Hyper IgE Syndrome: A Diagnostic Dilemma

By: Zam Zureena Binti Mohd Rani (zzmr_242153@yahoo.com)

Hyper IgE Syndrome (HIES) is a rare primary immunodeficiency disorder characterized by recurrent staphylococcal skin abscesses, recurrent lung infections, eczema, pulmonary infection, eosinophilia and high serum IgE levels. Most cases of HIES are sporadic, but some familial cases of HIES have been reported, with either an autosomal dominant HIES (AD-HIES) or autosomal recessive HIES (AR-HIES) mode of inheritance. Most AD-HIES are caused by genetic mutations in the STAT3 gene and is associated with connective tissue, skeletal, vascular and dental abnormalities. AR-HIES are rare combined immunodeficiencies where susceptibilities to viral infection, atopic eczema have been described.  AR-HIES has been shown to be mainly caused by mutations in DOCK8 (Dedicator of cytokinesis 8), the other being TYK2 deficiency (tyrosine kinase 2 deficiency)  and recently Phosphoglucomutase 3 (PGM3) deficiency.

The patient of this study presented with current infection since early infancy. He had elevated IgE level, T cell-NK lymphopenia and selective IgM deficiency consistent with AR-HIES. Other than that, he has pneumonia, atopy, T cell, CD4/CD8 lymphopenia, selective hypo IgM and elevated serum IgE, making AR-HIES a more tenable diagnosis. He had no coarse facies, eczema or pneumonia with pneumotocele to suggest AD-HIES. Instead of being infected with S. aureus (AD-HIES), he is afflicted with mycobacterial infection. Microscopy for AFB was positive on 2 occasions.

DOCK8 deficiency is one of the most common cause of AR-HIES, however, tuberculosis infection was not known to be associated with this genetic defect. Disseminated BCG infection had been described in patients withTyrosine Kinase 2 (TYK2) deficiency. escortannonce.net It is highly probable that TYK2 deficiency is the cause of AR-HIES in this patient. Phosphoglucomutase 3 (PGM3) deficiency may be another cause of AR-HIES. Mutational analysis by exome sequencing may reveal the answer of this diagnostic dilemma.