Autosomal dominant and sporadic monocytopenia with susceptibility to mycobacteria, fungi, papillomaviruses, and myelodysplasia

Abstract

We identified 18 patients with the distinct clinical phenotype of susceptibility to disseminated nontuberculous mycobacterial infections, viral infections, especially with human papillomaviruses, and fungal infections, primarily histoplasmosis, and molds. This syndrome typically had its onset in adulthood (age range, 7-60 years; mean, 31.1 years; median, 32 years) and was characterized by profound circulating monocytopenia (mean, 13.3 cells/microL; median, 14.5 cells/microL), B lymphocytopenia (mean, 9.4 cells/microL; median, 4 cells/microL), and NK lymphocytopenia (mean, 16 cells/microL; median, 5.5 cells/microL). T lymphocytes were variably affected. Despite these peripheral cytopenias, all patients had macrophages and plasma cells at sites of inflammation and normal immunoglobulin levels. Ten of these patients developed 1 or more of the following malignancies: 9 myelodysplasia/leukemia, 1 vulvar carcinoma and metastatic melanoma, 1 cervical carcinoma, 1 Bowen disease of the vulva, and 1 multiple Epstein-Barr virus(+) leiomyosarcoma. Five patients developed pulmonary alveolar proteinosis without mutations in the granulocyte-macrophage colony-stimulating factor receptor or anti-granulocyte-macrophage colony-stimulating factor autoantibodies. Among these 18 patients, 5 families had 2 generations affected, suggesting autosomal dominant transmission as well as sporadic cases. This novel clinical syndrome links susceptibility to mycobacterial, viral, and fungal infections with malignancy and can be transmitted in an autosomal dominant pattern.

Figure 1

Pedigrees of the kindreds with multiple affecteds demonstrating autosomal dominant pattern of transmission.

Figure 2

PAP in patient 3.I.1. Computed tomography (left) demonstrates significant bilateral airspace disease. Histopathology (right) demonstrates excessive accumulation of amorphous proteinaceous material in the alveolar spaces. Images were taken using an Olympus Bx41 microscope, objectives UPlanFI 40×/0.75 ∞/0.17, and UPlanFI 20×/05.0 ∞/0.17, with an adaptor U-TV0.5×C using a digital camera Q-imaging Micropublisher 5.0RTV. The images were captured using Q-Capture Version 3.1 and imported into Adobe Photoshop 7.0.

Figure 3

Skin biopsy demonstrating the presence of tissue macrophages and plasma cells, despite the virtual absence of circulating monocytes and B cells. Full-thickness skin biopsy from patient 1.II.1 demonstrating granulomatous inflammation within the dermis (left). Immunohistochemistry reveals the presence of macrophages, stained with monoclonal antibody to KP-1/CD68 (center). Plasmacytosis is also seen in the tissue (hematoxylin and eosin stain; right). Images were taken using an Olympus Bx41 microscope, objectives UPlanFI 40×/0.75 ∞/0.17, and UPlanFI 20×/05.0 ∞/0.17, with an adaptor U-TV0.5×C using a digital camera Q-imaging Micropublisher 5.0RTV. The images were captured using Q-Capture Version 3.1 and imported into Adobe Photoshop 7.0.

Figure 4

Altered cell function and signal pathways in patients as assessed by microarray analysis of PMN transcripts. Ten most significant BioFunctions were identified using Ingenuity Pathways Analysis (Ingenuity Systems; www.ingenuity.com). Data are based on PMN transcripts differentially expressed in the patients compared with healthy control subjects. The P value indicates the likelihood that association of the specific set of transcripts and the indicated process or pathway is the result of random chance. B-H P value indicates P values after Benjamini-Hochberg correction for multiple comparisons.