Harlequin syndrome

Key Points at a Glance

Key Points at a Glance

• A rare autonomic syndrome characterized by unilateral facial anhidrosis and pallor on the affected side, with compensatory flushing and hyperhidrosis on the contralateral side, due to unilateral disruption of sympathetic innervation.
• First reported by Lance et al. in 1988, with approximately 100 cases reported in the literature.
• Idiopathic cases account for about 54.6% of all cases, while the remaining 45.4% are secondary or iatrogenic.
• Most common in women and in their 30s, with Horner syndrome complicating up to 46% of cases.
• In adults, idiopathic cases are common, but in children, secondary causes are more frequent, requiring active exclusion.
• Idiopathic cases are benign and self-limiting; observation is the mainstay. Treatment is considered only when symptoms affect social life.
• In secondary cases, treatment of the underlying cause (e.g., tumor resection, radiation therapy) is the top priority.

1. What is Harlequin syndrome?

Harlequin syndrome is an autonomic nervous system syndrome caused by unilateral dysfunction of the sympathetic nervous system. It is characterized by anhidrosis and vasoconstriction (pallor) on the affected side of the face and upper body, and compensatory sweating and flushing on the opposite side.

It was first reported by Lance and Drummond in 1988 ¹⁾. The name is derived from the red-and-black divided mask of “Harlequin,” a character from 16th-century Italian commedia dell’arte ⁶⁾. Note that this is completely different from harlequin ichthyosis (a severe genetic skin disorder) ⁶⁾.

The “Harlequin sign” refers to the physical finding of asymmetric facial flushing and sweating, while “Harlequin syndrome” is a concept used in a broader clinical context, including idiopathic and congenital cases ⁶⁾.

Epidemiology

Approximately 100 cases have been reported in the literature ¹⁾⁴⁾. According to a review of 108 cases by Guilloton et al., idiopathic cases account for 54.6%, and secondary/iatrogenic cases account for 45.4% ⁴⁾⁶⁾. Congenital cases are estimated to be about 6% of all cases ⁶⁾. It is most common in women and in the third decade of life ¹⁾, with only 37 pediatric cases reported ¹⁾. In newborns, it is relatively frequently observed due to functional immaturity of the hypothalamus ²⁾.

Q Is Harlequin syndrome the same disease as harlequin ichthyosis?

A

It is a completely different disease. Harlequin syndrome is an autonomic nervous system disorder caused by sympathetic nervous system dysfunction, while harlequin ichthyosis is a severe hereditary skin disease. Although the disease names are similar, the pathophysiology, symptoms, and treatment are entirely different⁶⁾.

2. Main Symptoms and Clinical Findings

Harlequin??????????

Markus Miedl, Philipp Baumgartner, Leah Raffaela Disse et al. Harlequin syndrome in a patient with probable hemicrania continua and exertional headache – is there a link? a case report. BMC Neurology. 2024 Jul 17; 24:247. Figure 1. PMCID: PMC11253322. License: CC BY.

???????????????????????????????????????Harlequin????????????????????????

Subjective Symptoms

Symptoms appear intermittently and may occur at rest without any trigger.

• Unilateral facial flushing and sweating: Occurs intermittently. Flushing is observed on the side opposite to the lesion (the healthy side)¹⁾.
• Triggering factors: Symptoms are triggered by exercise, emotional excitement, and heat¹⁾²⁾³⁾.
• Subjective symptoms when Horner syndrome is present: Patients may notice ptosis and miosis (difference in pupil size between the eyes).
• Social impact: Symptoms are easily noticed by others, which can cause psychological burden and social embarrassment¹⁾⁴⁾.

Clinical Findings

• Affected side (sympathetic nerve dysfunction side): Facial anhidrosis and vasoconstriction (pallor).
• Healthy side (unaffected side): Compensatory vasodilation and hyperhidrosis causing flushing and excessive sweating¹⁾⁶⁾.
• Boundary between sides: Clearly demarcated at the midline⁶⁾.
• Distribution: May extend beyond the face to the neck, chest, and upper limbs¹⁾²⁾. In newborns, it can involve half of the entire body²⁾.
• Association with Horner syndrome: Ptosis, miosis, and anhidrosis. In the literature, Horner syndrome was found in up to 46% of cases. Cases have been reported with flushing in the V1/V2 area combined with partial ptosis and miosis on the opposite side⁶⁾.

3. Causes and Risk Factors

The pathogenesis involves interruption of sympathetic innervation at the preganglionic or postganglionic level. Sympathetic function is lost on the affected side, while the contralateral side becomes compensatorily overactive, leading to asymmetric findings. Associations with migraine and trigeminal autonomic cephalalgias have also been reported¹⁾³⁾.

Idiopathic (54.6%)

Idiopathic: The most common type with unknown cause⁴⁾⁶⁾. Benign and tends to resolve spontaneously.

Congenital: Accounts for about 6% of cases. In neonates, hypothalamic immaturity is involved²⁾⁶⁾.

Secondary (45.4%)

Compressive lesions: Pancoast tumor, mediastinal tumor, thyroid goiter (reported with a 62×52×32 mm multinodular goiter), carotid artery dissection¹⁾³⁾⁶⁾

Iatrogenic: After sympathectomy, after anesthetic procedures (e.g., ESP block), after catheter placement¹⁾⁵⁾

Systemic diseases: Guillain-Barré syndrome, diabetic neuropathy, multiple sclerosis, brainstem infarction, syringomyelia¹⁾²⁾³⁾

In children, actively rule out secondary causes

In children, there are few reported cases of harlequin syndrome (only 37 cases), and the proportion of secondary causes is higher than in adults¹⁾²⁾. When suspected in children, it is important to actively search for tumors, neurological diseases, and vascular diseases.

Q After anesthesia, one side of the face turned red. Is this harlequin syndrome?

A

Diffusion of anesthetic into the paravertebral space can temporarily block the sympathetic nerve, causing harlequin-like findings. There is also a report of delayed onset (5 hours later) after a T2-level paravertebral block using liposomal bupivacaine⁵⁾. This iatrogenic case usually resolves spontaneously within 6 to 12 hours⁵⁾.

4. Diagnosis and examination methods

Diagnosis is primarily a clinical diagnosis based on characteristic clinical findings⁶⁾.

Provocation tests and functional tests

• Exercise and heat stress test: Symptoms are induced by exercise or heat to confirm findings⁶⁾.
• Iodine-starch (Minor) test: Useful for visualizing sweat distribution.
• Laser Doppler flowmetry and forehead temperature measurement: Quantitatively assess asymmetry in blood flow and temperature between sides.
• Pupillary test (Horner evaluation): Apraclonidine eye drops have a reported sensitivity of 88–100%.

Imaging tests

Imaging tests are important to rule out secondary causes.

• MRI (cervical spine to thoracic T2 level): Searches for lesions along the sympathetic pathway¹⁾²⁾.
• Carotid ultrasound and magnetic resonance angiography (MRA): Evaluation of carotid artery dissection and vascular lesions¹⁾.

Differential Diagnosis

Differentiation from the following diseases is necessary.

Disease	Key differentiating points
Ross syndrome	Triad of widespread anhidrosis, loss of deep tendon reflexes, and Adie’s pupil
Horner syndrome	Only miosis, ptosis, and anhidrosis. No compensatory contralateral flushing.
Holmes-Adie syndrome	Pupillary abnormality and loss of deep tendon reflexes are predominant

5. Standard treatment

Treatment strategy varies depending on the cause.

For secondary cases, treatment of the underlying disease is the highest priority⁶⁾. Idiopathic cases are benign and self-limiting, and most are managed with counseling and observation alone²⁾³⁾.

Symptomatic treatment (when symptoms affect social life)

Pharmacotherapy

Propranolol: A beta-blocker. Used to suppress sweating and flushing³⁾.

Oxybutynin: Anticholinergic drug. Expected to be effective for hyperhidrosis³⁾.

Procedures and Surgical Treatments

Botulinum toxin injection: Local administration to compensatory hyperhidrosis sites¹⁾.

Stellate ganglion block: Symptom relief via sympathetic nerve blockade¹⁾³⁾.

VATS sympathectomy: A 43-year-old female patient reported complete symptom resolution immediately after surgery, with no recurrence at 4 months⁴⁾.

• Iatrogenic (local anesthesia-related): Observation only. Spontaneous resolution within 6–12 hours⁵⁾.
• Compressive lesions (e.g., goiter): Symptoms may persist after surgical removal³⁾.

Precautions in Treatment

• Sympathectomy is a nerve-destructive irreversible procedure. Its indication should be carefully considered only when the disease burden is significantly severe.
• Symptoms may persist even after resection of compressive lesions such as goiter. Provide adequate counseling before surgery.

Q Does Harlequin syndrome require treatment?

A

Idiopathic cases are benign and tend to resolve spontaneously, so treatment is not always necessary²⁾³⁾. Only when social or psychological distress is significant, consider botulinum toxin injection, stellate ganglion block, or sympathectomy. In secondary cases, treatment of the underlying disease takes priority.

6. Pathophysiology and Detailed Mechanism

Harlequin syndrome is based on a disruption of the three-neuron pathway of sympathetic innervation to the face and trunk³⁾.

Three-Neuron Pathway

• First-order neuron (central): From the hypothalamus through the brainstem to the intermediolateral column of the spinal cord (C8–T3).
• Second-order neuron (preganglionic): The oculosympathetic fibers originate from T1, and the facial sudomotor and vasomotor fibers originate from T2–T3, traveling to the superior cervical ganglion.
• Third-order neuron (postganglionic): It innervates most of the face via the external carotid plexus and the medial forehead via the internal carotid plexus. The innervation of the cheek varies greatly among individuals³⁾.

Correlation between lesion site and clinical presentation

Whether Horner syndrome is present depends on the level of the sympathetic pathway affected by the lesion³⁾⁶⁾.

Lesion site	Horner syndrome present	Clinical features
T1–T3 (oculosympathetic + sudomotor/vasomotor) lesion	Yes	Harlequin syndrome + Horner syndrome
T2 to T3 only impairment	None	Harlequin syndrome alone
Postganglionic lesion after superior cervical ganglion	Present (medial forehead anhidrosis)	Other facial areas may be spared

Compensatory mechanisms

When the sympathetic nerve on the affected side is blocked, sympathetic activity on the healthy side relatively increases, leading to compensatory flushing and hyperhidrosis¹⁾⁶⁾. The asymmetric findings along the midline are due to this mechanism. The possibility of reinnervation by parasympathetic nerves has also been suggested in some cases³⁾.

Q Why does only one side become red?

A

Loss of sympathetic nerve function on the affected side releases inhibition of vasodilation and sweating on that side. Meanwhile, the unaffected side exhibits relative sympathetic hyperactivity, resulting in compensatory flushing and hyperhidrosis¹⁾⁶⁾. The clear left-right difference at the midline reflects this asymmetric sympathetic activity.

---

7. Latest Research and Future Perspectives (Investigational Reports)

For patients: Please read this

The following content is currently under investigation or in clinical trials and is not standard treatment available at general hospitals. This is reference information for professionals regarding future medical developments.

Efficacy of VATS Sympathectomy

Tecik et al. (2025) reported performing VATS (video-assisted thoracoscopic) sympathectomy on a 43-year-old woman with idiopathic Harlequin syndrome persisting for 5 years, resulting in complete resolution of symptoms immediately after surgery with no recurrence at 4 months follow-up⁴⁾. A review by Guilloton et al. found that 54.6% of cases were idiopathic⁴⁾⁶⁾, suggesting the existence of a candidate group for surgical treatment.

Delayed Onset of Iatrogenic Harlequin Syndrome

Dalldorf et al. (2022) reported the first case of Harlequin syndrome occurring with a 5-hour delay after a T2-level erector spinae plane block (ESP block: liposomal bupivacaine 133 mg + 0.25% bupivacaine 20 mL each side)⁵⁾. This is the first report of delayed onset of local anesthetic-related iatrogenic Harlequin syndrome, which typically occurs within 1 hour, and is thought to be a characteristic onset pattern of sustained-release formulations (duration approximately 72 hours). The symptoms resolved spontaneously by the next morning.

Residual Symptoms After Treatment of the Primary Disease

Strong et al. (2025) reported a case of secondary Harlequin syndrome (49-year-old female) due to a 62×52×32 mm multinodular goiter, in which total thyroidectomy was performed, but symptoms persisted for about 1 year postoperatively³⁾. This finding is noteworthy as it suggests that chronic changes in the sympathetic pathway may become irreversible even after removal of a compressive lesion.

---

8. References

1. Korbi M, Boumaiza S, Achour A, Belhadjali H, Zili J. Harlequin syndrome: An asymmetric face. Clin Case Rep. 2022;10:e05833.
2. Sousa Dias M, Meneses M, Barroca Macedo R, Soares S. Harlequin syndrome in children: secondary until proven otherwise. BMJ Case Rep. 2023;16:e257719.
3. Strong A, Tu J, Kyi S, Wijeratne T. Harlequin Syndrome Caused by Multinodular Goitre. Cureus. 2025;17(3):e81298.
4. Tecik Z, Turker S, Caliskan E, Gençö O, Işık H, Yurekli A. Unmasking the Harlequin syndrome: A clinical transformation. JAAD Case Rep. 2025;63:17-18.
5. Dalldorf DA, Hart A, Grant SA, Teeter EG. Harlequin Syndrome Following Regional Liposomal Bupivacaine Use in a Partial Sternectomy. Cureus. 2022;14(8):e28005.
6. Li Y, Moon DJ, Linden KG. Harlequin sign associated with Horner syndrome secondary to an 11 cm left upper lung lobe adenocarcinoma. JAAD Case Rep. 2024;43:83-86.