Hyper Ige Syndrome (Job's Syndrome)

Beatriz Morillo-Gutierrez
When facing a patient with elevated IgE levels, rash and infections, the differential diagnosis includes HIES but also other conditions such as:
• HIES: STAT3 deficiency and DOCK8 deficiency, and less often TYK2 deficiency or PGM3 deficiency
• Severe atopic dermatitis
• Netherton syndrome
• Wiskott-Aldrich syndrome
• Omenn’s syndrome
• Atypical DiGeorge syndrome
These other diseases are normally very characteristic and difficult to confuse; however, to simplify the clinical approach, the NIH developed a clinical score in 1999 for patients with elevated IgE, eczema and infections, originally intended for the diagnosis of STAT3 deficiency but also useful for DOCK8 deficiency patients depending of the values and cut-offs used. Later in 2010, Woellner et all proposed another diagnostic guidelines reviewing a cohort of 100 patients with HIES to establish the likelihood of AD-HIES with the following parameters:
• Possible: IgE > 1000 IU/mL plus a weighted score of clinical features >30 based on recurrent pneumonia, newborn rash, pathologic bone fractures, characteristic face, and high palate.
• Probable: These characteristics plus lack of TH17 cells or family history for definitive HIES.
• Definitive: These characteristics plus a dominant-negative heterozygous mutation in STAT3.
Ultimately, in the case of a patient presenting with clinical characteristics of HIES and suggestive score, genetic analysis directed to STAT3, DOCK8, TYK2 and PGM3 mutations or whole exome sequencing is strongly recommended to achieve the confirmation diagnosis, as the management and treatment can vary. Other immunological tests that could help to differentiate the specific conditions are:
Increased levels of IgE, often above 2000 IU/mL and peripheral eosinophilia. Mild neutropenia. Generally normal absolute lymphocyte counts, with decreased number of CD4+ Th17 and T and B memory lymphocytes. Normal levels of IgG and IgM with variable levels of IgA and specific vaccine responses.
Increased levels of IgE levels above 1000 IU/mL and peripheral eosinophilia. It is a combined immunodeficiency, with decreased levels of CD8 and CD4 cells that worsens over time and impaired proliferation and activation of CD8 T cells, together with decreased memory B cells. Increased population of Th2. Variable decrease in B and NK compartment. Elevation of IgG serum levels, decrease in IgM and variable level on IgA, with poor antibody specific responses.

Hyper Ige Syndrome (Job's Syndrome) Hyper Ige Syndrome (Job's Syndrome) 09/05/2018
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