Summary Children with moderate-severe atopic dermatitis and food allergy (especially milk) exhibit reduced weight and height, while those with atopic dermatitis alone are often overweight or obese, and their body mass index correlates with eczema severity.

Antibody production and function represent an essential part of the immune response, particularly in fighting bacterial and viral infections. Multiple immunological phenotypes can result in dysregulation of the immune system humoral compartment, including class-switch recombination (CSR) defects associated with hyper-IgM (HIGM) syndromes. The CSR/HIGM syndromes are defined by the presence of normal or elevated plasma IgM levels in the context of low levels of switched IgG, IgA, and IgE isotypes. Recently described autosomal dominant gain-of-function (GOF) mutations in PIK3CD and PIK3R1 cause combined immunodeficiencies that can also present as CSR/HIGM defects. These defects, their pathophysiology and derived clinical manifestations are described in depth. Previously reported forms of CSR/HIGM syndromes are briefly reviewed and compared to the phosphoinositide 3-kinase (PI3K) pathway defects. Diseases involving the PI3K pathway represent a distinctive subset of CSR/HIGM syndromes, presenting with their own characteristic clinical and laboratory attributes as well as individual therapeutic approaches.

With the identification of gain-of-function mutations as a cause of immunodeficiency, new genetic pathophysiology mechanisms unveiled and new-targeted therapeutic approaches can be explored as potential rescue treatments for these diseases.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflict of Interest M.P. Borres and J. Jones are employees of Thermo Fisher Scientific (Uppsala, Sweden). P.A. Frischmeyer-Guerrerio has received material from Thermo Fisher to perform the IgE analyses in this project. The other authors have indicated they have no potential conflicts of interest to disclose.