MONOCYTOPENIA WITH SUSCEPTIBILITY TO MYCOBACTERIAL, FUNGAL, AND PAPILLOMAVIRUS INFECTIONS AND MYELODYSPLASIA
COMBINED IMMUNODEFICIENCY WITH SUSCEPTIBILITY TO MYCOBACTERIAL, VIRAL, AND FUNGAL INFECTIONS
DCML
Dentritic cell, monocyte, B and NK lymphoid deficiency
monocytopenia and mycobacterial infection syndrome
monomac
Combined immunodeficiency with susceptibility to mycobacterial, viral and fungal infections
Monocyte - B - natural killer - dendritic cell deficiency
This primary immunodeficiency, designated DCML or MONOMAC, is characterized by profoundly decreased or absent monocytes, B lymphocytes, natural killer (NK) lymphocytes, and circulating and tissue dendritic cells (DCs), with little or no effect on T cell numbers. Clinical ... This primary immunodeficiency, designated DCML or MONOMAC, is characterized by profoundly decreased or absent monocytes, B lymphocytes, natural killer (NK) lymphocytes, and circulating and tissue dendritic cells (DCs), with little or no effect on T cell numbers. Clinical features of DCML include susceptibility to disseminated nontuberculous mycobacterial infections, papillomavirus infections, opportunistic fungal infections, and pulmonary alveolar proteinosis. Bone marrow hypocellularity and dysplasia of myeloid, erythroid, and megakaryocytic lineages are present in most patients, as are karyotypic abnormalities, including monosomy 7 and trisomy 8. Both autosomal dominant transmission and sporadic cases occur (Bigley et al., 2011; Hsu et al., 2011).
Vinh et al. (2010) reported 6 male and 12 female patients from 13 white and 3 Hispanic kindreds with a clinical phenotype of susceptibility to disseminated nontuberculous mycobacterial infections, viral infections, especially with human papillomaviruses, and fungal infections, ... Vinh et al. (2010) reported 6 male and 12 female patients from 13 white and 3 Hispanic kindreds with a clinical phenotype of susceptibility to disseminated nontuberculous mycobacterial infections, viral infections, especially with human papillomaviruses, and fungal infections, primarily histoplasmosis. The patients ranged in age from 7 to 60 years, with a median age of 32 years. The syndrome typically had its onset in adulthood, and 5 of the patients had died. A literature review identified at least 7 potentially related cases. Five kindreds including 7 of the 18 patients exhibited likely autosomal dominant transmission, and anecdotal evidence suggested autosomal dominant transmission in 3 other kindreds. Immunophenotyping revealed profound monocytopenia, B-cell deficiency without hypogammaglobulinemia, and NK-cell deficiency, but usually normal or near normal T-lymphocyte numbers. Tissue macrophage and plasma cell numbers were normal. Ten patients developed 1 or more malignancies, including myelodysplasia/leukemia in 9 patients. Five patients developed pulmonary alveolar proteinosis. Three patients had abnormal cytogenetics, including trisomy 8, monosomy 7, and dicentric chromosome 6. Bigley et al. (2011) reported 4 additional patients with this immunodeficiency, which they called DCML. In addition to monocyte and B and NK lymphoid cell deficiency, they demonstrated a near absence of DCs in these patients, with preserved numbers of tissue macrophages and epidermal Langerhans cells. Multilymphoid progenitors were absent and granulocyte-macrophage progenitors were depleted in bone marrow. Serum FMS-like tyrosine kinase ligand (FLT3LG; 600007) was elevated, while circulating regulatory T cells were reduced. Bigley et al. (2011) concluded that DC deficiency is an integral part of the syndrome of autosomal and sporadic monocytopenia initially reported by Vinh et al. (2010).
Hsu et al. (2011) identified 12 distinct mutations in the GATA2 gene in 20 patients with DCML, which they termed MONOMAC due to monocyte deficiency and susceptibility to mycobacteria, typically M. avium complex (MAC). The mutations were identified ... Hsu et al. (2011) identified 12 distinct mutations in the GATA2 gene in 20 patients with DCML, which they termed MONOMAC due to monocyte deficiency and susceptibility to mycobacteria, typically M. avium complex (MAC). The mutations were identified in 12 patients from 10 of the 16 kindreds originally reported by Vinh et al. (2010) and in 8 patients from 8 different kindreds not previously reported. In 2 kindreds, the mutation identified in the proband was identified in an affected relative, confirming germline transmission. Of the remaining 6 kindreds reported by Vinh et al. (2010), mutations in GATA2 were not identified in 3, and 3 were not analyzed. Five of the 6 missense mutations, including 2 recurrent mutations, arg398 to trp (R398W; 137295.0001) and thr354 to met (T354M; 137295.0002), affected the zinc finger-2 domain in GATA2, suggesting dominant interference of protein function. The remaining missense mutation, pro254 to leu (P254L; 137295.0003), occurred before the zinc fingers and was predicted to be damaging. Six patients had insertion/deletion mutations, 4 of which (e.g., 137295.0004) led to frameshifts and premature termination and implicated haploinsufficiency. Hsu et al. (2011) concluded that GATA2, like RUNX1 (151385) and CEBPA (116897), is involved in familial leukemia and in a complex congenital immunodeficiency that evolves over decades and leads to predisposition to infection and myeloid malignancy. By exome sequence analysis of 4 unrelated patients with DCML previously reported by Bigley et al. (2011), including 3 with sporadic DCML, Dickinson et al. (2011) found that only mutations in GATA2 were shared by all 4 patients. Each patient harbored a unique mutation, but all were predicted to be deleterious. The mutations included 2 missense mutations within the zinc finger domain, R398W and T354M, a 1-bp insertion in codon 200 (137295.0007) predicted to cause a frameshift and premature termination, and a splice acceptor site mutation (137295.0008) predicted to cause skipping of exon 5 and a 42-amino acid deletion. The frameshift and splice acceptor mutations were expected to result in complete loss of the C-terminal zinc finger domain and to cause DCML through haploinsufficiency of GATA2. Johnson et al. (2012) identified a woman of European descent who developed a constellation of conditions characteristic of MONOMAC by the age of 27 years. The patient lacked mutations in her GATA2 cDNA, and 3 conserved GATA regulatory sites upstream of the GATA2 promoter were identical to wildtype. However, Johnson et al. (2012) identified a 28-bp deletion in intron 5 at +9.5 kb (137295.0015) that affected a conserved composite E-box/GATA element. The deletion excised an imperfect GATA motif (GATAG), the E-box of the conserved composite element (CATCTG), and 5 bp of the 8-bp spacer between the E-box and the GATA motif (AGATAA). Johnson et al. (2012) suggested that heterozygous mutation of the +9.5 site reduces GATA2 expression in vivo.