Hemophagocytic Lymphohistiocytosis Associated with NK Cell Dysfunction and Disseminated Herpesvirus Infection in GATA2 Deficiency/Monomac Syndrome
Authors: Spinner Michael A. , Odio Camila , Calvo Katherine R. , Hsu Amy P , Zerbe Christa S. , Cuellar-Rodriguez Jennifer , Ker Jennifer P. , Stoudenmire Charles J. , Fadare Oluwole , Ghosh Arunima , Mace Emily M. , Orange Jordan S. , Hickstein Dennis D. , Holland Steven M. 
Published: October 2019

Abstract
Background
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome of excessive immune activation. Herpesvirus infection is a common trigger of HLH, and in some patients may indicate an underlying immunodeficiency. Primary immunodeficiencies associated with HLH are often characterized by impaired cytotoxic function of NK cells and/or cytotoxic T lymphocytes and include Chediak-Higashi, Hermansky-Pudlak, and Griscelli syndromes and the X-linked lymphoproliferative disorders, SAP and XIAP deficiency.
GATA2 deficiency, also known as MonoMAC syndrome, is a primary immunodeficiency resulting from haploinsufficiency of the GATA2 transcription factor, a master regulator of hematopoiesis. Clinically, GATA2 deficiency is characterized by progressive cytopenias of monocytes, dendritic cells, and B and NK lymphocytes; susceptibility to infection with human papillomavirus, herpesviruses, nontuberculous mycobacteria, and invasive fungi; and bone marrow failure with risk for clonal evolution to myelodysplastic syndrome and acute myelogenous leukemia. Additional manifestations may include pulmonary alveolar proteinosis, congenital lymphedema, and sensorineural hearing loss. We report two patients with GATA2 deficiency/MonoMAC syndrome who developed aggressive HLH in the setting of marked NK cell dysfunction and disseminated herpesvirus infection.
Case 1
The patient was an African-American female with severe bilateral lymphedema since age 9 requiring multiple hospitalizations for lymphedema cellulitis. At age 12, she was hospitalized for severe pulmonary blastomycosis with necrotizing pneumonia. An immunologic workup revealed profound monocytopenia and B and NK lymphocytopenia, and NK functional testing revealed markedly reduced cytotoxicity and near absence of the CD56(bright) subset. Genetic testing for mutations in PRF1, UNC13D, and STX11 was negative. At age 18, she presented with septic shock and persistent fevers despite empiric antibiotics, and HSV-1 DNA was detected in the blood. The diagnosis of MonoMAC syndrome was strongly suspected in light of her congenital lymphedema and highly characteristic cytopenias and infections. Unfortunately, she rapidly decompensated and developed massive hyperferritinemia, hypofibrinogenemia, pancytopenia, and fulminant hepatitis concerning for HSV-1-driven HLH. An autopsy following her death revealed disseminated HSV-1 infection in the lungs, liver, and genitalia, and a hypocellular bone marrow with hemophagocytosis. The cause of death was HLH in the setting of NK cell deficiency and widespread HSV-1 infection. Genetic testing for GATA2 mutation was performed posthumously and is currently in progress.
Case 2
A Chinese female presented at age 20 with persistent fevers, cervical lymphadenopathy, and cutaneous ulcers. Mycobacterium avium complex was identified in the sputum and urine, and she was treated with clarithromycin, rifampin, and ethambutol. HIV testing was negative. Biopsy of her skin lesions revealed an EBV+ hydroa vaccineforme-like cutaneous T-cell lymphoma, and she was found to have significant EBV viremia with over 1 million copies/mL detected by quantitative PCR. An immunologic workup revealed profound B and NK lymphocytopenia. Monoallelic GATA2 mRNA expression was demonstrated leading to haploinsufficiency. She developed persistent fevers, worsening hyperferritinemia, hypofibrinogenemia, pancytopenia, and transaminitis. Bone marrow biopsy revealed a hypocellular marrow with EBV+ T cells and abundant hemophagocytosis. She was diagnosed with EBV-driven HLH and was treated with etoposide and dexamethasone followed by nonmyeloablative, haploidentical related donor stem cell transplant. She is currently 12-months post-transplant with an undetectable EBV viral load and complete resolution of her T cell lymphoma and HLH.
Conclusion
GATA2 deficiency is associated with NK cell dysfunction and disseminated herpesvirus infection, which can lead to aggressive HLH. Genetic testing for GATA2 mutation should be considered in patients with HLH and underlying NK cell deficiency and/or herpesvirus infection. NK functional testing typically shows markedly reduced cytotoxicity and near absence of the CD56(bright) subset. Allogeneic transplant represents a potentially curative approach in this setting.

Disclosures
No relevant conflicts of interest to declare.