Dermatologic Therapy, Vol. 27, 2014, 230–232 Printed in the United States · All rights reserved
© 2014 Wiley Periodicals, Inc.
DERMATOLOGIC THERAPY ISSN 1396-0296
THERAPEUTIC HOTLINE Intractable vascular autonomic dysregulation (Harlequin phenomenon) in two brothers: another indication for propranolol? S. R. Janmohamed*†‡, G. C. Madern*#, P. C. J. de Laat§# & A. P. Oranje†‡¶# *Department of Pediatric Surgery, †Division of Pediatric Dermatology, Department of Pediatrics, §Department of Pediatrics, Erasmus MC, University Medical Center, ‡KinderHaven, Havenziekenhuis and ¶Department of Dermatology, Maasstad Ziekenhuis, Rotterdam, The Netherlands
ABSTRACT: Vascular autonomic dysregulation, in the most extreme presentation known as Harlequin phenomenon, is a rare condition. It manifests as a sudden and brief paroxystic change in skin color, resulting in two different colors on the body. It is supposed that this condition occurs due to a vasomotor instability. This again is caused by sympathetic disautonomy, which is a consequence of hypothalamic peripheral vascular tone control immaturity in the newborn. Typically, there is spontaneous regression. We describe two brothers who both had this condition in their first life years. Clinical symptoms included frequent attacks of discoloration of extremities (up to four times per day) accompanied with terrifying crying fits, interpreted by the parents as pain. These patients were treated with propranolol, a nonselective beta-blocker, resulting in improvement of symptoms: only occasional attacks were seen. Beta-blockers act on β1-adrenoceptors in the heart, thereby preventing the positive chronotropic and inotropic effects mediated by these receptors. We hypothesize that propranolol, which is very lipophilic and therefore also acts on β-receptors of the central nervous system, acts on the sympathetic system. KEYWORDS: beta-blocker, Harlequin phenomenon, propranolol, therapy, vascular autonomic dysregulation
Address correspondence and reprint requests to: Arnold P. Oranje, MD, PhD, Pediatric Dermatologist, Division of Pediatric Dermatology, Department of Pediatrics, Erasmus MC – Sophia Children’s Hospital, P.O. Box 2060, 3000 CB – Rotterdam, The Netherlands, or email: [email protected]. # WEVAR team = workgroup on vascular abnormalities Rotterdam (multidisciplinary patient consultation group).
230
Introduction Vascular autonomic dysregulation, a sudden paroxystic change in skin color in one part of the body resulting in two different colors on the body, is a rare condition (1). In its most extreme presentation it is known as Harlequin phenomenon (HP).
Propranolol for vascular autonomic dysregulation
In the neonatal period it is benign and because of spontaneous regression, treatment is usually not necessary. We propose that propranolol, a nonselective beta-blocker mainly used to reduce high blood pressure, may be an effective therapy. Betablockers act on β1-adrenoceptors in the heart, thereby preventing the positive chronotropic and inotropic effects mediated by these receptors. Nonselective beta-blockers will also antagonize the vasorelaxant effect that occurs following stimulation of vascular β2-adrenoceptors. An increase in peripheral vascular resistance will occur both due to the direct vascular effects of propranolol and to activation of the baroreceptor reflex (2). Today, propranolol is also given in a very different field: in 2008 it was discovered that propranolol also inhibits the growth of infantile hemangiomas and speeds up regression (3). It is hypothesized that propranolol works in an early stage due to vasoconstriction, and later on by blocking of proangiogenic signals and even apoptosis (4). This study examines the successful use of propranolol in the treatment of two brothers with HP.
FIG. 1. Typical changes in a part of the skin during an episode of vascular autonomic dysregulation.
Case 1 We present a 3-month-old boy, referred to us by a peripheral hospital because of discoloration of arms and legs with unknown cause (see FIG. 1). The boy was otherwise healthy. Pregnancy and delivery were normal. Discoloration had started at the age of 2 months with three to four episodes per day often involving both lower legs and sometimes one or both arms, accompanied with pain (as evidenced by screaming and terrifying crying fits). Skin color changed from normal to livid (cutis marmorata like) and eventually into blue-purple. Episodes lasted for 5–15 minutes and no underlying cause was found. After the episodes the screaming stopped. It seemed progressive as frequency and duration increased over time. This phenomenon was objectified during hospitalization, and physical examination during episodes was otherwise normal. Furthermore, laboratory examination of blood and urine, radiologic examination (ultrasound of legs and heart, computed tomography of vascular system in legs and arms) and electrocardiogram were all normal. Ultimately, we attributed these complaints to a vasovagal reflex: vascular autonomic dysregulation. Considering the pain involved, we started propranolol at a test dosage of 1 mg/kg/day (in three times, i.e., 3 dd 0.33 mg/kg) in order to decrease the episodes and therefore the pain. We checked pulsations, an elec-
trocardiogram was performed and blood pressure and glucose were measured (all normal). There were fewer episodes (one to two per day), and we elevated the dosage to 1.5 mg/kg/day (in three times, i.e., 3 dd 0.50 mg/kg). With this dosage, only occasional attacks were seen (maximum one per month). At follow-up monitoring included measurements of blood pressure and glucose. Pulsations were checked as part of the physical examination. After 9 months, propranolol was tapered off (the dosage was not adjusted anymore for increasing weight of the child) and after 1 year it was stopped; episodes were not seen anymore.
Case 2 Two years later we saw his little brother with the same symptoms, also since the age of 2 months. However, he had fewer (one to two per day) but longer lasting (10–20 minutes) incidents. He also suffered from pain during the incidents, just like his older brother did. We did a full check up and made the same diagnosis as in the case of the older brother. We also started with propranolol, now in a dosage of 2 mg/kg/day in three times per day. This did not seem to have a great effect, and therefore we raised the dosage to 2.67 mg/kg/day in four times per day, after which only occasionally attacks
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were seen. The dosage was then lowered back to 2 mg/kg/day and gradually tapered off. Monitoring while on propranolol therapy and tapering was consistent with the previous case. Propranolol was stopped after 1 year and no incidents were seen anymore.
Discussion In 1952, Neligan and Strang first described a bizarre vasomotor manifestation in the neonatal period which they named “Harlequin color change” (5). It is a sudden and brief paroxystic change in skin color, resulting in a body with two skin colors: erythematous and pale. The normal skin color may change into both red and blue. It can be seen in just one extremity but up to half of the body may be involved. It also occurs beyond the neonatal period, even in older children or adults. The precise incidence is unknown; case reports suggest it may occur in up to 10% of newborns. The duration of HP can be anything from 30 seconds up to 20 minutes, with one or many episodes in a week. Despite the fact that we saw this phenomenon in two brothers, there are no genetic influences described in the literature. Eliciting factors may be pain, anesthesia, exercise, emotions, or autonomic seizures. In most patients, therapy is not necessary because HP is benign and goes away after a while (1). In our cases, however, the parents noted the children were in extreme pain during the episodes leading to much distress in the parents. This is not a common symptom of HP but in our cases we had to intervene. To our knowledge, there are no reported cases in the literature of HP treated with propranolol. With propranolol treatment, the number and duration of episodes immediately
232
declined dramatically, but we could not stop them completely. We continued propranolol for almost 1 year and then tapered it off (the dose was not adjusted with increasing weight). It is normal for HP to go in regression. Our dosage was relatively low and comparable with the dosage nowadays used in the treatment of infantile hemangioma (2–3 mg/kg daily). We hypothesize that propranolol, which is very lipophilic and therefore also acts on β-receptors of the central nervous system, acts on the sympathetic system. HP occurs due to vasomotor instability caused by sympathetic disautonomy, which is a consequence of hypothalamic peripheral vascular tone control immaturity in the newborn.
Funding None declared.
Conflict of interests None declared.
References 1. Januario G, Salgado M. The Harlequin phenomenon. J Eur Acad Dermatol Venereol 2011: 25: 1381–1384. 2. Rang HP, Dale MM, Ritter JM, Flower R, Henderson G. Rang & Dale’s pharmacology. Philadelphia: Elsevier Health Sciences, 2011. 3. Leaute-Labreze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taieb A. Propranolol for severe hemangiomas of infancy. N Engl J Med 2008: 358: 2649–2651. 4. Storch CH, Hoeger PH. Propranolol for infantile haemangiomas: insights into the molecular mechanisms of action. Br J Dermatol 2010: 163: 269–274. 5. Neligan GA, Strang LB. A “harlequin” colour change in the newborn. Lancet 1952: 2: 1005–1007.
© 2014 Wiley Periodicals, Inc.
DERMATOLOGIC THERAPY ISSN 1396-0296
THERAPEUTIC HOTLINE Intractable vascular autonomic dysregulation (Harlequin phenomenon) in two brothers: another indication for propranolol? S. R. Janmohamed*†‡, G. C. Madern*#, P. C. J. de Laat§# & A. P. Oranje†‡¶# *Department of Pediatric Surgery, †Division of Pediatric Dermatology, Department of Pediatrics, §Department of Pediatrics, Erasmus MC, University Medical Center, ‡KinderHaven, Havenziekenhuis and ¶Department of Dermatology, Maasstad Ziekenhuis, Rotterdam, The Netherlands
ABSTRACT: Vascular autonomic dysregulation, in the most extreme presentation known as Harlequin phenomenon, is a rare condition. It manifests as a sudden and brief paroxystic change in skin color, resulting in two different colors on the body. It is supposed that this condition occurs due to a vasomotor instability. This again is caused by sympathetic disautonomy, which is a consequence of hypothalamic peripheral vascular tone control immaturity in the newborn. Typically, there is spontaneous regression. We describe two brothers who both had this condition in their first life years. Clinical symptoms included frequent attacks of discoloration of extremities (up to four times per day) accompanied with terrifying crying fits, interpreted by the parents as pain. These patients were treated with propranolol, a nonselective beta-blocker, resulting in improvement of symptoms: only occasional attacks were seen. Beta-blockers act on β1-adrenoceptors in the heart, thereby preventing the positive chronotropic and inotropic effects mediated by these receptors. We hypothesize that propranolol, which is very lipophilic and therefore also acts on β-receptors of the central nervous system, acts on the sympathetic system. KEYWORDS: beta-blocker, Harlequin phenomenon, propranolol, therapy, vascular autonomic dysregulation
Address correspondence and reprint requests to: Arnold P. Oranje, MD, PhD, Pediatric Dermatologist, Division of Pediatric Dermatology, Department of Pediatrics, Erasmus MC – Sophia Children’s Hospital, P.O. Box 2060, 3000 CB – Rotterdam, The Netherlands, or email: [email protected]. # WEVAR team = workgroup on vascular abnormalities Rotterdam (multidisciplinary patient consultation group).
230
Introduction Vascular autonomic dysregulation, a sudden paroxystic change in skin color in one part of the body resulting in two different colors on the body, is a rare condition (1). In its most extreme presentation it is known as Harlequin phenomenon (HP).
Propranolol for vascular autonomic dysregulation
In the neonatal period it is benign and because of spontaneous regression, treatment is usually not necessary. We propose that propranolol, a nonselective beta-blocker mainly used to reduce high blood pressure, may be an effective therapy. Betablockers act on β1-adrenoceptors in the heart, thereby preventing the positive chronotropic and inotropic effects mediated by these receptors. Nonselective beta-blockers will also antagonize the vasorelaxant effect that occurs following stimulation of vascular β2-adrenoceptors. An increase in peripheral vascular resistance will occur both due to the direct vascular effects of propranolol and to activation of the baroreceptor reflex (2). Today, propranolol is also given in a very different field: in 2008 it was discovered that propranolol also inhibits the growth of infantile hemangiomas and speeds up regression (3). It is hypothesized that propranolol works in an early stage due to vasoconstriction, and later on by blocking of proangiogenic signals and even apoptosis (4). This study examines the successful use of propranolol in the treatment of two brothers with HP.
FIG. 1. Typical changes in a part of the skin during an episode of vascular autonomic dysregulation.
Case 1 We present a 3-month-old boy, referred to us by a peripheral hospital because of discoloration of arms and legs with unknown cause (see FIG. 1). The boy was otherwise healthy. Pregnancy and delivery were normal. Discoloration had started at the age of 2 months with three to four episodes per day often involving both lower legs and sometimes one or both arms, accompanied with pain (as evidenced by screaming and terrifying crying fits). Skin color changed from normal to livid (cutis marmorata like) and eventually into blue-purple. Episodes lasted for 5–15 minutes and no underlying cause was found. After the episodes the screaming stopped. It seemed progressive as frequency and duration increased over time. This phenomenon was objectified during hospitalization, and physical examination during episodes was otherwise normal. Furthermore, laboratory examination of blood and urine, radiologic examination (ultrasound of legs and heart, computed tomography of vascular system in legs and arms) and electrocardiogram were all normal. Ultimately, we attributed these complaints to a vasovagal reflex: vascular autonomic dysregulation. Considering the pain involved, we started propranolol at a test dosage of 1 mg/kg/day (in three times, i.e., 3 dd 0.33 mg/kg) in order to decrease the episodes and therefore the pain. We checked pulsations, an elec-
trocardiogram was performed and blood pressure and glucose were measured (all normal). There were fewer episodes (one to two per day), and we elevated the dosage to 1.5 mg/kg/day (in three times, i.e., 3 dd 0.50 mg/kg). With this dosage, only occasional attacks were seen (maximum one per month). At follow-up monitoring included measurements of blood pressure and glucose. Pulsations were checked as part of the physical examination. After 9 months, propranolol was tapered off (the dosage was not adjusted anymore for increasing weight of the child) and after 1 year it was stopped; episodes were not seen anymore.
Case 2 Two years later we saw his little brother with the same symptoms, also since the age of 2 months. However, he had fewer (one to two per day) but longer lasting (10–20 minutes) incidents. He also suffered from pain during the incidents, just like his older brother did. We did a full check up and made the same diagnosis as in the case of the older brother. We also started with propranolol, now in a dosage of 2 mg/kg/day in three times per day. This did not seem to have a great effect, and therefore we raised the dosage to 2.67 mg/kg/day in four times per day, after which only occasionally attacks
231
Janmohamed et al.
were seen. The dosage was then lowered back to 2 mg/kg/day and gradually tapered off. Monitoring while on propranolol therapy and tapering was consistent with the previous case. Propranolol was stopped after 1 year and no incidents were seen anymore.
Discussion In 1952, Neligan and Strang first described a bizarre vasomotor manifestation in the neonatal period which they named “Harlequin color change” (5). It is a sudden and brief paroxystic change in skin color, resulting in a body with two skin colors: erythematous and pale. The normal skin color may change into both red and blue. It can be seen in just one extremity but up to half of the body may be involved. It also occurs beyond the neonatal period, even in older children or adults. The precise incidence is unknown; case reports suggest it may occur in up to 10% of newborns. The duration of HP can be anything from 30 seconds up to 20 minutes, with one or many episodes in a week. Despite the fact that we saw this phenomenon in two brothers, there are no genetic influences described in the literature. Eliciting factors may be pain, anesthesia, exercise, emotions, or autonomic seizures. In most patients, therapy is not necessary because HP is benign and goes away after a while (1). In our cases, however, the parents noted the children were in extreme pain during the episodes leading to much distress in the parents. This is not a common symptom of HP but in our cases we had to intervene. To our knowledge, there are no reported cases in the literature of HP treated with propranolol. With propranolol treatment, the number and duration of episodes immediately
232
declined dramatically, but we could not stop them completely. We continued propranolol for almost 1 year and then tapered it off (the dose was not adjusted with increasing weight). It is normal for HP to go in regression. Our dosage was relatively low and comparable with the dosage nowadays used in the treatment of infantile hemangioma (2–3 mg/kg daily). We hypothesize that propranolol, which is very lipophilic and therefore also acts on β-receptors of the central nervous system, acts on the sympathetic system. HP occurs due to vasomotor instability caused by sympathetic disautonomy, which is a consequence of hypothalamic peripheral vascular tone control immaturity in the newborn.
Funding None declared.
Conflict of interests None declared.
References 1. Januario G, Salgado M. The Harlequin phenomenon. J Eur Acad Dermatol Venereol 2011: 25: 1381–1384. 2. Rang HP, Dale MM, Ritter JM, Flower R, Henderson G. Rang & Dale’s pharmacology. Philadelphia: Elsevier Health Sciences, 2011. 3. Leaute-Labreze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taieb A. Propranolol for severe hemangiomas of infancy. N Engl J Med 2008: 358: 2649–2651. 4. Storch CH, Hoeger PH. Propranolol for infantile haemangiomas: insights into the molecular mechanisms of action. Br J Dermatol 2010: 163: 269–274. 5. Neligan GA, Strang LB. A “harlequin” colour change in the newborn. Lancet 1952: 2: 1005–1007.
