Smith-Magenis Syndrome

Ann CM Smith; John Berens; Kerry E Boyd; Christine Brennan; Andrea Gropman; Barbara Haas-Givler; Christopher Vlangos; Rebecca Foster; Rachel Franciskovich; Santhosh Girirajan; Nancy Raitano Lee; Cora Taylor; Sinan Omer Turnacioglu; Sarah H Elsea

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Smith-Magenis Syndrome

Synonym: del(17)(p11.2)

Ann CM Smith, MA, DSc (hon), CGC, John Berens, MD, FAAP, FACP, Kerry E Boyd, MD, FRCP(C), Christine Brennan, PhD, CCC-SLP, Andrea Gropman, MD, FAAP, FACMG, FANA, FAAN, FCNS, Barbara Haas-Givler, MEd, BCBA, Christopher Vlangos, PhD, FACMG, Rebecca Foster, PhD, Rachel Franciskovich, MS, CGC, Santhosh Girirajan, MBBS, PhD, Nancy Raitano Lee, PhD, Cora Taylor, PhD, Sinan Omer Turnacioglu, MD, and Sarah H Elsea, PhD, FACMG.

Author Information and Affiliations

Initial Posting: October 22, 2001; Last Update: May 29, 2025.

Estimated reading time: 1 hour

Summary

Clinical characteristics.

Smith-Magenis syndrome (SMS) is characterized by distinctive physical features (particularly coarse facial features that progress with age), developmental delay, cognitive impairment, behavioral abnormalities, sleep disturbances, and childhood-onset abdominal obesity. Infants have feeding difficulties, failure to thrive, hypotonia, hyporeflexia, prolonged napping or need to be awakened for feeds, and generalized lethargy. Most individuals function in the mild-to-moderate range of intellectual disability. Behavioral manifestations, including significant sleep disturbances, stereotypies, and maladaptive and self-injurious behaviors, are generally not recognized until age 18 months or older and continue to change until adulthood. Sensory issues are frequently noted, including avoidant behavior and repetitive seeking of specific textures, sounds, and experiences. Significant anxiety is common as are problems with executive function, including inattention, distractibility, hyperactivity, and impulsivity. Maladaptive behaviors include frequent outbursts / temper tantrums, attention-seeking behaviors, opposition, aggression, and self-injurious behaviors including self-hitting, self-biting, skin picking, inserting foreign objects into body orifices (polyembolokoilamania), and yanking fingernails and/or toenails (onychotillomania). Among the stereotypic behaviors described, the spasmodic upper body squeeze or "self-hug" seems to be highly associated with SMS. An underlying developmental asynchrony, specifically emotional maturity delayed beyond intellectual functioning, may also contribute to maladaptive behaviors in people with SMS.

Diagnosis/testing.

The diagnosis of SMS is established in a proband with suggestive clinical findings and either a heterozygous deletion of chromosome 17p11.2 that includes RAI1 or a heterozygous intragenic RAI1 pathogenic variant identified by molecular genetic testing.

Management.

Treatment of manifestations: Early childhood intervention programs; individualized special education for school-age children; speech-language, physical, occupational, and behavioral therapy and vocational training support later in life. Affected individuals may also benefit from monitored trials of psychotropic medication to increase attention and/or decrease hyperactivity, and therapeutic management of sleep disorders. Consider treating sleep disorders using acebutolol, melatonin, tasimelteon, and beta-1-adrenergic antagonists. Standard treatment for epilepsy, obesity, gastroesophageal reflux disease, constipation, hypercholesterolemia, palate anomalies, scoliosis, ophthalmologic issues, recurrent otitis media, hearing loss, cardiac anomalies, renal anomalies, immunodeficiency, hypothyroidism, and growth hormone deficiency. Individuals with a 17p11.2 deletion that includes FLCN may require management of features of Birt-Hogg-Dubé syndrome (BHDS). Respite care and psychosocial support for family members are recommended.

Surveillance: Annual multidisciplinary evaluations for general health and well-being and to plan for educational and vocational or other individualized interventions. In particular, periodic neurodevelopmental assessments and/or consultation with a developmental pediatrician to monitor progress and refer for additional services, evaluations, or support. School-age children should have periodic comprehensive evaluation to give input to the individualized education program. Annual otolaryngology, audiology, and ophthalmology evaluations. Measurement of growth parameters and nutritional status at each visit. Monitor for the development and/or progression of seizures and scoliosis. Annual fasting lipid profile, screening urinalysis for occult urinary tract infections, and thyroid function tests. Annual family psychosocial assessments are also recommended to assess support for caregivers and sibs. Repeat quantitative immunoglobulins / vaccine titers as clinically indicated. Surveillance in adulthood for complications of BHDS in those with a 17p11.2 deletion that includes FLCN.

Agents/circumstances to avoid: When starting a new medication, care should be taken to track sleep and behavior changes over several days or weeks to monitor for potential side effects (e.g., increased appetite, weight gain) and adverse reactions and/or to determine potential efficacy.

Genetic counseling.

SMS is an autosomal dominant disorder typically caused by a de novo deletion of chromosome 17p11.2 that includes RAI1 or an intragenic RAI1 pathogenic variant. Almost all individuals reported to date with SMS whose biological parents have undergone genetic testing have the disorder as a result of a de novo genetic alteration. Rarely, individuals diagnosed with SMS have the disorder as the result of a 17p11.2 deletion or intragenic RAI1 pathogenic variant inherited from an unaffected or mildly affected mosaic parent; a 17p11.2 deletion resulting from a structural chromosome rearrangement in a parent; or an intragenic RAI1 pathogenic variant inherited from a heterozygous affected parent. If neither parent is found to have the genetic alteration identified in the proband and parental chromosome analysis is normal, the recurrence risk to sibs is likely less than 1%. Once the SMS-related genetic alteration has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Diagnosis

No consensus clinical diagnostic criteria for Smith-Magenis syndrome (SMS) have been published.

Suggestive Findings

Clinical findings. SMS should be suspected in individuals with the following clinical findings (see Clinical Description):

A subtly distinctive facial appearance that becomes more evident with age (See Figures 1-3.)
Developmental delay and/or intellectual disability, including early speech delays (expressive delays greater than receptive speech) with or without associated hearing loss
A distinct neurobehavioral phenotype that includes stereotypic and maladaptive behaviors, as well as self-injurious behaviors
Mild-to-moderate infantile-onset hypotonia
Feeding difficulties and poor growth
Sleep disturbances
Short stature (prepubertal)
Childhood-onset obesity
Scoliosis
Minor skeletal anomalies, including brachydactyly
Signs of peripheral neuropathy including infantile hypotonia, hyporeflexia, relative insensitivity to pain, and mild intention tremor of upper extremity. In later childhood, a characteristic appearance of the legs and feet observed in peripheral nerve syndromes or neuropathies (i.e., "inverted champagne bottle appearance") with pes cavus or pes planus deformity and unusual broad-based gait (foot flap) may be apparent.
Ophthalmologic abnormalities including strabismus, progressive myopia, iris anomalies, microcornea, refractive errors, and retinal detachment. In adults, keratoconus and glaucoma are seen.
Otolaryngologic abnormalities including middle ear dysfunction (frequent otitis media, fluctuating hearing loss leading to tympanostomy tube placement), hyperacusis, laryngeal anomalies (polyps, nodules, edema, or partial vocal cord paralysis), velopharyngeal insufficiency and/or structural vocal fold abnormalities, and hoarse/deep voice

Figure 1.

Infants with Smith-Magenis syndrome (SMS). Female age nine months (left) and male age 30 months (right). Note brachycephaly, broad forehead, upslanting palpebral fissures, short, upturned nose, and characteristic downturned "tent"-shaped vermilion of (more...)

Figure 3.

Adolescent females with Smith-Magenis syndrome (SMS) caused by RAI1 heterozygous pathogenic variant (left) and deletion of 17p11.2 including RAI1 (right). Note short philtrum with relative prognathism resulting from midface retrusion that persists with (more...)

Laboratory findings

Inverted diurnal circadian melatonin rhythm (diurnal secretion profile)
Hyperlipidemia (during childhood) including increased total cholesterol and/or low-density lipoprotein cholesterol
Immune function abnormalities (especially low immunoglobulin A)

Imaging findings. Non-specific brain abnormalities identified by imaging are reported in more than 50% of affected individuals including:

Cortical atrophy
Ventriculomegaly

Family history. Because SMS is typically caused by a de novo genetic alteration, most probands represent a simplex case (i.e., a single occurrence in a family). Rarely, the family history may be consistent with autosomal dominant inheritance (i.e., affected males and females in multiple generations).

Establishing the Diagnosis

The diagnosis of SMS is established in a proband with suggestive clinical findings and one of the following identified by molecular genetic testing (see Table 1):

A heterozygous deletion of 17p11.2 that includes RAI1
A heterozygous pathogenic (or likely pathogenic) variant involving RAI1

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous RAI1 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of chromosomal microarray analysis (CMA), gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 1

CMA uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including RAI1) that cannot be detected by sequence analysis.

Note: Although a visible interstitial deletion of chromosome 17p11.2 can be detected in all individuals with the common approximately 3.7-Mb deletion by a routine G-banded karyotype analysis, provided the resolution is adequate (≥550 band), it is not uncommon for the deletion to be overlooked, particularly when the indication for the cytogenetic study is other than SMS. Therefore, CMA has replaced G-banded cytogenetic analysis and FISH analysis as a first-line test in the diagnosis of SMS.

If CMA does not detect a deletion of 17p11.2 and the diagnosis of SMS is still suspected, single-gene testing of RAI1 or a multigene panel that includes RAI1 may be considered. Exome or genome sequencing may also be performed.

Single-gene testing. Sequence analysis of RAI1, which detects missense, nonsense, splice site variants and small intragenic deletions/insertions, may be considered next. If no pathogenic variant is detected through sequence analysis of RAI1, gene-targeted deletion/duplication analysis, which can detect intragenic deletions or duplications of RAI1, may be considered. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.

A multigene panel that includes RAI1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the diagnosis of SMS has not been considered because an individual has atypical phenotypic features, comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. ACMG recommends exome and genome sequencing as first- or second-tier diagnostic testing for children with intellectual disability and/or multiple congenital anomalies [Manickam et al 2021]. To date, the majority of RAI1 pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified by exome sequencing.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Smith-Magenis Syndrome

Gene ¹	Method	Proportion of Pathogenic Variants ² Identified by Method
RAI1	CMA (recommended first) ³	~80%-90% ⁴
	Sequence analysis ^5, 6	~10%-20% ⁴
	Gene-targeted deletion/duplication analysis ⁷	Unknown

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on variants detected in this gene.
3.: A chromosomal microarray (CMA) that includes probe coverage of RAI1 can detect deletions of 17p11.2 (interstitial deletion, complex rearrangements, or derivative chromosomes) [Boot et al 2021].
4.: Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]
5.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
6.: Sequence analysis (particularly of exon 3, in which >99% of all pathogenic and likely pathogenic variants have been found to date) detects RAI1 pathogenic variants in individuals with SMS when cytogenetic and FISH studies are negative for the 17p11.2 deletion [Vilboux et al 2011, Vieira et al 2012, Dubourg et al 2014, Falco et al 2017, Boot et al 2021].
7.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Breakpoints of large deletions and/or deletion of adjacent genes may not be determined. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.

Clinical Characteristics

Clinical Description

To date, more than 400 individuals with a deletion or pathogenic variant involving RAI1 have been reported [Edelman et al 2007, Vilboux et al 2011, Perkins et al 2017, Linders et al 2023]. The following description of the phenotypic features associated with Smith-Magenis syndrome (SMS) is based on these reports.

SMS has a clinically recognizable phenotype that includes physical, developmental, and behavioral features (see Table 2). The phenotypic features can be subtle in infancy and early childhood, frequently delaying diagnosis until school age, when the characteristic facial appearance and behavioral manifestations may be more readily apparent.

Table 2.

Clinical Features of Smith-Magenis Syndrome

Frequency	System	Finding
>75% of individuals	Craniofacial/ Skeletal/ Growth	Brachycephaly Midface retrusion Relative prognathism w/age Broad, square-shaped face Everted, "tented" vermilion of the upper lip Deep-set, close-spaced eyes Short broad hands Dental anomalies (missing premolars, taurodontism) Obesity (>90th centile for weight), w/abdominal fat deposition (esp after age 10 yrs)
	Neurobehavioral	Infantile hypotonia Generalized lethargy (infancy) Oral sensorimotor dysfunction (early childhood) Sensory processing issues Developmental delay / cognitive impairment Speech-language impairment Sleep disturbances & inverted circadian rhythm Attention-seeking behaviors Inattention ± hyperactivity Tantrums, behavioral dysregulation Impulsivity Stereotypic behaviors Self-injurious behaviors Hyporeflexia Signs of peripheral neuropathy
	Otolaryngologic	Middle ear & laryngeal anomalies Hearing loss (79%) Hyperacusis (74%) Hoarse/deep voice
Common (50%-75% of individuals)		Short stature ¹ (esp in those w/deletions; <10% in those w/RAI1 PVs) Scoliosis Mild ventriculomegaly on brain imaging Hyperacusis Tracheobronchial problems Velopharyngeal insufficiency Ocular abnormalities (strabismus, myopia, iris anomalies, &/or microcornea) REM sleep abnormalities Hypercholesterolemia/hypertriglyceridemia Chronic constipation Features of autism spectrum disorder Immune function abnormalities (esp low IgA)
Less common (25%-50% of individuals)		Cardiac defects Thyroid function abnormalities Seizures (11%-30%); pubertal onset of catamenial seizures in females
Occasional (<25% of individuals)		Renal / urinary tract abnormalities EEG abnormalities (slowing, spikes) in absence of clinical seizures ¹ (25%) Forearm abnormalities Cleft lip/palate Retinal detachment; keratoconus (adulthood) Dystonia

: Ig = immunoglobulin; PV = pathogenic variant
: Based on Greenberg et al [1996], Chen et al [1997], Allanson et al [1999], Smith et al [2002], Potocki et al [2003], Gropman et al [2006], Smith et al [2006], Edelman et al [2007], Burns et al [2010], Perkins et al [2017], Smith & Gropman [2021]
1.: Frequency varies by study.

Facial Appearance

The facial appearance in SMS is characterized by a broad, square-shaped face, brachycephaly, prominent forehead, synophrys, mildly upslanted palpebral fissures, deep-set eyes, broad nasal bridge, midfacial retrusion (formerly known as midfacial hypoplasia), short, full-tipped nose with reduced nasal height, micrognathia in infancy changing to relative prognathia with age, and a distinct appearance of the mouth, with fleshy everted vermilion of the upper lip (see Figure 1).

The facial appearance in SMS becomes more recognizable in early childhood (see Figure 2 and Figure 3), with persisting midfacial retrusion, relative prognathism, and heavy brows with coarsening facial appearance.

Figure 2.

Early school-age children with Smith-Magenis syndrome (SMS). Male age four years (left) and female age five years (right); the female is also pictured at age 15 years in Figure 3. Note broad forehead, deep-set eyes, and midface retrusion. Images courtesy (more...)

Neurologic Manifestations

Hypotonia is reported in virtually all infants, accompanied by hyporeflexia (84%) and generalized lethargy.

Clinical signs of peripheral neuropathy are seen in approximately 75% of individuals with SMS, regardless of the deletion size [Gropman et al 2006].

In infancy and early childhood, these include infantile hypotonia, hyporeflexia, relative insensitivity to pain, and mild intention tremor (6-8 Hz) of the upper extremities [Gropman et al 2006].
In later childhood, affected children often exhibit a characteristic appearance of the legs and feet observed in peripheral nerve syndromes or neuropathies (i.e., "inverted champagne bottle appearance") with pes cavus or pes planus deformity and unusual broad-based gait (foot flap). This can cause pain and discomfort.
Some individuals with a large deletion extending into PMP22 may have insensitivity to pain, resulting in injuries that are not apparent to them. This is associated with recurrent acute focal sensory and motor neuropathies mainly at entrapment sites, painless nerve palsy after minor trauma or compression, and evidence on physical examination of previous nerve palsy such as focal weakness, atrophy, or sensory loss.

Toe walking (60%) may persist despite the absence of tight heel cords [Smith & Gropman 2021].

Microcephaly. Head circumference at birth is generally in the normal range with microcephaly developing over time [Gropman et al 2006].

Seizures. Seizures are reported in 11%-30% of individuals, and abnormal EEG without overt clinical seizures has been documented in 25% of individuals. Pubertal onset of catamenial seizures has also been observed in some females coinciding with menses [Merideth et al 2016, Smith & Gropman 2021]. Other seizure types have been reported but are not common in SMS, including tonic-clonic seizures [Maya et al 2014, Abad et al 2018] and absence seizures [Truong et al 2010].

One adult was reported to have a history of psychogenic seizures consisting of hyperventilation with tremors and a rapid pulse [Yeetong et al 2016]. Previous research has not found a correlation between the age of individuals with SMS and onset of seizures [Goldman et al 2006].

Stroke-like episodes have been reported in three individuals with SMS to date including:

A male born with bilateral cleft lip/palate and congenital heart defect who developed left hemiparesis at age 4.5 years [Smith & Gropman 2021];
A 10-year-old female with a ventricular septal defect who was also diagnosed with moyamoya disease and had evidence of ischemic changes at age five years [Girirajan et al 2007];
A 32-year-old female with evidence of severe atherosclerotic disease of the intracranial vessels documented after she experienced an ischemic infarct postoperatively following repeat cardiac surgery [Chaudhry et al 2007].

Neurodevelopmental Features

Developmental delays are evident in early childhood, with most individuals with SMS functioning in the mild-to-moderate range of intellectual disability. When reported, measured developmental or intelligence quotients range from 20 to 78, with a majority falling in the moderate range. Individuals with heterozygous deletions of 17p11.2 are more cognitively impaired than those with intragenic RAI1 pathogenic variants [Edelman et al 2007, Linders et al 2023]. Comprehensive literature review by Korteling et al [2024] found that many neuropsychiatric manifestations that commonly emerge in childhood and adolescence persist into adulthood, including mild-to-moderate intellectual disability, features related to autism spectrum disorder (ASD) and/or attention-deficit/hyperactivity disorder (ADHD) (40%), self-injurious and physically aggressive behaviors (>50%), self-hugging behavior, circadian sleep-wake disorder, and seizures (20%).

Note: Due to the maladaptive behaviors and sleep deficits, cognitive functioning may not be accurately assessed in many individuals and test scores may be an underestimation of an individual's true cognitive capacity.

Gross and fine motor skills are delayed in the first year of life and may be exacerbated by generalized hypotonia. Issues related to sensory integration are frequently noted [Hildenbrand & Smith 2012].

Speech and language

In infancy, crying is infrequent and often hoarse.
Most infants show markedly decreased babbling and vocalization for age.
By age two to three years, significant expressive language deficits relative to receptive language skills are recognized [Wolters et al 2009].
Analysis of data from the PRISMS SMS Patient Registry revealed that 60% of individuals with SMS in the data set communicated verbally, 79% began speaking words at/after age 24 months, 92% combined words at/after age 36 months, and 41% used sign language before speech [Brennan et al 2024].
With appropriate intervention and a total communication program that includes sign/gesture language and other augmentative communication approaches, verbal speech generally develops by school age; however, articulation problems usually persist. Speech intensity may be mildly elevated with a rapid rate and moderate explosiveness, accompanied by hypernasality and hoarse vocal quality.
A high percentage of children and adults (50%-80%) present with a hoarse vocal quality [Greenberg et al 1991, Hidalgo-De la Guía et al 2020, Brennan et al 2024].
Deficits in verbal comprehension, vocabulary, and word reasoning are common [e.g., Greenberg et al 1996, Udwin et al 2001, Osório et al 2012].
A comparison of individuals with SMS with a 17p11.2 deletion had similar profiles related to speech-language milestones, mode of communication, intelligibility, vocal quality, language abilities, and literacy ability. Slight differences were found when communication profiles of individuals with SMS due to an RAI pathogenic variant were compared to those with a deletion. Specifically, individuals with a deletion had slightly more pronounced speech delay and a lower percentage for verbal communication with lower reading abilities [Brennan & Baiduc 2024].
Communication strengths noted in more than 40% of individuals with SMS included social interest, humor, and memory for people, past events, and/or facts [Brennan et al 2024].
While socialization and social interest may be relative strengths [Udwin et al 2001, Martin et al 2006, Madduri et al 2006, Wolters et al 2009, Brennan et al 2024, Brennan & Baiduc 2024], social skills have been noted to be impaired In individuals with SMS [Dykens & Smith 1998, Brennan et al 2024].

Cognitive abilities

Affected individuals typically have relative weaknesses observed in sequential processing and short-term memory [Dykens et al 1997].
Relative strengths include long-term memory and perceptual closure (i.e., a process whereby an incomplete visual stimulus is perceived to be complete: "parts of a whole") [Dykens et al 1997, Udwin et al 2001].

Behavioral Manifestations

The behavioral manifestations of SMS, which includes sleep, maladaptive and self-injurious behaviors (SIB), and stereotypies, is generally not recognized until age 18 months or older and escalates with age, often coinciding with expected life cycle stages: 18-24 months, school age, and onset of puberty [Gropman et al 2006].

Maladaptive behaviors in people with SMS reflect a complex interplay between physiology and environment that may be further compounded by an underlying developmental asynchrony; specifically, emotional maturity is delayed relative to intellectual functioning [Finucane & Haas-Givler 2009].

With age, the gap between intellectual attainment and emotional development appears to widen for many people with SMS, and this disparity poses significant behavioral and programmatic challenges in older children and adults [Haas-Givler & Finucane 2014]. For example, adults with SMS may exhibit academic achievement at the 6- to 8-year-old level while emotional reactions are more reflective of the developmental level of a 1- to 3-year-old (i.e., referred to as the "inner toddler").
One study found that 90% of individuals with SMS (ages 4 and 18 years) demonstrated significant social impairment (35% in the mild-to-moderate range and 55% in the severe range per the Social Responsiveness Scale) per parent report, with manifestations that overlapped those of children with ASD or other developmental disorders [Laje et al 2010b].
A large-scale investigation of children and adults with SMS (ages 4 to 30 years) and six other genetic syndromes associated with intellectual or learning disabilities reported high levels of autistic features on the Social Responsiveness Scale, 2nd edition (SRS-2), a parent report measure [Lee et al 2022]. Of the autism subdomains investigated, the Restricted Interests and Repetitive Behavior scale was the most impacted. The SMS group received a higher score on this scale than the six other genetic syndromes studied. It was also the highest score received of the five SRS-2 scales within SMS group. When examining scores on the social scales of the SRS-2 among SMS participants only, parents reported the lowest level of concern on the Social Motivation scale and intermediate concerns on the Social Communication, Cognition, and Awareness scales.
The degree of sleep disturbance remains one of the strongest predictors of maladaptive behavior [Dykens & Smith 1998, Arron et al 2011, Sloneem et al 2011, Smith et al 2019].

Self-injurious behaviors (SIB) are present in most individuals after age two years [Arron et al 2011, Sloneem et al 2011].

A direct correlation exists between the number of different types, intensity, and frequency of SIB and the level of intellectual impairment.
Three behaviors distinctive to SMS include nail yanking (onychotillomania), skin picking, and insertion of foreign objects into body orifices (polyembolokoilamania); prevalence rates for these behaviors range from 25% to 90% of affected individuals depending on the age and group studied (see Genotype-Phenotype Correlations).
- Nail yanking generally does not become a major problem until late childhood.
- Object insertion in ears is most relevant in both children and adults; other body orifices (nose, vagina, and rectum) are generally not reported until late teens / adulthood [Gropman et al 2007].
The overall prevalence of SIB increases with age, as does the number of different types of SIB exhibited [Finucane et al 2001], which may include self-hitting (71%), self-biting (77%), and skin picking (65%).

Note: Given the high rates of SIB, including self-insertion of objects or digits into body orifices, caution must be taken when evaluating individuals with SMS for maltreatment or abuse. Although individuals with intellectual disability are at high risk for maltreatment, abuse may also be incorrectly suspected due to SIB or self-insertion behaviors.

Sensory integration issues are present and persist throughout childhood. A prominent pattern of sensory processing difficulties is recognized, characterized by an imbalance in neurologic thresholds and a fluctuation between active and passive self-regulation [Hildenbrand & Smith 2012].

Other maladaptive behaviors may include the following:

Head banging, which may begin as early as age 18 months
Frequent outbursts / temper tantrums
Attention-seeking behaviors (especially from adults)
Impulsivity, which may increase over time, particularly in females [Martin et al 2006]
Inattention with or without hyperactivity
Oppositional behaviors
Aggression
Rapid mood shifts
Anxiety, which can become a significant issue in adolescence and adulthood
Toileting difficulties

Stereotypies common to SMS include the following:

The spasmodic upper body squeeze or "self-hug" behavior, which may provide an effective clinical diagnostic marker for the syndrome [Finucane et al 1994]
Mouthing of hands or objects, which persists from early childhood to ages where this is not socially acceptable
Teeth grinding
Vocal stereotypies, "crickets" sound (comforting, self-regulating)
Body rocking
Spinning or twirling objects
Finger lick and repetitive page turning ("lick and flip") behavior [Dykens & Smith 1998, Vieira et al 2012]

Sleep disturbances. The abnormal diurnal (inverted) circadian rhythm of melatonin appears pathognomonic in SMS and is documented in more than 90% of affected individuals with studied profiles [Potocki et al 2000b, De Leersnyder et al 2001, Boudreau et al 2009, Chik et al 2010, Boone et al 2011, Nováková et al 2012]. Further studies suggest that sleep disturbances cannot be caused solely by aberrant melatonin synthesis and/or degradation as previously suggested [Boudreau et al 2009]. While not inverted, the 24-hour circadian rhythm of body temperature is phase advanced by about three hours relative to controls [Smith et al 2019].

Sleep disturbances are characterized by fragmented and shortened sleep cycles with frequent nocturnal and early morning awakenings and excessive daytime sleepiness [Greenberg et al 1996, Smith et al 1998, Potocki et al 2000b, De Leersnyder et al 2001, Smith & Duncan 2005].

Parents usually do not recognize significant sleep problems before age 12-18 months, although fragmented sleep with reduced total sleep time has been documented as early as age six months [Duncan et al 2003, Gropman et al 2006].
Diminished REM sleep was documented in more than half of those who underwent polysomnography [Greenberg et al 1996, Potocki et al 2000b].
Actigraphy-based sleep estimates document developmental differences in nocturnal arousal patterns by age and time of night [Gropman et al 2007, Smith et al 2019].
- Affected individuals have a reduction in 24-hour and night sleep compared to healthy pediatric controls, with estimated sleep about one hour less than expected across all ages. This is evidenced by decreased total night sleep, lower sleep efficiency, earlier sleep onset and final sleep offset, increased waking after sleep onset (WASO), and increased duration of daytime naps (beyond typical age) [Smith et al 2019].
- Developmental sleep changes from childhood through adolescence/adulthood are evidenced by an age-related variation in the timing of wake onset (but not sleep onset) and WASO [Smith et al 2019].
- Age differences are also associated with different patterns of sleep for SMS compared to healthy controls [Smith et al 2019]: In those younger than age ten years, late-night activity was greater in individuals with SMS than in pediatric controls. Older individuals with SMS (age >10 years) exhibited less late-night activity but increased early-night activity, consistent with poor "settling" and delayed sleep pattern.
Due to the propensity of weight gain as affected individuals age, obstructive sleep apnea may also develop and can contribute to the overall sleep disturbance.
Disrupted sleep becomes a significant problem in early childhood and is a major issue for caregivers, who themselves may become sleep deprived [Foster et al 2010, Agar et al 2022]. Most caregivers report experiencing major sleep deprivation and stress that significantly impacts their ability to function and support their child [Agar et al 2022]. Safety concerns and need to monitor their child overnight to prevent/avert wandering, food foraging, and/or self-injury requires use of a range of mitigating strategies (e.g., enclosed bed system / "safe space" for containment during sleep, bedroom adaptations, locked kitchen cabinets).

Growth and Feeding

At birth, weight, length, and head circumference are generally in the normal range.

Feeding difficulties in infancy leading to failure to thrive are common, including marked oral motor dysfunction with poor suck and swallow and textural aversion.

In early infancy, length and weight gradually decelerate; short stature (height <5th centile) is frequently observed (67%), especially at young ages, but may not persist into adulthood.

Dietary preferences, hyperphagia, and food foraging at night (especially at older ages), coupled with a general sedentary lifestyle and psychotropic medication side effects (affecting appetite / weight gain), contribute to obesity (increased BMI), typically beginning in school-age children (age 6-9 years) [Gandhi et al 2022, Elatrash et al 2024, Lazareva et al 2024].

Obesity may lead to increased risk for related health issues (e.g., diabetes mellitus type 2) in adulthood.
Individuals with SMS display unique food-related behaviors manifested by a constant obsession with and hyperfixation on food that is not entirely driven by hunger alone [Elatrash et al 2024].

Hyperlipidemia. Hypercholesterolemia that is not associated with diet or BMI values is recognized in more than 50% of individuals with SMS [Smith et al 2002]. In a pediatric study of 49 individuals with SMS caused by a deletion of 17p11.2 younger than age 18 years, one third had total cholesterol (TC) or low-density lipoprotein (LDL) cholesterol in the borderline range, and more than one third had values in the high range. Fewer than one third had normal values for all three variables (TC, LDL, triglycerides) [Smith et al 2002]. In an older Italian SMS group (mean age 13.9 years) [Cipolla et al 2023], TC and LDL cholesterol were high in 20% of individuals and 63% had low HDL cholesterol. Dyslipidemia was not documented in individuals with RAI1 pathogenic variants.

Gastrointestinal

Gastroesophageal reflux and constipation are frequently reported.

Oral and Dental Anomalies

Oral sensorimotor dysfunction is a significant issue, including the following:

Lingual weakness, asymmetry, and/or limited mobility
Weak bilabial seal (64%)
Palate abnormalities (64%), although cleft lip and/or palate occur in fewer than 25% of affected individuals
Open-mouth posture with tongue protrusion and frequent drooling

A high prevalence (~90%) of dental anomalies, specifically tooth agenesis (especially premolars) and taurodontism, has been reported. This is accompanied by an age-related increase in dental caries and poor gingival health due to decreased oral hygiene, supporting the need for increased dental care in adolescent years [Tomona et al 2006].

Musculoskeletal Manifestations

Mild-to-moderate scoliosis, most commonly of the mid-thoracic region, is seen in approximately 60% of affected individuals age four years and older, although vertebral anomalies are seen in only a few to date.

A tethered cord has been reported in three individuals with RAI1 deletions at ages four, eight, and 34 years, respectively [Wigby & Reiner 2024].

Hands and feet are usually small for age.

Markedly flat or highly arched feet and unusual gait are generally observed.

Ocular Abnormalities

Ocular abnormalities are present in approximately 85% of affected individuals and include strabismus, progressive myopia, iris anomalies, and/or microcornea. About 20% of affected individuals older than age ten years experience retinal detachment, which may be due to a combination of aggressive/self-injurious behaviors and high myopia. Adults may experience keratoconus and glaucoma.

Ears and Hearing

Otitis media occurs frequently (≥3 episodes/year) and often leads to tympanostomy tube placement (85%).

Hearing loss is documented in more than 79% of affected individuals [Brendal et al 2017], with conductive loss most common before age ten years.

A pattern of fluctuating and progressive hearing decline occurs with age, including sensorineural hearing loss (48%) after age 11 years [Brendal et al 2017].

Hyperacusis, or oversensitivity to certain frequencies/sounds tolerable to listeners with normal hearing, is reported in approximately 74% [Brendal et al 2017].

Laryngeal Anomalies

Laryngeal anomalies, including polyps, nodules, edema, or partial vocal cord paralysis, are common.

Velopharyngeal insufficiency and/or structural vocal fold abnormalities without reported vocal hyperfunction are seen in most individuals with SMS.
Functional impairments in voice (hoarseness) may contribute to the marked delays in expressive speech.

Cardiovascular Defects

Cardiovascular defects are identified in fewer than 50% of affected individuals with SMS who have a deletion of 17p11.2. Congenital heart defects remain rare among individuals with SMS due to heterozygous pathogenic RAI1 variants, with only a single reported infant born with severe congenital pulmonary valve stenosis to date [Onesimo et al 2022]. Cardiac anomalies may include mild tricuspid or mitral valve stenosis or regurgitation, ventricular septal defects, supravalvular aortic or pulmonic stenosis, atrial septal defects, tetralogy of Fallot, and total anomalous pulmonary venous connection [Onesimo et al 2021, Smith & Gropman 2021].

Genitourinary Anomalies

Genitourinary anomalies are found in 15%-35% of affected individuals who have a deletion of 17p11.2 but have not been reported in those who have a heterozygous pathogenic variant in RAI1. Anomalies may include the following [Smith et al 1986, Greenberg et al 1996, Chou et al 2002, Myers et al 2007]:

Duplicated collecting renal system
Unilateral renal agenesis and ectopic kidney
Ureterovesical obstruction
Malposition of the ureterovesical junction

Additionally, the majority of affected individuals have nocturnal enuresis in childhood. Genital anomalies reported include cryptorchidism, shawl, or undeveloped scrotum in males, and infantile cervix and/or hypoplastic uterus in females [Smith & Gropman 2021].

Immunologic Manifestations

More than 50% of affected individuals have low serum immunoglobulin (Ig) profiles, which may increase susceptibility to sinopulmonary infections. A systematic study of serum Ig profiles (IgA, IgG, IgM) in a large cohort (age 4-27 years) documented diminished immunologic function in most affected individuals (60%). Recurrent otitis media (88%), upper respiratory infections (61%), pneumonia (47%), and/or sinusitis (42%) requiring antibiotics are frequently reported [Perkins et al 2017].

Endocrine

The specific incidence of endocrine abnormalities in individuals with SMS remains undefined.

About 25% of affected individuals have mild hypothyroidism.
Puberty typically occurs within the normal time frame; however, precocious puberty (premature adrenarche), premature ovarian failure [A Smith, personal observation], and delayed sexual maturation have been observed.
While short stature occurs in SMS, only one published case of isolated growth hormone deficiency has been reported to date [Itoh et al 2004]. When growth hormone profiles are studied, peak levels appear in the proper phase of the day with levels only slightly below normal controls [De Leersnyder et al 2001, De Leersnyder et al 2006].
Adrenal aplasia/hypoplasia was described in one affected male infant who died unexpectedly after palatoplasty [Denny et al 1992].

Dermatologic Manifestations

In addition to skin problems due to self-injurious behaviors, a minority of affected individuals have rosy cheeks (which may be related to drooling and/or eczema) and/or hyperkeratosis (~20%) over the hands, feet, or knees.

Complaints of dry skin remain common, especially among those with an RAI1 pathogenic variant (100%) compared to those with a 17p11.2 deletion (44%) [Edelman et al 2007].
Hair and skin color often appears fairer compared to other family members.
Fibrofolliculomas associated with deletion of FLCN may also be present in late childhood and throughout adulthood.

Malignancy and Other Features of Birt-Hogg-Dubé Syndrome (BHDS)

The risk of cancer appears to be no greater than in the general population for most individuals with SMS. However, SMS due to a heterozygous 17p11.2 deletion often results in haploinsufficiency of FLCN, which is associated with BHDS, an adult-onset hereditary cancer syndrome characterized by cutaneous fibrofolliculomas, pulmonary cysts, spontaneous pneumothorax, and renal tumors.

Individuals with SMS due to a deletion that contains FLCN have an increased chance of developing BHDS, but the diagnosis should never be made in children or adults who show no evidence of features. One hit (an SMS deletion) does not mean that a person has or ever will develop the clinical features of BHDS.

Features of BHDS have been described in several individuals with SMS [Vocke et al 2023]:

Typically, BHDS-related spontaneous pneumothorax occurs in adults younger than age 40 years [Schmidt & Linehan 2015]. However, among the four reported individuals with SMS caused by a 17p11.2 deletion and spontaneous pneumothorax, the pneumothoraces occurred at younger ages than expected (range: 2-22 years) [Finucane et al 2021].
To date, renal tumors have been reported in four adults with heterozygous deletions of 17p11.2 [Vocke et al 2023]:
- A male with bilateral renal tumors on imaging (histopathology not available) and no skin or lung findings at age 57 years [Dardour et al 2016];
- A female with bilateral pathologically confirmed hybrid oncocytic tumors without evidence of skin lesions or lung findings at age 50 years [Smith et al 2014, Vocke et al 2023];
- A male who died of unrelated causes at age 45 years was found on autopsy to have an oncocytic neoplasm with features of chromophobe renal cell carcinoma; tumor tissue contained a second FLCN pathogenic variant [Smith et al 2014, Vocke et al 2023];
- A female with renal oncocytoma and confirmed second FLCN pathogenic variant without evidence of skin lesions or lung findings at age 41 years [Vocke et al 2023].
A female with biopsy-documented fibrofolliculoma and a 4-mm lung cyst showed no evidence of renal tumors at age 25 years based on an MRI surveillance study.
An online survey of parents of individuals with SMS (due to either heterozygous deletions of 17p11.2 or RAI1 pathogenic variants) assessed the prevalence of three features of BHDS (spontaneous pneumothorax, pathognomonic skin findings, and renal cancer). Among 117 respondents, five individuals reported spontaneous pneumothorax (4 of the 5 had a deletion of 17p11.2), and two individuals with deletions of 17p11.2 had fibrofolliculoma. No instances of renal cancer were reported [Finucane et al 2021].

Other Manifestations

A male with SMS due to a confirmed RAI1 nonsense variant had three spontaneous pneumothoraces between ages five and ten years [Truong et al 2010].

A female with SMS and a confirmed RAI1 pathogenic variant had a spontaneous pneumothorax at age nine years [Truong et al 2010, Finucane et al 2021].

Neuroimaging Abnormalities

The most common structural brain abnormalities identified on imaging are non-specific and include ventriculomegaly and cortical atrophy. Also reported are enlarged posterior fossa, periventricular gray matter heterotopia, and decreased grey matter in the insula and lenticular nucleus [Greenberg et al 1996, Boddaert et al 2004]. In addition, heterotopias and thin corpus callosum have been reported in several individuals [Capra et al 2014, Maya et al 2014].

Co-occurrence of moyamoya disease and SMS has been reported in an individual with a large deletion of 17p11.2 [Girirajan et al 2007].

Neuropathologic Abnormalities

Foreshortened frontal lobes with a choroid plexus hemangioma have been reported on neuropathologic examination [Smith et al 1986].

Prognosis

Insufficient longitudinal data are available to accurately determine life expectancy. One would expect that in the absence of major organ involvement the life expectancy of individuals with SMS would not differ from that of individuals with intellectual disability at large. Anecdotally, the oldest known individual with SMS lived to age 88 years [A Smith & E Magenis, unpublished data]. In the month prior to her death, she was reportedly her usual alert, happy, "SMS" self with ongoing sleep issues and was being treated for chronic recurrent sinusitis. Four days prior to death, she suffered an apparent right-sided stroke with left-sided weakness. No autopsy was performed.

Recurrence of SMS in two sibs, a 37-year-old male and his older 54-year-old sister, with deletion of 17p11.2 due to gonadal mosaicism and transmission from their 79-year-old mosaic mother (62% mosaicism in lymphocytes), has been reported [Smith et al 2006]. The brother, who died at age 45 years from aggressive B-cell lymphoma, showed postmortem central nervous system white matter findings in addition to unsuspected BHDS with chromophobe renal cell carcinoma and a confirmed second FLCN pathogenic variant [Smith et al 2006, Vocke et al 2023]. The mother, cognitively normal in her youth, had a medical history significant for behavior/emotional problems and aggressive mood swings, obesity, idiopathic thrombocytopenia, hysterectomy for uterine cancer at age 42 years, cholecystectomy at age 69 years, adult-onset diabetes from age 77 years, and early-onset dementia accompanied by explosive behaviors at age 79 years. She died at age 85 years from an intraventricular hemorrhage. Brain histopathology showed significant white matter atrophy and degenerative Alzheimer disease.

Genotype-Phenotype Correlations

Several genotype-phenotype correlations have been proposed for individuals with SMS depending on the molecular mechanism.

Deletions of 17p11.2 Including RAI1

Individuals with a heterozygous deletion of 17p11.2 including RAI1 are more cognitively impaired than those with an intragenic RAI1 pathogenic variant [Edelman et al 2007, Linders et al 2023]. Individuals with a deletion have more marked speech delays and a lower percentage of verbal language and reading abilities [Brennan & Baiduc 2024].

Cardiovascular defects are identified in fewer than 50% of affected individuals with SMS who have a deletion of 17p11.2. Only a single individual with a heterozygous pathogenic variant in RAI1 has been reported with severe congenital pulmonary valve stenosis to date [Onesimo et al 2022].

Genitourinary anomalies are reported in 15%-35% of affected individuals who have a deletion of 17p11.2 but have not been reported in those with a heterozygous pathogenic variant in RAI1.

Parental origin of the 17p deletion has not been documented to affect the phenotype, suggesting that imprinting does not play a role in the expression of the typical SMS phenotype.

Note: See Genetically Related Disorders for information about individuals who have larger deletions of 17p that extend distally to include PMP22.

Pathogenic Variants in RAI1

Higher rates of onychotillomania and polyembolokoilamania (90%) have been reported in individuals with a heterozygous pathogenic variant in RAI1 compared to those with 17p11.2 deletions (40%) [Edelman et al 2007].

The risk of obesity and obesity-related health issues is higher in individuals with a heterozygous pathogenic variant in RAI1 compared to those with a 17p11.2 deletion [Alaimo et al 2014].

Individuals with a heterozygous pathogenic variant in RAI1 typically do not have short stature or other organ system involvement [Slager et al 2003, Bi et al 2004, Girirajan et al 2005].

Prevalence

The birth incidence of SMS is estimated to be 1:25,000 births [Greenberg et al 1991]; the actual prevalence may be closer to 1:15,000 [Smith et al 2005].

Genetically Related (Allelic) Disorders

RAI1 repeat expansions. A pentanucleotide repeat expansion in intron 4 of RAI1 was reported in a Malian/African family with benign adult familial myoclonic epilepsy [Yeetong et al 2024]. Intronic pentanucleotide expansions are thought to act as gain-of-function variants resulting in focal RNA aggregation and RNA-mediated toxicity in cortical neurons and cerebellar Purkinje cells [Ishiura & Tsuji 2020]. No features of Smith-Magenis syndrome (SMS) were described in affected family members.

Deletions/duplications of the 17p11.2 region

Individuals with larger deletions extending distally to include PMP22 are also at risk for hereditary neuropathy with liability to pressure palsies (HNPP).
Individuals with 17p11.2 duplication syndrome (Potocki-Lupski syndrome) have the recombination reciprocal of the SMS deletion and differ phenotypically and behaviorally from those with SMS [Potocki et al 2000a, Potocki et al 2007].
Yuan-Harel-Lupski (YUHAL) syndrome (OMIM 616652) is caused by a contiguous gene duplication of chromosome 17p12-p11.2 that includes RAI1 and PMP22. YUHAL syndrome is a complex neurodevelopmental disorder characterized by developmental delay and early-onset peripheral neuropathy. The disorder comprises features of both demyelinating Charcot-Marie-Tooth hereditary neuropathy type 1A (caused by duplication of PMP22) and Potocki-Lupski syndrome [Yuan et al 2015].

Differential Diagnosis

Smith-Magenis syndrome (SMS) should be distinguished from other syndromes that include developmental delay, infantile hypotonia, short stature, distinctive facies, and behavioral manifestations. The pervasive behavioral aspects and circadian sleep disorder associated with inverted melatonin secretion can help distinguish SMS from other neurodevelopmental disorders. However, because the phenotype of SMS is broad and changes with time, all disorders with intellectual disability without other distinctive findings should be considered in the differential diagnosis. See OMIM Phenotypic Series for genes associated with:

The most common of the neurodevelopmental disorders of interest in the differential diagnosis of SMS include Down syndrome (trisomy 21) and those listed in Table 3.

Table 3.

Disorders with Developmental Delay / Intellectual Disability of Interest in the Differential Diagnosis of Smith-Magenis Syndrome

Gene / Genetic Mechanism	Disorder	MOI	Overlapping Clinical Features w/SMS (in addition to DD/ID):
22q11.2 deletion	22q11.2 deletion syndrome	AD	Hypotonia Early feeding issues & speech delay CHD (<25% in SMS) Velopharyngeal insufficiency Cleft palate Low Igs Strabismus Hearing loss Psychiatric comorbidities (e.g., ASD, ADHD, anxiety) Skeletal anomalies (scoliosis, vertebral anomalies)
Abnormal methylation w/in PWCR at 15q11.2-q13)	Prader-Willi syndrome	See footnote 1.	Infantile hypotonia Lethargy Early growth abnormalities Childhood obesity (hyperphagia) Strabismus Behavior issues (tantrums, autistic features, ADHD, anxiety) Sleep disturbances
CHD2	CHD2-related neurodevelopmental disorders ²	AD ³	Early-onset seizure disorder (photic stimulation triggers) Language impairment ASD, ADHD Challenging behaviors, aggression
DEAF1 ⁴	Vulto-van Silfout-de Vries syndrome ⁵ (OMIM 615828)	AD ³	Speech delays Hypotonia, gait issues Seizures High pain threshold Autistic features Sleep issues
Deficient expression or function of maternally inherited UBE3A allele	Angelman syndrome	See footnote 1.	Speech-language delay Strabismus Scoliosis Behavioral features (autistic features, aggression, anxiety) Sleep disturbances w/multiple awakenings
9q34.3 deletion that includes EHMT1 or intragenic EHMT1 PV	Kleefstra syndrome ⁶	AD ³	Hypotonia Lethargy Broad forehead, hypertelorism, synophrys, & midface retrusion Significant speech-language delay Sleep disturbance Challenging behaviors, stereotypies, self-injury, mood disorder
FMR1	Fragile X syndrome (See FMR1 Disorders.)	XL	Hypotonia Autistic-like behaviors
2q37.3 deletion that includes HDAC4 or intragenic HDAC4 PV ^6, 7, 8	2q37 deletion syndrome (OMIM 600430)	AD ³	Hypotonia Facial features (broad, upslanting palpebral fissures, midface hypoplasia, synophrys) Seizures Brachydactyly, hypermobile joints, scoliosis Short stature & obesity Visceral malformations (20%-30%), e.g., CHD, GU Decreased pain sensitivity Sleep disorder Behavioral issues (self-injury, ASD)
IQSEC2 ⁵	IQSEC2-related ID syndrome (OMIM 309530)	XL	Hypotonia Speech-language delay Strabismus Feeding issues / GERD Seizures Scoliosis Sleep disturbance Self-injurious, stereotypic, autistic-like behaviors
KAT5	KAT5-related NDD w/dysmorphic facies, sleep disturbance, & brain abnormalities ^5, 9	AD ³	Facial dysmorphism Short stature Seizures Urogenital anomalies Disruptive behavior / ADHD Sleep disturbance
2q23.1 deletion that includes MBD5 or intragenic MBD5 PV	MBD5 haploinsufficiency ⁴	AD ³	Speech impairment Ocular abnormalities Hypotonia Seizures Sleep disturbances (circadian rhythm disruption, i.e., downregulation of clock genes) Abnormal behaviors (e.g., autistic-like features, self-injury, aggression) Hyperphagia
TCF20 ¹⁰	TCF20-related NDD (OMIM 618430)	AD ³	Hypotonia Autistic features, ADHD, anxiety Vision abnormalities (strabismus, myopia, keratoconus)
18q21.2 deletion that includes TCF4 or intragenic TCF4 PV	Pitt-Hopkins syndrome	AD ³	Dysmorphic facial features (short philtrum, downturned mouth, exaggerated Cupid's bow, relative prognathia, coarsening w/age) Hypotonia Severe myopia Scoliosis Obesity Sleep issues Stereotypies & behavioral issues (ADHD, anxiety, aggression)
POGZ	White-Sutton syndrome	AD ³	Dysmorphic facial features (brachycephaly, brachydactyly) ID (learning disabilities to ASD) Obesity Sleep disturbance Stereotypies & behavioral issues (ADHD, anxiety, aggression)

: AD = autosomal dominant; ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder;
: CHD = congenital heart defect; DD = developmental delay; GERD = gastroesophageal reflux disease; GU = genitourinary; ID = intellectual disability; Ig = immunoglobulin; MOI = mode of inheritance; NDD = neurodevelopmental disorder; PV = pathogenic variant; PWCR = Prader-Willi critical region
1.: Recurrence risk depends on the underlying genetic mechanism in the proband.
2.: Cogliati et al [2024]
3.: Typically de novo
4.: Transcriptionally regulates RAI1 expression
5.: Berger et al [2017]
6.: Rinaldi et al [2022]
7.: Possible RAI1 transcriptional regulator
8.: Gavril et al [2023]
9.: Humbert et al [2020]
10.: Paralog to RAI1

Management

Management guidelines for Smith-Magenis syndrome (SMS) have been published by PRISMS. See Medical Management Guidelines and Management Checklist (revised/approved 24 January 2018).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SMS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Table 4.

Smith-Magenis Syndrome: Recommended Evaluations Following Initial Diagnosis

System/Concern	Evaluation	Comment
Neurologic	EEG in those w/clinical seizures or suspected seizures Neuroimaging (MRI or CT scan) in accordance w/findings such as seizures &/or motor asymmetry	For those w/o overt seizures, EEG may be helpful to evaluate for possible subclinical events in which treatment may improve attention &/or behavior; a change in behavior or attention warrants reevaluation.
Development	Developmental assessment	To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education
Behavior	Neuropsychological eval	In persons age >12 mos: screen for issues incl sleep disturbances, ADHD, anxiety, &/or ASD features.
Sleep/ Respiratory	Sleep history w/particular attention to sleep/wake schedules & signs/symptoms of obstructive sleep apnea Polysomnogram (overnight sleep study) to evaluate for obstructive sleep apnea in those w/evidence of sleep-disordered breathing	Sleep diaries or actigraphy may prove helpful in documenting sleep/wake schedules.
Growth/ Feeding	Assessment of growth parameters for failure to thrive in infancy & obesity in older persons	Consider referral to gastroenterologist for those w/failure to thrive; consider nutrition &/or full feeding eval.
	Consider assessment of oral motor dysfunction & suck/swallowing issues in infancy.
	Fasting lipid profile in childhood, adolescents, & adults	Eval for hypercholesterolemia
Gastrointestinal	Assessment for: Signs/symptoms of GERD Constipation Caloric intake
Mouth	Assessment for palatal defects & dental anomalies (if teeth have erupted)	Consider referral to pediatric dentist.
Musculoskeletal	Spine radiographs to assess for vertebral anomalies & scoliosis	MRI if concern for tethered cord or spinal stenosis (few adults)
Eyes	Ophthalmologic eval	Attention to evidence of strabismus, microcornea, iris anomalies, & refractive error In adults: keratoconus & glaucoma
ENT	Audiologic assessment for CHL &/or SNHL Consider eval for velopharyngeal insufficiency in those w/functional impairments.
Cardiovascular	Echocardiogram to assess for congenital heart defects
Genitourinary	Ultrasound exam for renal/urologic anomalies	Further urologic evals may be needed if history of frequent urinary tract infections.
Immunologic	Qualitative Igs ¹ incl vaccine titers (incl pneumococcus) Susceptibility to sinopulmonary infections, aspiration pneumonia	Consider eval by immunologist, as prophylactic antibiotics strategies to prevent infections may benefit some persons.
Endocrine	Thyroid function studies to include TSH & either thyroxine or free thyroxine ²
Dermatologic	Skin assessment	For evidence of self-injurious behaviors, eczema, & hyperkeratosis
Dermatologic	In those w/17p11.2 deletion incl FLCN (see BHDS): Detailed dermatologic exam Biopsy of suspicious lesion(s)	To assess for dermatologic features of BHDS incl melanoma
Pulmonary	In those w/17p11.2 deletion incl FLCN & signs/symptoms of pneumothorax (see BHDS): Chest radiograph Chest CT
Renal	In those w/17p11.2 deletion incl FLCN (see BHDS): abdominal MRI to assess for renal tumors	Beginning at age 21 yrs
Safety considerations	Assess safety concerns /need to monitor overnight to prevent/avert wandering, food foraging, &/or self-injury. Assess for aggressive behaviors.	Range of mitigating strategies (e.g., enclosed bed system / "safe space" for containment during sleep, bedroom adaptations, locked kitchen cabinets) Safety eval for person w/SMS & caregivers
Genetic counseling	By genetics professionals ³	To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of SMS to facilitate medical & personal decision making
Family support & resources	By clinicians, wider care team, & family support organizations	Assessment of family & social structure to determine need for: Community or online resources such as Parent to Parent Social work involvement for parental support Home nursing referral

: ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; BHDS = Birt-Hogg-Dubé syndrome; CHL = conductive hearing loss; GERD = gastroesophageal reflux disease; Ig = immunoglobulin; SMS = Smith-Magenis syndrome; SNHL = sensorineural hearing loss; TSH = thyroid-stimulating hormone
1.: To include quantitative serum Igs (IgG, IgA, IgM)
2.: Screening for adrenal function should be considered in individuals with larger deletions extending into 17p12.
3.: Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Treatment of Manifestations

There is no cure for SMS. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Table 5.

Smith-Magenis Syndrome: Treatment of Manifestations

Manifestation/Concern	Treatment	Considerations/Other
Developmental delay / Intellectual disability	See Developmental Delay / Intellectual Disability Management Issues.
Epilepsy	Standard treatment w/ASMs by experienced neurologist	Many ASMs may be effective; none has been demonstrated effective specifically for SMS. Importantly, several ASMs may cause sleepiness, so this & timing of dosing should be kept in mind & adjusted as needed given the circadian disturbance in SMS & possible exacerbation. Avoid ASMs assoc w/weight gain (i.e., valproic acid) Education of parents/caregivers ¹
Speech-language delay	Identify & treat swallowing/feeding problems & optimize oral sensorimotor development. Develop skills related to swallowing & speech production by ↑ sensory input, fostering movement of articulators, ↑ oral motor endurance, & ↓ hypersensitivity.
Behavioral issues ^2, 3	Develop a comprehensive behavioral support plan for home & school at onset of maladaptive behaviors (typically starting in early elementary school). Develop structured school program w/one-on-one support & curricula matched to known cognitive & behavior profile of SMS. Behavioral therapies include special education techniques emphasizing individualized instruction, structure, & routine to minimize behavioral outbursts in school.	Assess for underlying reasons for changes in behavior (HELP model). ^2, 4 Insight about vulnerabilities & relative strengths in sensory processing patterns (i.e., visual processing & oral sensory processing) may aid caregivers in adapting activity demands, modifying environments, & facilitating appropriate & supportive social interactions. ^2, 3 Atypical patterns of sensory processing & more problematic/atypical behaviors may become more prominent w/age. ³
Psychiatric disorders	Specialized developmental psychiatric & psychological services for assessment & treatment for psychiatric or mental health concerns Psychotropic medication & psychological services to ↓ maladaptive behaviors, ↑ attention &/or ↓ hyperactivity, ↓ anxiety, & stabilize mood	No single medication regimen has been shown to be consistently effective. ⁵
Sleep disorder ⁶	Melatonin	Early anecdotal reports of therapeutic benefit from melatonin (low dose; <3 mg) taken at bedtime suggest variable improvement of sleep w/o major adverse reactions. ⁷
	Tasimelteon	Melatonin receptor agonist: 1st FDA-approved treatment of nighttime sleep disturbance in SMS. ⁸ A randomized crossover study using tasimelteon showed effective improvement of sleep quality & total sleep time. ⁸
	Oral beta-1-adrenergic antagonist	A single uncontrolled study reported suppression of daytime melatonin peaks & subjectively improved behavior. ⁹
	Acebutolol w/melatonin	An uncontrolled trial combined daytime dose of acebutolol w/evening oral dose of melatonin & found that nocturnal plasma concentration of melatonin was restored & nighttime sleep improved w/disappearance of nocturnal awakenings. ¹⁰
	Enclosed bed system for containment during sleep	Safety concerns / need to monitor overnight to prevent/avert wandering, food foraging, &/or self-injury require use of range of mitigating strategies (e.g., enclosed bed system / "safe space" for containment during sleep, bedroom adaptations, locked kitchen cabinets).
Obesity	Dietary changes w/portion mgmt & appropriate individualized nutritional counseling in addition to ↑ movement & physical activity, ↓ sedentary activity, & discouraging nighttime eating ¹¹	Mgmt strategies to limit access to food due to biologically based intense food-related behaviors in SMS (i.e., hyperphagia, obsessions/fixations on food, impaired satiety) require a multicomponent individualized approach to ↓ obesity health risks. ¹² A trial using an MC4R agonist, setmelanotide, for obesity in persons w/SMS failed to significantly ↓ body weight but did impact self-reported "hunger." ¹³
Gastroesophageal reflux disease	Standard treatment
Constipation	Standard treatment	Family-friendly treatment recommendations ¹⁴
Hypercholesterolemia	Dietary modifications &/or medication in accordance w/standard practice
Palatal anomalies	Standard treatment	Consider referral to multidisciplinary craniofacial clinic.
Scoliosis	Standard treatment per orthopedist
Ophthalmologic abnormalities	Standard treatment per ophthalmologist &/or optometrist
Recurrent otitis media	Standard treatment	May include insertion of tympanostomy tubes
Hearing loss	Hearing aids may be helpful per otolaryngologist.	Community hearing services through early intervention or school district
Cardiac anomalies	Standard treatment
Renal anomalies	Standard treatment
Immunodeficiency	Standard treatment	Consider referral to immunologist for recurrent infections for consideration of antibody replacement therapy or prophylactic antibiotics.
Hypothyroidism	Thyroid replacement therapy
Growth hormone deficiency	Growth hormone treatment	Growth hormone treatment has been reported; ¹⁵ controlled studies have not evaluated its efficacy.
Clinical manifestations of BHDS *in those w/deletion incl FLCN* (majority of SMS deletion cases)**	Skin. Dermatologic exam after puberty; biopsy to confirm fibrofolliculoma Lungs. High-res chest CT to detect lung cysts in adulthood & establish baseline; repeat imaging not necessary if normal. Renal. Baseline abdominal imaging (MRI w/contrast preferred) to assess for renal tumors; repeat screening every 3 yrs thereafter	There are published cases of renal cancer in adults w/SMS w/deletion of 17p11.2. ¹⁶ Recommendations include kidney cancer surveillance starting at 20 yrs & eval for both skin & lung manifestations of BHDS.
Transition to adult care	Prepare affected persons for the adult health care system & optimize autonomy through the use of family & community supports as needed. ¹⁷	Discuss transition starting at age 12-14 yrs w/consideration of medical, psychosocial (vs emotional, social), educational, recreational, & vocational aspects that contribute to improved long-term health outcomes.
Impact on parents & sibs	Respite care, annual family psychosocial screenings, & family psychosocial support ¹⁸	Combination of ID, severe behavioral abnormalities, & sleep disturbance takes significant toll on caretakers/parents & sibs. Incl family support services & resources as essential components of a holistic mgmt plan.

: ASM = anti-seizure medication; BHDS = Birt-Hogg-Dubé syndrome; ID = intellectual disability; SMS = Smith-Magenis syndrome
1.: Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, See Epilepsy Foundation Toolbox
2.: See 2024 PRISMS Clinical and Research Consortium treatment recommendation: Strategies to Address Emotional and Behavioral Challenges in Smith-Magenis Syndrome (SMS).
3.: The potential for more problematic or atypical behaviors with increased age underscores the need for early and ongoing intervention and caregiver education [Hildenbrand & Smith 2012].
4.: Bradley et al [2020]
5.: Based on an extensive review of psychotropic medication use in a large cohort of individuals with SMS (n=62), use of polypharmacy and/or serial trials with minimal effectiveness was observed. Benzodiazepines obtained the lowest mean efficacy score in the "slightly worse" range, suggesting that use of these drugs may be detrimental to individuals with SMS [Laje et al 2010a].
6.: Sleep management is a challenge for physicians and parents. Prior to beginning any trial, a child's medical status and baseline sleep pattern must be considered.
7.: Dosages should be kept low (≤3 mg). However, melatonin dispensed over the counter is not regulated by the FDA; thus, dosages may not be exact. No early and controlled melatonin treatment trials have been conducted. A monitored trial of four to six weeks on melatonin may be worth considering in affected individuals with sleep disturbance.
8.: Polymeropoulos et al [2021]
9.: Nine individuals with SMS were treated with oral beta-1-adrenergic antagonists (acebutolol, 10 mg/kg) [De Leersnyder et al 2001]. This treatment, however, did not restore nocturnal plasma concentration of melatonin.
10.: Parents also reported subjective improvement in daytime behaviors with increased concentration. Contraindications to the use of beta-1-adrenergic antagonists include asthma, pulmonary problems, some cardiovascular disease, and diabetes mellitus.
11.: Dietary changes with portion management in addition to increased movement and physical activity, limiting sedentary activity, and discouraging nighttime eating
12.: Elatrash et al [2024]
13.: Lazareva et al [2024]
14.: See Constipation Treatment Recommendations for SMS.
15.: Itoh et al [2004], Spadoni et al [2004]
16.: Vocke et al [2023]
17.: See Got Transition, Six Core Elements of Health Care Transition.
18.: Parents report high rates of depression and anxiety, and family stress is significantly higher in families of individuals with SMS than in those of children with non-specific developmental disabilities [Hodapp et al 1998, Foster et al 2010, Agar et al 2022].

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay and/or intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an Early Intervention (EI) program for infants and toddlers (birth to age 3 years) is recommended and generally placed by the child's pediatrician. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs. Services determined as necessary may include occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. The number of hours vary, and parents may choose to augment with private therapies. The primary document for families enrolled in their EI program is the Individualized Family Service Plan (IFSP).

Ages 3-5 years. In the US, preschool services for children age three to five years with disabilities are implemented by the public school system. The number of hours vary, and services may be provided in a specialized school program, childcare setting or in the home. A multidisciplinary team including the parent/caregivers develop an Individualized Education Program (IEP), which is the legal document that guides the program, outlines specific services, accommodations, specially designed instruction, and behavioral supports. It is reviewed annually or as requested by the parent/caregiver or school personnel.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some considerations include:

IEP services:
- An IEP provides specially designed instruction and related services to children who qualify.
- IEP services will be reviewed annually to determine whether any changes are needed.
- Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
- Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
- PT, OT, and speech-language services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
- As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years.
A 504 Plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox^®, anti-parkinsonian medications, or orthopedic procedures.

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Oral motor dysfunction should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, a nasogastric (NG)-tube or gastric (G)-tube may be necessary.

Communication issues. Consider evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.

Neurobehavioral/Psychiatric Concerns

Consultation with specialized services (developmental pediatric, psychiatric, psychological) for concerns about emotions and behavior may be helpful in guiding parents through management strategies and options. A specialized physician (developmental pediatrician or psychiatrist) may discuss prescription medication trials when necessary (e.g., for attention-deficit/hyperactivity disorder).

Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.

Individuals may qualify and benefit from interventions used in treatment of neurodevelopmental disorders and autism spectrum disorder, including applied behavior analysis (ABA). ABA interventions are science based and targeted to the individual's behavioral, social, and adaptive strengths and weaknesses. Strategies for supports and interventions are typically developed with the team led by a board-certified behavior analyst (BCBA).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Table 6.

Smith-Magenis Syndrome: Recommended Surveillance

System/Concern	Evaluation	Frequency
Neurologic	Monitoring of those w/seizures as clinically indicated ¹	At each visit & as clinically indicated
Development	Multidisciplinary team eval (incl physical, occupational, & speech-language therapy evals & psychological assessment) to assist in development of IEP ^2, 3	Annually
Neurobehavioral/ Psychiatric	Assessment for anxiety, ADHD, ASD, aggression, & self-injury	At each visit
Growth/Feeding	Measurement of growth parameters Eval of nutritional status & safety of oral intake	At each visit
Cardiac	Fasting lipid profile	Annually in adolescents & adults Presurgical eval for possible premature cerebrovascular disease is recommended for persons w/SMS who require open-heart surgery in adolescence or adulthood. ⁴
ENT/Mouth	Otolaryngologic follow up for assessment & mgmt of otitis media & other sinus abnormalities Audiologic eval to monitor for CHL or SNHL annually or as clinically indicated	Annually
Musculoskeletal	Monitoring for scoliosis (may be progressive)	Annually
Musculoskeletal	Older persons w/symptoms ⁵ of suspected tethered cord should prompt MRI/CT of lumbar spine (incl prone positioning)	As clinically indicated
Eyes	Ophthalmologic eval	Annually
Genitourinary	Routine urinalysis to evaluate for occult urinary tract infections Gynecologic eval per gynecologist
Endocrine	Thyroid function, incl free thyroxine & TSH
Immunologic	Repeat qualitative Igs incl vaccine titers (esp pneumococcus)	As clinically indicated
Sleep-disordered breathing / snoring	Polysomnogram / sleep study to evaluate for OSA	As clinically indicated
Recommended surveillance of BHDS in those w/deletion incl FLCN	Renal. Baseline abdominal imaging (MRI w/contrast) to assess for kidney tumors. If MRI is not feasible due to required sedation for non-cooperation, high-res ultrasound may be used. Repeat renal screening every 3 yrs thereafter. Skin. Dermatologic exam after puberty; biopsy to confirm fibrofolliculoma Lungs. High-res chest CT to detect lung cysts in adulthood to establish baseline; repeat imaging not necessary	Age ≥20 yrs Since BHDS is an adult-onset disorder, additional screening for symptoms related to BHDS in children w/SMS is not indicated.
Family/Community	Assess family need for social work support (e.g., respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).	At each visit

: BHDS = Birt-Hogg-Dubé syndrome; CHL = conductive hearing loss; IEP = individualized educational program; Ig = immunoglobulin; OSA = obstructive sleep apnea; SNHL = sensorineural hearing loss; TSH = thyroid-stimulating hormone
1.: Assess for new manifestations such as seizures or changes in behavior.
2.: Particularly in school-age children
3.: Periodic neurodevelopmental assessments and/or developmental/behavioral pediatric consultation can be an important adjunct to the team evaluation.
4.: Chaudhry et al [2007]
5.: Symptoms include onset of neurologic deficits of lower extremities, gait disturbance, loss of bowel/bladder control, progressive deformities of feet, and/or spinal stenosis.

Agents/Circumstances to Avoid

Use of psychoactive medications in SMS often begins in childhood with use of sleep aids and trials of different psychoactive medications to reduce/manage maladaptive behavior, with mixed response; no single regimen has shown consistent efficacy, and adverse reactions to some medications have been reported [Laje et al 2010a]. Polypharmacy is also a concern. Additionally, weight gain is a concern with many antipsychotics.

Lacking well-controlled trials, when starting a new medication, care should be taken to track sleep and behavior changes over several days/weeks to monitor for potential side effects (e.g., increased appetite, weight gain) and adverse reactions and/or to determine potential efficacy.

Pharmacologic intervention should be considered on an individual basis with recognition that some medications may exacerbate sleep or behavioral issues and may cause weight gain. Pharmacogenetic testing panels to identify potential gene-drug interactions may aid in tailoring therapeutic strategies for the individual.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Smith-Magenis syndrome (SMS) is an autosomal dominant disorder typically caused by a heterozygous de novo deletion at chromosome 17p11.2 that includes RAI1 or a heterozygous intragenic RAI1 pathogenic variant.

Risk to Family Members

Parents of a proband

Almost all individuals reported to date with SMS whose biological parents have undergone genetic testing have the disorder as the result of a de novo 17p11.2 deletion including RAI1 or intragenic RAI1 pathogenic variant.
Rarely, individuals diagnosed with SMS have the disorder as the result of:
- A 17p11.2 deletion [Zori et al 1993, Smith et al 2006] or intragenic RAI1 pathogenic variant [Smith et al 2006, Campbell et al 2014] inherited from an unaffected or mildly affected mosaic parent;
- A 17p11.2 deletion resulting from a structural chromosome rearrangement in a parent [Yang et al 1997, Park et al 1998];
- An intragenic RAI1 pathogenic variant inherited from a heterozygous affected parent [Acquaviva et al 2017].
Genomic or molecular genetic testing that will detect the genetic alteration present in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. In addition, chromosome analysis of the parents should be performed for all newly diagnosed individuals found to have a 17p11.2 deletion; complex familial chromosome rearrangements leading to 17p11.2 deletion and SMS are rare but have been reported [Yang et al 1997, Park et al 1998].
If the 17p11.2 deletion or intragenic RAI1 pathogenic variant identified in the proband is not identified in either parent, parental chromosome analysis is normal, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
- The proband has a de novo genetic alteration.
- The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) mosaicism [Zori et al 1993, Smith et al 2006, Campbell et al 2014].
  Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a genetic alteration that is present in the germ (gonadal) cells only.

Note: Parents found to have an RAI1 pathogenic variant or 17p11.2 deletion should be assessed for neuropsychiatric and behavioral concerns.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

If neither parent is found to have the genetic alteration identified in the proband and parental chromosome analysis is normal, the recurrence risk to sibs is likely less than 1% (recurrence risk attributable to the possibility of gonadal mosaicism in a parent) [Zori et al 1993; Smith et al 2006; Campbell et al 2014; Authors, personal observation].
If a parent has a balanced structural chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement and the possibility of other variables.
If a parent of the proband is affected and/or has the genetic alteration identified in the proband, the risk to the sibs is 50%.

Offspring of a proband

The offspring of an individual with SMS are at a 50% risk of having SMS, assuming the other biological parent does not also have SMS.
Individuals (females) with SMS are known to have given birth to a child with SMS [Smith et al 2006, Acquaviva et al 2017].
Fertility issues in SMS remain unstudied.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has an SMS-related genetic alteration or chromosome rearrangement, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults from families in which a chromosome rearrangement has been identified.

Prenatal Testing and Preimplantation Genetic Testing

High-risk pregnancies. SMS usually occurs as the result of a de novo genetic alteration; however, rare instances of vertical transmission from an affected parent to a child, parental mosaicism, and complex familial chromosome rearrangements leading to deletion of 17p11.2 and SMS have been reported.

Once the SMS-related genetic alteration has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
In the rare instance of a complex familial chromosome rearrangement, prenatal testing is possible for a pregnancy at increased risk using prenatal chromosomal microarray analysis (CMA) and sequencing on fetal cells.
Note: Although a visible interstitial deletion of chromosome 17p11.2 can be detected in all individuals with the common approximately 3.7-Mb deletion by a routine G-banded analysis provided the resolution is adequate (≥550 band), this approach is not recommended for prenatal testing because it is not uncommon for the deletion to be overlooked.

Low-risk pregnancies. Unsuspected prenatal detection of a 17p11.2 deletion has been described among women undergoing amniocentesis for other reasons. Prenatal detection of SMS following amniocentesis performed because of low maternal serum alpha-fetoprotein (MSAFP) on routine screening has been reported at least twice [Fan & Farrell 1994, Thomas et al 2000]. A large prenatal series identified ten affected fetuses from a total of 455,121 consecutive prenatal cytogenetic studies [Qin & Huang 2007].

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these concerns may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Association of Smith-Magenis France (ASM17)
France
Email: asm17.presidence@gmail.com
smithmagenis17.org/L-Association
MedlinePlus
Smith-Magenis syndrome
Parents and Researchers Interested in Smith-Magenis Syndrome (PRISMS)
Within the PCRC, SMS Clinics (currently 8 locations across the USA) provide multi-specialty, comprehensive and clinically appropriate care for persons with SMS in the USA.
Medical Management Guidelines and associated Checklist for Smith-Magenis Syndrome
SIRIUS e.V. (Germany’s Support Network for Smith-Magenis Syndrome)
Germany
Phone: 49 (0)151 201 215 69
smith-magenis.de
Smith-Magenis Syndrome Australia
Member of PRISMS International Partnership Program
Australia
Email: info@smsaustralia.org
smsaustralia.org
SMS Foundation UK
United Kingdom
Phone: 0300 101 0034
smith-magenis.co.uk
PRISMS Smith-Magenis Syndrome Patient Registry
prisms.org/research/sms-patient-registry

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Smith-Magenis Syndrome: Genes and Databases

Gene	Chromosome Locus	Protein	Locus-Specific Databases	HGMD	ClinVar
RAI1	17p11.2	Retinoic acid-induced protein 1	RAI1 @ LOVD	RAI1	RAI1

: Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Smith-Magenis Syndrome (View All in OMIM)

182290	SMITH-MAGENIS SYNDROME; SMS
607642	RETINOIC ACID-INDUCED GENE 1; RAI1

Molecular Pathogenesis

RAI1 encodes retinoic acid-induced protein 1 (RAI1), which is thought to function in transcription regulation [Bi et al 2004, Burns et al 2010, Carmona-Mora et al 2010, Williams et al 2012]; however, additional studies are required to more fully assess protein function in the cell. Studies of model organisms have confirmed and extended understanding of the functions of RAI1. In murine models, Rai1 is a transcriptional regulator that preferentially binds to promoters and actively transcribes neuronal genes [Huang et al 2016, Williams et al 2012]. Further, mice lacking Rai1 display exaggerated light-induced behaviors and disruption of circadian rhythm [Diessler et al 2017]. Genetic studies in humans [Claes et al 2014] and mice [Bi et al 2005, Burns et al 2010] as well as experiments in Xenopus [Tahir et al 2014] have also shown a role for RAI1/Rai1 in craniofacial development. Consistent with observations in individuals with SMS, studies of mice have shown that Rai1 haploinsufficiency affects feeding, satiety, and fat deposition patterns [Burns et al 2010, Alaimo et al 2014, Javed et al 2023].

Smith-Magenis syndrome is caused by either a microdeletion of 17p11.2 including RAI1 or a pathogenic variant in RAI1 (see Table 1). A common deletion interval spanning approximately 3.7 Mb is identified in approximately 70% of affected individuals [Potocki et al 2003, Vlangos et al 2003], with larger or smaller deletions occurring in approximately 20%.

Mechanism of disease causation. Loss of function

RAI1-specific laboratory technical considerations. None

Chapter Notes

Author Notes

The authors of the GeneReview "Smith-Magenis Syndrome" are members of the PRISMS Professional Advisory Board (PAB). Members noted with an asterisk (*) served as the PAB Working Group for the comprehensive 2025 update of the GeneReview.

Inquiries/questions received by PRISMS at gro.SMSIRP@ofni are triaged to PAB members as appropriate.

Author History

Judith E Allanson, MD; Children's Hospital of Eastern Ottawa (2001-2009)
Albert J Allen, MD, PhD; Eli Lilly Laboratories, Inc (2001-2005)
John Berens, MD, FAAP, FACP (2025-present)
Kerry E Boyd, MD, FRCP(C) (2009-present)
Christine Brennan, PhD, CCC-SLP (2019-present)
Jane Charles, MD; Medical University of South Carolina (2019-2025)
Elisabeth Dykens, PhD; University of California, Los Angeles (2001-2005)
Sarah H Elsea, PhD, FACMG (2001-present)
Brenda M Finucane, MS, CGC; Autism & Developmental Medicine Institute (2001-2025)
Rebecca Foster, PhD (2019-present)
Rachel Franciskovich, MS, CGC (2025-present)
Santhosh Girirajan, MBBS, PhD (2019-present)
Andrea Gropman, MD, FAAP, FACMG (2005-present)
Barbara Haas-Givler, MEd, BCBA (2005-present)
Kyle P Johnson, MD; Oregon Health and Science University (2004-2012)
Gonzalo Laje, MD; National Institute of Mental Health (2012-2019)
James R Lupski, MD, PhD, FAAP, FACMG, FAAAS; Baylor College of Medicine (2001-2012)
Ellen Magenis, MD, FAAP, FACMG; Oregon Health and Science University (2001-2019)
Lorraine Potocki, MD, FACMG; Baylor College of Medicine (2001-2019)
Nancy Raitano Lee, PhD (2025-present)
Ann CM Smith, MA, DSc (hon), CGC (2001-present)
Beth Solomon, MS; National Institutes of Health (2001-2012)
Cora Taylor, PhD (2025-present)
Sinan Omer Turnacioglu, MD (2025-present)
Christopher Vlangos, PhD, FACMG (2025-present)

Revision History

29 May 2025 (gm) Comprehensive update posted live
20 June 2019 (ma) Comprehensive update posted live
28 June 2012 (me) Comprehensive update posted live
7 January 2010 (me) Comprehensive update posted live
11 August 2006 (me) Comprehensive update posted live
15 March 2004 (me) Comprehensive update posted live
22 October 2001 (me) Review posted live
23 May 2001 (as) Original submission

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Smith ACM, Berens J, Boyd KE, et al. Smith-Magenis Syndrome. 2001 Oct 22 [Updated 2025 May 29]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025.
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GeneReviews® [Internet].

Smith-Magenis Syndrome

Summary

Clinical characteristics.

Diagnosis/testing.

Management.

Genetic counseling.

Diagnosis

Suggestive Findings

Figure 1.

Figure 3.

Establishing the Diagnosis

Option 1

Option 2

Table 1.

Clinical Characteristics

Clinical Description

Table 2.

Facial Appearance

Figure 2.

Neurologic Manifestations

Neurodevelopmental Features

Behavioral Manifestations

Growth and Feeding

Gastrointestinal

Oral and Dental Anomalies

Musculoskeletal Manifestations

Ocular Abnormalities

Ears and Hearing

Laryngeal Anomalies

Cardiovascular Defects

Genitourinary Anomalies

Immunologic Manifestations

Endocrine

Dermatologic Manifestations

Malignancy and Other Features of Birt-Hogg-Dubé Syndrome (BHDS)

Other Manifestations

Neuroimaging Abnormalities

Neuropathologic Abnormalities

Prognosis

Genotype-Phenotype Correlations

Deletions of 17p11.2 Including RAI1

Pathogenic Variants in RAI1

Prevalence

Genetically Related (Allelic) Disorders

Differential Diagnosis

Table 3.

Management

Evaluations Following Initial Diagnosis

Table 4.

Treatment of Manifestations

Table 5.

Developmental Delay / Intellectual Disability Management Issues

Motor Dysfunction

Neurobehavioral/Psychiatric Concerns

Surveillance

Table 6.

Agents/Circumstances to Avoid

Evaluation of Relatives at Risk

Therapies Under Investigation

Genetic Counseling

Mode of Inheritance

Risk to Family Members

Related Genetic Counseling Issues

Prenatal Testing and Preimplantation Genetic Testing

Resources

Molecular Genetics

Table A.

Table B.

Molecular Pathogenesis

Chapter Notes

Author Notes

Author History

Revision History

References

Literature Cited

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