Haraguchi et al. BMC Infectious Diseases (2021) 21:502 https://doi.org/10.1186/s12879-021-06203-7 CASE REPORT Open Access Disseminated nontuberculous mycobacteriosis and fungemia after second delivery in a patient with MonoMAC syndrome/GATA2 mutation: a case report Mizuki Haraguchi1, Norihiro Harada1,2,3* , Junko Watanabe1, Hitomi Yoshikawa1, Yukina Shirai1, Moegi Komura1, Mika Koyama1, Jun Ito1,2,3, Yutaka Tsukune4, Yoshiya Horimoto5, Takuo Hayashi5, Tetsutaro Nagaoka1,3, Toshimasa Uekusa6 and Kazuhisa Takahashi1,2,3 Abstract Background: Heterozygous mutations in the transcription factor GATA2 result in a wide spectrum of clinical phenotypes, including monocytopenia and Mycobacterium avium complex (MAC) infection (MonoMAC) syndrome. Patients with MonoMAC syndrome typically are infected by disseminated nontuberculous mycobacteria, fungi, and human papillomavirus, exhibit pulmonary alveolar proteinosis during late adolescence or early adulthood, and manifest with decreased content of dendritic cells (DCs), monocytes, and B and natural killer (NK) cells. Case presentation: A 39-year-old woman was diagnosed with MonoMAC syndrome postmortem. Although she was followed up based on the symptoms associated with leukocytopenia that was disguised as sarcoidosis with bone marrow involvement, she developed disseminated nontuberculous mycobacterial infection, fungemia, and MonoMAC syndrome after childbirth. Genetic testing revealed a heterozygous missense mutation in GATA2 (c.1114G > A, p.A372T). Immunohistochemistry and flow cytometry showed the disappearance of DCs and decreased frequency of NK cells in the bone marrow, respectively, after childbirth. Conclusions: To the best of our knowledge, this is the first study reporting that MonoMAC syndrome can be exacerbated after childbirth, and that immunohistochemistry of bone marrow sections to detect decreased DC content is useful to suspect MonoMAC syndrome. Keywords: Fungemia, GATA2 mutation, MonoMAC syndrome, Nontuberculous mycobacteriosis * Correspondence: [email protected] 1Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, 3-1-3 Hongo, Bunkyo-ku, Tokyo 113-8431, Japan 2Clinical Research Center for Allergy and Rheumatology, National Hospital Organization, Sagamihara National Hospital, Kanagawa, Japan Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 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BMC Infectious Diseases (2021) 21:502 Page 2 of 7 Background Case presentation Inherited or sporadic heterozygous mutations in the A 39-year-old Japanese female presented with high fever transcription factor GATA2 (guanine-adenine-thymine- 1 week after her second childbirth by Cesarean section. adenine 2) causes a germline disease manifesting a wide She subsequently developed acute pericarditis with dys- spectrum of clinical phenotypes including monocytope- pnea, bilateral pleural effusion, pericardial effusion, asci- nia and Mycobacterium avium complex (MAC) infection tes, systemic lymphadenopathy, hepatosplenomegaly, (MonoMAC) syndrome [1, 2]; dendritic cell (DC), and leukopenia. Acute pericarditis was improved spon- monocyte, B and natural killer (NK) lymphoid (DCML) taneously after admission to our cardiology department. deficiency [3]; familial myelodysplastic syndrome However, her fever continued and leukopenia worsened. (MDS)/acute myeloid leukemia (AML) [4]; Emberger Complete blood counts showed pancytopenia with 800 syndrome (congenital deafness, primary lymphedema, leukocytes/μL (32 monocytes/μL), hemoglobin content and predisposition to MDS and AML) [5]; and classic of 9.9 g/dL, and 108,000 platelets/μL 50 days postpartum NK cell deficiency [6]. Patients typically develop Mono- (Table 1). Bone marrow aspirates and biopsy showed MAC syndrome and DCML deficiency during late ado- normal cellularity and non-caseating granuloma, without lescence or early adulthood as a result of opportunistic myelodysplastic features. infections, such as disseminated nontuberculous myco- The patient was the second child born to unrelated bacterial (NTM) infections, fungal infections, and severe parents. She was healthy until 31 years of age except for or recurrent human papillomavirus infections, pulmon- an ectopic pregnancy at 28 years and recurrent warts; ary alveolar proteinosis, and decrease in DCs, mono- during this time, she gradually developed lymphadenop- cytes, and NK and B cells [1, 7, 8]. These patients are athy on her neck. Moreover, her peripheral blood associated with an increased risk of MDS and AML [2]. showed mild pancytopenia. She was histopathologically Herein, we report a female patient with leukocytopenia diagnosed, at 32 years, with sarcoidosis with involvement which was disguised as a sarcoidosis with bone marrow of the cervical lymph node (Fig. 1a) and bone marrow involvement. She was followed up for 7 years to assess (Fig. 1b), based on the presence of non-caseating granu- the accuracy of the diagnosis and developed dissemi- lomas with a background of normocellular bone marrow nated NTM infection and fungemia along with Mono- (Fig. 1c). Ziehl–Neelsen staining was negative for both MAC syndrome after childbirth. To the best of our the lymph node and bone marrow specimens (data not knowledge, this is the first report on the importance of shown). Cytogenetic analysis of the bone marrow cells immunohistochemistry of bone marrow to detect de- showed a normal 46 XX chromosomal pattern. The re- creased DC content to suspect MonoMAC syndrome. sults of the bone marrow aspiration and peripheral Table 1 Results of blood examinations and bone marrow aspirations Postpartum period Bone marrow aspiration Reference range −6.3 years − 6 years 56 days 5 months T cells (CD3+), % of lymphocytes 59–88 45.3 95.7 56.6 73.7 CD4 + T cells, % of lymphocytes 29–65 36.1 n/a n/a 15 CD8 + T cells, % of lymphocytes 13–40 26.7 n/a n/a 49.6 CD4/CD8 ratio 0.6–2.9 1.4 n/a n/a 0.3 B cells (CD19+), % of lymphocytes 4–26 1.1 1.3 1.2 1.4 NK cells (CD3-CD56+), % of lymphocytes 2–26 9.3 n/a 0.3 0.3 Complete blood counts Reference range −6.3 years −6 years −3 years 19 days 50 days 5 months 9 months White blood cells, cells/μL 3600–8900 1800 2000 1900 1400 800 700 200 Neutrophils, % 37–72 30.5 32.5 39 43 42 79 n/a Lymphocytes, % 25–48 53.5 55.5 44 51 52 12 n/a Monocytes, % 2–12 14 12 16 4 4 3 n/a Monocytes, cells/μL 252 240 304 56 32 21 n/a Hemoglobin, g/dL 11.1–15.2 12.1 11.8 9.6 10 9.9 9.7 5.7 Platelets, 103 counts/μL 153–346 92 88 92 176 108 74 10 Serum Reference range −6 years 19 days 83 days 5 months 9 months IgG, mg/dL 870–1700 1304 1081 858 540 57 Abbreviations: n/a not applicable, NK natural killer Haraguchi et al. BMC Infectious Diseases (2021) 21:502 Page 3 of 7 Fig. 1 Histopathological analysis of the cervical lymph node biopsy (a) and bone marrow biopsy specimens (b and c) 7.5 and 6.5 years before giving birth, respectively and 56 days postpartum (d and e). Normal cellularity and non-caseating granulomas were observed (hematoxylin and eosin staining, magnification × 200; a, c, and d, × 400; b). Ziehl-Neelsen-positive stained sections (magnification × 400; e) blood counts obtained 6.3 years before the second child- L), lactate dehydrogenase (1436 IU/L), and soluble birth of the patient are shown in Table 1. Although cyto- interleukin-2 receptor (10,100 U/mL), positron emission penia was observed, there were neither symptoms nor tomography-computed tomography scans, and previous signs of deterioration in the laboratory findings, and she pathological findings. Since she suffered from prolonged was suspended from hospital visits. She presented again fever and severe general exhaustion, an axillary lymph with regrowth of cervical lymphadenopathy during preg- node biopsy was performed to confirm the diagnosis, nancy at 36 years, her peripheral blood counts at the and steroid therapy (prednisone, 1 mg/kg) for sarcoidosis time are shown in Table 1 as “3 years before her second was initiated 86 days postpartum. Her clinical condition, childbirth” (Table 1). After her first childbirth, the fever, and general condition improved after 2 weeks of lymphadenopathy disappeared spontaneously. Moreover, steroid therapy along with reduction in hepatosplenome- her bone marrow sarcoidosis was believed to have galy. Lymph node biopsy showed reactive histiocytic caused leukopenia. She was followed up without treat- hyperplasia that did not enable a definitive diagnosis. ment (Table 1). Fever, splenomegaly, and leukopenia