Harlequin syndrome: using clinical features and autonomic testing to unmask the disorder

Harlequin syndrome is a rare autonomic disorder characterized by unilateral facial flushing and contralateral anhidrosis. We sought to delineate underlying causes, clinical presentations, and autonomic testing profiles of patients with Harlequin syndrome.

Retrospective chart review was performed of the Mayo Clinic electronic health record for patients with a Harlequin syndrome diagnosis from 1998 to 2024. Clinical, laboratory, imaging, and autonomic function testing results, including autonomic reflex screen (ARS) and thermoregulatory sweat test (TST), were reviewed.

Of 51 patients with Harlequin syndrome, 39 (76%) were women. Median age of onset was 52 years (range 8-73 years). Harlequin syndrome was often idiopathic (N = 19; 37%), followed by postsurgical (N = 9; 17%), neoplasm (N = 5; 9.8%), trauma (N = 4; 7.8%), small fiber neuropathy (N = 4; 7.8%), systemic causes (N = 3; 5.9%), autoimmune (N = 3; 5.9%), pure autonomic failure (N = 2; 3.9%), and multiple sclerosis (N = 1; 2%). Pupil abnormalities were found in 13 patients (25.5%) with abnormal muscle stretch reflexes in 17 (33.3%). Headache was a comorbidity in 20 patients (39%). Of those with postsurgical onset, various surgeries preceded Harlequin syndrome onset, including heart, lung, and neck operations. Onset was acute or subacute in the majority of postsurgical patients (57%), while insidious onset was most common in nonsurgical patients (89%; p = 0.001). Median anhidrosis on TST was 9% (range 0.6-63%; N = 27). Median composite autonomic severity score was 1 (interquartile range (IQR) 0-3; N = 31).

Harlequin syndrome commonly has an insidious onset and occurs without an identifiable cause, which could be considered primary Harlequin syndrome. Secondary Harlequin syndrome can occur following surgeries in the vicinity of sympathetic pathways, which most commonly leads to an acute or subacute presentation.