MonoMAC syndrome was first described in 2010 in a group of 18 adult patients with disseminated NTM and other opportunistic infections [
6]. Half of the patients were diagnosed with MDS/AML, characterized by reduced numbers of circulating monocytes, B cell, and NK cells [
6]. Since then, patients with persistent cytopenia, even in the absence of diagnostic morphologic dysplasia, are suspected of having MonoMAC syndrome. In 2011, the MonoMAC syndrome was linked to 12 distinct
GATA2 mutations, including the T354 M in the second zinc-finger domain that was also found in our patient [
5]. Although
GATA2 mutations might be found in a large number of sporadic cases, disease phenotype follows an autosomal dominant inheritance pattern [
5]. To date, nearly 380
GATA2-deficient patients have been reported, with an estimated prevalence of myeloid neoplasia of at least 75% [
7]. The most frequent clinical features described in
GATA2 deficient patients according to literature reviews and in our patient are summarized in Table
1. Non-infectious conditions also have been described in MonoMAC cases, especially endocrine, rheumatologic, and dermatological manifestations with hypothyroidism, panniculitis/erythema nodosum, arthritis and vasculitis. MonoMAC-associated MDS is usually hypocellular, shows atypical megakaryocytes, and fibrosis [
8]. The 2016 revision of the World Health Organization classification for myeloid neoplasms has incorporated a subgroup of cases associated with germline mutations, that includes
GATA2 [
9].
GATA2mut is associated with MonoMAC syndrome despite of variable GATA2 expression and initial presentation spanning from early childhood to late adulthood, with a median age of presentation of 32 years with viral, mycobacterial or fungal infections [
6]. The ubiquitous influence of NTM and other infections, accompanied by co-occurrence of monocytopenia, lymphopenia, neoplasia and a vast possibility of symptoms make the initial diagnosis of MonoMAC syndrome difficult for physicians. Clinical suspicion of MonoMAC syndrome is critical to make an early genetic diagnosis and to direct an appropriate management. Other gene mutations, such as mutations in
IL12R or
IFNγR receptors or
STAT1, are also important for differential diagnosis, however, CD4+, T cell and monocyte numbers are often normal in these conditions [
1]. Genetic counselling should be offered to at-risk individuals [
10]. The proband’s father died prematurely from a coronary artery disease (CAD). Because
GATA2 has been functionally involved in the pathophysiology of thrombosis and CAD [
11], we hypothesized that
GATA2 mut would be present in the first generation of this patient’s family, but we didn’t have biological material to test him. In healthy carriers of
GATA2 mutations, antimicrobial prophylaxis with azithromycin and immunization against human papilloma virus (HPV) are suggested as follow-up treatments [
10]. Other recommendations at diagnosis are screening for HPV infection and HPV-related cervical, head and neck and anogenital cancer as well as baseline pulmonary evaluation [
10]. It is also important to educate patients and physicians about the increased risk of opportunistic infections, especially NTM. Vigilant BM monitoring, immunoglobulin replacement when low or with recurrent infections, screening for congenital deafness and avoidance of ototoxic drugs are all recommended [
10]. Even though characterized as autosomal dominant inheritance,
GATA2 mutations are germline heterozygous and might have incomplete penetrance [
12]. Allogenic HSCT has been curative for haematopoietic disease in some cases using nonmyeloablative conditioning regimens [
13]. Among individuals with
GATA2 deficiency progressing to MDS/AML, acquired secondary mutations in the
ASXL1 that encoding chromatin-binding protein ASXL1 are detected in approximately 30% of cases, despite being negative in our patient (data not shown) [
14]. The prognosis after MDS/AML diagnosis appears to be poor, with the best outcomes reported among individuals undergoing allogeneic HSCT in the early stages of the disease, with an overall survival rate of 57% at 36 months [
4]. In conclusion, we presented a patient with long history of NTM infection, MDS, monocytopenia, autoimmune and thrombotic phenomena, hypothyroidism and carrying a
GATA mutation. The delay in diagnosis of MonoMAC syndrome is explained by the diversity of clinical features and lack of medical knowledge by the period of disease presentation. With this report, we hope to call attention to the importance of early diagnosis of this immunodeficiency syndrome. Genetic counselling, clinical management, and HSCT in early disease stages can be safely offered.
Table 1
Principal clinical features of GATA2 deficiency described previously and presented in this case report
MDS/AML | Early-onset, familial history, bone marrow fibrosis, aggressive disease, associated with secondary mutations | 30–50% at presentation, 30 years- old median onset, 90% lifetime risk | Yes |
Warts, severe Viral infection | HPV all serotypes, herpesviruses | 60–70% at presentation, 10–20% disseminated CMV, VZV and EBV | No |
Pulmonary alveolar proteinosis or decreased lung function | PAP (GM-CSF antibody negative), pulmonary arterial hypertension, loss of volume or diffusion, pneumonia | 18% proven PAP 10% PAH 50% abnormal PFT 14% pneumonia | Yes (he had only pulmonary infiltrate) |
Mycobacterial or fungal infection | NTM (MAC and others) aspergillosis, histoplasmosis | 20–50% NTM 16% aspergillosis, 9% histoplasmosis | Yes |
Recurrent upper respiratory tract infection | Otitis, sinusitis | 10–20% | Yes |
Autoimmune manifestations | Panniculitis, arthritis, lupus-like, hypothyroidism, hepatitis/PBC | 30% panniculitis, arthritis in up to 50% overall | Yes |
Solid malignancy | HPV and EBV- mesenchymal related, breast, prostate and kidney cancer, metastatic melanoma | 20–35% intra-epithelial neoplasia, 22% of women with > 35 years breast cancer, other skin cancer 10% | No |
Lymphedema | Childhood or adolescence | 11–20% | No |
Thrombosis | DVT, PE, Catheter-related | 25% risk overall | Yes |
Deafness | Neurosensorial | 20% abnormal audiograms | No |