Jornal de Imunologia Clínica e Celular
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Hyper IgM Syndromes: A Brief Review of the Pathogenesis, Clinical Features and Management

Prithivi Raaj Prakash, Gaurav Gupta*, Adarsh Aayilliath K, Sai Sashank, Sanjeev Sinha

Primary Immuno Deficiency (PID) disorders are heterogeneous disorders of the innate or the adaptive immune system, leading to recurrent infections that can also predispose to autoimmune diseases and malignancies. Hyper IgM Syndromes (HIGM) are rare disorders characterized by defective Class Switch Recombination (CSR) and/or Somatic Hypermutation (SHM) resulting in decreased levels of IgG, IgE and IgA antibodies and normal or elevated IgM levels. Various genetic defects have been identified to cause HIGM syndromes. These include intrinsic B cell defects or defects in the interaction between T and B cells, leading to a clinical phenotype of either pure humoral immunodeficiency or combined immunodeficiency respectively. HIGM syndromes with combined immunodeficiency present with recurrent opportunistic infections, notably Pneumocystis jiroveci and Cryptosporidium parvum infections, neutropenia and autoimmune complications, whereas the milder HIGM syndromes with humoral immunodeficiency are characterized by recurrent sinopulmonary and gastrointestinal infections with encapsulated bacteria. Patients with clinical suspicion of HIGM syndromes should undergo measurement of serum immunoglobulin levels followed by flow cytometry for lymphocyte subset analysis. Genetic testing is required for the final confirmation of all HIGM syndromes. Early identification and timely referral to the clinical immunologist for management is vital for the prevention of significant patient morbidity. Therapeutic options include immunoglobulin replacement therapy for the humoral immunodeficiency variants and Hematopoietic Cell Transplantation (HCT) for the more severe CD40 Ligand (CD40L) deficiency. This review aims to provide a concise clinical approach to PID disorders in general, followed by an overview of the pathogenesis, clinical features and management of various HIGM syndromes.