EAHP Bone Marrow Workshop Familial GATA-2 mutation resulting in MonoMAC syndrome Frances Rosario Quinones, MD Memorial Sloan Kettering Cancer Center

Clinical History 50 F with history of borderline neutropenia (ANC 1.0-1.4) Skin rashes Perianal warts Waxing and waning panniculitis Family history Mother of two teenage boys with monosomy 7 MDS S/P unrelated HSCT at our institution One child with uveal melanoma and papillary thyroid cancer Past medical history Mycobacterium kansasii infection in lymph node (04/2011) Work up revealed pancytopenia and the patient underwent a bone marrow biopsy

Clinical History Bone marrow (2011) Refractory cytopenia with multilineage dysplasia and no increase in blasts Cytogenetics: 46 XX [20] Bone marrow (2013) No morphologic features of dysplasia The patient presents to our institution for follow up in July 2015

Mildly hypocellular marrow Low Power View Mildly hypocellular marrow

Few hypolobated megakaryocytes (green arrow) Medium Power View Few hypolobated megakaryocytes (green arrow)

Occasional bi-nucleated erythroids Bone Marrow Aspirate Occasional bi-nucleated erythroids

Flow Cytometry, Monocyte Gate Normal Control Monocytes (pink) comprised 0.07% of the patient’s white blood cells. Patient, marked monocytopenia

Flow Cytometry, Myelomonocytic Tube Normal granulocyte maturation (green), mild increase in eosinophils (yellow), and near absence of monocytes (pink) Near absence of monocytes and CD123-positive plasmacytoid dendritic cells (red arrow)

Flow Cytometry, Blast Tube Mild expansion of CD34-positive blasts, with reduced expression of CD33 and abnormal expression of CD7.

Comprehensive Genomic Profiling DNA sequencing identified a GATA2 G199fs*22 mutation in the patient as well as her two sons. ASXL1 (G646fs*12) mutation in patient’s bone marrow

Final Diagnosis Bone marrow, right posterior iliac crest, trephine biopsy and aspirate smears: Hypocellular marrow with maturing trilineage hematopoiesis, minimal dysplastic changes, and no increase in blasts. Flow cytometry Near absence of monocytes (0.07% of WBC) and plasmacytoid dendritic cells, as well as a mild expansion of CD34-positive blasts, with reduced expression of CD13 and CD117 and abnormal expression of CD7. Molecular Studies GATA2 G199fs*22 mutation in patient and sons

Interesting Features Evolution of a myeloid neoplasm in a patient with GATA-2 mutation which resulted in MonoMAC syndrome ASXL1 mutations as “trigger” for the development of overt MDS The onset of MonoMAC syndrome may precede full blown MDS by years Increased awareness of the role of GATA2 in hematopoiesis can lead to earlier detection of MonoMAC syndrome and proper risk stratification.

References Spinner MA, Sanchez LA, Hsu AP, Shaw PA, et al. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood. 2014 Feb 6;123(6):809-21. Hsu AP, Sampaio EP, Khan J, Calvo KR, et al. Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood. 2011 Sep 8;118(10):2653-5. Vinh DC, Patel SY, Uzel G, Anderson VL, Freeman AF, et al. Autosomal dominant and sporadic monocytopenia with susceptibility to mycobacteria, fungi, papillomaviruses, and myelodysplasia. Blood. 2010 Feb 25;115(8):1519-29 Bödör C, Renneville A, Smith M, Charazac A, Igbal S, et al. Germ-line GATA2 p.THR354MET mutation in familial myelodysplastic syndrome with acquired monosomy 7 and ASXL1 mutation demonstrating rapid onset and poor survival. Haematologica June 2012 97: 890-894