Differential diagnosis of multiple Café-au-lait macules in the context of clinical presentation and genetic background

Abstract

Café-au-lait macules (CALMs) are common hyperpigmented macules that can present in solitary or multiple forms. Approximately 2-3% of healthy newborns are affected by café-au-lait spots; however, their multiplex appearance may indicate an underlying genetic syndrome. The authors provide a comprehensive overview of the differential diagnosis of café-au-lait macules (CALMs) and their associated conditions, including the clinical features and genetic background of each syndrome. Among the discussed conditions are RASopathies, including neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), Legius syndrome, Noonan syndrome, Noonan syndrome with multiple lentigines (LEOPARD syndrome), Costello syndrome, and Watson syndrome. Furthermore, the review includes phakomatoses such as tuberous sclerosis and McCune-Albright syndrome, alongside constitutional mismatch repair deficiency syndrome (CMMRD) and other syndromes that exhibit a weaker association with CALMs. The publication emphasizes the importance of a multidisciplinary approach for patients presenting with multiple CALMs, as well as highlights the significance of early diagnosis and genetic counseling for establishing an appropriate therapeutic plan and improving prognosis.