amy P
AP
Hsu
Pamela A
PA
Shaw
Christa S
CS
Zerbe
Katherine R
KR
Calvo
Diane C
DC
Arthur
Wenjuan
W
Gu
Christine M
CM
Gould
Carmen C
CC
Brewer
Edward W
EW
Cowen
Alexandra F
AF
Freeman
Kenneth N
KN
Olivier
Gulbu
G
Uzel
Adrian M
AM
Zelazny
Janine R
JR
Daub
Christine D
CD
Spalding
Reginald J
RJ
Claypool
Neelam K
NK
Giri
Blanche P
BP
Alter
Emily M
EM
Mace
Jordan S
JS
Orange
Jennifer
J
Cuellar-Rodriguez
Dennis D
DD
Hickstein
Steven M
SM
Holland
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D005260:Female; D050989:GATA2 Transcription Factor / Q000172:deficiency / Q000235:genetics*; D056726:Genetic Association Studies; D057895:Haploinsufficiency; D006410:Hematopoiesis; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D008208:Lymphatic System; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D011379:Prognosis; D011446:Prospective Studies; D015996:Survival Rate; D055815:Young Adult
D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human