Neurological features of Noonan syndrome and related RASopathies: Pain and nerve enlargement characterized by nerve ultrasound.

This study aimed to assess the nature of peripheral nervous system (PNS) involvement in three patients with Noonan syndrome (NS) or NS with multiple lentigines (NSML) as a related RASopathy, presenting primary with intractable neuropathic pain. We studied three unrelated adult patients with severe neuropathic pain and muscle weakness of the limbs. Nerve conduction studies and needle electromyography (EMG) were performed and PNS involvement was assessed by nerve ultrasound imaging, complemented with spinal magnetic resonance imaging (MRI) for the evaluation of proximal nerve segments. Targeted whole-exome sequencing analysis was performed when the diagnosis of NS was suspected. Two patients showed a PTPN11-related dominant and one a LZTR1-related recessive NS or NSML phenotype. The nature of PNS involvement was documented using nerve ultrasound and MRI, showing generalized or multifocal thickening of nerve roots, plexuses and peripheral nerves in all three patients. Nerve imaging using ultrasound and MRI aids in further detailing the nature of neuropathic pain and nerve hypertrophy in patients with NS. This study underlines the relevance of nerve ultrasound in neuropathies and pain syndromes. A NS diagnosis should not be overlooked in longstanding, unexplained neuropathic pain syndromes, with or without muscular weakness. Nerve ultrasound studies can help raise the suspicion for this relatively prevalent inherited multisystem disorder, which is still rather unknown among neurologists, particularly when other potential syndromic features are inconspicuous.