Autosomal-recessive (AR) HIES was described in 2004 due to mutation of tyrosine kinase 2 gene, and subsequently, another mutation in dedicator of cytokinesis 8 gene was discovered in 2009.
The leukocytes and fibroblasts of all seven newly identified TYK2-deficient patients, unlike those of P1, responded normally to IL-6, possibly accounting for the lack of HIES in these patients.
A single case of homozygous deficiency of the signal protein Tyk2 has been reported as well as a recessive syndrome with some features overlapping AD-HIES, but for which the genetic etiology is unknown.
A striking phenotype associated with inactivating Jak3 mutations is severe combined immunodeficiency syndrome, whereas mutation of Tyk2 results in another primary immunodeficiency termed autosomal recessive hyperimmunoglobulin E syndrome.
Recent studies have demonstrated that hypomorphic mutations in signal transducer and activator of transcription 3 result in the classical multisystem form of HIES, whereas a null mutation in tyrosine kinase 2 causes the autosomal recessive form of HIES that is associated with viral and mycobacterial infections.
We recently identified hypomorphic mutations in the signal transducer and activator of transcription 3 (STAT3) gene in type 1 HIES and a null mutation in the tyrosine kinase 2 (Tyk2) gene, accompanied by susceptibility to intracellular bacteria in type 2 HIES.
We recently identified a homozygous four base-pair deletion in the coding region of the tyrosine kinase 2 gene in a hyperimmunoglobulin E syndrome patient who exhibited susceptibility to intracellular bacteria.