Major histocompatibility complex (MHC) class II deficiency is one of the autosomal recessive primary immune deficiency disorders that leads to combined immunodeficiency [1]. This mode of inheritance explains the increased frequency of this disease in consanguineous populations like the Middle East [2, 3].

This disorder is due to defects in the MHC class II regulatory genes that encode for CIITA, RFXANK, RFX5, and RFXAP. These proteins are required for the expression of MHC II molecule on the surface of antigen presenting cells (dendritic cells, B-cells and monocyte/macrophage lineage cells). This molecule is also expressed in other type of cells after activation by interferon gamma (IFN- γ) or other inflammatory signals [2, 4, 5].

Defects in MHC class II protein affect T cell development and function as this protein accounts for the development, activation, and homeostasis of T-helper (TH) cells. This ultimately will affect the B-cells function which explains the impaired cellular and humoral immunity in patients with MHC class II deficiency [6].

Therefore, MHC class II deficient patients are prone to severe viral, bacterial, fungal, and protozoal infections that might occur early in life [4, 6]. Accordingly, they might present with recurrent sino-pulmonary infections, oral thrush, and protracted diarrhea with severe malabsorption leading to failure to thrive. Interestingly, a huge number of MHC class II deficient patients had received Bacille Calmette-Guerin (BCG) vaccine as part of the national vaccination program in many countries, the majority of these patients did not develop disseminated infection [3, 4]. In fact, disseminated BCGitis was reported in only two MHC class II deficient patients [7, 8]. The rare occurrence of mycobacterial infections in patients with MHC calls II deficiency is not well understood.

Despite knowing the fact that this monogenic disorder usually leads to an immunodeficiency phenotype, few patients were reported to have autoimmune and hyperinflammatory features. A study of 35 MHC class II deficient patients with a same founder RFXANK mutation showed that two patients had autoimmune cytopenia [4]. Another retrospective study of 25 patients described two siblings with CIITA mutation who had hyperinflammatory and autoimmune phenomena. The first sibling was initially diagnosed with polyarticular juvenile idiopathic arthritis (JIA) at 14 months of age, which was resistant to multiple biological agents. At the age of 7 years, she was diagnosed with MHC class II deficiency following an immunological evaluation of prolonged fever. Her younger sister was investigated, as she had chronic diarrhea since birth, and found to have the same mutation. According to the report, both siblings developed picture of macrophage activation syndrome (MAS)/HLH with fever, cytopenia, high ferritin, elevated triglycerides and low fibrinogen prior to bone marrow transplantation (BMT). Both patients were managed with steroid and cyclosporine with good response [8].

HLH is a life-threatening condition due to uncontrolled hyperinflammation and organ infiltrations by multiple immune cells including Histiocytes, Cytotoxic T (CTLs), and Natural Killer (NK) cells. The clinical criteria for this disorder include the following: prolonged fever, splenomegaly, pancytopenia, hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, low or absent NK-cell activity, elevated soluble interleukin-2 receptor, and hemophagocytosis in bone marrow, spleen, or lymph nodes [9]. This disorder is usually classified as either primary monogenic or secondary disorder. Primary HLH is due to defects in CTL and NK cytotoxicity, caused by genetic defects in perforin or molecules required for lytic granule exocytosis. On the other hand, secondary HLH is a complication of a variety of conditions including malignancy and inborn error of immunity like chronic granulomatous disease, severe combined immunodeficiency disease and others [10,11,12,13,14].

In this report, we present one MHC class II deficient patient with a novel presentation with hyperinflammation and HLH. In addition, this patient will be the third reported case of MHC class II deficiency who had disseminated BCGitis.