Introduction
The non-receptor tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family consisting of three additional members (JAK1-3). Cytokine binding to respective receptor complexes (type I or type II) activates JAKs, which subsequently phosphorylate intracellular receptor chain residues and activate a family of transcription factors termed signal transducers and activators of transcription (STATs, comprised of STAT1-4, STAT5A, STAT5B and STAT6) [1].
Within the JAK-STAT family of proteins, several primary immunodeficiencies have been described, ranging from autosomal recessive severe combined immunodeficiency (AR-SCID) in the case of JAK3 mutations, over a moderately severe phenotype in the case of autosomal dominant Hyper-IgE syndrome (AD-HIES) involving STAT3 mutations, into a heterogeneous clinical presentation in STAT1 deficiency with autosomal recessive Mendelian susceptibility to mycobacterial disease (AR-MSMD), and finally to a relatively mild phenotype in the case of TYK2 deficiency [2].
To date, there are 13 cases in total in English literature[3-8]. The first TYK2-deficiency patient was reported in 2006, a 22-years-old male Japanese, who displayed BCG lymphadenitis, S. aureus infections and recurrent viral infection, which were attributed to almost abolished responses of patient’s cells to IL-23, IL-12 and type I interferon (type I IFN) treatment, respectively [3]. Most interestingly, he also presented with the triad of signs characteristic of HIES: atopic dermatitis, high circulating IgE levels, and recurrent cutaneous staphylococcal infections, which led to the proposal that TYK2-deficiency should be a subset of AR-HIES. However, this notion was challenged lately by a comprehensive study of seven TYK2-deficiency patients showing normal IgE levels and absent of atopic dermatitis or cutaneous staphylococcal infection [4]. Later on, both HIES-like and non-HIES TYK2-deficiency cases were reported[5-8] and more confusingly, it has been shown identical TYK2 mutation can result in both HIES-like and non-HIES phenotypes [5,7]. Thus, more cases and further investigations are required to fully understand the nature of TYK2-deficiency.
Here, we present five cases of TYK2-deficiency with novel mutations from five unrelated Chinese families. Briefly, a 2+-yr-old boy (P1) suffered from repeated pneumonia, stomatitis, perilabial herpes and thrush since the age of 3 months; a 3-yrs-old boy (P2) suffered from recurrent respiratory tract infections and diarrhea since the age of 6 months; a 10-yrs-old girl (P3) suffered from recurrent respiratory infection since 2 years old and she had a history of refractory eczema; a 5-yrs-old boy (P4) suffered from recurrent suppurative otitis media and severe pneumonia and he also had a history of eczema and was highly allergic; a 5-yrs-old boy (P5) suffered from recurrent pneumonia and refractory eczema and he also displayed hypothyroidism. By investigating these cases and comparing with previously reported cases, we aim to uncover a more complete picture of TYK2 deficiency.