MonoMAC versus idiopathic CD4+ lymphocytopenia. Comment to Haematologica. 2011;96(8):1221–5

We read with interest a recent article in Haematologica describing a novel defined disorder known as MonoMAC (monocytopenia with Mycobacterium avium complex).1 It is not infrequent for patients with MonoMAC to present with a low CD4 count, leading to a consideration of idiopathic CD4-positive (CD4) lymphocytopenia (ICL).2 Here we describe a case of MonoMAC who was initially thought to have ICL and aplastic anemia. However, the combination of pancytopenia, profound monocytopenia, and bone marrow (BM) findings support a diagnosis of MonoMAC.

A 24-year old Hispanic male presented with 2 ulcers on the lower extremities that he had had for two months. These ulcers were 1.0 to 3.5 cm in size at their widest point and had slightly raised erythematous borders with pink-glistening to black eschar bases (Figure 1A). Over the previous months he had developed fatigue, weight loss, fevers and chills, and had had a non-productive cough for three weeks. There were no HIV-associated risk factors. No family members with opportunistic infections or malignancy were reported. Physical findings included a low-grade fever, pallor, and decreased breath sounds and crackles in the lung. Laboratory results are summarized in Table 1. HIV antibody was negative by ELISA and HIV viral load was undetectable (< 400 copies/mL).

Figure 1.Skin findings. (A) Necrotic ulcers on the lower extremity with erythematous and eschar centers and raised peripheral borders; (B) epidermal and dermal necrosis and granulomatous inflammation throughout the dermis (H&E, magnification ×20); (C) dermal necrosis with collection of epithelioid histiocytes (H&E, magnification ×200); (D) acidfast positive bacilli (arrows) (Fite stain, magnification ×400).

Table 1.Summary of patient’s laboratory findings.

Figure 2.Bone marrow findings. (A) Markedly hypocellular marrow (H&E, magnification ×40); (B) moderate reticulin fibrosis (reticulin stain, magnification ×200). (C) Erythroid dysplasia: nuclear budding; (D) nuclear cytoplasmic dyssynchrony; (E) binucleation. (F) Myeloid dysplasia: hypogranulated granulocyte with uneven distribution of cytoplasmic granules; (G) pelgeroid nuclei; (H) ring nucleus. (I, J, K) Megakaryocytic dysplasia: megakaryocytes with multiple separated nuclear lobes; (K) widely separated nuclei.

The patient was admitted for pancytopenia and constitutional symptoms, and was started on broad-spectrum antibiotics. Workup included a punch biopsy of the left medial thigh ulcer which revealed necrotizing granulomatous dermatitis with acid-fast bacilli detected on Fite stain (Figure 1B–D). He also had a lymph node biopsy in the mediastinum which yielded acid-fast bacilli. Sputum cultures grew Mycobacterium avium-intracellulare complex (MAC) and were negative for M. tuberculosis. He was started on an anti-tuberculosis multi-drug therapy and was discharged on long-term therapy with clarithromycin, ethambutol, and rifampin. His skin lesions resolved within a month of starting therapy. The cause of pancytopenia was initially thought to be due to BM suppression associated with disseminated MAC infection. However, pancytopenia did not resolve and a BM biopsy was performed. This showed a markedly hypocellular marrow with moderate reticulin fibrosis, and mild erythroid dysplasia (Figure 2A–E). A diagnosis of aplastic anemia was made, and he was treated with antithymocyte globulin and methylprednisolone regimen. Megakaryocytic and myeloid dysplasia was identified retrospectively (Figure 2F–K). His disease course was complicated by several hospital admissions for neutropenic fever, respiratory distress, pleural and cardiac effusions, and persistently positive MAC cultures in the bone marrow, blood, and pleural fluid. Three years after the initial presentation, he succumbed to fulminant disseminated aspergillosis and sepsis.

Table 2.Features of MonoMAC in comparison to ICL.

MAC is one of the non-tuberculous mycobacteria (NTM), and is the most common cause of disseminated infection by NTM in AIDS patients. In HIV-negative patients, ICL is one of the known underlying immunological causes of non-tuberculous mycobacterial infections, which is the major presenting opportunistic infection in this disorder.3,4 Our patient was found to have persistently low CD4 T-cell counts for more than 18 months, ranging from 18 to 150 cells/μL. A provisional diagnosis of ICL was, therefore, made. ICL is a rare heterogeneous syndrome defined by CD4 T-cell counts of less than 300 cells/μL on two occasions, negative HIV testing, and no defined immunodeficiency or therapy associated with decreased CD4 T-cell count.4,5

MonoMAC is a newly defined immunodeficiency syndrome with bone marrow failure in young adulthood, disseminated NTM and fungal infections, monocytopenia, and the propensity to develop myelodysplasia or acute myeloid leukemia. There are familial and sporadic forms of MonoMac.1,2,6 Mutations in the GATA2 gene, a regulator of hematopoietic stem cell integrity, in both familial and sporadic forms were recently identified to play a pivotal role in this disease.6–9

ICL and MonoMAC share many overlapping clinical features and laboratory findings (Table 2).1–4,7,8 Both present in the young adult age group, although the mean age at diagnosis of patients with ICL is slightly higher. The majority of patients of both entities present with NTM (including MAC), HPV and fungal infection. Warts and autoimmune phenomena are also shared features. Pancytopenia can occur in ICL due to infection-associated bone marrow suppression. Moreover, lymphocyte subset testing will frequently identify CD4 lymphocytopenia, CD8 lymphocytopenia, as well as NK and B-cell lymphocytopenia in both entities. The differential features then rely on an awareness of MonoMAC and multidisciplinary correlation including family history and peripheral blood findings, especially the presence or absence of cytopenia and profound monocytopenia. Finally, bone marrow examination may be indicated to help differentiate between these two entities. GATA2 mutation analysis may also be helpful.