HETEROZYGOUS MUTATIONS OF THE MAJOR HISTOCOMPATIBILITY CLASS-II ASSOCIATED MOLECULES

Introduction Major histocompatibility class II (MHC-II) molecules are transmembrane proteins that have a fundamental role in the development and control of the immune system. The expression of MHC-II molecules is tightly regulated. Four disease-causing genes have been identified that control the transcription of MHC-II genes including MHC-II transactivator (CIITA) and Regulatory Factor X Associated Ankyrin Containing Protein (RFXANK). Homozygous mutations affecting the transcription of these genes leads to a primary immunodeficiency known as MHC-II deficiency. Here we report two cases with severe clinical manifestations of immunodeficiency in patients with heterozygous mutations of the CIITA and RFXANK proteins. Case Description Case 1: A 34-year-old female presented for recurrent respiratory tract infections since childhood. She had previously been treated with prophylactic antibiotics and intravenous immunoglobulin (IVIG) therapy without improvement. She continued to require hospitalization every two months for resistant infections. Immunodeficiency workup demonstrated a decrease of B cells and immunoglobulins. Genetic testing showed a heterozygous variant in CIITA. Case 2: An 18-year-old female presented for autoimmune cytopenias, large lymphadenopathy, and recurrent infections since childhood including recurrent otitis media, sinusitis, and bronchitis. Immunodeficiency workup demonstrated a decrease in immunoglobulin levels, B cells, and T cells. Genetic testing showed a heterozygous variant in RFXANK. Discussion Homozygous mutations of transcription factors of MHC-II molecules leads to a primary immunodeficiency known as MHC-II deficiency. Although difficult to classify, heterozygous mutations of the MHC-II deficiency related genes may still present with clinically significant immunodeficiency.