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Smith-Magenis Syndrome Treated with Ramelteon and Amphetamine-

dextroamphetamine: Case Report and Review of the Literature

Article · January 2016

DOI: 10.4172/2327-5790.1000145

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Baek and Elsea, J Genet Disor Genet Rep 2016, 5:4
DOI: 10.4172/2327-5790.1000147 Journal of Genetic
Disorders & Genetic
Reports
Case Report a SciTechnol journal

managing SMS [3,4].

Smith-Magenis Syndrome We report a case of SMS where the combination of ramelteon
Treated with Ramelteon and amphetamine-dextroamphetamine salts was safe and effective in
treating this condition.
and Amphetamine- Case Presentation
dextroamphetamine: Case A 7-year-old girl presented with developmental delay, insomnia,

Report and Review of the and behavioral problems.

She was born at 35 weeks and weighed 5 lbs. at birth. She had
Literature respiratory distress of the newborn. She had syndactyly on both
hands but received surgery only for the right third and fourth digits.
Baek WS1* and Elsea SH2
Her first words were at 18 months, and she started walking at 5
years of age. At age 7, she was in special education and at times, would
Abstract hit other children. She had severe insomnia with daytime sleepiness.
Objective: Smith-Magenis syndrome (SMS) is a monogenetic She was impulsive, hyperactive, and inattentive. She demonstrated
disorder caused by haploinsufficiency of the retinoic acid-induced severe temper tantrums, self-injurious behavior such as head banging
1 (RAI1) gene on 17p11.2. SMS patients are dysmorphic with or finger biting, polyembolokoilamania (insertion of objects into
developmental delay, autism, attention-deficit hyperactivity body orifices), but not self-hugging.
disorder (ADHD), and insomnia. Treating the insomnia, ADHD, and
disruptive behavior are key in managing SMS; however, to date She had normal brain MRIs at 3 months and 2 years of age. EEG
there are no treatment guidelines or FDA-approved medications. could not be performed due to lack of cooperation. Family history
was unremarkable.
Methods: We present a case of a 7-year-old girl with developmental
delay, insomnia, and behavioral problems whom we had diagnosed On her initial visit at age 7, she was 49 inches tall, weighed 66
with SMS, and treated her insomnia and ADHD. lbs. with a body mass index of 19. Exam revealed a broad, square-
Results: Ramelteon 4 mg at night decreased her CSHQ (Children shaped facial appearance, brachycephaly, a prominent forehead,
Sleep Habits Questionnaire) score from 91 to 79, and amphetamine- hypertelorism, small upslanting palpebral fissures, a broad bridged
dextroamphetamine salt 30 mg daily lowered her Vanderbilt ADHD nose, and mild truncal obesity (Figure 1, top). She did not talk at all
parent rating scale from 70 to 54. and was scribbling with her left hand. She had synbrachydactyly of
Conclusions: Ramelteon may be effective in treating insomnia the left third and fourth digits (Figure 1, bottom).
in SMS; larger randomized studies would be beneficial in
Her working diagnosis was developmental delay, autism, and
demonstrating the efficacy and safety of these medications in the
future.
ADHD. Risperidone 1 mg twice daily helped her behavior at school
but increased her appetite even further. Risperidone was switched to
Keywords lamotrigine, which only initially improved her behavior. Melatonin
SMS; RAI1; Ramelteon; ADHD, Amphetamine-dextroamphetamine; initially improved her insomnia but then became ineffective.
CSHQ; Vanderbilt ADHD parent rating scale We increased lamotrigine to 50 mg twice daily and added
guanfacine 1 mg at night to alleviate her insomnia, but she was
Abbreviations: SMS: Smith-Magenis syndrome; RAI1: Retinoic lethargic on this dose of lamotrigine; hence, this was decreased to 25
acid-induced 1; ADHD: Attention deficit hyperactivity disorder; mg in the morning and 50 mg in the evening.
CSHQ: Children Sleep Habits Questionnaire Her baseline CSHQ score was 91. On the Vanderbilt ADHD
parent rating scale, her baseline total score was 70 (and a total score
Introduction
of 30 for the last 8 questions), supporting her diagnosis of ADHD,
SMS is a monogenetic disorder caused by haploinsufficiency combined type.
of the RAI1 gene on chromosome 17p11.2 [1,2]. It is a complex
Karyotyping revealed an interstitial deletion of 17p11.2
neurobehavioral disorder with features of brachycephaly,
encompassing the RAI1 gene, which was consistent with SMS (Figure
brachydactyly, intellectual and speech delay. Treating the insomnia,
2). Chromosomal microarray was denied by her insurance. Her
ADHD, obesity, and disruptive behavior is the main focus of clinically
echocardiogram was normal.
Lamotrigine and guanfacine were discontinued and ramelteon
*Corresponding author: Dr. Baek WS, MD,Parkside Medical Group, 1310 San (Rozerem®) 4 mg at night was initiated. She was able to sleep 3 more
Bernardino Rd, Suite 102, Upland, CA 91786, USA, Tel: 909 608 2008, Fax: 909 608 hours (from 3.5 hours to 6.5 hours) during the night with ramelteon
7705, E-mail: [email protected] (Rozerem®) 4 mg at night, and her CSHQ score decreased to 79,
Received: October 18, 2016 Accepted: November 02, 2016 Published: which was a significant improvement, over the course of 3 months
November 09, 2016 and stabilized (Figure 3).

All articles published in Journal of Genetic Disorders & Genetic Reports are the property of SciTechnol, and is protected by
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Technology and Medicine
Citation: Baek WS, Elsea SH (2016) Smith-Magenis Syndrome Treated with Ramelteon and Amphetamine-dextroamphetamine: Case Report and Review of the
Literature. J Genet Disor Genet Rep 5:4.

doi: 10.4172/2327-5790.1000147

of 3 months and stabilized (Figure 3). She was able to shake hands,
play with videogames, and answer questions in short sentences. She
remains stable 6 months after starting both medications.

Discussion
This was a case of SMS presenting with developmental delay,
autism and ADHD, where refractory insomnia and ADHD were both
successfully managed with off-label ramelteon and amphetamine-
dextroamphetamine.
SMS affects at least 1 out of 25,000 individuals worldwide and is
typically not inherited.
SMS (OMIM 182290) was first described by Smith and
Magenis in 1986 [3] and is caused by haploinsufficiency of RAI1on
chromosome 17p11.2 [1,2]. SMS is a complex neurobehavioral
disorder with features such as brachycephaly, brachydactyly, midface
hypoplasia, prognathism, hoarse voice, intellectual and speech delay,
insomnia, obesity, polyembolokoilamania (insertion of objects into
body orifices), ‘self-hugging’, and disruptive behavior [3,4]. Most
of the SMS features are due to RAI1 haploinsufficiency resulting in
reduction of total RAI1 transcription factor activity [5], while the
variability and severity of the disorder are modified by other genes in
the 17p11.2 region [2].
Figure 1: Characteristic facies of Smith-Magenis syndrome. Note the broad, Management of SMS requires a multidisciplinary approach and
square-shaped facial appearance, brachycephaly, a prominent forehead,
includes treatment of the sleep disturbance, speech and occupational
small eyes with upslanting palpebral fissures, hypertelorism, a broad nasal
bridge, and mild truncal obesity (top). Synbrachydactyly of the right third and therapy, minor medical interventions, and management of the
fourth digits; her left hand was surgically corrected (bottom). behaviors [6].
SMS and inversion of the circadian rhythm
The disrupted circadian rhythm in SMS manifests as difficulty
falling asleep, shortened sleep cycles, frequent and prolonged
nocturnal awakenings, excessive daytime sleepiness, daytime
napping, snoring, and bed-wetting [7]. The inverted melatonin
rhythm (i.e., melatonin peaks during the day instead of at night) and
associated sleep-phase disturbances in SMS, as well as a short-period
circadian rhythm in mice with a chromosomal deletion of RAI1,
support SMS as a circadian-rhythm-dysfunction disorder. RAI1 is
a positive transcriptional regulator of circadian locomotor output
cycles kaput (CLOCK), a key component of the mammalian circadian
oscillator that transcriptionally regulates many critical circadian
genes. Haploinsufficiency of RAI1 in SMS fibroblasts and Rai1 in the
mouse hypothalamus results in transcriptional dysregulation of the

Figure 2: Karyotyping showing 46, XX, del (17) (p11.2p11.2). An ideogram

of a normal 17 is shown below (deletion site marked with an arrow).

After treating her insomnia, we first treated her ADHD with

methylphenidate ER 18 mg daily. She was unable to swallow the pills,
therefore this was switched to amphetamine-dextroamphetamine
sprinkles 10 mg daily with mild improvement, so her dose was Figure 3: Combined treatment with ramelteon and amphetamine-
dextroamphetamine decreased the CSHQ score and the ADHD Vanderbilt
gradually increased to 30 mg daily. At this dose, her Vanderbilt Parent Rating score.
ADHD parent rating score decreased from 70 to 54 over the course

Volume 5 • Issue 4 • 1000147 • Page 2 of 3 •

Citation: Baek WS, Elsea SH (2016) Smith-Magenis Syndrome Treated with Ramelteon and Amphetamine-dextroamphetamine: Case Report and Review of the
Literature. J Genet Disor Genet Rep 5:4.

doi: 10.4172/2327-5790.1000147

circadian clock, causing altered expression and regulation of multiple In this case, we were able to demonstrate the efficacy and tolerability
circadian genes [8]. of ramelteon and amphetamine-dextroamphetamine salts in treating
SMS; large-scale, randomized, placebo-controlled trials are required
Therefore, based on the aforementioned underlying
to demonstrate the true benefits of these medications in the future.
pathophysiology, the original therapeutic approach in SMS was
blockade of endogenous melatonin production during the day References
combined with exogenous melatonin administration in the evening 1. Seranski P, Hoff C, Radelof U, Hennig S, Reinhardt R, et al. (2001) RAI1
[9]. There have been case reports of administering beta (1)-adrenergic is a novel polyglutamine encoding gene that is deleted in Smith-Magenis
antagonists in the morning to suppress the diurnal melatonin syndrome patients. Gene 270: 69-76.
secretion and melatonin in the evening to generate a nocturnal peak 2. Elsea SH, Girirajan S (2008) Smith-Magenis syndrome. Eur J Hum Genet
of melatonin [10]. However, in this present case, the patient did not 16: 412-21.
respond to melatonin. We had considered enrolling the patient in the 3. Smith AC, McGavran L, Robinson J, Gail W, Jean M, et al. (1986) Interstitial
tasimelteon (Hetlioz) clinical trial [11], but the patient was less than deletion of (17) (p11.2p11.2) in nine patients. Am J Med Genet 24: 393-414.
16 years of age and not part of the Vanda Pharmaceutical’s Hetlioz 4. Edelman EA, Girirajan S, Finucane B, Patel PI, Lupski JR, et al. (2007)
Solutions program; hence, we started the patient on ramelteon Gender, genotype, and phenotype differences in Smith-Magenis syndrome: a
(Rozerem®) 4 mg at night as a last resort, although this is not indicated meta-analysis of 105 cases. Clin Genet 71: 540-50.
for use in children. 5. Carmona-Mora P, Canales CP, Cao L, Perez IC, Srivastava AK, et al. (2012)
RAI1 transcription factor activity is impaired in mutants associated with Smith-
Ramelteon is the first in a new class of hypnotics that selectively Magenis Syndrome. PLoS One 7: e45155.
binds to the MT1 and MT2 receptors in the suprachiasmatic nucleus. 6. Willekens D, De Cock P, Fryns JP (2000) Three young children with Smith-
Ramelteon is approved by the U.S. Food and Drug Administration Magenis syndrome: their distinct, recognisable behavioural phenotype as the
(FDA) for insomnia only in adults. most important clinical symptoms. Genet Couns 11: 103-10.

There are no standard outcome measures to assess insomnia in 7. Smith AC, Dykens E, Greenberg F (1998) Sleep disturbance in Smith-
Magenis syndrome (del 17 p11.2). Am J Med Genet 81: 186-91.
SMS; we had chosen the CSHQ. The CSHQ is a useful sleep screening
instrument to identify both behaviorally based and medically-based 8. Williams SR, Zies D, Mullegama SV, Grotewiel MS, Elsea SH, et al. (2012)
Smith-Magenis syndrome results in disruption of CLOCK gene transcription
sleep problems in school-aged children [12]. A cut-off total CSHQ and reveals an integral role for RAI1 in the maintenance of circadian
score of 41 yields a sensitivity of 0.80 and specificity of 0.72; our rhythmicity. Am J Hum Genet 90: 941-9.
patient’s baseline CSHQ score was very high at 91, which decreased to
9. De Leersnyder H (2013) Smith-Magenis syndrome. Handb Clin Neurol 111:
79 with ramelteon (Rozerem®) 4 mg at night. We did not increase the 295-6.
dose further, as the optimal dose has yet to be established for children.
10. De Leersnyder H, Bresson JL, de Blois MC, de Blois MC, Souberbielle JC,
et al. (2003) Beta 1-adrenergic antagonists and melatonin reset the clock
SMS and the behaviors, obesity, and ADHD and restore sleep in a circadian disorder, Smith-Magenis syndrome. J Med
Our patient demonstrated severe temper tantrums, hyperactivity, Genet 40: 74-8.

aggressive and self-injurious behavior such as head banging or 11. Neubauer DN (2015) Tasimelteon for the treatment of non-24-hour sleep-
finger biting, all of which have been reported in SMS. She also had wake disorder. Drugs Today (Barc) 51: 29-35.
polyembolokoilamania but not self-hugging, both of which are more 12. Owens JA, Spirito A, McGuinn M (2000) The Children’s Sleep Habits
characteristic for SMS [7]. Risperidone has been reported to decrease Questionnaire (CSHQ): psychometric properties of a survey instrument for
school-aged children. Sleep 23: 1043-51.
aggression in SMS [13], which was also observed in our case but led
to weight gain, which is common in SMS, as RAI1 regulates genes 13. Niederhofer H (2007) Efficacy of risperidone treatment in Smith-Magenis
syndrome (del 17 pll. 2). Psychiatr Danub 19: 189-92.
involved in lipid metabolism [14].
14. Chen L, Mullegama SV, Alaimo JT, Elsea SH (2015) Smith-Magenis
ADHD has been previously reported in SMS [6]. Our patient syndrome and its circadian influence on development, behavior, and obesity
manifested symptoms of ADHD which we quantified using the - own experience. Dev Period Med 20: 149-156.
Vanderbilt ADHD parent rating scale. Although stimulants 15. Laje G, Bernert R, Morse R, Pao M, Smith AC (2010) Pharmacological
have been reported to be ineffective in SMS [15], we were able to treatment of disruptive behavior in Smith-Magenis syndrome. Am J Med
demonstrate that amphetamine- dextroamphetamine sprinkles 30 Genet C Semin Med Genet 154C: 463-468.

mg daily significantly decreased her Vanderbilt ADHD parent rating

score from 70 to 54. We chose a stimulant instead of the anecdotally-
used beta (1)-adrenergic antagonist for several reasons: A. To control
her symptoms of ADHD, B. To help control her body weight (which
unfortunately was unsuccessful; her BMI nonetheless increased from
19 at 7 years of age to 26 at 9 years of age), and C. To counteract
her daytime sleepiness. We had switched to the sprinkle form of
amphetamine-dextroamphetamine mixed salts as the patient could
not swallow pills.

Conclusions Author Affiliation Top

SMS is a rare genetic disorder that presents with 3 main points 1
Parkside Medical Group, 1310 San Bernardino Rd, Suite 102, Upland, CA
in clinical management: insomnia, ADHD, and autism-related 91786, USA
behavior. Understanding the underlying pathophysiology of the Department of Molecular and Human Genetics, Baylor College of Medicine,
2

condition is crucial for designing a pharmacological treatment plan. One Baylor Plaza, NAB 2015, Houston, TX 77030, USA

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