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for the most up-to-date Resources information.—ED.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Disease characteristics. Smith-Magenis syndrome (SMS) is characterized by distinctive facial features that progress with age, developmental delay, cognitive impairment, and behavioral abnormalities. The majority of individuals function in the mild to moderate range of mental retardation. Gross and fine motor skills and expressive language skills are delayed in the first year of life. The behavioral phenotype, including significant sleep disturbance, stereotypies, and maladaptive and self-injurious behaviors, is generally not recognized until age 18 months or older and continues to change until adulthood. Infants have feeding difficulties, failure to thrive, hypotonia, hyporeflexia, prolonged napping or need to be awakened for feeds, and generalized lethargy. Sensory integration issues are frequently noted. Children and adults have inattention, hyperactivity, maladaptive behaviors including frequent outbursts/temper tantrums, attention seeking, impulsivity, distractibility, disobedience, aggression, toileting difficulties, and self-injurious behaviors (SIB) including self-hitting, self-biting, and/or skin picking, inserting foreign objects into body orifices (polyembolokoilamania), and yanking fingernails and/or toenails (onychotillomania). Two stereotypic behaviors, spasmodic upper-body squeeze or "self-hug" and hand licking and page flipping ("lick and flip"), seem to be specific to SMS.
Diagnosis/testing. The diagnosis of Smith-Magenis syndrome is based on clinical findings and confirmed by detection of an interstitial deletion of 17p11.2 by G-banded cytogenetic analysis and/or by fluorescence in situ hydridization (FISH). A visible interstitial deletion of chromosome 17p11.2 can be detected in all individuals with the common deletion by a routine G-banded analysis, provided the resolution is adequate (550 band or higher). It is not uncommon for the deletion to be overlooked particularly when the indication for the cytogenetic study is not SMS. Molecular cytogenetic analysis by FISH using a DNA probe specific for the SMS critical region is required in cases of submicroscopic deletions and/or to resolve equivocal cases. Molecular genetic testing of RAI1, the only gene known to account for a majority of features in SMS, is clinically available for individuals in whom a FISH-detectable deletion has been excluded.
Management. Treatment of Smith-Magenis syndrome includes early childhood intervention programs, special education, vocational training later in life, and speech/language, physical, occupational, behavioral, and sensory integration therapies. Affected individuals may also benefit from use of psychotropic medication to increase attention and/or decrease hyperactivity, and therapeutic management of sleep disorders. Respite care and psychosocial support for family members are recommended. Surveillance includes: annual multidisciplinary evaluations to assist in development of an individualized education program (IEP), evaluation of thyroid function, fasting lipid profile, routine urinalysis, monitoring for scoliosis, ophthalmologic examination, periodic neurodevelopmental assessments and/or developmental/behavioral pediatric consultations, otolaryngologic follow-up for assessment and management of otitis media and other sinus abnormalities, and audiologic evaluation to monitor for conductive or sensorineural hearing loss annually or as clinically indicated.
Genetic counseling. Smith-Magenis syndrome is caused by deletion or mutation of the RAI1 gene on chromosome 17p11.2. Virtually all occurrences are de novo. Familial chromosomal complex rearrangements leading to del(17)(p11.2) and SMS occur but are rare. If parental chromosome analysis is normal, the risk to sibs of the proband is likely to be less than 1%. The small recurrence risk takes into account the possibility of germline mosaicism. If a parent of the proband has a balanced chromosome rearrangement, at-risk family members can be tested by chromosome analysis and FISH. In the rare instance of a complex familial chromosomal rearrangement, prenatal testing is available for pregnancies at risk using a combination of routine cytogenetic studies and FISH.
The clinical diagnosis of SMS is suspected in individuals who present with a complex pattern of findings including the following:
A subtly distinctive facial appearance (see Clinical Description) that becomes more evident with age
Mild to moderate infantile hypotonia with feeding difficulties and failure to thrive
Minor skeletal anomalies
Short stature
Brachydactyly
Ophthalmologic abnormalities
Otolaryngologic abnormalities
Early speech delays with or without associated hearing loss
Peripheral neuropathy
Some level of cognitive impairment and developmental delay
A distinct neurobehavioral phenotype that includes sleep disturbance and stereotypic and maladaptive behaviors [Finucane et al 1994, Dykens & Smith 1998, Smith et al 1998a, Finucane et al 2001]. Sleep disturbance is chronic and associated with an abnormal circadian rhythm of melatonin [Potocki, Glaze et al 2000; De Leersnyder et al 2001].
Cardiac and renal anomalies and cleft palate occur in fewer than 25% of individuals.
The phenotypic features can be subtle in infancy and early childhood, frequently delaying diagnosis until school age when the characteristic facial appearance and behavioral phenotype may be more readily apparent.
Cytogenetic testing. Diagnosis of SMS requires detection of an interstitial deletion of 17p11.2 by G-banded cytogenetic analysis and/or by FISH analysis. Probes for FISH testing must include the RAI1 gene. A visible interstitial deletion of chromosome 17p11.2 can be detected in all individuals with the common deletion by a routine G-banded analysis provided the resolution is adequate ( ≥550 band). Studies indicate that approximately 90% have a FISH-detectable deletion, with about 70% having the common approximately 3.5-Mb deletion [Potocki et al 2003, Vlangos et al 2003].
Note: It is not uncommon for the deletion to be overlooked particularly when the indication for the cytogenetic study is other than SMS. Thus, repeat cytogenetic study including FISH is indicated for individuals with prior "normal" routine cytogenetic analysis in whom a diagnosis of SMS is strongly suspected.
Gene. RAI1 is the only gene known to account for the majority of features in Smith-Magenis syndrome [Slager et al 2003, Bi et al 2004, Girirajan et al 2005].
Molecular genetic testing: Clinical uses
Confirmatory diagnostic testing
Molecular genetic testing: Clinical methods
FISH. Approximately 70% of individuals with SMS who have a 17p11.2 deletion have a common approximately 3.5-Mb deletion. Other affected individuals have atypical (smaller or larger) deletions involving 17p11.2 [Potocki et al 2003, Vlangos et al 2003]. All 17p11.2 deletions associated with SMS include a deletion of RAI1 [Vlangos et al 2005]. Molecular cytogenetic analysis by FISH using a DNA probe specific for the SMS critical region (D17S258 or other probe containing RAI1) detects approximately 95%-100% of 17p11.2 deletions. Such testing is required in cases of submicroscopic deletions and/or to resolve equivocal cases.
Note: Not all commercially available FISH probes contain RAI1 [Vlangos et al 2005].
Sequence analysis. Sequence analysis (particularly of exon 3, in which all mutations have been found to date) detects RAI1 mutations when cytogenetic and FISH studies do not detect the 17p11.2 deletion [Slager et al 2003, Bi et al 2004, Girirajan et al 2005].
Table 1 summarizes molecular genetic testing for this disorder.
| Test Methods | Mutations Detected | Mutation Detection Rate 1 | Test Availability |
|---|---|---|---|
| FISH 2 | Deletion 17p11.2 | ~90% | Clinical
 |
| Sequence analysis | Sequence alterations in RAI1 | 5%-10% |
Note: There remain a few individuals with clinical features of SMS but without confirmed deletions and/or RAI1 mutations who may represent an SMS-like syndrome yet to be defined.
1. Percent of individuals with SMS who have either a deletion or an RAI1 sequence alteration
2. FISH probe that contains RAI1 or D17S258
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
Cytogenetic analysis at greater than 550-band resolution
If cytogenetic testing is normal, FISH testing; the probe used must contain RAI1 or D17S258 [Vlangos et al 2005]. Some commercial probes used in the past that did not contain RAI1 or D17S258 may have given a false-negative result.
If FISH testing (RAI1 or D17S258 probe) does not reveal a deletion, sequencing of RAI1 should be considered.
Persons with larger deletions extending distally to include PMP22 are also at risk for hereditary neuropathy with liability to pressure palsies (HNPP).
Persons with duplication 17p11.2 harbor the recombination reciprocal of the SMS deletion and differ phenotypically and behaviorally from those with SMS [Potocki, Chen et al 2000].
Smith-Magenis syndrome (SMS) has a clinically recognizable phenotype that includes physical, developmental, and behavioral features (Table 2). Males and females are affected equally. The facial appearance is characterized by a broad square-shaped face, brachycephaly, prominent forehead, synophrys, mildly upslanting palpebral fissures, deep-set eyes, broad nasal bridge, 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 upper lip with a "tented" appearance.
With progressing age, the facial appearance becomes more distinctive and coarse, with persisting midfacial hypoplasia, relative prognathism, and heavy brows with a "pugilistic" appearance. An increased frequency of dental anomalies, specifically tooth agenesis (especially premolars) and taurodontism,f was recently reported [Tomona et al, in press].
SMS has a wide degree of variability in cognitive and adaptive functioning, with the majority of individuals with SMS functioning in the mild to moderate range of mental retardation [Greenberg et al 1996].
The behavioral phenotype, which includes sleep disturbance, stereotypies, and maladaptive and self-injurious behaviors, is generally not recognized until age 18 months or older and continues to change throughout early childhood to adulthood [Dykens & Smith 1998, Smith et al 1998a, Sarimski et al 2004, Gropman et al 2006]. The sleep disturbance is 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 1998b; Potocki, Glaze et al 2000; De Leersnyder et al 2001; Smith & Duncan 2005]. The abnormal (inverted) circadian rhythm of melatonin identified in SMS suggests that aberrant melatonin synthesis and/or degradation may be the underlying cause of this common sleep disturbance [Potocki, Glaze et al 2000; De Leersynder et al 2001].
| Frequency | System | Finding |
|---|---|---|
| >75% of individuals | Craniofacial/ skeletal | -Brachycephaly -Midface hypoplasia -Relative prognathism with age -Broad, square-shaped face -Everted, "tented" upper lip -Deep-set, close-spaced eyes -Short broad hands -Dental anomalies (missing premolars; taurodauntism) |
| Otolaryngologic | -Middle ear and laryngeal anomalies -Hoarse, deep voice | |
| Neuro/ behavioral | -Cognitive impairment/developmental delay -Generalized complacency/lethargy (infancy) -Infantile hypotonia -Sleep disturbance -Inverted circadian rhythm of melatonin -Stereotypic behaviors -Self-injurious behaviors -Speech delay -Hyporeflexia -Signs of peripheral neuropathy -Oral sensorimotor dysfunction (early childhood) | |
| Common features (50%-75% of individuals) | -Hearing loss -Short stature -Scoliosis -Mild ventriculomegaly of brain -Tracheobronchial problems -Velopharyngeal insufficiency (VPI) -Ocular abnormalities (iris anomalies; microcornea) -REM sleep abnormalities -Hypercholesterolemia/hypertriglyceridemia -History of constipation -Abnormal EEG without overt seizures | |
| Less common (25-50% of individuals) | -Cardiac defects -Thyroid function abnormalities -Seizures -Immune function abnormalities (esp. low IgA) | |
| Occasional (<25% of individuals) | -Renal/urinary tract abnormalities -Seizures -Forearm abnormalities -Cleft lip/palate -Retinal detachment |
Physical features. Prenatal histories are notable for decreased fetal movement in 50%. The infant with SMS is generally born at term, with normal birth weight, height, and head circumference. Height and weight gradually decelerate in early infancy. In about 20% of children with SMS, the head circumference is less than the third percentile for age [Smith & Gropman 2005].
The subtle facial dysmorphology in infancy, often characterized by midface hypoplasia, short upturned nose, fleshy everted upper lip with a "tented" appearance, and micrognathia, may be recognizable in early infancy. Feeding difficulties leading to failure to thrive are common, including marked oral motor dysfunction with poor suck and swallow, textural aversion, and gastroesophogeal reflux. Infantile hypotonia is reported in virtually all individuals, accompanied by hyporeflexia (84%) and generalized lethargy and complacency, similar to that found in Down syndrome.
Neurobehavioral features. Gross and fine motor skills are delayed in the first year of life. Issues related to sensory integration are frequently noted. Crying is infrequent and often hoarse, and the vast majority of infants show markedly decreased babbling and vocalization for age.
Parents usually do not recognize significant sleep problems before age 12-18 months; they often describe their infants as "perfect" babies with "smiling" dispositions, who cry infrequently and are "good sleepers." However, recent actigraphy-estimated sleep suggests that the disrupted sleep pattern begins as early as age nine months and shows a progressive decline from infancy through childhood [Duncan et al 2003, Gropman et al 2006].
Physical features. The facial appearance of SMS becomes more recognizable in early childhood and is accompanied by the emergence of the SMS behavioral phenotype. Ocular abnormalities, including strabismus, progressive myopia, iris anomalies, and/or microcornea, are usually recognized and may progress with age. Mild to moderate scoliosis, most commonly of the mid-thoracic region, is seen in approximately 60% of affected individuals four years and older. Underlying vertebral anomalies are seen in only a few. Hands and feet remain small and short stature (height <5th percentile) is frequently observed (67%). Markedly flat or highly arched feet and unusual gait are generally observed. Constipation is frequently reported.
Otolaryngologic problems are common throughout childhood. Otitis media occurs frequently (≥3 episodes/year) and often leads to tympanostomy tube placement (85%) and risk for conductive hearing loss (65%). 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 the vast majority of individuals with SMS. Oral sensorimotor dysfunction is a major issue, including lingual weakness, asymmetry and/or limited mobility, weak bilabial seal (64%), palatal abnormalities (64%), and open-mouth posture with tongue protrusion and frequent drooling. Sinusitis requiring antibiotics is frequently reported.
The high incidence of otolaryngologic findings provides a physiologic explanation for the functional impairments in voice (hoarseness) and may contribute to the marked delays in expressive speech. With appropriate intervention and a total communication program that includes sign/gesture language, 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 harsh, hoarse vocal quality. Hearing impairment is found in over two-thirds of affected individuals. Hypercholesterolemia is recognized in over 50% of individuals with SMS.
Neurobehavioral features. Developmental delays are evident in early childhood, and the majority of older children and adults function within the mild to moderate range of retardation. A cognitive profile has been described with relative weaknesses observed in sequential processing and short-term memory; relative strengths were found in long-term memory and perceptual closure (i.e., a process whereby an incomplete visual stimulus is perceived to be complete: "parts of a whole").
The behavioral phenotype of SMS is evident by early childhood/school age and escalates with age, often coinciding with expected life-cycle stages: 18-24 months, school age, and onset of puberty. Head banging may begin as early as 18 months. Sensory integration issues are present and persist throughout childhood. Most individuals with SMS exhibit inattention with or without hyperactivity.
Maladaptive behaviors are prevalent and represent the major management problem for families and caretakers. These include frequent outbursts/temper tantrums, attention seeking (especially from adults), impulsivity, distractibility, disobedience, aggression, self-injury, and toileting difficulties. While age and degree of developmental delay correlate with maladaptive behaviors, the degree of sleep disturbance appears to be the strongest predictor of maladaptive behavior [Dykens & Smith 1998].
Self-injurious behaviors (SIB) occur in the vast majority of individuals with SMS after age two years. The most common include self-hitting (71%), self-biting (77%), and/or skin picking (65%) [Dykens & Smith 1998]. The overall prevalence of SIB increases with age, as does the number of different types of SIB exhibited [Finucane et al 2001]. A direct correlation exists between the number of different types and extent of SIB exhibited and the level of intellectual functioning. Two behaviors distinctive to SMS, nail yanking (onychotillomania) [Greenberg et al 1991] and insertion of foreign objects into body orifices (polyembolokoilamania), are seen in 25%-30% of affected individuals. Nail yanking generally does not become a major problem until later childhood. Mouthing of hands or objects appears to persist from early childhood.
Two stereotypic behaviors, the spasmodic upper-body squeeze or "self-hug" and a hand licking and page flipping ("lick and flip") behavior provide an effective clinical diagnostic marker for the syndrome [Finucane et al 1994, Dykens et al 1997, Dykens & Smith 1998]. Additional stereotypies include mouthing objects or insertion of hand in mouth (54%-69%), teeth grinding (54%), body rocking (43%), and spinning or twirling objects (40%).
Sleep disturbance is a major issue for caretakers, who themselves may become sleep deprived. Disrupted sleep becomes a major problem in early childhood. Studies of individuals with SMS confirm difficulties falling asleep, frequent and prolonged night-time awakenings, and excessive daytime sleepiness. With increasing age, the number and frequency of naps increases and total sleep time at night decreases. Diminished REM sleep was documented in over half of those undergoing polysomnography [Greenberg et al 1996, Potocki et al 2000]. Actigraphy-based sleep estimates from infancy (<1 year) to age eight years demonstrate a reduction in 24-hour and night sleep in SMS when compared to healthy pediatric controls [Gropman et al 2006].
Sexual and/or child abuse may be wrongly suspected secondary to self-inflicted injuries and/or insertion of objects in body orifices (e.g., vaginal insertion).
Physical features. The facial appearance becomes more angulated, with persisting midface hypoplasia and relative prognathism, frontal bossing with synophrys, heavy brows (often pugilistic), and a general coarsening. Puberty generally occurs within the normal time frame; however, precocious puberty and delayed sexual maturation have been seen.
Neurobehavioral features. Behaviors generally escalate with pubertal onset, and sleep disturbance remains a concern. Polyembolokoilamania and onychotillomania may become more prevalent.
Insufficient longitudinal data are available to accurately determine life expectancy; however, the oldest known living individual with SMS is currently in her mid 80's. One would expect that in the absence of major organ involvement, the life expectancy would not differ from that of the cognitively impaired population at large.
Physical features. The facial appearance is coarser with persisting midface hypoplasia and relative prognathism as a result of pointed chin. Scoliosis becomes more severe with age and short stature may or may not persist [Smith et al 2004]. Behavioral outbursts, aggression, and SIB may continue, but many have noted a relative "calming" of behavior in adulthood.
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 Smith-Magenis syndrome phenotype.
Individuals so far reported with RAI1 mutations are obese, do not exhibit short stature, and do not have organ system involvement [Slager et al 2003, Bi et al 2004, Girirajan et al 2005]. All other features typically associated with SMS are seen in individuals with mutations in RAI1. The effects of possible modifier genes within 17p11.2 are not known.
The birth incidence is estimated at 1/25,000 births [Greenberg et al 1991], but this probably represents an underestimate. The actual prevalence may be closer to 1/15,000. The vast majority of individuals have been identified in the last five to ten years as a result of improved cytogenetic techniques.
The syndrome has been identified worldwide in all ethnic groups.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
SMS should be distinguished from other syndromes that include developmental delay, infantile hypotonia, short stature, distinctive facies, and a behavioral phenotype. The most common of these include the following, which can be distinguished using cytogenetic (FISH) and/or molecular analysis:
22q11.2 deletion syndrome (including velocardiofacial [VCF] syndrome, DiGeorge syndrome)
Prader-Willi syndrome (PWS)
Down syndrome (trisomy 21; in the newborn period)
Clinically, many children with SMS are given psychiatric diagnoses — including autism and/or attention deficit/hyperactivity disorder (ADHD),obsessive-compulsive disorder (OCD), and/or mood disorders — because of speech delays and maladaptive and stereotypic behaviors.
Delayed diagnosis of SMS is common. Repeat cytogenetic analysis using FISH-specific probes for SMS is warranted in individuals suspected of having SMS who had a prior "normal" chromosome analysis. Infants with SMS are often thought to have Down syndrome based on the findings of infantile hypotonia, facial stigmata suggestive of this diagnosis (brachycephaly, flat mid face, upslanting palpebral fissures), and/or congenital heart disease. Failure to confirm trisomy 21 in a child with suggestive findings warrants further analysis by FISH using a SMS-specific probe [Smith et al 2005].
Complete review of systems at the time of diagnosis
Physical and neurologic examination
Renal ultrasound examination to evaluate for possible renal/urologic anomalies (~20% of individuals with SMS), including urologic workup if a history of frequent urinary tract infections exists
Echocardiogram to evaluate for possible cardiac anomalies (<45% of individuals with SMS); follow-up depending upon the severity of any cardiac anomaly identified
Spine radiographs to evaluate for possible vertebral anomalies and scoliosis (~60%)
Routine blood chemistries, qualitative immunoglobulins, fasting lipid profile (evaluation for hypercholesterolemia), and thyroid function studies
Ophthalmologic evaluation with attention to evidence of strabismus, microcornea, iris anomalies, and refractive error
Comprehensive speech/language pathology evaluation
Assessment of caloric intake, signs and symptoms of gastroesophageal reflux disease (GERD), swallowing abilities, and oral motor skills with referral as warranted for full diagnostic evaluation
Otolaryngologic evaluation to assess ear, nose, and throat problems, with specific attention to ear physiology and palatal abnormalities (clefting; velopharyngeal insufficiency)
Audiologic evaluation at regular intervals to monitor for conductive and/or sensorineural hearing loss
Multidisciplinary developmental evaluation, including assessment of motor, speech, language, personal-social, general cognitive, and vocational skills
Early evaluation by physical and/or occupational therapists
Sleep history with particular attention to sleep/wake schedules and respiratory function. Sleep diaries may prove helpful in documenting sleep/wake schedules. Evidence of sleep-disordered breathing warrants a polysomnogram (overnight sleep study) to evaluate for obstructive sleep apnea.
EEG in individuals who have clinical seizures to guide the choice of antiepileptic agents. For those without overt seizures, EEG may be helpful to evaluate for possible subclinical events in which treatment may improve attention and/or behavior; a change in behavior or attention warrants reevaluation
Neuroimaging (MRI or CT scan) in accordance with findings such as seizures and/or motor asymmetry
In individuals with SMS documented to have larger deletions extending into 17p12:
Specific screening for adrenal function
Detailed assessment and attention to peripheral neurologic function in individuals with SMS with large deletions involving the PMP22 gene, which is associated with hereditary neuropathy with liability to pressure palsy (HNPP)
Assessment of family support and psychosocial and emotional needs to assist in designing family interventions
Ongoing pediatric care with regular immunizations
From early infancy, referrals for early childhood intervention programs, followed by ongoing special education programs and vocational training in later years
Therapies including speech/language, physical, occupational, and especially sensory integration:
During early childhood, speech/language pathology services should initially focus on identifying and treating swallowing and feeding problems as well as optimizing oral sensorimotor development.
Therapeutic goals of increasing sensory input, fostering movement of the articulators, increasing oral motor endurance, and decreasing hypersensitivity are needed to develop skills related to swallowing and speech production.
The use of sign language and total communication programs as adjuncts to traditional speech/language therapy is felt to improve communication skills and also to have a positive impact on behavior. The ability to develop expressive language appears dependent upon the early use of sign language and intervention by speech/language pathologists.
Use of psychotropic medication to increase attention and/or decrease hyperactivity (No single regimen shows consistent efficacy.)
Behavioral therapies including special education techniques that emphasize individualized instruction, structure, and routine to help minimize behavioral outbursts in the school setting
Therapeutic management of the sleep disorder. Sleep management in SMS remains a challenge for physicians and parents. No well-controlled treatment trials have been reported:
Early anecdotal reports of therapeutic benefit from melatonin remain encouraging. Dosages of 2.5-5.0 mg (6 mg maximum) taken at bedtime have been tried, providing general improvement of sleep without reports of major adverse reactions. 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 (1-5 mg) may be worth considering in affected individuals with major sleep disturbance.
A single uncontrolled study of nine individuals with SMS treated with oral ß-1-adrenergic antagonists (acebutolol 10 mg/kg) reported suppression of daytime melatonin peaks and subjectively improved behavior [De Leersnyder et al 2001]. This treatment, however, did not restore nocturnal plasma concentration of melatonin.
A second uncontrolled trial by the same group [De Leersynder et al 2003] combined the daytime dose of acebutolol with an evening oral dose of melatonin (6 mg at 8PM) and found that nocturnal plasma concentration of melatonin was restored and nighttime sleep improved with disappearance of nocturnal awakenings. Parents also reported subjective improvement in daytime behaviors with increased concentration. Contraindications to the use of ß-1-adrenergic antagonists include asthma, pulmonary problems, cardiovascular disease, and diabetes mellitus.
Prior to beginning any trial, the child's medical status and baseline sleep pattern must be considered.
Enclosed bed system for containment during sleep
Respite care and family psychosocial support to help assure the optimal environment for the affected individual
Monitoring of hypercholesterolemia (recognized in >50% of individuals with SMS); treatment with diet or medication as indicated
Treatment with corrective lenses as indicated by ophthalmologic abnormalities
Treatment of recurrent otitis media with tympanostomy tubes as needed
Auditory amplification if hearing loss is identified
Management of seizures in accordance with standard practice
Treatment of cardiac and renal anomalies and scoliosis in accordance with standard medical care. While growth hormone treatment has been reported [Itoh et al 2004, Spadoni et al 2004], controlled studies have not evaluated its effectiveness.
Recommended annually:
Multidisciplinary team evaluation (including physical and occupational and speech therapy evaluations and pediatric assessment) to assist in development of an individualized educational program (IEP). Periodic neurodevelopmental assessments and/or developmental/behavioral pediatric consultation can be an important adjunct to the team evaluation.
Thyroid function
Fasting lipid profile
Routine urinalysis
Monitoring for scoliosis
Ophthalmologic evaluation
Otolaryngologic follow-up for assessment and management of otitis media and other sinus abnormalities
Audiologic evaluation to monitor for conductive or sensorineural hearing loss annually or as clinically indicated
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Pharmacologic intervention should be considered on an individual basis with recognition that some medications may exacerbate sleep or behavioral problems and may cause weight gain.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
Genetic counseling is the process of providing individuals and families with information on the nature, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Smith-Magenis syndrome is caused by deletion or mutation of the RAI1 gene on chromosome 17p11.2.
Parents of a proband
Virtually all cases of SMS occur de novo. There is no evidence to suggest an obvious parental age contribution for the deletion.
One case reported by Zori et al (1993) identified maternal mosaicism for del(17)(p11.2). Other cases of parental mosaicism are known but not reported [S Elsea and A Smith, personal communications].
Familial chromosomal complex rearrangements leading to del(17)(p11.2) and SMS are rare, but have been reported [Zori et al 1993, Yang et al 1997, Park et al 1998]. Consequently, chromosome analysis of the parents should be performed for all newly diagnosed individuals.
Sibs of a proband
The risk to sibs depends on the results of parental chromosome analysis.
If parental chromosome analysis is normal, the risk to sibs of the proband is likely less than 1% (recurrence risk attributable to the possibility of germline mosaicism in a parent).
If a parent has a balanced structural chromosome rearrangement, the risk to sibs is increased and is dependent upon the specific chromosome rearrangement and the possibility of other variables.
Offspring of a proband
No instances of individuals with SMS having an affected child have been reported.
Theoretically, the offspring of an individual with SMS are at a 50% risk of having SMS.
Fertility issues in SMS remain unstudied.
Other family members of a proband. The risk to other family members depends upon the genetic status of the proband's parents. If a parent is found to have a chromosome abnormality, his or her family members are at risk and can be offered chromosome analysis and FISH.
Family planning. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
If a parent of the proband has a balanced chromosome rearrangement, at-risk family members can be tested by chromosome analysis and FISH.
High-risk pregnancies. Because SMS usually occurs as the result of a de novo deletion of 17p11.2, virtually all individuals with SMS represent a simplex case (i.e., a single occurrence in a family). In the rare instance of a complex familial chromosomal rearrangement, prenatal testing is available for pregnancies at risk using a combination of routine cytogenetic studies and FISH on fetal cells obtained by chorionic villus sampling (CVS) at 10-12 weeks' gestation or amniocentesis usually performed at about 15-18 weeks' gestation.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Low-risk pregnancies. Unsuspected prenatal detection of del(17)(p11.2) has been reported among women undergoing amniocentesis for other reasons. At least two cases have been detected prenatally following amniocentesis performed because of low maternal serum AFP (MSAFP) on routine screening [Fan & Farrell 1994; Thomas et al 2000, personal observation].
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|
| RAI1 | 17p11.2 | Retinoic acid-induced protein 1 |
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
| Gene Symbol | Entrez Gene | HGMD |
|---|---|---|
| RAI1 | 10743 (MIM No. 607642) | RAI1 |
For a description of the genomic databases listed, click here.
Smith-Magenis syndrome is a contiguous gene deletion syndrome. A common deletion interval spanning approximately 3.5 Mb is identified in about 70% of individuals [Potocki et al 2003, Vlangos et al 2003]. The SMS critical region maps to 17p11.2 and spans less than 650 kb [Schoumans et al 2005, Vlangos et al 2005].
Dominant mutations in the RAI1 gene have been identified in individuals with the SMS phenotype who do not have a detectable 17p11.2 deletion [Slager et al 2003, Bi et al 2004, Girirajan et al 2005].
Normal allelic variants: The gene has six exons (see Table 3).
| Nucleotide Change | Amino Acid Change | SNP | |
|---|---|---|---|
| Polymorphisms | 269G>C | G90A | SNPrs3803763 |
| 493C>A | P165T | SNPrs11649804 | |
| 837G>A | Q279Q | SNPrs11078398 | |
| 1992G>A | P664P | SNPrs8067439 | |
| 5334G>A | R1778R | ||
| 5601T>C | I1867I | SNPrs3818717 | |
| PolyQ (CAG/CAA) | 9-15 repeats, no expansions seen |
Pathologic allelic variants: (see Table 4)
| Nucleotide Change | Amino Acid Change | Remarks | |
|---|---|---|---|
| Mutations | 253del19 | Frameshift of 60 amino acids | Deletion |
| 1449delC | Frameshift of 34 amino acids | Deletion | |
| 2773del29 | Frameshift of 8 amino acids | Deletion | |
| 2878C>T | R960Stop | Nonsense mutation | |
| 3103insC | Frameshift of 30 amino acids | Insertion | |
| 3801delC | Frameshift of 46 amino acids | Deletion | |
| 4685A>G | Q1562R | Missense mutation | |
| 5423G>A | S1808N | Missense mutation | |
| 5265delC | Frameshift of 74 amino acids | Deletion |
Normal gene product: The normal protein is thought to function in transcriptional regulation [Bi et al 2004]; however, additional studies are required to more fully assess protein function in the cell.
Abnormal gene product: The mechanisms by which the mutations in RAI1 affect gene/protein function are not known. The mechanism by which RAI1 is thought to result in disease phenotype is haploinsufficiency; thus it is assumed that intragenic mutations result in a nonfunctional protein product.
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
Association of Smith-Magenis France (ASM France)
http://membres.lycos.fr/asm17france/
National Library of Medicine Genetics Home Reference
Smith-Magenis syndrome
Parents and Researchers Interested in Smith-Magenis Syndrome (PRISMS)
PO Box 741914
Dallas TX 75374-1914
Phone: 972-231-0035
Fax: 413-826-6539
Email: info@prisms.org
www.prisms.org
Smith-Magenis Syndrome Foundation in United Kingdom
PO Box 3352
Ascot Berkshire SL5 8WS
United Kingdom
Phone: (+44) 0288 7750050
Email: info@smith-magenis.co.uk
www.smith-magenis.co.uk
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
The authors of the Smith-Magenis syndrome GeneReview are members of the PRISMS Professional Advisory Board.
Judith E Allanson, MD (2001-present)
Albert J Allen, MD, PhD; Eli Lilly Laboratories, Inc (2001-2005)
Elisabeth Dykens, PhD; University of California Los Angeles (2001-2005)
Sarah H Elsea, PhD, FACMG (2001-present)
Brenda M Finucane, MS, CGC (2001-present)
Andrea Gropman, MD, FAAP, FACMG (2005-present)
Barbara Haas-Givler, MEd (2005-present)
Kyle P Johnson, MD (2004-present)
James R Lupski, MD, PhD, FAAP, FACMG, FAAAS (2001-present)
Ellen Magenis, MD, FAAP, FACMG (2001-present)
Lorraine Potocki, MD, FACMG (2001-present)
Ann CM Smith, MA, DSc (hon), CGC (2001-present)
Beth Solomon, MS (2001-present)
11 August 2006 (me) Comprehensive update posted to live Web site
26 August 2005 (cd) Revision: sequence analysis of RAI1 clinically available
15 March 2004 (me) Comprehensive update posted to live Web site
15 January 2002 (as) Author revisions
22 October 2001 (me) Review posted to live Web site
23 May 2001 (as) Original submission
