Legius Syndrome, Other Café-au-lait Diseases and Differential Diagnosis of NF1

Legius syndrome is characterized by the presence of multiple cafe-au-lait macules (CALMs), axillary freckling, macrocephaly and clinically overlaps with neurofibromatosis type 1 (NF1). However, Legius syndrome patients show a milder phenotype with tumoral complications systematically absent. Inactivating SPRED1 mutations were identified in Legius syndrome. SPRED1 interacts with neurofibromin and both proteins are negative regulators of the RAS-MAPK pathway. Constitutive Mismatch Repair Deficiency (CMMRD) is a differential diagnosis of NF1. CMMRD patients show in addition to multiple CALMs supplementary clinical features of NF1. Similar NF1 syndromes with CALMs are piebaldism, neurofibromatosis type 2, schwannomatosis, Noonan syndrome with multiple lentigines, McCune-Albright syndrome, and isolated cafe-au-lait spots. Differential diagnoses of NF1 are infantile myofibromatosis, Proteus syndrome, orbital neurofibromas, hyaline fibromatosis syndrome, and hybrid nerve sheath tumors.