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Neurologic and Developmental Features of theSmith-Magenis Syndrome (del 17p11.2)

Andrea L. Gropman, MD*† Wallace C. Duncan, PhD‡ andAnn C. M. Smith, MA, DSc (Hon)§�

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he Smith-Magenis syndrome is a rare, complex mul-isystemic disorder featuring, mental retardation andultiple congenital anomalies caused by a heterozy-

ous interstitial deletion of chromosome 17p11.2. Thehenotype of Smith-Magenis syndrome is character-

zed by a distinct pattern of features including infantileypotonia, generalized complacency and lethargy in

nfancy, minor skeletal (brachycephaly, brachydac-yly) and craniofacial features, ocular abnormalities,iddle ear and laryngeal abnormalities including

oarse voice, as well as marked early expressive speechnd language delays, psychomotor and growth retar-ation, and a 24-hour sleep disturbance. A strikingeurobehavioral pattern of stereotypies, hyperactivity,olyembolokoilamania, onychotillomania, maladaptivend self-injurious and aggressive behavior is observedith increasing age. The diagnosis of Smith-Magenis

yndrome is based upon the clinical recognition of aonstellation of physical, developmental, and behav-oral features in combination with a sleep disorderharacterized by inverted circadian rhythm of melato-in secretion. Many of the features of Smith-Magenisyndrome are subtle in infancy and early childhood,nd become more recognizable with advancing age.nfants are described as looking “cherubic” with aown syndrome–like appearance, whereas with age

he facial appearance is that of relative prognathism.arly diagnosis requires awareness of the often subtlelinical and neurobehavioral phenotype of the infanteriod. Speech delay with or without hearing loss isommon. Most children are diagnosed in mid-child-ood when the features of the disorder are mostecognizable and striking. While improvements in cy-

rom the *Departments of Pediatrics (Genetics and Metabolism) andeurology, Georgetown University, Washington, DC; †Medicalenetics Branch, National Human Genome Research Institute,ational Institutes of Health, Bethesda, Maryland; ‡Mood and Anxietyisorders Program, National Institute of Mental Health; §Departmentf Oncology, Georgetown University, Washington, DC; �Office of the
linical Director, National Human Genome Research Institute,ational Institutes of Health, Bethesda, Maryland.
2006 by Elsevier Inc. All rights reserved.oi:10.1016/j.pediatrneurol.2005.08.018 ● 0887-8994/06/$—see front matter

ogenetic analysis help to bring cases to clinical recog-ition at an earlier age, this review seeks to increaselinical awareness about Smith-Magenis syndrome byresenting the salient features observed at differentges including descriptions of the neurologic and be-avioral features. Detailed review of the circadianhythm disturbance unique to Smith-Magenis syn-rome is presented. Suggestions for management of theehavioral and sleep difficulties are discussed in theontext of the authors’ personal experience in theetting of an ongoing Smith-Magenis syndrome naturalistory study. © 2006 by Elsevier Inc. All rightseserved.

ropman A, Duncan W. Neurologic and Developmentaleatures of the Smith-Magenis Syndrome (del 17p11.2).ediatr Neurol 2006;34:337-350.

ntroduction

The Smith-Magenis syndrome is a clinically recogniz-ble, probable contiguous gene syndrome comprisingultiple congenital anomalies and mental retardation [1].

t is caused by an interstitial deletion of chromosome7p11.2 (Fig 1), first described by Smith et al. in 1982,ith the full clinical spectrum delineated in additionalatients in 1986 [2]. Smith-Magenis syndrome occurs inll ethnic groups with an overall frequency estimated to be/25,000 [3]. The diagnosis of Smith-Magenis syndromes based upon clinical recognition of a unique phenotypenvolving physical, developmental, and behavioral as-ects. The diagnosis is confirmed cytogenetically or by

ommunications should be addressed to:r. Gropman; Department of Pediatrics; Georgetown Universityedical Center; 3800 Reservoir Road; N.W. 2PHC;ashington, DC 20007.

-mail: [email protected] April 7, 2005; accepted August 11, 2005.

337Gropman et al: Smith-Magenis Syndrome

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luorescence in situ hybridization in the majority of cases.n addition, a small cohort of patients with the Smith-

agenis syndrome phenotype, but without a detectableeletion by fluorescence in situ hybridization, was recentlyound to harbor a frame shift mutation of the RAI1 geneRetinoic acid induced-1) [4-6] contained in the criticalegion, which encodes a novel gene of unknown functionelieved to play a role in neuronal differentiation [6], andossibly responsible for the major features of the syn-rome [7,8].Patients with Smith-Magenis syndrome present with a

linically recognizable craniofacial appearance that in-ludes brachycephaly, midface hypoplasia, a prominentorehead, upslanting palpebral fissures, epicanthal folds,ynophyrs, and age-dependent development of relativerognathism due to persisting midfacial hypoplasia (Table). The facial appearance may be quite subtle in infancy,hus diagnosis may not be apparent [9]. Other commoneatures of Smith-Magenis syndrome include short stature,rachydactyly, ophthalmologic problems (myopia, strabis-us, microcornea, retinal detachment), hearing loss, in-

antile hypotonia, mental retardation, maladaptive behav-ors, expressive language delay, oral motor dysfunction,eripheral neuropathy, and sleep disorder partially attrib-ted to inversion of the circadian rhythm of melatoninecretion [10-12]. Behavioral problems, including self-

igure 1. Smith-Magenis syndrome (SMS) deletion 17p.11.2. Schematicyndrome (46,XY, del 17 (p11.2p11.2); arrows point to deleted 17 chroluorescence in situ hybridization FISH analysis using RA11 FISH proeanne Meck, PhD, Director of Cytogenetics Laboratory, Georgetowneorgetown University Medical Center, Washington, DC.

njury, tantrums, and stereotypies are observed in the s

38 PEDIATRIC NEUROLOGY Vol. 34 No. 5

ajority of patients with Smith-Magenis syndrome andepresent a major challenge for parents, caregivers, androfessionals [13-15].

Despite increased clinical awareness of Smith-Magenisyndrome as well as improved cytogenetic technologies,any children are not definitively diagnosed until early

hildhood or even school age [9,16]. The majority ofhildren with Smith-Magenis syndrome have been identi-ied in the last decade owing to improved cytogeneticechniques and the availability of fluorescence in situybridization probes specific for the Smith-Magenis syn-rome critical region [7,17-20,21].With few exceptions, the deletion in Smith-Magenis

yndrome occurs de novo [22,23], thus imparting a lowecurrence risk. However, parental cytogenetic analysis isecommended in new cases. There is no evidence touggest either a parental age contribution, or skewed sexistribution in deletion cases, and random parental originor the 17p deletion has been demonstrated, thus suggest-ng that genomic imprinting is not a factor [3,24]. The

echanism of the deletion in Smith-Magenis syndrome isue to homologous recombination of a flanking repeatene cluster, leading to mismatch pairing [25].While the molecular cause of Smith-Magenis syndrome

s uncertain, it is believed to be due to a contiguous gene

(A) and partial G-banded karytoype (B) from male with Smith-Magenis. Normal chromosome 17 (left) and deleted 17 (right). (C) Metaphasemith-Magenis syndrome critical region. Partial karyotype courtesy ofsity, Washington, DC. FISH analysis courtesy of Jan Blancato, PhD,

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able 1. Clinical and behavioral aspects of Smith-Magenis syndrome across the age span

Infancy Toddler/Early Childhood School Age Adolescence to Adulthood

linical features BrachycephalyMild facial dysmorphismBroad, square-shape faceUpslanting palpebral fissures“Cherubic” appearance“Down syndrome–like” appearanceMid-face hypoplasiaCupid-bow mouth with tented

upper lipOpen mouth postureEye problems: strabismus;

microcornea; pigmented fleckingof iris

Short broad hands and feetCentral nervous system: mildly

enlarged ventricles

Recognizable facial appearance withmid-face hypoplasia; rosy cheeks

Frequent/chronic otitis mediaHearing loss (predominantly

conductive)Vision problems (myopia)Fair hair and coloring compared with

familyShort statureHoarse voiceUnusual gait/toe walkingHigh cholesterol

Characteristic facies with persisting midfacehypoplasia, relative prognathia, heavybrows extending laterally;

Hoarse voiceProgressive myopiaHearing loss (conductive vs sensorineural)Short statureScoliosisBroad-based flapping gait

Coarser facial appearance withdeep-set eyes, relative prognathia,heavy brows, synophyrs

Progressive myopiaHearing loss (conductive and/or

sensorineural)Females: premature adrenarche;

irregular menses; hygiene concernsTendency to obesityHoarse voiceShort stature (5–10%)ScoliosisBroad-based flapping gait

euro-develop-mental

Feeding difficulties (major oral-sensorimotor dysfunction

Failure to thriveGeneralized hypotoniaAlert and responsiveHypotonia (low muscle tone)HyporeflexiaSocial skills—age-appropriateDelayed gross/fine motor skills

Developmental delays; Gross/finemotor delays

Marked speech delay (expressive �receptive)

Decreased pain sensitivityPes planus (flat) or pes cavus

(high arch)Delayed potty trainingSensory Integration issues

Cognitive delaysweaknesses: sequential processing and

short-term memorystrengths: long-term memory and

perceptual closureVisual learners, Pes planus or pes cavus,

Bedwetting, sensory integration issues

Cognitive delaysExcellent long-term memory

Reports of exercise intolerancePoor adaptive function

ehavior Diminished vocalizations and crying“Quiet good babies”ComplacentParent perception of “good sleeper”Decreased total sleep for ageLethargic

Stereotypic behaviors: self-hugginglick and flip behaviors

Self-abusive behaviors head banging;hitting: self wrist bitting; skinpicking

Sleep disturbance: short sleep cycle;early risers (5:30–6:30 am);frequent night awakeningsand daytime naps

Engaging personalityAffinity for electronic toys, buttons,

etc.

Attention-seeking behaviorsAdult-orientedFrequent outbursts/tantrumsSudden mood shiftsYes/No gameImpulsivity/aggressionHyperactivityAttention deficitsChronic sleep disturbance:

short sleep cycle;early risers (4:30–6:30 am);frequent night awakeningsand daytime sleepiness

Stereotypic behaviors Self-injuriousbehaviors: Hitting self, nail biting orpulling; object insertion (older ages)

Very communicativeExcellent long-term memoryAffinity for computers or electronics

Chronic sleep disturbance; decreasedtotal sleep time; increased napswith age* (parental reports)

Major behavioral outbursts or ragebehaviors, property destruction,attention seeking

Aggressive/explosive outburstsImpulsive, disobedientMood shifts (rapid) without major

provocationAttention deficitsArgumentativeSelf-injurious behaviors (hitting self/

objects; nail yanking; objectinsertion)

Mouthing of objects, bruxismLick and flip of pages in a book,Self-hug, upper bodySpasmodic squeezeBody rockingSpinning and twirling of objectsVery communicativeExcellent long-term memoryAffinity for computers and

electronics

Adapted from Smith ACM, as presented at the Smith-Magenis syndrome parent conference (SIRIUS) Heidelberg, Germany, November 13, 2004.
Behavioral data adapted from Dykens and Smith [13].

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he critical region contributes collectively to the phenotype26].

We have been engaged in a natural history study of themith-Magenis syndrome initiated at the National Insti-

utes of Health from 1997. Research collaborators consistf an interdisciplinary team of physicians and allied healthrofessionals (medical genetics, psychology, developmen-al pediatrics, child neurology, audiology, speech andanguage, occupational and physical therapy, radiology,phthalmology, and sleep physiology). The study haseveral aims. One aim is to characterize the physical,iochemical, developmental, and neurobehavioral aspectsf Smith-Magenis syndrome from infancy to adulthoodnd develop diagnostic criteria for early clinical recogni-ion and diagnosis.

Another aim of the natural history study is to follow thelinical, neurologic, and neurobehavioral features ofmith-Magenis syndrome throughout the lifespan and toetermine intervention and management strategies for theeurodevelopmental delays and maladaptive behaviors. Aajor aspect of the research is to document indices of

bnormal sleep physiology [11,12]. It is anticipated thatuch findings will assist in the design of rational interven-ions to address this complex aspect of the disorder.dditionally, the study also seeks to understand pheno-

ypic variability of Smith-Magenis syndrome as related toeletion size and other genetic modifiers.

linical Manifestations of Smith-Magenis Syndrome

iagnostic Criteria

The diagnosis of Smith-Magenis syndrome is basedpon clinical recognition of the unique phenotype, withiagnostic confirmation of an interstitial deletion of7p11.2 or mutation in the RAI1 gene. Those featureshich are observed consistently in the majority of indi-iduals with Smith-Magenis syndrome are referenced inable 1.

eurologic and Neurobehavioral Features of Smith-agenis Syndrome

The neurologic phenotype of Smith-Magenis syndromes variable depending upon the age of initial clinicalresentation. These developmentally dependent pheno-ypes are described in the next several sections.

mith-Magenis Syndrome in Infancy

Infants with Smith-Magenis syndrome may have mildysmorphic features and developmental delays; however,ecause of agreeable temperament and social skills, diag-osis is often not made at this age. To discern whether aecognizable Smith-Magenis syndrome infant phenotypexists, we conducted a prospective analysis and retrospec-
ive chart review of the initial 19 children with cytogenet- f

cally confirmed Smith-Magenis syndrome. These chil-ren were evaluated at the National Institutes of Healthrom 1997 to 2001 as part of a multidisciplinary institu-ional review board approved study of the natural historynd molecular genetic features of Smith-Magenis syn-rome. Subjects were recruited through physician referralr parent self-referral through PRISMS (parent supportroup).Among this initial National Institutes of Health group of

9 children (11 female, 8 male), two groups of patientsith confirmed diagnosis of Smith-Magenis syndromeere identified (Table 2): Group 1 consisted of 10 infants

nd children who were diagnosed at a mean age of 9onths (range 2 days to 17 months). Group 2 consisted of

ine older children in whom the diagnosis was made at aean age of 5.4 years (range 22 months to 12 years).estational and pregnancy histories were notable forecreased fetal movement in 9 (50%).Infantile characteristics were ascertained by parent

uestionnaire, interview, and examinations. In addition, inll children older than 24 months at the time of the study,ither a retrospective chart and photographic review, or arospective detailed neurologic examination was con-ucted. In the five children who were younger than 24onths of age at the time of the review, parental inter-

iews, direct evaluation, and detailed examinations wereonducted. The comprehensive evaluation includedraniofacial measurements, neurologic and behavioral as-essments, dysmorphology examination, developmentalnd cognitive testing, and videotaping in which fiveehaviors were assessed including task-oriented behavior,nterpersonal and social behavior, affective behavior, sen-orimotor and communicative behaviors. All children hadspeech and language evaluation as well as audiology andtolaryngology evaluations. Some children underwenterve conduction velocity and electromyographic testing.Based on these studies, a clinically recognizable infant

mith-Magenis syndrome phenotype emerged that addedo previous published clinical series (Table 3). Infants withmith-Magenis syndrome display normal growth withirth weight, length, and head circumference generally inhe normal range at birth. By age 1 year, however,vidence of decline in height velocity and often pooreight gain may lead to concern for failure to thrive thatay persist into early childhood [27]. Even as infants, the

able 2. Demographics of infants with Smith-Magenis syndrometudied at the National Institutes of Health

Group I: Diagnosed<18 Months of Age

Group 2:Diagnosed >18Months of Age

10 (M/F) 9 (M/F)ean age at diagnosis 9 mo (range 2 day-

17 mo)5.4 yr (range 22 mo-

12 yr)irth year 1991–1997 1980–1991

acial phenotype of Smith-Magenis syndrome was ob-

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erved to be quite distinctive, with an overall facial shapehat is broad and square. With age, the mid-face hypopla-ia persists, yielding to an appearance of relative progna-hism (Table 1). There is phenotypic overlap with Downyndrome early in life. Both Smith-Magenis syndrome andown syndrome share upslanting palpebral fissures,rachycephaly, flat mid face, and short, broad nose. Facialepth in Smith-Magenis syndrome is less than that inown syndrome, and total facial height as well as ear size

s greater in Smith-Magenis syndrome compared withown syndrome [28].Neurobehavioral features of the Smith-Magenis syn-

rome infant included hypotonia, lethargy, increasedleepiness, and daytime napping [29]. Often, the infantseeded to be awakened for feedings. In most cases, thereere no behavioral problems in the first 18 months of life,

nd in fact, many of these infants were felt to be “perfectabies”.Recent objective sleep data derived from actigraphy

ndicate a sleep disturbance in infancy that continues intoater childhood and beyond [30]. Data on three infantsnder 1 year of age indicate fragmented sleep witheduced 24-hour total sleep time as early as 6 months ofge. Because of their relatively quiet behavior patternuring sleep, these infants can be described as “quietabies sleeping poorly”.The incidence of crying, babbling, and vocalizing wasarkedly decreased for age in virtually all infants withmith-Magenis syndrome, despite normal hearing [31].hese observations apparently led to parent reports ofypersomnolence and lethargy in infants, because infantsere often not “signaling” parents upon waking.Motor delays were evident in all infants and children,

ith gross motor delays of 2-24 months; however, social-motional function was within the normal range or onlylightly delayed [9,27]. All infants with Smith-Magenisyndrome displayed oral motor dysfunction including pooreeding in some, manifest by poor tongue protrusion,

able 3. Characteristics of the infant phenotype of Smith-agenis syndrome

ecreased fetal movement by history 9/19ypotonia 19/19yporeflexia 17/19

ncreased daytime sleepiness and napping; perceivedto be “good sleepers”

19/19

romotor dysfunction 19/19elayed gross motor skills (2–24 months behind) 19/19elayed fine motor skills 19/19arked speech delay (Expressive language�Receptive language)

19/19

ear or age-appropriate social skills 16/19ajor behavioral problems documented in first 18 mo(Average age onset of behavioral abnormalities 18–24 mo)

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leep disorder 19/19herubic facial appearance that is perceived asdysmorphic

19/19

ingual weakness, weak bilabial seal, open mouth posture, s

oft cry, and excessive drooling [31]. Despite motor andpeech delays, the majority (16/19 or 84%) exhibitedge-appropriate social skills (Table 3).

Other features of the neurologic examination in infantsith Smith-Magenis syndrome include reduced reflexes in4% in the absence of abnormal electromyographic orerve conduction velocities and a 6-8 Hz postural tremorn the upper, distal extremities. Once ambulatory, peslanus or cavus was observed in two thirds of the initialtudy (n � 19) population. Infants with Smith-Magenisyndrome manifested some decreased sensation to pain,ut nerve conduction velocities measured in six infantsere normal.The most common diagnosis entertained in infancy is

own syndrome, prompting request for karyotype in theajority of children during infancy. Among the 19 Smith-agenis syndrome children in our initial National Insti-

utes of Health study, 30% were thought to have Downyndrome; other diagnoses included Angelman syndromen � 1), Cornelia de Lange’s syndrome (n � 1), andrader-Willi syndrome (n � 1). Karyotypes were obtained

n two children with cleft palate and one child witholydactyly. Overall, only six children were described asooking dysmorphic. Other diagnoses considered after theirst year of life were atypical Prader-Willi syndrome andragile X, autism, and pervasive developmental delay.espite early karyotypes, the diagnosis was made on the

irst karyotype in 8 of 10 children in Group 1 comparedith only 4 of 9 children in Group 2. All 19 children wereiagnosed by the third karyotype. Those Group 1 childreniagnosed in early infancy were born between 1991 and997, whereas those in Group 2 with a mean age of 5.4ears (Group 2) at diagnosis were born between 1980 and991.Based on our assessment, we found that several distinc-

ive features characterize the infantile phenotype of Smith-agenis syndrome [9,27,29,32] (Table 3).

mith-Magenis Syndrome in Childhood (Age 18onths to 12 Years)

While the clinical and neurobehavioral features ofmith-Magenis syndrome in infancy may be overlooked,

he more classic physical and neurobehavioral aspects ofmith-Magenis syndrome come to be appreciated duringhildhood. Sleep disturbance is manifest, and is often theost pervasive feature of the disorder that may aid in

iagnostic suspicion. Some degree of developmental delayr mental retardation, or both, is observed in all patientsith Smith-Magenis syndrome. A more distinctive neu-

obehavioral pattern emerges during the toddler years andontinues into childhood, characterized by maladaptive,elf-injurious, and stereotypic behaviors that have beenell described [2,13,15,33-35]. Self-injurious behaviorsegin to emerge around 18 months of age, with head-anging being rather frequent. Overall, the prevalence of
elf-injurious behaviors is 96% [13] and has been demon-

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trated to correlate directly with age and level of intellec-ual functioning [15]. In our experience, this representsrustration related to inability to communicate. In addition,omatic disturbances, such as gastrointestinal problemsay be contributory but are often overlooked. Onychotil-

omania (nail yanking) and polyembolokoilamania (bodilynsertions beyond mouthing objects) appear to be uniqueehaviors in this disorder, and thus may help facilitate theiagnosis [15]. Generally, these latter two behaviors doot become major issues until adolescence or older agesTable 4).

Clinically, many of the children with Smith-Magenisyndrome have been given the diagnosis of autism/perva-ive developmental disorder because of abnormalities ofanguage and stereotypic behaviors [29]. Although chil-ren with Smith-Magenis syndrome share behaviors ob-erved in autistic children (self-injurious behaviors, de-ayed verbal language), scores on scales of childhoodutism (Childhood Autism Rating Scale) demonstrateifferences between the two groups. Typically childrenith Smith-Magenis syndrome fall at the low end of theild classification for autism on the Childhood Autismating Scale [36]. Sensory aversions are typical in thisroup, presenting as both tactile and auditory aversions.arly data derived using the Sensory Profile Caregiveruestionnaire [37] for an initial group of 21 Smith-agenis syndrome children (ages 3-10 years) examined at

he National Institutes of Health demonstrate significantroblems in modulating responses to sensory input andifficulties in the ability to perform sustained activity andeet performance demands [38]. In addition to hypersen-

itivity to sound, oral motor dysfunction, and decreasedesponse to pain, there is also evidence of vestibularysfunction and suggested difficulties with depth percep-ion (climbing down stairs), affecting balance and gravi-

able 4. Self injurious behaviors in Smith-Magenis syndrome [41]

Dykens andSmith [13]

n � 35Mean � 9 yr (%)

elf-injurious behavior 92ites self 77its/slaps self 71ead bangingits self against surface 40ulls hair or skin 31its self with object 20kin picking/scratching 29bject insertion 25Ears NNNose NNRectum NNVagina NN

bbreviation:NN � Not noted or differentiated

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Significant speech/language delay, with or without as-ociated hearing loss, occurs in over 90% of individualsith Smith-Magenis syndrome [31,39]. In general, expres-

ive language delays are out of proportion to receptiveanguage skills, especially during early childhood1,14,29]. Toddlers and school-age children with Smith-

agenis syndrome manifest delayed expressive languagekills into early childhood. Thus, the clinician evaluating aysmorphic child with absent age-appropriate vocaliza-ions should consider testing for Smith-Magenis syn-rome.Children with Smith-Magenis syndrome overall demon-

trate significant delays in adaptive behavior, includingommunication and socialization skills as well as theiraily living skills. While delays in communication andaily living skills tend to be consistent with cognitiveunctioning, socialization skills were significantly higherhan cognitive functioning, suggesting potential strengthsn this area [36]. In addition, it has been observed thatdults with Smith-Magenis syndrome remain more depen-ent on caregivers and require a higher degree of supporthan might be predicted based on their cognitive level ofunctioning as described below [40] (A.C.M. Smith, per-onal experience).

In general, children (and adults) with Smith-Magenisyndrome have difficulties modulating both bodily func-ions (eating/sleep) and behaviors, especially those thatnvolve integration of sensory stimuli [13]. This difficultys clinically manifest by delayed toilet training, persistingighttime enuresis, impulsivity and aggression, oversensi-ivity to touch or decreased pain tolerance, difficulty withransitions, and clumsiness.

The relationship between self-abusive behaviors andecreased pain sensitivity (i.e., peripheral neuropathy) hasot been determined and is a topic of further interest and

Finucane et al. [15]n � 15

Mean � 6.46 yr (%)n � 14

Mean � 25.01 yr (%)

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any believe that the early behavioral problems, includ-ng head banging, self-biting, and self-hitting, are in partelated to the general frustrations experienced with poorxpressive language skills [1,14]. The sleep disturbancend self-abusive behaviors also appear to escalate withge, often at expected developmental life stages, specifi-ally at 18-24 months, at school age, and with pubertalnset.

dolescents and Adults With Smith-Magenisyndrome

Little has been detailed about the adolescent or adultith Smith-Magenis syndrome [40]. Cognitive function inmith-Magenis syndrome appears to be preserved intodulthood without any evidence for degeneration or pro-ressive dementia. In addition, the number and severity ofaladaptive behaviors may increase with cognitive ability

nd age [15]. There is no published evidence of neuromo-or deterioration, and the majority of adolescents anddults with Smith-Magenis syndrome appear to have lessssues with balance and incoordination as they mature.owever, two patients developed strokes associated with

oss of milestones (Smith and Gropman, personal obser-ations). In at least one of these cases, cardiac embolusas the etiology.Typical behavioral problems observed in this age group

nclude stereotypies, mood instability, attentional disor-ers, and anxiety.When compared with age- and sex-matched subjects

ith Prader-Willi syndrome or mixed mental retardation,he majority of subjects with Smith-Magenis syndrome89%) demonstrate significantly elevated maladaptive be-avior scores compared with their counterparts. In addi-ion, 12 characteristic behaviors differentiate Smith-Ma-enis syndrome from either Prader-Willi syndrome orixed mental retardation with 100% accuracy. Specifi-

ally, those with Smith-Magenis syndrome demonstratedignificantly higher rates of temper tantrums (94%), dis-bedience (97%), attention-seeking (100%), property de-truction (86%), impulsivity (86%), aggression (57%),yperactivity (94%), distractibility (89%), toileting diffi-ulties (80%), sleep disturbance (94%), and nail-bitingehaviors (72%). Self-injurious behaviors were observedn 92% of the Smith-Magenis syndrome study group,ncluding biting or hitting self (71-77%), onychotillomania29%), and polyembolokoilamania (25%) (Table 4). Ste-eotypic behaviors were demonstrated by all Smith-Mage-is syndrome subjects including mouthing objects orands in mouth (54-69%), teeth grinding (54%), “lick-andlip” behavior (51%), self-hug or upper body spasmodicqueeze (46%), body rocking (43%), and spinning orwirling objects (40%) [13].

Individuals with Smith-Magenis syndrome also differedrom their counterparts in terms of regulation of basicodily functions (sleeping, modulating activity and affect,
ating, and toileting), and in social and repetitive behav- m
ors [13]. Patients with Smith-Magenis syndrome sleptess, were more hyperactive, and were more emotionallyabile. Enuresis and encopresis were singularly frequent inmith-Magenis syndrome compared with Prader-Williyndrome and mixed mentally retarded subjects. Socially,hose with Smith-Magenis syndrome demand more atten-ion than their counterparts. Adolescents and adults withmith-Magenis syndrome exhibit obsessive thinking, pri-arily about specific topics, and anxiety manifest as

epetitive behaviors. In the authors’ experience, flighteactions without an apparent trigger or provocation haveeen observed in teenagers and adults.

entral and Peripheral Neurologic Systemnvolvement in Smith-Magenis Syndrome

Individuals with Smith-Magenis syndrome present fea-ures of both central and peripheral nervous system dys-unction [1,29]. Cognitive functioning in Smith-Magenisyndrome ranges from borderline to profound mentaletardation [41]. Epileptic seizures occur in 11-30% ofndividuals with Smith-Magenis syndrome [1,3,29]. Elec-roencephalographic abnormalities have been documentedn approximately 25% of patients in the absence of alinical history of seizures in one series [1,29]. There is noingle seizure type or electroencephalographic pattern thats characteristic of Smith-Magenis syndrome, althoughomplex partial seizures appear more frequent (authors’ersonal experience). An isolated case of infantile spasmsas reported in a 9-month-old female with Smith-Magenis

yndrome [42]. Recognition and treatment of seizures ismportant as it may improve attention, behavior, sleep, andverall cognitive functioning. The prognosis depends onhe type of seizure and response to antiepileptics. Adverseide effects of medications have been reported with highrequency in Smith-Magenis syndrome (Gropman andmith, unpublished observations, 1997); these includexcessive lethargy, paradoxical hyperactivity, and irrita-ility. There are at least two teenage females with Smith-agenis syndrome who appear to have significant cate-enial seizures.Nonspecific central nervous system structural abnor-alities documented by neuroimaging may be observed in

ver half of affected individuals, with an increased fre-uency of ventriculomegaly reported [1]. However, theres no other specific neuroimaging finding associated withmith-Magenis syndrome. Computed tomographic scanserformed in 25 patients with Smith-Magenis syndromeemonstrated ventriculomegaly in 9, enlargement of theisterna magna in 2, and partial absence of the cerebellarermis in 1 [1]. Similar findings were observed among aroup of 10 children who had undergone previous mag-etic resonance imaging: 5 had ventriculomegaly; 2 hadnlarged posterior fossa; and 3 had normal scans [9].ecent studies employing magnetic resonance imagingolume-based morphometrics and positron emission to-
ography have reported significant bilateral decrease of

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ray matter concentration in the insular and lenticularucleus in Smith-Magenis syndrome children [43]. Inddition, a significant hypoperfusion was evident in theame regions. The only known neuropathologic study on aatient with Smith-Magenis syndrome in whom the entire7p11.2 band was deleted, demonstrated microcephalynd foreshortened frontal lobes with neuronal depletion; amall choroid plexus hemangioma was also observed inhe lateral ventricle [2].

Clinical signs of peripheral neuropathy are reported inpproximately 75% of patients with Smith-Magenis syn-rome [1,9]. Individuals with Smith-Magenis syndromeave a characteristic appearance of the legs and feet that isften observed in peripheral nerve syndromes or neurop-thies. Decreased sensitivity to pain is common. Becausef their relative insensitivity to pain, individuals withmith-Magenis syndrome may cause injury to themselvesy object insertion, persistent skin picking, biting, oritting oneself or striking hard surfaces during uncon-rolled rages [44]. During early infancy and childhood,igns of peripheral nervous system involvement includeypotonia (100%) with hyporeflexia (84%) and decreasedensitivity to pain [29], although these could be caused byentral abnormality. Marked pes planus or cavus deformi-ies and unusual gait (flapping feet) are generally observedn childhood. Children with Smith-Magenis syndromeend to toe walk despite absence of tightened heel cords.

Peroneal motor nerve conduction velocities are gen-rally normal in childhood. Delayed motor nerve con-uction velocities due to biopsy-confirmed segmentalemyelination and remyelination, similar to that ob-erved in hereditary neuropathy with liability to pres-ure palsy [1,2] occur rarely in patients with contiguouseletion of the PMP22 gene, located at 17p12 (distal tohe Smith-Magenis syndrome critical region) [45,46].igns of a nonprogressive peripheral neuropathy none-

heless are present in individuals with Smith-Magenisyndrome. It is unclear whether other genes in the
ritical region are responsible. p

leep Disturbance in Smith-Magenis Syndrome

Sleep disturbance occurs in all cases of Smith-Magenisyndrome [1,47], from infancy into adulthood. In infantshe sleep disturbance is manifest by excessive daytimeethargy as well as decreased 24-hour sleep. Older toddlersnd children manifest fragmented and shortened totalleep cycles, frequent and prolonged nocturnal awaken-ngs, early morning awakening, excessive daytime sleep-ness, daytime napping, snoring, and enuresis [1,12,47].he decreased nocturnal sleep, early awakenings, andaytime naps extends into adolescence [12]. Althoughther neurologic dysfunction may contribute, an abnormalattern of melatonin in which daytime levels are high andighttime levels are low [11,12] (i.e., opposite the normalattern) may be associated with some of these abnormalleep features.

leep Methodologies in Smith-Magenis Syndrome

Three methods have been used to quantify the sleep ofatients with Smith-Magenis syndrome: clinical polysom-ography, actigraphy, and subjective questionnaires oriaries. Each has relative advantages and disadvantages,nd the findings drawn from the use of each methodhould be considered in view of their strengths andeaknesses. Polysomnography is the gold standard used to

valuate sleep and sleep disorders. The use of standardests that rely on polysomnography, such as sleep apneavaluations and multiple sleep latency tests can be clini-ally important, and the test results can be compared withormal standards. Further, sleep stages (e.g., rapid eyeovement, delta sleep) can only be measured using the

lectroencephalogram from polysomnographic recordings.owever, in individuals with Smith-Magenis syndromeho frequently have sensory (especially involving head

nd face) and settling issues, the use of polysomnographyo estimate sleep amounts may be suspect, particularly ifhe electrodes and clinical setting are uncomfortable to the

Figure 2. Seventeen days of continuous wristactivity are depicted from a male 5 years of agewith fluorescence in situ hybridization–con-firmed Smith-Magenis syndrome. The clock time(48 hours) is indicated at the top of the panel;consecutive days are plotted beneath each otheras indicated on the left margin. In addition,consecutive days are plotted adjacent to eachother on the same horizontal line in order toview the nighttime transition from one day to thenext. The bars at the top identify the approxi-mate hours of day and night. Vertical black barsindicate minute-to-minute activity counts. Rest isindicated by the absence of the vertical bars.Note that most rest occurs during the night, andmost activity occurs during the day. However,this pattern is often interrupted by episodes ofnight waking, and daytime naps. The arrows atthe bottom identify one (of many) episodes ofnight arousal (left) and daytime nap (right).

atient and disturb sleep. It is often difficult to record a

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epresentative night of sleep if only one or two nights arevaluated and the patient is uncomfortable. A secondbjective method for estimating sleep is wrist actigraphyFig 2). Wrist actigraphy provides an estimate of sleepased on the wrist motion. The disadvantages of thisethod are that it does not measure electroencephalo-

raphic activity, but physical motion. A second disadvan-age of actigraphy is that it sometimes produces anverestimate of sleep. Actigraphy is less invasive than theolysomnography and is therefore more tolerable to pa-ients at all ages. The device can be worn for a prolongederiod of time (6 weeks or more) in the home setting, andan provide a continuous estimate of the activity-rest cycleuring the study period. It therefore can provide objectivenformation regarding the dynamics of home sleep in theontext of behavioral and developmental changes.

Questionnaires and sleep diaries have been demon-trated to be quite useful in describing core features ofleep disturbance in Smith-Magenis syndrome [1,47]. Thisnformation can be used to evaluate treatment effects onleep. In the absence of more objective measures, sleepiaries can be a simple method for clinicians and parentso quantify and evaluate sleep changes during treatmentsnd behavioral interventions. The disadvantage of theleep diary and questionnaires is that parents are oftennaware of when and for how long their children arewake during the night, which is a great disadvantage intudying a syndrome like Smith-Magenis syndrome. Suchnformation can only be obtained by continuous observa-ion, or by polysomnographic and actigraphic methods.

olysomnographic Findings

Reduced sleep time has been documented by polysom-ography in virtually all Smith-Magenis syndrome pa-ients studied [1,11,12]. The reduced total sleep time isariably related to difficulty falling asleep, staying asleep,r waking early, thus highlighting increased variability ofleep homeostasis in these individuals. For example, 29%f 24 patients had reduced sleep secondary to frequentwakening [1]. Reduced sleep in the remaining 71% mighte associated with difficulty falling asleep, or waking uparly. Interestingly, polysomnography of 23 patients withmith-Magenis syndrome (age range 2.7-31 years) indi-ated reduced total sleep time in 43% of the group, but noelationship between total sleep time and age or sex [11].n contrast to this latter point, recent actigraphy datauggest that estimated sleep varies with age [30,48]. Theunctional consequence of reduced nighttime sleep is anncreased sleep debt that consequently increases daytimeleepiness. The Multiple Sleep Latency Test is an objec-ive measure used to quantify excessive daytime sleepi-ess. Not surprisingly, individuals with Smith-Magenisyndrome have an abnormally reduced latency to fallsleep during the daytime [11], a finding that is consistentith increased daytime napping in Smith-Magenis syn-
rome. a
Specific sleep stage abnormalities in Smith-Magenisyndrome with respect to rapid eye movement and slowave sleep have been identified with polysomnography.ifty percent of patients with Smith-Magenis syndromeanifest abnormalities of rapid eye movement sleep

3,11,12]. Forty-three percent [11] and 50% [1] of theopulations had reduced rapid eye movement sleep, and innother study, rapid eye movement sleep was disrupted byrousals in all children [12]. As was the case with totalleep time, rapid eye movement sleep percentage did notorrelate with age [11] and was reduced in patients withmith-Magenis syndrome (age range 4-17 years) [12].

ctigraphy Findings

Sleep estimates from wrist actigraphy support persistentleep disturbance in Smith-Magenis syndrome that ex-ends from infancy into late childhood (Fig 3). Wristctivity was recorded continuously from individuals in theome for 4-6 weeks; these data are then used to estimate4-hour sleep, as well as night sleep between 7 pm and 7m. Preliminary data collected from 12 individuals withluorescence in situ hybridization–confirmed Smith-Ma-enis syndrome indicate that reduced sleep begins atnfancy (�1 year) with reduced 24-hour sleep comparedith healthy control subjects. The pattern continues withreschool (3 years), early school (5 years), and later schoolhildren (6-8 years) who sleep 1-2 hours less per 24 hourshan healthy age-matched control children. Reduced 24-our sleep stems largely from the reduction of night sleepn each of the age groups. The sleep debt is compensatedor by daytime napping (Fig 2). In contrast to polysom-ographic studies in which no relationship between agend sleep amounts were observed, home-based 24-hournd night estimated sleep declines in Smith-Magenisyndrome from infancy to 8 years. Thus, the decline inotal sleep that occurs from infancy to later childhoodeems to be present in Smith-Magenis syndrome as inontrol subjects. However, with less sleep in Smith-agenis syndrome, the Smith-Magenis syndrome curve is

hifted to the right (Fig 4). Actigraphy appears to be aseful technique to estimate sleep in Smith-Magenis syn-rome and would appear to have applications beyondssessment of developmental changes. One clear applica-ion would be to objectively measure sleep changes thatccur during the course of Smith-Magenis syndromereatment trials.

nverted Circadian Pattern of Melatonin in Smith-agenis Syndrome

In mammals, levels of plasma melatonin begin toncrease in the evening and continue to be elevated at nights a consequence of noradrenalin stimulation of B recep-ors located on pinealocyte cells on the pineal organ.

elatonin levels decline at dawn and are low or undetect-
ble during the daytime. As described below, this night-

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ime rise and daytime decline is conserved across the plantnd animal kingdoms—with the exception of Smith-agenis syndrome.The inverted circadian rhythm of melatonin secretion

Fig 5) in which daytime levels are elevated, whereasighttime levels of melatonin are virtually nondetectableas been described for both the major urinary metabolitef melatonin, 6 sulphatoxymelatonin [11] as well aslasma melatonin levels [12]. The inverted melatoninattern supports the view that the sleep disturbance ob-erved in Smith-Magenis syndrome could be due tobnormalities in the production, secretion, distribution, oretabolism of melatonin [11]. Attempts to correct the

isturbed sleep in Smith-Magenis syndrome by a) treat-ent with nighttime melatonin and/or b) treatment with

eta-blockers to prevent the daytime elevation of melato-

Figure 3. Twenty-four hour actigraphyestimated sleep (left) and nighttime sleep(right) are illustrated in children withSmith-Magenis syndrome (SMS) (lightgray), in comparison with other patientgroups (gray) and healthy children (darkgray). The different populations areidentified beneath the bar graphs. Fourage groups are arranged from top tobottom: infants (�1 year, row one), pre-school (3 years, row two), early school (5years, row three), and later school (6-8years, row four). Note the lower esti-mated 24-hour and night sleep in chil-dren with Smith-Magenis syndrome espe-cially compared with healthy controlsubjects of the same age. Children withSmith-Magenis syndrome often have lesssleep than other children with develop-mental disabilities although some chil-dren with more severe mental retarda-tion (MR) appear to have more seversleep problems. Also note the decrease inthe total 24-hour estimated sleep in chil-dren with Smith-Magenis syndrome from1 year to 8 years of age. The numbers inparentheses indicate the cited studiesfrom which the comparison data weredrawn: [50-62]. The estimated sleepfrom the comparison child groups wasderived from actigraphy, video, sleeplogs, or electroencephalography.

in, have had limited success [49]. These uncontrolledwt


igure 4. Comparison of actigrpahy-estimated night and total 24-hourleep in Smith-Magenis syndrome (SMS) and healthy control subjects.atients with Smith-Magenis syndrome range in age from �1 year to 7ears. control data are from Roffwarg et al. [50]. Both 24-hour sleep as
ell as nighttime sleep are reduced in Smith-Magenis syndrome relative
o healthy control subjects.

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rials were successful in raising nighttime melatonin andeducing daytime melatonin, as well as reducing daytimeantrums. Objective evaluation of treatment effects onleep is required as well as a double-blind trial thatontrols for parent bias.

leep, Smith-Magenis Syndrome, and Circadianhythms

As mentioned earlier, the 24-hour pattern of melatonins inverted in individuals with Smith-Magenis syndrome:evels are high during the daytime and low at night. Thisighly unusual pattern is uniquely present in Smith-agenis syndrome patients; the inverted pattern of mela-

onin is not without consequence.In mammals, 24-hour rhythms in sleep, behavior, and

ormone levels are controlled by a central clock in theuprachiasmatic nucleus of the hypothalamus. Lesionsf the suprachiasmatic nucleus abolish these 24-hourhythms, indicating that this clock provides the 24-hourignal to systems that directly produce sleep, behavior,nd hormones. In fact, the signal provided by the centrallock to the pineal gland to produce melatonin is sotrong that in humans, the pattern of melatonin is oftensed as a surrogate biologic marker for the timing of thelock itself. The fact that the pattern of melatonin isnverted in Smith-Magenis syndrome might suggest thathe central clock is inverted. If this hypothesis wereorrect, all 24-hour rhythms of sleep, behavior, andormones would also be inverted. This does not appearo be the case. Twenty-four hour rhythms of cortisol androwth hormone are not inverted in patients withmith-Magenis syndrome. Growth hormone peaked af-

er nighttime sleep onset, and cortisol levels increasedrom an evening low to a morning high [12]. In

igure 5. The inverted pattern of plasma melatonin is depicted in eighthildren with Smith-Magenis syndrome (solid line, filled circles) com-ared with 15 healthy control subjects (dotted line, open circles). Theines represent the best-fit sine curves to each data set based on minimaleast-squares criteria. The peak of the 24-hour curve is at night(�3-4am)n healthy control subjects; the peak occurs during the day (noon) inatients with Smith-Magenis syndrome. The data are redrawn fromigure 2 of De Leersnyder [12].

ddition, the 24-hour rhythm in body temperature, a (

econd surrogate biologic marker of the central clock,as not inverted in Smith-Magenis syndrome [48].hus, the inverted melatonin rhythm is not driven by an

nverted central clock, but by inverted regulatory ele-ents that more directly control the release of the

ormone by the pineal gland.

leep Hygiene in Patients and Families Living Withmith-Magenis Syndrome

Persons with Smith-Magenis syndrome have de-reased nocturnal sleep and sleep debt, manifest byncreased daytime sleepiness. This increased daytimeleepiness may partially be reduced by properly sched-led naps. Naps during midday (12:00-15:00) are moreeneficial than late day naps which interfere withapacity to fall asleep at scheduled bedtime. In addition,bnormally high daytime melatonin levels will lead toaytime sleepiness and potentiate the requirement foraytime naps. Clinical signs of increased sleep require-ent include napping at unscheduled times, increased

ap duration, and the need to awaken a child from a napr in the morning. Increased sleep debt also is a likelyontributor to the behavioral disturbances observed inmith-Magenis syndrome.

anagement of Smith-Magenis Syndrome

Accurate assessment of the cognitive and developmen-al status of individuals with Smith-Magenis syndrome isifficult and often complicated by the presence of mal-daptive behaviors and marked speech delay which makesraditional cognitive test batteries inappropriate in theseatients owing to difficulty with interpretation and assur-nce of validity.

Speech and language evaluations in the infant withmith-Magenis syndrome should be pursued early tossess for speech and language delays and feeding diffi-ulties, to optimize functional communication and oralotor abilities, and to develop intervention strategies. The

arly use of sign language and a total communicationpproach reduces maladaptive behaviors by improvingommunication [3].

Development of a behavioral treatment plan should beonsidered as soon as problem behaviors arise. A searchor organic causes of behavior should be explored includ-ng gastrointestinal disorders (gastroesophageal reflux,onstipation), otitis media, or other organ or joint pain.he use of medications to control behaviors has had mixed

esults in this population [16], and this is an active area ofnterest. Adverse reactions to some medications have alsoeen reported. Unpublished medication history data on 12hildren with Smith-Magenis syndrome ages 3-16 yearsield a median number of five medication trials; only twohildren were not on medication therapy, and one of theseas enrolled in a strict behavior-modification program

Allen and Smith, 1997, unpublished).


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Older stimulant drugs, in our experience, are not par-icularly useful in controlling behavior nor increasingttention span in patients with Smith-Magenis syndromeAllen and Smith, unpublished observations, 1997). How-ver, there is not enough experience with the newerreparations of this class of medications to deduce effi-acy. Nevertheless, preliminary experience with atomox-tine would indicate that this should not be a first-linetrategy for children with Smith-Magenis syndrome owingo increased incidence of psychotic behaviors (Gropman,npublished observation). A compilation of a comprehen-ive review of medications used in Smith-Magenis syn-rome, adverse effects, and efficacy is in progress (Allen,mith, and Gropman, unpublished, 2005).Typical behavioral problems observed in Smith-Mage-

is syndrome are effectively controlled with mood-stabi-izing agents such as lithium and valproic acid as well ashe antipsychotic rispirodone that acts on the dopamineeceptor. Low dosage of risperidone may reduce aggres-ion and impulsivity. In addition, in some patients withnxiety, selective serotonin reuptake inhibitors appearelpful. A propensity towards weight gain in adolescentsith Smith-Magenis syndrome makes medication selec-

ion particularly tricky. For example, valproic acid andisperidone, and some of the newer mood-stabilizinggents are not first-line choices in Smith-Magenis syn-rome patients because of problems with excessive rapideight gain and alterations of lipid profiles.Symptomatic treatments for aggression and self-injuri-

us behavior including beta-blockers, particularly for in-ividuals with rage attacks or chronic states of over-rousal, mood stabilizers such as lithium, neuroleptics, andelective serotonin reuptake inhibitors such as fluoxetineave all been tried with variable results. A pilot uncon-rolled trial using the beta-blocker acebutolol suggests thathere may be some benefit derived as a result of secondaryffects of inhibition of melatonin [12,49].

Stimulants alone generally are not adequate for patientsith Smith-Magenis syndrome, as they do not medicate

he co-morbid mood disorders. Polypharmacy is typical inhildren with Smith-Magenis syndrome, as a single drugenerally is inadequate to control all symptoms. Thereforehe cumulative potential side effects should be monitored.

ith any trial, tracking sleep patterns and mood ismportant to judge efficacy.

A careful neurologic evaluation in all patients withmith-Magenis syndrome ideally should occur at diagno-is and thereafter, the frequency should be based onlinical indices. Electroencephalography should be ob-ained in all affected individuals who have clinical sei-ures to guide the choice of antiepileptic treatment. Forhose without overt seizures, electroencephalography maye helpful to rule out subclinical events in which treatmentay improve attention or behavior, especially those with

utism spectrum features. Neuroimaging should be accom-lished in accordance with clinical findings, such as
eizures, abnormalities of cranial circumference, motor G

symmetries or abnormalities, and oral motor dysfunctiono rule out an anatomic basis.

Change in behavior or attention warrant reevaluation ofoth seizures and possible medication effects. Electromyo-raphy may be of benefit in individual situations, espe-ially in the setting of clinical evidence of peripheraleuropathy.With regard to sleep management, there have been no

ell-controlled treatment trials to date for Smith-Magenisyndrome. However, due to the presence of elevatedaytime melatonin levels with low nocturnal levels, Deeersnyder et al. [12,49] used the daytime B1-adrenergicntagonist acebutolol (10 mg/kg administered at 8:00 am)o reduce daytime melatonin secretion, combined with anvening oral dose of control-release melatonin (6 mg at 8m) in an attempt to restore normal nocturnal plasmaelatonin levels. Although this uncontrolled trial demon-

trated improved circadian rhythm of melatonin secretionnd possibly improved behavior in nine children withmith-Magenis syndrome, the results may have beeniased as a result of high parental expectations. Objectiveeasures were lacking.Anecdotal single case reports of therapeutic benefit

rom melatonin in Smith-Magenis syndrome exist [47], aso an equivalent number of reports with no benefits. Theime of its administration is important, because melatoninan have phase shifting properties when taken at differentimes. Low dosages (i.e., 0.5-2.5 mg) are preferred,ecause higher dosages (5-10 mg) can result in increasedaytime levels of melatonin and increased daytime sleep-ness. A double-blind controlled trial is required to fullyvaluate the effect of melatonin treatment in improving theuality of sleep in Smith-Magenis syndrome.

onclusions and Perspectives

Although the phenotype of Smith-Magenis syndromeas first recognized in 1982, our knowledge of theisorder continues to accumulate. Advances in the fieldsf cytogenetics and molecular genetics will enable morefficient diagnosis as well as identification of the genesnvolved in the Smith-Magenis syndrome critical regionnd their contribution to aspects of the phenotype. How-ver, the greater challenges are the timely diagnosis andnderstanding of the phenotype across the lifespan as wells the daily management of many of the problems uniqueo Smith-Magenis syndrome.

his research was supported in part by the Intramural Research Programf the National Human Genome Research Institute, National Institutes ofealth.

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neurologic and developmental features of the smith-magenis ... · all ethnic groups with an overall...

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