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.