The clinical and molecular spectrum of monogenic eczema

Eczematous dermatitis is a hallmark of numerous primary atopic disorders (PADs), often serving as the initial clinical presentation for complex underlying inborn errors of immunity. While common atopic dermatitis (AD) is largely considered polygenic and multifactorial, the identification of monogenic causes of atopy has revolutionized our understanding of the immune pathways governing skin barrier integrity and T2-mediated inflammation. This article examines the various genetic clusters, ranging from JAK/STAT signaling defects and cytoskeletal actinopathies to primary skin barrier protein deficiencies and metabolic disorders, that manifest as severe, persistent eczema. We highlight the diagnostic “red flags” that differentiate these monogenic conditions from common atopic dermatitis discuss the therapeutic implications of identifying specific molecular drivers, moving toward a new era of precision medicine.