B-Cell Lymphoma in a Patient with Complete Interferon Gamma Receptor 1 Deficiency

Abstract

Immunosuppression-associated lymphoproliferative disorders can be related to primary as well as acquired immune disorders. Interferon gamma receptor (IFN-γR) deficiency is a rare primary immune disorder, characterized by increased susceptibility to mycobacterial infections. Here we report the first case of an Epstein Barr Virus (EBV) related B-cell lymphoma in a patient with complete IFN-γR1 deficiency. The patient was a 20-year-old man with homozygous 22Cdel in IFNGR1 resulting in complete absence of IFN-γR1 surface expression and complete lack of responsiveness to IFN-γ in vitro. He had disseminated refractory Mycobacterium avium complex and Mycobacterium abscessus infections. At age 18 he presented with new spiking fever and weight loss that was due to an EBV-positive B-cell non-Hodgkin lymphoma. Two years later he died of progressive lymphoma. IFN-γ plays an important role in tumor protection and rejection. Patients with IFN-γR deficiencies and other immune deficits predisposing to mycobacterial disease seem to have an increased risk of malignancies, especially those related to viral infections. As more of these patients survive their early infections, cancer awareness and tumor surveillance may need to become a more routine part of management.

Diagnostic and therapeutic challenges in a child with complete Interferon‐γ Receptor 1 deficiency

“…However, HSCT does not completely correct this pathology as the IFN‐γR is also expressed on cells and tissue types not directly derived from lymphoid tissue or bone marrow . Malignancies such as lymphoma, Kaposi sarcoma, and a pineal germinoma have been reported . Tumor surveillance seems reasonable for all patients with IFN‐γR deficiency independently of their transplant status.…”

Biallelic JAK1 mutations in immunodeficient patient with mycobacterial infection

“…Recently, somatic loss-of-function mutations in JAK1 have been associated with gynaecologic cancers12. Tumours also have been reported in patients with other defects in the IL-12/IFN-γ pathway, including Kaposi sarcoma29, B cell lymphoma30, disseminated cutaneous squamous cell carcinoma31, oesophageal squamous cell carcinoma32 and pineal germinoma33. These observations and the findings reported here demonstrate that impaired IL-12/IFN-γ signalling predisposes not only to mycobacterial infection, but also to malignancy, probably owing to impaired immune surveillance.…”

Mendelian susceptibility to mycobacterial disease: Genetic, immunological, and clinical features of inborn errors of IFN-γ immunity

“…Thirty-one patients from 26 families and 25 different mutations (deletions n =10, insertions n =4, nonsense n =2, missense n =5 and splice site n =4) have been described to date (Figure 1). Two genetic forms of AR complete IFN-γR1 deficiency have been described, with [46, 53, 84, 85] or without surface expression of the receptor [37, 46, 48, 50, 65, 66, 86–101] (Table 1). A case of paternal uniparental disomy of chromosome 6, including IFNGR1, has been described in a patient with mycobacterial infectious disease and a complex phenotype including neonatal hyperglycemia, neuromuscular disease, and dysmorphic features [88].…”

“…Salmonellosis has rarely been documented in these patients ( n =3) [46, 65, 66]. One patient had a B-cell lymphoma and a second had a pineal germinoma [50, 54]. Treatment with IFN-γ is not indicated, owing to the lack of specific receptors.…”

“…Viral infections have also been reported, including diseases caused by cytomegalovirus (CMV), human herpes virus 8 (HHV8), parainfluenza virus type 3 (PRV-3), respiratory syncitial virus (RSV) and varicella zoster virus (VZV) [46–49]. Six cases of malignancies, namely B-cell lymphoma, esophageal carcinoma, cutaneous squamous cell carcinoma, Kaposi sarcoma, liver cancer and pineal germinoma have also been reported [27, 50–54]. The pathogenesis of viral and tumoral diseases may not necessarily involve the underlying MSMD-causing inborn error, instead potentially involving an immunodeficiency acquired secondary to mycobacterial or other infections [55–61].…”