Human hyper-IgE syndrome: singular or plural?

Area of Science:

• Immunology
• Genetics
• Clinical Medicine

Background:

• Human hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by atopy, high serum IgE, recurrent infections, and developmental issues.
• Historically, autosomal dominant (AD) STAT3 deficiency, autosomal recessive (AR) DOCK8 deficiency, and AR PGM3 deficiency have been associated with HIES.
• These conditions affect different molecular pathways and present with varying clinical manifestations, complicating the definition of HIES.

Purpose of the Study:

• To review the history and characterization of HIES over the past 50 years.
• To critically evaluate the disorders currently included under the HIES umbrella.
• To propose a refined definition of HIES based on distinct molecular and clinical phenotypes.

Main Methods:

• Review of historical clinical descriptions and scientific literature on HIES.
• Analysis of molecular pathways, cell types, and clinical phenotypes associated with STAT3, DOCK8, and PGM3 deficiencies.
• Examination of available mouse models for STAT3, DOCK8, and PGM3 deficiencies and their utility in studying HIES-related aspects.

Main Results:

• AD STAT3 deficiency aligns with the original HIES definition.
• AR DOCK8 and PGM3 deficiencies present with overlapping but distinct features, not fully matching the typical HIES phenotype.
• Mouse models have limitations in recapitulating the full spectrum of HIES, particularly the high IgE phenotype, except for specific Stat3 mutant strains.

Conclusions:

• The term HIES should be restricted to AD STAT3 deficiency and the recently described AR ZNF341 deficiency.
• AR DOCK8 and PGM3 deficiencies, while causing immune dysregulation with high IgE, should be considered distinct entities.
• This redefinition clarifies the nosology of primary immunodeficiencies and guides future research and clinical management.