Smith-Magenis Syndrome

Clinical characteristics.

Smith-Magenis syndrome (SMS) is characterized by distinctive physical features (particularly facial features that progress with age), developmental delay, cognitive impairment, behavioral abnormalities, sleep disturbance, 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. The majority of individuals function in the mild-to-moderate range of intellectual disability. 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. Sensory issues are frequently noted; these may include avoidant behavior, as well as repetitive seeking of textures, sounds, and experiences. Toileting difficulties are common. Significant anxiety is common as are problems with executive functioning, 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 who has suggestive clinical findings and either a heterozygous deletion at chromosome 17p11.2 that includes RAI1 or a heterozygous intragenic RAI1 pathogenic variant.

Management.

Treatment of manifestations: Early-childhood intervention programs; individualized special education for school-aged children; speech/language, physical, occupational, and behavior 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. Standard treatment for epilepsy, obesity, gastroesophageal reflux disease, constipation, hypercholesterolemia, palatal anomalies, scoliosis, ophthalmologic issues, recurrent otitis media, hearing loss, cardiac anomalies, renal anomalies, mild immunodeficiency, hypothyroidism, and growth hormone deficiency. 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-aged children should have periodic comprehensive evaluation to give input to the individualized education program (IEP). 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, thyroid function tests, and screening urinalysis for occult urinary tract infections. Annual family psychosocial assessments are also recommended to assess support for caregivers and sibs. Repeat quantitative immunoglobulins/vaccine titers as clinically indicated.

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.

Smith-Magenis syndrome (SMS) is caused by a heterozygous deletion of or a heterozygous pathogenic variant in RAI1 on chromosome 17p11.2. The majority of 17p11.2 deletions are de novo, while deleterious variants in RAI1 can be de novo or inherited. Complex familial chromosome rearrangements leading to del(17)(p11.2) and SMS occur but are rare. Although SMS usually occurs as the result of a de novo deletion of 17p11.2, rare instances of vertical transmission from an affected parent to a child, parental germline mosaicism, and complex familial chromosome rearrangements leading to del(17)(p11.2) and SMS have been reported. If the SMS-related genetic alteration has been identified in an affected family member, prenatal testing for a pregnancy at increased risk 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) or FISH on fetal cells.

Suggestive Findings

Smith-Magenis syndrome (SMS) should be suspected in individuals with the following clinical findings:

• A subtly distinctive facial appearance (see Clinical Description) that becomes more evident with age (see Figure 1, Figure 2, Figure 3)
• Mild-to-moderate infantile hypotonia with feeding difficulties and failure to thrive
• Peripheral neuropathy
• Some level of developmental delay and/or intellectual disability, including early speech delays (expressive greater than receptive speech) with or without associated hearing loss
• A distinct neurobehavioral phenotype that includes stereotypic and maladaptive behaviors and sleep disturbance (see Clinical Description)
• Short stature (prepubertal)
• Minor skeletal anomalies, including brachydactyly
• Ophthalmologic abnormalities
• Otolaryngologic abnormalities

Figure 1.

Infants with 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 the upper lip with mild micrognathia. (more...)

Figure 2.

Early school-age SMS showing 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, midface retrusion.

Figure 3.

Adolescent females with SMS caused by mutation of RAI1 (left) and deletion 17p11.2 (right). Note short philtrum with relative prognathism resulting from midface retrusion that persists with age; downturned upper lip is more notable at rest (non-smiling). (more...)

Establishing the Diagnosis

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

• A heterozygous deletion of 17p11.2
• A heterozygous pathogenic variant involving RAI1

When the phenotypic findings suggest the diagnosis of SMS, molecular genetic testing approaches can include chromosomal microarray analysis, single-gene testing, or use of a multigene panel:

• Chromosomal microarray analysis (CMA) typically is performed first. 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 3.5-Mb deletion by a routine G-banded 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 now 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.
• Single-gene testing. Sequence analysis of RAI1, which detects small intragenic deletions/insertions and missense, nonsense, and splice site variants, 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.
• An intellectual disability multigene panel that includes RAI1 and other genes of interest (see Differential Diagnosis) may also be considered. 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 this disorder, a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

When the phenotype is indistinguishable from many other inherited disorders characterized by developmental delay / intellectual disability, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.

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

Clinical Description

Smith-Magenis syndrome (SMS) has a clinically recognizable phenotype that includes physical, developmental, and behavioral features (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 phenotype may be more readily apparent.

Facial appearance. The facial appearance 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 (see Figure 1) changing to relative prognathia with age, and a distinct appearance of the mouth, with fleshy everted vermilion of the upper lip.

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

Neurologic

• Hypotonia is reported in virtually all infants, accompanied by hyporeflexia (84%) and generalized complacency and lethargy.
• Clinical signs of peripheral neuropathy are seen in approximately 75%, regardless of deletion size [Gropman et al 2006].
• In infancy / early childhood, these include infantile hypotonia, hyporeflexia, relative insensitivity to pain, and mild intention tremor (6-8 Hz) of upper extremity.
• 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 gait (foot flap).
• Toe-walking (60%) may persist despite the absence of tight heel cords [Smith & Gropman 2010].
• By childhood approximately 20% of affected individuals have a head circumference below the third centile [Smith & Gropman 2010].
• Pubertal onset of catamenial seizures has also been observed in some females coinciding with menses [Smith & Gropman 2010].
• Stroke-like episodes have been reported in three individuals with SMS, including:
  • A male born with bilateral cleft lip/palate and congenital heart defect who developed a left hemiparesis at age 4.5 years [Smith & Gropman 2010];
  • A female age ten years with ventricular septal defect, who was diagnosed with Moyamoya disease and had evidence of ischemic changes at age five years [Girirajan et al 2007];
  • A female age 32 years with evidence of severe atherosclerotic disease of the intracranial vessels documented after she suffered an ischemic infarct postoperatively following repeat cardiac surgery [Chaudhry et al 2007].
  Therefore, pre-surgical evaluation for possible premature cerebrovascular disease is recommended for individuals with SMS who require open-heart surgery in adolescence or adulthood [Chaudhry et al 2007].

Neurodevelopmental features. Developmental delays are evident in early childhood, with the majority of individuals with SMS functioning in the mild-to-moderate range of intellectual disability. Due to the maladaptive behaviors and sleep deficits, true intellectual ability may not be accurately assessed in many individuals and test scores may not be representative of an individual's current level of functioning. When reported, measured developmental or intelligence quotients range from 20 to 78 with a mean score of approximately 50.

• 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/language
  • In infancy, crying is infrequent and often hoarse.
  • The vast majority of 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].
  • 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.
• Cognitive abilities
  • Affected individuals typically have relative weaknesses observed in sequential processing and short-term memory.
  • Relative strengths are 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").

Behavioral phenotype. The behavioral phenotype, which includes sleep disturbance (see Sleep disturbance), 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 delayed beyond 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.
  • One study found that 90% of individuals with SMS (between ages 4 and 18 years) demonstrated significant social impairment (35% mild/moderate; 55% severe range per the Social Responsiveness Scale) per parent report, with symptoms similar to children with autistic disorder or other developmental disorders [Laje et al 2010b].
• 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].
• Although maladaptive behaviors, aggression, and SIB may continue, a relative "calming" of behavioral concerns may occur in adulthood.

Self-injurious behaviors (SIB) are present in the vast majority of 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.
• Two behaviors distinctive to SMS, nail yanking (onychotillomania) and insertion of foreign objects into body orifices (polyembolokoilamania), 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 later childhood.
  • Object insertion in ear(s) is most prevalent 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%)
  • 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 impairment 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:

• 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 major issue in adolescence and adulthood
• Toileting difficulties

Sterotypies common to SMS include:

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

Sleep disturbance. The abnormal diurnal (inverted) circadian rhythm of melatonin appears pathognomic in SMS, documented in an estimated 95% of affected individuals [Boone et al 2011, Spruyt et al 2016]. Further data [Boudreau et al 2009] suggest that the sleep disturbance cannot be caused solely by aberrant melatonin synthesis and/or degradation as previously suggested [Potocki et al 2000b, De Leersnyder et al 2001, Chik et al 2010, Nováková et al 2012]. 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].

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 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].
• Disrupted sleep becomes a major problem in early childhood and is a major issue for caregivers, who themselves may become sleep deprived [Foster et al 2010].
• Diminished REM sleep was documented in more than half of those undergoing 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 pediatric 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 (>10 years) exhibited less late-night activity but increased early-night activity, consistent with poor "settling" and delayed sleep pattern observed in adolescent controls.
• 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.

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-aged children (ages 6-9 years).
  • Obesity may lead to increased risk for related health issues (e.g., type 2 diabetes) in adulthood.
  • Hypercholesterolemia that is not associated with diet or BMI values is recognized in more than 50% of individuals with SMS [Smith et al 2002].

Gastrointestinal. Gastroesophageal reflux and constipation are frequently reported.

Oral and dental anomalies

• Oral sensorimotor dysfunction is a major issue, including:
  • Lingual weakness, asymmetry, and/or limited mobility
  • Weak bilabial seal (64%)
  • Palatal 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, restored teeth, and poor gingival health due to decreased oral hygiene, supporting the need for increased dental care in adolescent years [Tomona et al 2006].

Musculoskeletal

• 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.
• Hands and feet remain small.
• Markedly flat or highly arched feet and unusual gait are generally observed.

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.

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% [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 loss (48%) between age 11 years and adulthood [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, 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.
• Functional impairments in voice (hoarseness) may contribute to the marked delays in expressive speech.

Cardiovascular defects are identified in fewer than 50% of affected individuals with SMS who have a deletion of 17p11.2 but have not been reported in those who have a heterozygous pathogenic variant in RAI1. Cardiac anomalies may include mild tricuspid or mitral valve stenosis or regurgitation, ventricular septal defects, supravalvular aortic or pulmonic stenosis, atrial septal defects, and tetralogy of Fallot [Smith & Gropman 2010].

Genitourinary anomalies are found in between 15% and 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]:

• Duplication of the collecting system
• Unilateral renal agenesis and ectopic kidney
• Ureterovesicular obstruction
• Malposition of the ureterovesicular junction

Additionally, a vast 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 2010].

Immunologic. More than 50% of affected individuals have low serum immunoglobulin profiles, which may increase susceptibility to sinopulmonary infections. 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 [Smith, personal communication], 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 [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 age 11 months who died unexpectedly after palatoplasty [Denny et al 1992].

Dermatology. 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.

Malignancy. Risk of cancer appears to be no greater than in the general population for most individuals with SMS.

• At least two affected individuals who developed melanoma are known [Smith, personal experience].
• The common deletion results in haploinsufficiency of FLCN that is associated with Birt-Hogg- Dubé (BHD) syndrome, raising a theoretic concern for increased risk of renal carcinoma in individuals with SMS [Menko et al 2009]. BHD syndrome is a hereditary cancer syndrome characterized by increased risk of cutaneous fibrofolliculomas, pulmonary cysts, spontaneous pneumothorax, and renal tumors. While unstudied, the co-occurrence of renal tumors in a few unrelated adults with SMS [Smith et al 2014, Dardour et al 2016] suggests that precautionary cancer surveillance may be considered in adulthood for individuals with co-occurring BHD syndrome.

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 cognitive impairment at large. Anecdotally, the oldest known individual with SMS lived to age 88 years [Smith & Magenis, personal communication]. 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.

Genotype-Phenotype Correlations

Deletion of 17p11.2. 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 variant in RAI1

• Higher rates of onychotillomania and polyembolokoilamania (90%) have been reported in those with a heterozygous pathogenic variant in RAI1 compared to those with a 17p11.2 deletion (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 is estimated at 1:25,000 births [Greenberg et al 1991]; the actual prevalence may be closer to 1:15,000 [Smith et al 2005]. The vast majority of individuals have been identified in the last five to ten years as a result of improved whole-genome analysis techniques.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Smith-Magenis syndrome (SMS), the recommended evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.