Myelodysplasia in autosomal dominant and sporadic monocytopenia immunodeficiency syndrome: diagnostic features and clinical implications

Abstract

A novel, genetic immunodeficiency syndrome has been recently described, herein termed "MonoMAC". It is characterized by severe circulating monocytopenia, NK- and B-lymphocytopenia, severe infections with M. avium complex (MAC), and risk of progression to myelodysplasia/acute myelogenous leukemia. Detailed bone marrow analyses performed on 18 patients further define this disorder. The majority of patients had hypocellular marrows with reticulin fibrosis and multilineage dysplasia affecting the myeloid (72%), erythroid (83%) and megakaryocytic (100%) lineages. Cytogenetic abnormalities were present in 10 of 17 (59%). Despite B-lymphocytopenia, plasma cells were present but were abnormal (e.g. CD56(+)) in nearly half of cases. Increased T-cell large granular lymphocyte populations were present in 28% of patients. Chromosomal breakage studies, cell cycle checkpoint functions, and sequencing of TERT and K-RAS genes revealed no abnormalities. MonoMAC appears to be a unique, inherited syndrome of bone marrow failure. We describe distinctive bone marrow features to help in its recognition and diagnosis. (Clinicaltrials.gov identifiers: NCT00018044, NCT00923364, NCT01212055).

Figure 1.

Bone marrow features of MonoMAC. (A) Hypocellular bone marrow (H&E stain of core biopsy from a 43-year old male); (B) prominent reticulin fibrosis; (C) scattered hemophagocytic histiocytes. Megakaryocytic atypia in MonoMAC, including micromegakaryocytes; (D) small megakaryocytes with separation of nuclear lobes; (E) large osteoclast-like megakaryocytes with multiple separated nuclear lobes; (F) which were positive for the megakaryocytic marker Factor VIIIvw by immunohistochemistry. (G) Dysplastic megakaryocytic hyperplasia with mononuclear megakaryocytes in the marrow of a MonoMAC patient; (H) (H&E) and (I) immunohistochemistry for Factor VIIIvw. (J) Myeloid dysplasia: binucleated or mitotic promyelocyte; (K) cytoplasmic vacuoles, hyposegmentation, abnormal maturation; (L) ring nucleus; (M) binucleated or hypersegmented eosinophil; (N) hyposegmented neutrophil; (O, P, Q) hypogranulated granulocytes; (R, S) erythroid dysplasia: binucleation; (T, U) nuclear budding; (U) megaloblastic changes. (V, X) Abnormal plasma cells: multinucleated plasma cells; (W) plasma cells with nuclear budding; and (Y) Mott cells with numerous Russell bodies (arrow) representing stored immunoglobulin.

Figure 2.

Flow cytometric analysis of bone marrow in MonoMAC. (A) Side scatter [SSC] versus CD45. Bone marrow from monoMAC patient shows characteristic pattern of decreased SSC of granulocytes (hypogranular), markedly decreased to absent monocytes, decreased lymphocytes, and increased blasts. (B) Flow cytometric analysis of CD13, CD16 and CD11b expression during myeloid maturation of normal bone marrow and bone marrow from MonoMAC patient. MonoMAC bone marrow shows abnormal dyssynchronous expression patterns of CD13, CD16 and CD11b during myeloid maturation. (C) Flow cytometric analysis of gated plasma cell population in monoMAC patient shows immunophenotypically abnormal plasma cell population (CD56⁺ and CD19⁻).