Clinical Phenotypes of Hyper-IgM Syndromes

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Primary immunodeficiency (PID) diseases are inherited disorders affecting immune function.
• Advances in genomic sequencing have accelerated the discovery of genetic causes for PIDs.
• Hyper IgM (HIGM) syndromes are a subset of PIDs characterized by elevated IgM levels.

Purpose of the Study:

• To review immunodeficiency disorders associated with hyper IgM (HIGM).
• To provide a clinical differential diagnosis for HIGM syndromes.
• To compile information on clinical phenotypes, diagnostics, genetics, and therapeutics for HIGM.

Main Methods:

• Review of literature on HIGM syndromes.
• Compilation of clinical manifestations, immunologic testing, inheritance patterns, molecular diagnosis, pathogenesis, and OMIM numbers.
• Review of available therapeutic options.

Main Results:

• HIGM syndromes present with recurrent infections and characteristic immunoglobulin profiles (elevated IgM, low/absent other isotypes).
• These disorders stem from defects in immunoglobulin class switch recombination (CSR), often involving DNA repair machinery like mismatch repair (MMR).
• The review compiles detailed information for various congenital HIGM defects.

Conclusions:

• HIGM syndromes are mechanistically linked to defects in CSR and DNA repair pathways.
• Understanding the genetic basis and clinical phenotypes is crucial for diagnosis and management.
• This review serves as a comprehensive resource for clinicians and researchers investigating HIGM disorders.