A case of monogenic immune deficiency and autoimmunity

We report a 40 year old female referred for investigation of a possible primary immunodeficiency. She had an 18 month history of recurrent sino-pulmonary infections and bronchiectasis. She had been treated for pulmonary tuberculosis in early adulthood and also had a history of oral and vaginal candidiasis, oral herpes simplex and recurrent shingles. Postpartum Listeria sepsis complicated a previous pregnancy, and she had chronic hepatitis B infection requiring lamivudine and then tenofovir therapy. She also developed an acute illness with skin nodules and Mycobacterium haemophilum was isolated. She also had a past history of immunemediated thrombocytopaenic purpura, which had been managed by splenectomy. During follow up, she developed synovitis and rash, which was diagnosed as psoriatic arthritis, and was commenced on sulfasalazine. She exhibited short stature but no other dysmorphic features. Initial assessment revealed hypogammaglobulinaemia (IgG 5.7 g/L, IgA 0.43 g/L, normal IgM), with suboptimal antibody responses to pneumococcus and tetanus toxoid vaccinations. She had a lymphocytosis (6.34 × 109) with severe reduction of both switched and unswitched memory B cells and increased CD21-lo cells placing her in the Freiberg IA category of common variable immunodeficiency (CVID) with a predisposition to autoimmune presentations. She was subsequently commenced on intravenous immunoglobulin therapy. She was enrolled in the ANZADA study and underwent whole exome sequencing. We identified a heterozygous missense mutation in STAT3 that results in a methionine-to-threonine substitution at position 394 (M394T) in the DNA binding domain. This genotype confers a gain of function, which results in the autoimmunity, hypogammaglobulinaemia, and in some cases, lymphoproliferative disease. This case illustrates how complex phenotypes can be elucidated by whole exome sequencing.