Advertisement

GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics and immunity

Michael A. Spinner, Lauren A. Sanchez, Amy P. Hsu, Pamela A. Shaw, Christa S. Zerbe, Katherine R. Calvo, Diane C. Arthur, Wenjuan Gu, Christine M. Gould, Carmen C. Brewer, Edward W. Cowen, Alexandra F. Freeman, Kenneth N. Olivier, Gulbu Uzel, Adrian M. Zelazny, Janine R. Daub, Christine D. Spalding, Reginald J. Claypool, Neelam K. Giri, Blanche P. Alter, Emily M. Mace, Jordan S. Orange, Jennifer Cuellar-Rodriguez, Dennis D. Hickstein and Steven M. Holland

Key points

  • GATA2 deficiency has a broad phenotype encompassing immunodeficiency, MDS/AML, pulmonary disease, and vascular/lymphatic dysfunction.

  • Early genetic diagnosis is critical to direct clinical management, prophylaxis, transplantation, and family screening.

Abstract

Haploinsufficiency of the hematopoietic transcription factor GATA2 underlies monocytopenia and mycobacterial infections (MonoMAC); dendritic cell, monocyte, B and NK lymphoid (DCML) deficiency; familial MDS/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 NIH from January 1, 1992-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%, AML14%, CMML 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 (HPV+ tumors 35%, EBV+ 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=0.038, p=0.006, respectively). Monocytopenia, B, NK, and CD4 lymphocytopenia correlated with the presence of disease (p<0.001). 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.

  • Submitted July 16, 2013.
  • Accepted October 28, 2013.