Patil and Bartley (1984) reported a 4-year-old girl with an interstitial deletion of chromosome 17p11.2. She had mental retardation, hypotonia, speech delay, small ears, conductive hearing loss, esotropia, dental enamel dysplasia, and prominent premaxilla. Cardiac examination was normal. ... Patil and Bartley (1984) reported a 4-year-old girl with an interstitial deletion of chromosome 17p11.2. She had mental retardation, hypotonia, speech delay, small ears, conductive hearing loss, esotropia, dental enamel dysplasia, and prominent premaxilla. Cardiac examination was normal. Smith et al. (1986) described in detail the phenotype associated with an interstitial deletion of 17p11.2 in 9 unrelated patients. Clinical features included brachycephaly, midface hypoplasia, prognathism, hoarse voice, and speech delay with or without hearing loss, psychomotor and growth retardation, and behavioral problems. A partial deletion was present in 8 patients; 1 patient with complete deletion of band 17p11.2 was more severely affected with facial malformations, cleft palate, and major anomalies of the cardiac, skeletal, and genitourinary systems. Stratton et al. (1986) described 6 additional patients with this chromosome deletion syndrome. Greenberg et al. (1991) suggested that some SMS patients may have peripheral neuropathy since the disorder is due to deletion of an area of chromosome 17 where a form of Charcot-Marie-Tooth disease (CMT1A; 118220) maps. However, they noted that no patients with CMT1A had shown signs of SMS. Among 32 SMS cases, all unrelated and all with an interstitial deletion of 17p11.2, Greenberg et al. (1991) observed broad flat midface with brachycephaly, broad nasal bridge, brachydactyly, speech delay, and a hoarse deep voice. Fifty-five percent of patients had signs suggestive of peripheral neuropathy, including decreased or absent deep tendon reflexes, pes planus or pes cavus, decreased sensitivity to pain, and decreased leg muscle mass. However, unlike patients with CMT1A, patients with SMS had normal nerve conduction velocities. Two-thirds of the patients demonstrated self-destructive behavior, including head-banging, onychotillomania (pulling out fingernails and toenails), and polyembolokoilamania (insertion of foreign bodies into their ears). Sixty-two percent of patients showed significant symptoms of sleep disturbance such as difficulty falling asleep, difficulty staying asleep, and frequent awakening during the night. Polysonographic studies in 2 patients showed absence of REM sleep. Absence of REM sleep had previously been reported in association with CMT1A; the possibility that a gene associated with REM sleep is in the proximity of the CMT1A locus had been suggested by Tandan et al. (1990). The deletion was determined to be paternal in origin in 9 patients and maternal in 6. The apparent random parental origin suggested that genomic imprinting does not play a role in expression of the SMS clinical phenotype. Greenberg et al. (1991) concluded that SMS is a contiguous gene deletion syndrome. Moncla et al. (1991) added 3 patients to the 21 previously reported. Hearing loss had been described in 10 of 20 cases. Most had speech delay, hyperactivity, and behavioral problems. Craniofacial changes were described and pictured. Zori et al. (1993) described an infant with del(17)(p12p11.2) and manifestations consistent with SMS. The mother, who was mosaic for the same deletion, had minor craniofacial changes as well as brachydactyly, consistent with partial manifestation. Greenberg et al. (1996) reported on a multidisciplinary clinical study of 27 SMS patients. Significant findings included otolaryngologic abnormalities in 94%, eye abnormalities in 85%, sleep abnormalities (especially reduced REM sleep) in 75%, hearing impairment in 68% (approximately 65% conductive and 35% sensorineural), scoliosis in 65%, brain abnormalities (predominantly ventriculomegaly) in 52%, cardiac abnormalities in at least 37%, renal abnormalities (especially duplication of the collecting system) in 35%, low thyroxine levels in 29%, low immunoglobulin levels in 23%, and forearm abnormalities in 16%. The measured IQ ranged between 20 and 78, most patients falling in the moderate range of mental retardation at 40-54, although several patients scored in the mild or borderline range. Greenberg et al. (1996) noted that the diagnosis of SMS is usually secured by cytogenetic analysis during the evaluation of developmental delay and/or congenital anomalies. However, in older individuals the phenotype is distinctive enough that a diagnosis can be made by an experienced clinician before cytogenetic confirmation.
Natacci et al. (2000) reported a 22-year-old woman with a deletion in the short arm of chromosome 17 who presented with the clinical manifestations of both Smith-Magenis syndrome and Joubert syndrome (JBTS; 213300). Facial anomalies, brachydactyly, severe mental ... Natacci et al. (2000) reported a 22-year-old woman with a deletion in the short arm of chromosome 17 who presented with the clinical manifestations of both Smith-Magenis syndrome and Joubert syndrome (JBTS; 213300). Facial anomalies, brachydactyly, severe mental retardation, and self-injuring behavior were attributed to SMS, whereas the cerebellar vermis hypoplasia, hypotonia, ataxic gait, developmental delay, and abnormal respiratory pattern suggested JBTS. By fluorescence in situ hybridization analyses with YAC mapping to the 17p11.2 region, as well as locus-specific probes generated through a novel procedure, they established that the deletion encompasses a 4-Mb interval. The deletion differed from that commonly found in SMS in its telomeric boundary, and was more distal than usually observed. The presence of the JBTS phenotype in this patient and the detection of an unusual SMS deletion suggested the presence of a JBTS gene in close proximity to the SMS locus. Although Joubert syndrome has been linked to 9q34.3 in some families, no linkage to this area had been demonstrated in other families. Girirajan et al. (2005) reported 4 individuals in which SMS was caused by mutation in the RAI1 gene. The authors noted that the clinical features of the patients differed from those found in patients with the 17q11.2 deletion by general absence of short stature and lack of visceral anomalies. All 4 patients had developmental delay, reduced motor and cognitive skills, craniofacial and behavioral anomalies, and sleep disturbances. Seizures, not previously thought to be associated with RAI1 mutations, were present in 1 individual. A patient with an S1808N mutation (607642.0004) had had neonatal jaundice, sleep disturbance, and mildly delayed motor and cognitive milestones as major features during early childhood. He had high myopia, a loud and hoarse voice, a waddling gait, pes planus, and dry skin. Abnormal behavior included sleep disturbances (hypersomnolence as an infant, moving to frequent and early awakenings and daytime napping), reported bipolar episodes, head banging, tantrums, and aggressive and intrusive behavior. He also had deep scarring from obsessively picking his skin. At age 14, he had the developmental age of a 9-year-old child, with an IQ of 89. A boy with a 1-bp deletion (607642.0006) had severely disturbed sleep, head banging, and occasionally self mutilation. He destroyed his toys and the furniture in his bedroom. His intelligence at the age of 9.5 years was evaluated as full scale IQ of 73, verbal IQ of 85, and performance IQ of 65. Craniofacial features included brachycephaly, midface hypoplasia, tented upper lip, and a broad, square face. He also had a hoarse voice. A 19-year-old woman with a 19-bp deletion (607642.0007) was noted as a neonate to have floppy muscle tone, upslanting palpebral fissures, and midface hypoplasia. Down syndrome was initially diagnosed. At 15 years of age she had a developmental age of 8 to 10 years, with an IQ of 67. Her facial and behavioral features were considered consistent with SMS. She had a waddling gait, loud and hoarse voice, decreased sensitivity to pain, and short fingers and hands. She also shared significant sleep disturbance and skin picking. Edelman et al. (2007) retrospectively analyzed the clinical features of 105 patients with SMS, including 95 (90.5%) with 17p11.2 deletions and 10 (9.5%) with RAI1 mutations. Patients with RAI1 mutations were more likely to exhibit overeating, obesity, polyembolokoilamania, self-hugging, muscle cramping, and dry skin. Those with 17p11.2 deletions were more likely to have short stature, hearing loss, ear infections and heart defects. Female SMS patients were significantly more likely to have myopia, eating problems, cold hands and feet, and frustration with communication compared to male patients, regardless of genotype. Girirajan et al. (2006) reported the molecular and genotype-phenotype analyses of 31 patients with SMS who carry 17p11.2 deletions or intergenic mutations, respectively, and were compared for 30 characteristic features of the disorder by the Fisher exact test. Eight of the 31 individuals carried a common 3.5-Mb deletion, whereas 10 of 31 individuals carried smaller deletions, 2 individuals carried larger deletions, and 1 individual carried an atypical 17p11.2 deletion. Ten patients with nondeletion harbored a heterozygous mutation in RAI1. Phenotype comparison between patients with deletions and patients with RAI1 mutations showed that 21 of 30 SMS features are the result of haploinsufficiency of RAI1, whereas cardiac anomalies, speech and motor delay, hypotonia, short stature, and hearing loss are associated with 17p11.2 deletions rather than RAI1 mutations (P less than 0.05). Further, patients with smaller deletions show features similar to those with RAI1 mutations. Girirajan et al. (2006) concluded that although RAI1 is the primary gene responsible for most features of SMS, other genes within 17p11.2 contribute to the variable features and overall severity of the syndrome. As indicated, mutations of the RAI1 gene seem to be responsible for the main features found with heterozygous 17p11.2 deletions. Andrieux et al. (2007) studied DNA from 30 patients with SMS using comparative genome hybridization. Three patients had large deletions. Two of the 3 had cleft palate, which was not found in any of the other patients with SMS. The smallest extra-deleted region associated with cleft palate in SMS was 1.4 Mb, containing less than 16 genes and located at 17p12-p11.2. Gene expression array data showed that the ubiquitin B precursor gene (UBB; 191339) is significantly expressed in the first branchial arch in the fourth and fifth weeks of human development. Together, the data supported UBB as a candidate gene for isolated cleft palate.
Chevillard et al. (1993) described a 5-Mb YAC contig spanning the CMT1A duplicated segment and the distal part of 4 SMS microdeletions. They identified the first expressed sequence located in the SMS critical region: the gene coding for ... Chevillard et al. (1993) described a 5-Mb YAC contig spanning the CMT1A duplicated segment and the distal part of 4 SMS microdeletions. They identified the first expressed sequence located in the SMS critical region: the gene coding for small nuclear RNA U3 (180710). Koyama et al. (1996) localized the human homolog of the murine Llglh gene (LLGL1; 600966) to chromosome 17p11.2. In SMS patients, a probe representing LLGL1 failed to hybridize with 1 of the 2 chromosome 17 homologs, suggesting that this gene may play a role in the pathogenesis of SMS. Elsea et al. (1999) assessed the potential effect of haploinsufficiency of SGN3 (COPS3; 604665), which encodes subunit 3 of the COP9 signalosome and maps to the distal portion of the SMS critical region, in SMS patient lymphoblastoid cell lines. Although SMS patients were haploinsufficient for SGN3, analyses showed that the SGN3 protein was present at equivalent levels in patient and parental control cells, and that the COP9 signalosome complex was assembled and in normal quantities in transformed lymphoblastoid cell lines from patients. The authors concluded that SGN3 probably does not play a significant role with respect to SMS, although its involvement could not be ruled out since the importance of the COP9 signalosome in embryogenesis or differentiation was not well understood. Lucas et al. (2001) created a contiguous physical and transcription map of the 1.5-Mb SMS critical interval. Within this interval, they identified 13 known genes, 14 ESTs, and 6 genomic markers. To identify possible candidate genes, they performed sequence analysis and determined the tissue expression pattern of 10 novel ESTs mapping to the SMS critical interval. Lucas et al. (2001) also presented a detailed review of 6 SMS candidate genes, of which NT5M (605292) was considered especially intriguing because of the possible role of the NT5M protein on the modulation of dTTP substrate pools in the mitochondria. Lucas et al. (2001) speculated that some of the characteristics of SMS, including hypotonia, mental retardation, and behavioral abnormalities, may be an effect of excess dTTP and defective mitochondria. Slager et al. (2003) studied 3 individuals who had clinical features consistent with SMS but did not have 17p11.2 deletions detectable by standard fluorescence in situ hybridization techniques. They found that 2 patients had deletion of a single cytosine in a run of Cs in the RAI1 gene (607642.0001, 607642.0002). They compared clinical findings in these 2 patients with those with the typical deletion, with a small deletion, and with a 29-bp deletion (607642.0003). This led to the conclusion that SMS may be similar to previously described microdeletion syndromes in which a single gene is implicated in most of the features but other deleted genes may modify the overall phenotype, e.g., Williams syndrome (194050) and Angelman syndrome (105830). Haploinsufficiency of RAI1 is probably responsible for the behavioral, neurologic, otolaryngologic, and craniofacial aspects of this syndrome, but more variable features such as heart and renal defects are probably due to hemizygosity of other genes in the 17p11.2 region. Kaminsky et al. (2011) presented the largest copy number variant case-control study to that time, comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing on recurrent deletions and duplications involving 14 copy number variant regions. Compared with controls, 14 deletions and 7 duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic. The 17p11.2 deletion was identified in 16 cases and no controls for a p value of 0.00045 and a frequency of 1 in 984 cases. - Molecular Mechanisms of Deletion and Duplication Chen et al. (1997) identified 3 copies of a low-copy-number repeat located within and flanking the SMS common deletion region. They showed that this repeat, called SMS-REP by them, represents a repeated gene cluster. They isolated a corresponding cDNA clone that identified a novel junction fragment from 29 unrelated SMS patients and a different-sized junction fragment from a patient with duplication of 17p11.2. Their results suggested that homologous recombination of a flanking repeat gene cluster is a mechanism for this common microdeletion syndrome. Recombination between repeated sequences at various regions of the human genome are known to give rise to DNA rearrangements associated with many genetic disorders (Lupski, 1998). Perhaps the most extensively characterized genomic region prone to rearrangement is 17p12, which is associated with peripheral neuropathies, hereditary neuropathy with liability to pressure palsies (HNPP; 162500), and CMT1A. Homologous recombination between 24-kb flanking repeats, termed CMT1A-REPs, results in a 1.5-Mb deletion that is associated with HNPP, and the reciprocal duplication product is associated with CMT1A. In the case of Smith-Magenis syndrome, more than 90% of patients carry deletions of the same genetic markers in 17p11.2, defining a common deletion (Potocki et al., 2000). Shaw et al. (2002) analyzed the haplotypes of 14 families of patients with SMS and 6 families of patients with duplication of the same region using microsatellite markers directly flanking the SMS common deletion breakpoints. The data indicated that the deletion and its reciprocal duplication of chromosome 17p11.2 result from unequal meiotic crossovers mediated through nonallelic homologous recombination (NAHR) that occurs via both interchromosomal and intrachromosomal exchange events between the proximal and distal SMS repeats. There appeared to be no parental-origin bias associated with common SMS deletions and the reciprocal duplications. Bi et al. (2003) reported a recombination hotspot associated with both the common SMS deletion and the reciprocal duplication, dup(17)(p11.2p11.2), demonstrating the reciprocity of the crossover events as had been demonstrated for HNPP and CMT1A. Shaw et al. (2004) reported an additional recombination hotspot within 2 large low-copy repeats (LCRs), which serve as alternative substrates for nonallelic homologous recombination that results in large (approximately 5 Mb) deletions of 17p11.2, which include the SMS region. Liu et al. (2011) assembled 2 patient cohorts with reciprocal genomic disorders, deletion-associated SMS and duplication-associated Potocki-Lupski syndrome (610883). By assessing the full spectrum of rearrangement types from the 2 cohorts, Liu et al. (2011) found that complex rearrangements (those with more than 1 breakpoint) are more prevalent in copy-number gains (17.7%) than in copy-number losses (2.3%), an observation that supports a role for replicative mechanisms in complex rearrangement formation. Interestingly, for nonallelic homologous recombination-mediated recurrent rearrangements, Liu et al. (2011) showed that crossover frequency is positively associated with the flanking low-copy repeat (LCR) length and inversely influenced by the inter-LCR distance. To explain this, they proposed that the probability of ectopic chromosome synapsis increases with increased LCR length, and that ectopic synapsis is a necessary precursor to ectopic crossing-over.
The diagnosis of SMS depends on genetic testing that demonstrates either a 17p11.2 deletion that includes RAI1 or a mutation of RAI1....
DiagnosisThe diagnosis of SMS depends on genetic testing that demonstrates either a 17p11.2 deletion that includes RAI1 or a mutation of RAI1.Smith-Magenis syndrome (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 (see Figures 1, 2, 3) Mild-to-moderate infantile hypotonia with feeding difficulties and failure to thriveMinor skeletal anomaliesShort stature (prepubertal)BrachydactylyOphthalmologic abnormalitiesOtolaryngologic abnormalitiesEarly speech delays with or without associated hearing lossPeripheral neuropathySome level of cognitive impairment and developmental delayA 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, Martin et al 2006]. Sleep disturbance is chronic and associated with an abnormal diurnal circadian rhythm of melatonin [Potocki et al 2000b, De Leersnyder et al 2001, Boone et al 2011].FigureFigure 1. Infants with SMS. Nine-month-old female (left) and 30-month-old male (right). Note brachycephaly, broad forehead, upslanting palpebral fissures, short upturned nose, and characteristic down-turned “tent” shaped upper lip vermilion (more...)FigureFigure 2. Early school-age SMS showing four-year-old male (left) and five-year-old female (right); the female is also pictured at age 15 years in Fig 3. Note broad forehead, deep-set eyes, midface retrusion. FigureFigure 3. Adolescent females with Smith-Magenis syndrome caused by RAI1 mutation (left) and deletion 17p11.2 (right). Note short philtrum with relative prognathism resulting from midface retrusion that persists with age; down-turned upper lip is more (more...)Renal anomalies and cleft lip and/or 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.TestingCytogenetic testing. SMS is typically diagnosed by detection of an interstitial deletion of 17p11.2 by G-banded cytogenetic analysis and/or by FISH analysis. Probes for FISH testing must include RAI1 [Vlangos et al 2005]. 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% of individuals with SMS have a FISH-detectable deletion, with approximately 70% having the common approximately 3.5-Mb deletion [Potocki et al 2003, Vlangos et al 2003, Girirajan et al 2006].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 or aCGH is indicated for individuals with prior "normal" routine cytogenetic analysis in whom a diagnosis of SMS is strongly suspected.Molecular Genetic TestingGene. RAI1 is the only gene in which mutation or deletion is known to account for the majority of features in Smith-Magenis syndrome (SMS) [Slager et al 2003, Bi et al 2004, Girirajan et al 2005, Truong et al 2010, Vilboux et al 2011].Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Smith-Magenis SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityRAI1FISH 2Deletion 17p11.2 involving RAI13~95%ClinicalSequence analysisSequence variants 45%-10% 5Deletion / duplication analysis 6Deletions involving RAI13~95% 7Note: A few individuals with clinical features of SMS but without confirmed deletions and/or RAI1 mutations may represent an SMS-like syndrome yet to be defined.1. The ability of the test method used to detect a mutation that is present in the indicated gene2. FISH probe that contains RAI1 or D17S258. Note: Not all commercially available FISH probes contain RAI1 [Vlangos et al 2005].3. Extent of deletion detected may vary by method and by laboratory. RAI1deletions have been detected by aCGH, real-time PCR, and MLPA [Truong et al 2008]. Deletion/duplication analysis of the critical region and beyond will define the size of the deleted region.4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. 5. Sequence analysis (particularly of exon 3, in which all mutations have been found to date) detects RAI1 mutations in individuals with SMS when cytogenetic and FISH studies are negative for the 17p11.2 deletion [Slager et al 2003, Bi et al 2004, Girirajan et al 2005, Truong et al 2010, Vilboux et al 2011].6 Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. 7. Wide availability of CMA testing may lead to increased diagnostic detection of previously unsuspected cases.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a probandArray CGH should be performed as an initial study. This test will identify all 17p11.2 deletions and will also identify phenotypically overlapping genomic disorders. If there is a strong clinical suspicion of SMS and aCGH is normal, deletion/duplication analysis specific for RAI1 may be performed.If the above deletion analyses are normal, sequencing of RAI1 should be considered.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing deletion or mutation in the family.Genetically Related (Allelic) DisordersPersons 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 syndrome (Potocki-Lupski syndrome) harbor the recombination reciprocal of the SMS deletion and differ phenotypically and behaviorally from those with SMS [Potocki et al 2000a, Potocki et al 2007].
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 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. ...
Natural HistorySmith-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 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. With progressing age, the facial appearance becomes more distinctive and coarse, with persisting midfacial retrusion, relative prognathism, and heavy brows with a "pugilistic" appearance. An increased frequency of dental anomalies, specifically tooth agenesis (especially premolars) and taurodontism, has been reported [Tomona et al 2006].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 intellectual disability.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 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 et al 2000b, De Leersnyder et al 2001, Smith & Duncan 2005]. Fragmented sleep with reduced total sleep time has been documented as early as age six months [Duncan et al 2003, Gropman et al 2006] and remains a chronic issue into adulthood. Actigraphy-based sleep estimates document developmental differences in nocturnal arousal patterns by age and time of night [Gropman et al 2007].The abnormal diurnal (inverted) circadian rhythm of melatonin appears pathognomic in SMS; it is documented in 95% (26/28) of individuals with a deletion studied to date [Potocki et al 2000b, De Leersnyder et al 2001, Boudreau et al 2009], in addition to individuals with mutation of RAI1 [Boone et al 2011]. New 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]. Table 2. Clinical Features of Smith-Magenis SyndromeView in own windowFrequencySystemFinding>75% of individualsCraniofacial/skeletal Brachycephaly Midface retrusion Relative prognathism with 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) OtolaryngologicMiddle ear and laryngeal anomalies Hoarse, deep voiceNeuro/behavioralCognitive impairment/developmental delay Generalized complacency/lethargy (infancy) Infantile hypotonia Sleep disturbance Inverted circadian rhythm of melatonin Attention seeking Attention deficit (+/-hyperactivity) disorder Tantrums, behavioral outbursts Impulsivity Stereotypic behaviors Self-injurious behaviors Speech delay Hyporeflexia Signs of peripheral neuropathy Oral sensorimotor dysfunction (early childhood) Sensory processing issuesCommon (50%-75% of individuals)Hearing loss Short stature Scoliosis Mild ventriculomegaly of brain Hyperaccusis Tracheobronchial problems Velopharyngeal insufficiency (VPI) Ocular abnormalities (iris anomalies; microcornea) REM sleep abnormalities Hypercholesterolemia/hypertriglyceridemia History of constipation Abnormal EEG without overt seizures Autism spectrum disorder (ASD)Less common (25%-50% of individuals)Cardiac defects Thyroid function abnormalities Seizures 1Immune function abnormalities (esp. low IgA)Occasional (<25% of individuals)Renal/urinary tract abnormalities Seizures 1Forearm abnormalities Cleft lip/palate Retinal detachmentGreenberg et al [1996], Chen et al [1997], Allanson et al [1999], Smith et al [2002], Potocki et al [2003], Gropman et al [2006], Edelman et al [2007], Smith et al [2007], Smith & Gropman [2010]1. Frequency varies by study.InfancyPhysical features. Prenatal histories are notable for decreased fetal movement in 50%. The infant with SMS is generally born at term, with normal birth weight, length, and head circumference. Length and weight gradually decelerate in early infancy. In approximately 20% of children with SMS, the head circumference is less than the third percentile for age [Smith & Gropman 2010].The subtle facial dysmorphology in infancy, often characterized by midface retrusion, short upturned nose, fleshy everted vermilion of the upper lip with a "tented" appearance, and micrognathia, may be recognizable in early infancy (see Figure 1). Feeding difficulties leading to failure to thrive are common, including marked oral motor dysfunction with poor suck and swallow, textural aversion, and gastroesophageal reflux. Hypotonia is reported in virtually all infants, 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 [Hildenbrand & Smith 2012]. Prospective assessment of infants younger than age one year document generalized hypotonia, oral-motor dysfunction, and middle ear abnormalities with age-appropriate social skills and minimal maladaptive behaviors [Wolters et al 2009]. Crying is infrequent and often hoarse, and the vast majority of infants show markedly decreased babbling and vocalization for age. By age two to three years, global developmental delays, significant expressive language deficits relative to receptive language skills, and emerging maladaptive behaviors are recognized [Gropman et al 2006, Wolters et al 2009].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, actigraphy-estimated sleep suggests that the disrupted sleep pattern begins as early as age nine months and worsens progressively from infancy through childhood [Duncan et al 2003, Gropman et al 2006].Childhood/School AgePhysical features. The facial appearance of SMS becomes more recognizable in early childhood (see Figure 2, Figure 3) 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 age 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.Hypercholesterolemia is recognized in over 50% of individuals with SMS [Smith et al 2002].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%). Hyperacusis, or oversensitivity to certain frequencies/sounds tolerable to listeners with normal hearing, is reported in 78% [Smith et al 2007]. 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 hoarse vocal quality. Hearing impairment is found in more than two thirds of affected individuals. 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 intellectual disability. 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 age 18 months. Sensory integration issues are present and persist throughout childhood. A prominent pattern of sensory processing is recognized that is characterized by an imbalance in neurologic thresholds and a fluctuation between active and passive self-regulation [Hildenbrand & Smith 2012]. Most individuals with SMS exhibit inattention with or without hyperactivity.A recent study using the SRS (Social Responsiveness Scale) found that 90% of individuals with SMS had scores within the autism range (35% mild/moderate; 55% severe range) and, from a clinical perspective, met criteria for an axis I diagnosis of pervasive developmental disorder [Laje et al 2010b]. The diagnosis of SMS should be considered in the differential diagnosis of children with autism spectrum disorders, especially those with characteristic behaviors or stereotypies recognized in SMS, significant feeding problems and oromotor dysfunction, or sleep disturbance associated with excessive daytime sleepiness [Smith & Gropman 2010]. Therapeutic interventions for autism are likely to benefit individuals with SMS. 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 remains a strong predictor of maladaptive behavior [Dykens & Smith 1998, Arron et al 2011, Sloneem et al 2011]. Due to the maladaptive behaviors, true intellectual ability may not be accurately assessed in many individuals. Self-injurious behaviors (SIB) occur in the vast majority of individuals with SMS after age two years [Arron et al 2011, Sloneem et al 2011]. 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 to ages where this is not socially acceptable. 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 between intellectual functioning and emotional maturity [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.The spasmodic upper-body squeeze or "self-hug" behavior may provide an effective clinical diagnostic marker for the syndrome [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%). The finger lick and page flipping ("lick and flip") behavior first recognized by Dykens et al [1997] may be less prevalent than initially reported [Authors, personal observation]. Sleep disturbance is a major issue for caretakers, who themselves may become sleep deprived [Foster et al 2010]. 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 2000b]. Actigraphy-based sleep estimates from infancy (age <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]. Children younger than age ten years show few difficulties getting to sleep (settling), but exhibit increased activity (arousals) in the second half of the night [Gropman et al 2007]. Older children and adolescents show more difficulties settling to sleep [Gropman et al 2007].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).AdolescencePhysical features. The facial appearance (Figure 3) becomes more angulated, with persisting midface retrusion and relative prognathism, frontal bossing with synophrys, heavy brows (often pugilistic), and a general coarsening. Puberty typically occurs within the normal time frame; however, precocious puberty and delayed sexual maturation have been seen. Neurobehavioral features. Behaviors often escalate with onset of puberty, and sleep disturbance remains a concern. Actigraphy-based sleep estimates indicate more difficulties settling to sleep than in earlier childhood [Gropman et al 2007]. Increased impulsivity, especially in females, is recognized [Martin et al 2006]. Rapid mood shifts, increased anxiety with/without tendency for fright/flight reaction becomes a major issue in adolescence and adulthood. Aggressive outbursts are common, escalating with age. Pubertal onset of catamenial seizures has also been observed in some females coinciding with menses [Smith & Gropman 2010]. Polyembolokoilamania and onychotillomania may become more prevalent. 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 [Finucane et al 2001]. AdulthoodInsufficient longitudinal data are available to accurately determine life expectancy; however, the oldest known individual with SMS lived to age 88 years [Magenis, personal communication]. In the month prior to her death she was her usual alert happy “SMS” self 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. 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 retrusion 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 SMS phenotype....
Genotype-Phenotype CorrelationsParental 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.Individuals so far reported with RAI1-specific 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.
Smith-Magenis syndrome (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:...
Differential DiagnosisSmith-Magenis syndrome (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)Williams syndromeDown syndrome (trisomy 21; in the newborn period)Fragile X syndrome2q37 deletion syndrome 2q23.1 deletion syndromeKleefstra syndrome (9q34.3 deletion or intragenic EHMT1 mutation)Clinically, many children with SMS are given psychiatric diagnoses — including autism/autism spectrum disorders (ASD), attention deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and/or mood disorders. Accurate diagnosis is more difficult in the presence of speech delays and maladaptive or stereotypic behaviors.Delayed diagnosis of SMS is common. Repeat cytogenetic analysis using aCGH or FISH-specific probes for SMS is warranted in individuals suspected of having SMS who had a prior "normal" chromosome analysis. Current clinical use of aCGH in children referred with “developmental delay” alone has led to increased detection of clinically unsuspected SMS deletion cases [Authors’ experience]. 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 midface, 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 an SMS-specific probe [Smith et al 2005].Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with Smith-Magenis syndrome (SMS), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Smith-Magenis syndrome (SMS), the following evaluations are recommended:Complete review of systems at the time of diagnosisPhysical and neurologic examinationRenal 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 existsEchocardiogram to evaluate for possible cardiac anomalies (<45% of individuals with SMS); follow-up depending on the severity of any cardiac anomaly identifiedSpine radiographs to evaluate for possible vertebral anomalies and scoliosis (~60%)Routine blood chemistries, qualitative immunoglobulins, fasting lipid profile (evaluation for hypercholesterolemia), and thyroid function studiesOphthalmologic evaluation with attention to evidence of strabismus, microcornea, iris anomalies, and refractive errorComprehensive speech/language pathology evaluationAssessment of caloric intake, signs and symptoms of gastroesophageal reflux disease (GERD), swallowing abilities, and oral motor skills with referral as warranted for full diagnostic evaluationOtolaryngologic 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 lossMultidisciplinary developmental evaluation, including assessment of motor, speech, language, personal-social, general cognitive, and vocational skillsEarly evaluation by physical and/or occupational therapistsSleep 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 asymmetryIn individuals with SMS documented to have larger deletions extending into 17p12:Specific screening for adrenal functionDetailed assessment and attention to peripheral neurologic function in individuals with SMS with large deletions involving PMP22, 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 interventionsMedical genetics consultationTreatment of ManifestationsThe following are appropriate:Ongoing pediatric care with regular immunizationsFrom early infancy, referrals for early childhood intervention programs, followed by ongoing special education programs and vocational training in later yearsTherapies 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, such as computer assisted devices and tablets, 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 on the early use of sign language and intervention by speech/language pathologists.Atypical patterns of sensory processing may become more prominent with increased age. Insight about the vulnerabilities and relative strengths in patterns of sensory processing may aid caregivers of individuals with SMS in adapting activity demands, modifying the environment, and facilitating appropriate and supportive social interactions. In addition, 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].A comprehensive behavior support plan for home and school should be considered as soon as problem behaviors arise, typically starting in early elementary school. A structured school program with one-on-one support and curricula matched to the known cognitive and behavioral profile of SMS can be effective in addressing the needs of these students. The combination of intellectual disability, severe behavioral abnormalities, and sleep disturbance takes a significant toll on parents and siblings. Parents report high rates of depression and anxiety, and family stress is significantly higher in families of people with SMS than in those of children with nonspecific developmental disabilities [Hodapp et al 1998, Foster et al 2010]. Family support services and resources should be included as essential components of a holistic management plan for people with SMS.Use of psychotropic medication to increase attention and/or decrease hyperactivity. No single regimen shows consistent efficacy [Laje et al 2010a]. 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].Behavioral therapies including special education techniques that emphasize individualized instruction, structure, and routine to help minimize behavioral outbursts in the school settingTherapeutic 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 taken at bedtime remain encouraging, providing variable improvement of sleep without reports of major adverse reactions. 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. 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 Leersnyder 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, some 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 sleepRespite care and family psychosocial support to help assure the optimal environment for the affected individualMonitoring of hypercholesterolemia (recognized in >50% of individuals with SMS); treatment with diet or medication as indicatedTreatment with corrective lenses as indicated for ophthalmologic abnormalitiesTreatment of recurrent otitis media with tympanostomy tubes as neededAuditory amplification if hearing loss is identifiedManagement of seizures in accordance with standard practiceTreatment 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.SurveillanceRecommended annually:Multidisciplinary team evaluation (including physical, 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, including free T4 and TSH Fasting lipid profileRoutine urinalysis to evaluate for occult urinary tract infections Monitoring for scoliosisOphthalmologic evaluationOtolaryngologic follow-up for assessment and management of otitis media and other sinus abnormalitiesAudiologic evaluation to monitor for conductive or sensorineural hearing loss annually or as clinically indicatedAgents/Circumstances to AvoidIn at least one case, a teenage female with SMS was documented to have a serious adverse event taking Strattera® (atomoxetine hydrochloride) with extreme escalation of behaviors and aggression leading to hospitalization. Significant changes in her sleep pattern were also documented. Care should be taken to track sleep parameters and behavior with this medication. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management To date, there are no published cases of individuals with SMS who have had children. Therapies Under InvestigationSearch ClinicalTrials.gov 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.OtherPharmacologic intervention should be considered on an individual basis with recognition that some medications may exacerbate sleep or behavioral problems and may cause weight gain.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDRAI117p11.2Retinoic acid-induced protein 1RAI1 @ LOVDRAI1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Smith-Magenis Syndrome (View All in OMIM) View in own window 182290SMITH-MAGENIS SYNDROME; SMS 607642RETINOIC ACID-INDUCED GENE 1; RAI1Molecular Genetic PathogenesisSmith-Magenis syndrome is a contiguous gene deletion syndrome. A common deletion interval spanning approximately 3.5 Mb is identified in approximately 70% of individuals [Potocki et al 2003, Vlangos et al 2003]. The SMS critical region maps to 17p11.2 and spans fewer than 650 kb [Schoumans et al 2005, Vlangos et al 2005]. SMS also results from intragenic mutations of RAI1 (see Table 3).Normal allelic variants. The gene has six exonsPathologic allelic variants. Dominant mutations in RAI1 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, Truong et al 2010]. See Table 3.Table 3. Selected RAI1 Pathologic Allelic Variants View in own windowNucleotide ChangeAmino Acid Change 1Reference Sequencesc.253_271del19p.Leu85Cysfs*55NM_030665.3 NP_109590.3c.1119delCp.Gln374Serfs*65c.1449delCp.Glu484Lysfs*35c.2773_2801del29p.Val1925Argfs*9c.2878C>Tp.Arg960Xc.3103delCp.Gln1035Argfs*29c.3103dupCp.Gln1035Profs*31c.3801delCp.Thr1268Profs*47c.4649delCp.Ser1550Phefs*37c.4685A>Gp.Gln1562Argc.4933_4936delp.Ala1645Glyfs*35c.5423G>Ap.Ser1808Asnc.5265delCp.Arg1756Glyfs*94See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).References for pathologic variants: Slager et al [2003], Bi et al [2004], Girirajan et al [2005], Girirajan et al [2006], Truong et al [2010]1. Nomenclature for frameshift mutatons includes the amino acid change occurring at the site of the frame shift (fs), followed by an "X#" indicating the codon position at which the new reading frame ends in a stop codon (X). The position of the stop in the new reading frame is calculated starting at the first changed amino acid that is created by the frame shift, and ending at the first stop codon (X#) (See www.hgvs.org). Normal gene product. Normal retinoic acid-induced protein 1 is thought to function in transcriptional regulation [Bi et al 2004, Burns et al 2010, Carmona-Mora et al 2010]; 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 retinoic acid-induced protein 1 is thought to result in disease phenotype is haploinsufficiency; thus it is assumed that intragenic mutations result in a nonfunctional protein product.