Monocytopenia frequently accompanies granulocytopenia with chemotherapy, aplastic anemia, or other BM-suppressive insults. Isolated or disproportionate monocytopenia is rarely recognized, but observations suggest that this can have serious clinical sequelae when it occurs. In hairy cell leukemia and monoMAC syndrome (GATA2 deficiency), there is a clear association with severe opportunistic infections, particularly those normally engendering a granulomatous response.
Hairy Cell Leukemia
This disorder, considered in detail elsewhere, classically presents with pancytopenia and splenomegaly, often in middle-aged men. The WBC count is sometimes high because of hairy cell proliferation, but monocytes are invariably severely depressed. (Monocytopenia is not seen with “variant hairy cell leukemia.”) Neutropenia only partly explains the very high infectious morbidity and mortality. An extraordinary incidence of opportunistic granulomatous infections has been encountered, including atypical mycobacteria, tuberculosis, histoplasmosis, and other fungi. These are linked to mono cytopenia, with impaired granuloma formation. With remission induced by modern therapies (e.g., cladribine, pentostatin or moxetumomab pasudotox), monocytopenia and infectious risks have been mitigated.
GATA2 Deficiency
In 2010, investigators at the National Institutes of Health and in the UK simultaneously described an immunodeficiency syndrome characterized by decreased or absent monocytes, NK cells, B cells, and dendritic cells; this clinical syndrome was named MonoMAC or dendritic cell, monocyte and lymphoid deficiency.25 This was largely diagnosed in young adults (median age: 33 years). All patients have opportunistic infections, particularly Mycobacterium avium complex and other mycobacteria, opportunistic fungi, and viruses, particularly human papillomavirus. Both autosomal dominant and sporadic cases are described, all linked to mutations in the hematopoietic stem cell regulator GATA2. Heterozygous mutations in GATA2 are also responsible for Emberger syndrome (primary lymphedema and a predisposition to AML) and familial MDS/AML. BM examination findings are almost always abnormal, usually hypocellular, with increased reticulin fibrosis, multilineage dysplasia with characteristic separated nuclei in megakaryocytes, and absent B and NK precursors. Clonal cytogenetic abnormalities are seen in most patients, particularly monosomy 7 in 16% and trisomy 8 in 24%. Because leukemic progression with or without death from infection is high, stem cell transplantation is recommended when feasible. When a family member is used as a BM donor, GATA2 sequencing must be performed to rule out asymptomatic carrier status before donating. When monocytopenia out of proportion to neutropenia is detected in a patient with or without human papillomavirus-associated warts or MAC infection, examination of B- and NK-cell count by flow cytometry will be informative. Detailed family history may reveal additional patients with infectious complications or MDS/AML.
