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SynopsisLegius syndrome (also known as neurofibromatosis type 1 [NF1]-like syndrome) is an autosomal dominant genetic RASopathy caused by a mutation in the SPRED1 gene. Inactivating SPRED1 mutations at 15q14 lead to dysfunction of the Ras-MAPK signal transduction pathway, causing irregularities in cell division and differentiation.
Legius syndrome is a rare, likely underrecognized diagnosis with fewer than 200 cases reported in the literature. Up to 2% of diagnosed NF1 cases have been found to have SPRED1 mutations on genetic testing, increasing concerns for potential underdiagnosis.
Legius syndrome is classically characterized by the presence of multiple café au lait macules at birth or developing in childhood. Other common symptoms include axillary freckling, macrocephaly, dysmorphic facies, sternal abnormalities, attention deficit hyperactivity disorder (ADHD), and developmental delay. Patients tend to develop an increasing number of café au lait macules throughout childhood.
Legius syndrome is often misdiagnosed as NF1 due to the presence of multiple café au lait macules. However, Legius syndrome can be distinguished both by genetic testing and by the lack of classic neurofibromas, optic gliomas, or nerve sheath tumors.
Q85.01 – Neurofibromatosis, type 1
703541007 – Legius syndrome
Differential Diagnosis & PitfallsSelect conditions with café au lait macules:
- Neurofibromatosis type 1 (NF1) – Associated with optic gliomas, Lisch nodules, and neurofibromas. It is easier to distinguish later in life as these signs become more prevalent.
- Noonan syndrome with multiple lentigines (LEOPARD syndrome) – Associated with congenital heart defects and genital abnormalities.
- McCune-Albright syndrome – Associated with endocrinopathies and fibrous dysplasia. Typically, the café au lait macules in McCune-Albright syndrome are much larger and have "coast of Maine-like" borders.
- Noonan syndrome – Associated with congenital heart defects and optic abnormalities.