An 11-year-old girl presented to the epilepsy clinic. She was the first child of non-consanguineous parents, born at term with a history of placental abruption at 22 weeks gestational age. Family history was positive for neurofibromatosis (mother) and febrile convulsions (maternal uncle). At 11 months of age, she had febrile convulsions (10–12 episodes) with normal EEG. Her first afebrile seizure started at 5 years old and was characterized by gaze fixation, loss of consciousness, facial redness, and bilateral clonic jerking of limbs and eyelids. A seizure cluster (5 events) required rescue treatment in the emergency department. EEG at that time showed left temporo-­occipital slowing and spikes during both sleep and wake states.

At 6 years of age, she presented with recurrent focal seizures of possible left posterior onset. Carbamazepine therapy was initiated. Due to persistence of focal seizures at follow-up, clobazan was added for better seizure control. She also received a diagnosis of attention deficit/hyperactivity disorder (ADHD).

Dermatology evaluation performed at 9 years of age detected facial plexiform neurofibroma, right lower limb neurofibroma, multiple café-au-lait spots of varying sizes ( Fig. 57.1A ), axillary and inguinal freckling ( Fig. 57.1B ). Ophthalmologic evaluation showed iris Lisch nodules ( Fig. 57.1C ).

Neurofibromatosis type 1. (A) Cafè-au-lait spots, (B) axillary freckling, and (C) Lisch nodules.

Genetic testing showed the heterozygous pathogenic mutations c.7949dupT and p.Leu2650PhefsTer22 in NF1 gene.

Brain MRI at 5 years of age showed multiple T2/fluid attenuated inversion recovery (FLAIR) hyperintense nonenhancing foci, most prominent in the bilateral basal ganglia. These gradually resolved on follow-up MRIs ( Fig. 57.2 ).

Neurofibromatosis type 1. Brain MRI, axial T2 at (A) 5 years shows multifocal hyperintensities in the bilateral basal ganglia compatible with dysmyelination ( arrows ), with (B) partial involution and remyelination at 10 years.

An optic pathway glioma was present with expansion and signal abnormality of the anterior optic pathway ( Fig. 57.3 ).

Neurofibromatosis type 1. Brain MRI, axial postcontrast T1 shows optic pathway glioma with expansile heterogeneously enhancing infiltration of the optic pathway ( arrowheads ).

At 7 years of age, face/neck MRI showed transspatial plexiform neurofibromas involving the left perivertebral muscles and pterygopalatine fossa ( Fig. 57.4 ).

Neurofibromatosis type 1. Brain MRI, axial T2 shows transspatial plexiform neurofibromas with multilocular targetoid lesions in the left perivertebral muscles ( circle ) and left pterygopalatine fossa ( arrow ).

Multisystem disorders with café-au-lait spots include various RASopathies such as neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), Noonan syndrome, Noonan syndrome with multiple lentigines (LEOPARD), and Legius syndrome. In NF1, the café-­au-lait spots have a smooth “coast of California” morphology. In NF2, patients demonstrate multiple schwannomas, meningiomas, and ependymomas (MISME), and juvenile posterior subcapsular cataracts. Noonan and LEOPARD syndromes often present with congenital heart disease, deafness, and more severe craniofacial anomalies. In Legius syndrome, the café-au-lait spots appear similar to NF1, but Lisch nodules and neurofibromas are absent. In McCune-Albright syndrome, caused by somatic mutations of GNAS1 , café-au-lait spots tend to have more irregular margins (“coast of Maine”).