Smith–Magenis Syndrome

Sarah H Elsea, Virginia Commonwealth University, Richmond, VA, USA
Brenda Finucane, Elwyn, Elwyn, PA, USA

Published online: March 2009

DOI: 10.1002/9780470015902.a0021428

Smith–Magenis syndrome (SMS) is a complex neurobehavioural disorder caused by haploinsufficiency of the RAI1 gene on chromosome 17p11.2. Key clinical features include intellectual disability, self-injurious behaviours, sleep disturbance and craniofacial and skeletal anomalies. Diagnostic strategies are focused towards identification of a 17p11.2 microdeletion encompassing RAI1 or a mutation of RAI1. G-banding and fluorescent in situ hybridization are classical methods used to detect the SMS deletions, whereas multiplex ligation-dependent probe amplification, comparative genomic hybridization and real-time quantitative PCR (polymerase chain reaction) are the newer technologies. Most SMS features are due to RAI1 haploinsufficiency, whereas variability and severity are modified by other genes in the 17p11.2 region. The functional role for RAI1 is not completely understood, but it is likely involved in transcription and functions in several different biological pathways. Management of SMS is a multidisciplinary approach and involves treatment for sleep disturbance, speech and occupational therapies, minor medical interventions and management of behaviours.

Synonyms: SMS, del(17)(p11.2), del(17)(p11.2p11.2), RAI1 mutation

Key concepts

  • Smith–Magenis syndrome (SMS) is a multiple congenital anomalies disorder caused by an interstitial deletion of chromosome 17p11.2 containing the retinoic acid induced 1 (RAI1) gene or by mutation of RAI1.
  • Typically a sporadic genomic disorder with an estimated prevalence of 1:15 000–25 000.
  • Individuals with SMS have intellectual disability, distinctive behavioural features, craniofacial and skeletal anomalies, speech and developmental delay and sleep disturbance.
  • Hypotonia, hearing loss and chronic ear infections, eye abnormalities, cardiac and renal defects, and occasionally, cleft lip and/or palates are also observed.
  • Approximately 90% of SMS cases have a FISH detectable 17p11.2 microdeletion (ranging from 650 kb to 9 Mb), whereas the remaining 10% have a mutation in RAI1.
  • Haploinsufficiency of RAI1 results in most features of SMS, but variabliity and severity are modified by other genes in the 17p11.2 deletion region.
  • RAI1 is a putative transcription factor functioning in multiple biological pathways resulting in the pleiotropic effects seen in SMS.
  • Management includes therapy for sleep disturbance, early childhood intervention programmes, special education and vocational training, and multidisciplinary evaluation for behavioural and systemic manifestations.
  • Recurrence risk for sibs of the proband, if the parental chromosome/gene analyses are normal, is less than 1%. Risk increases if a parent of the proband carries a balanced chromosomal rearrangement or if mosaicism for either a deletion or RAI1 mutation is present in either parent. Mosaicism in a parent of an affected child is estimated at 3–5%.

Keywords: intellectual disability; sleep disturbance; self-injury; aggressive behaviours; 17p11.2; RAI1

Figure 1. Smith–Magenis syndrome. (a) Typical SMS infant phenotype with ‘tented’ upper lip and depressed nasal bridge. Reproduced with permission from Lorna Harris. (b) Male, age 19 years, with SMS. Note, although recognizable, the characteristic facial features associated with SMS are often subtle. Reproduced from Genetic Causes of Developmental Disabilities Brochure, with permission. © Genetic Services at Elwyn.
Figure 2. The SMS region on 17p11.2. A schematic showing the SMS region with representative genes and proximal, middle and distal repeats. Different sized 17p11.2 deletions identified in SMS cases including common, large, small and atypical deletions are shown by the solid coloured bars. Note that all deletions include the RAI1 gene, shown in red. Commercially available FISH probes useful for SMS diagnosis are also represented.
Figure 3. RAI1 gene and mutations. The genomic structure of the RAI1 gene with coding (blue) and noncoding (black) exons is shown. All RAI1 mutations identified and reported are represented. Mutations include single and multiple nucleotide deletions and insertions and missense and nonsense mutations.
close
 References
    Allanson JE, Greenberg F and Smith AC (1999) The face of Smith-Magenis syndrome: a subjective and objective study. Journal of Medical Genetics 36: 394–397.
    Bi W, Saifi GM, Girirajan S et al. (2006) RAI1 point mutations, CAG repeat variation, and SNP analysis in non-deletion Smith-Magenis syndrome. American Journal of Medical Genetics A 140: 2454–2463.
    Bi W, Saifi GM, Shaw CJ et al. (2004) Mutations of RAI1, a PHD-containing protein, in nondeletion patients with Smith-Magenis syndrome. Human Genetics 115: 515–524.
    Chen KS, Manian P, Koeuth T et al. (1997) Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome. Nature Genetics 17: 154–163.
    De Leersnyder H, Bresson JL, de Blois MC et al. (2003) Beta 1-adrenergic antagonists and melatonin reset the clock and restore sleep in a circadian disorder, Smith-Magenis syndrome. Journal of Medical Genetics 40: 74–78.
    Dykens EM, Finucane BM and Gayley C (1997) Brief report: cognitive and behavioral profiles in persons with Smith-Magenis syndrome. Journal of Autism & Developmental Disorders 27: 203–211.
    Edelman EA, Girirajan S, Finucane B et al. (2007) Gender, genotype, and phenotype differences in Smith-Magenis syndrome: a meta-analysis of 105 cases. Clinical Genetics 71: 540–550.
    Elsea SH and Girirajan S (2008) Smith-Magenis syndrome. European Journal of Human Genetics 16: 412–421.
    book Finucane B (2008) Embracing the Inner Toddler in People with Smith-Magenis Syndrome. Spectrum, vol 12. Reston, VA: PRISMS.
    Finucane B, Dirrigl KH and Simon EW (2001) Characterization of self-injurious behaviors in children and adults with Smith-Magenis syndrome. American Journal of Mental Retardation 106: 52–58.
    Finucane BM, Jaeger ER, Kurtz MB, Weinstein M and Scott CI Jr (1993) Eye abnormalities in the Smith-Magenis contiguous gene deletion syndrome. Americal Journal of Medical Genetics 45: 443–446.
    Finucane BM, Konar D, Haas-Givler B, Kurtz MB and Scott CI (1994) The spasmodic upper-body squeeze: a characteristic behavior in Smith-Magenis syndrome. Developmental Medicine and Child Neurology 36: 70–83.
    Girirajan S, Elsas LJ 2nd, Devriendt K and Elsea SH (2005) RAI1 variations in Smith-Magenis syndrome patients without 17p11.2 deletions. Journal of Medical Genetics 42: 820–828.
    Girirajan S, Mendoza-Londono R, Vlangos CN et al. (2007) Smith-Magenis syndrome and Moyamoya disease in a patient with del(17) (p11.2p13.1). American Journal of Medical Genetics A 143A: 999–1008.
    Girirajan S, Vlangos CN, Szomju BB et al. (2006) Genotype-phenotype correlation in Smith-Magenis syndrome: evidence that multiple genes in 17p11.2 contribute to the clinical spectrum. Genetics in Medicine 8: 417–427.
    Greenberg F, Guzzetta V, Montes de Oca-Luna R et al. (1991) Molecular analysis of the Smith-Magenis syndrome: a possible contiguous-gene syndrome associated with del(17) (p11.2). American Journal of Human Genetics 49: 1207–1218.
    Greenberg F, Lewis RA, Potocki L et al. (1996) Multi-disciplinary clinical study of Smith-Magenis syndrome (deletion 17p11.2). American Journal of Medical Genetics 62: 247–254.
    Gropman AL, Duncan WC and Smith AC (2006) Neurologic and developmental features of the Smith-Magenis syndrome (del 17p11.2). Pediatric Neurology 34: 337–350.
    Hicks M, Ferguson S, Bernier F and Lemay JF (2008) A case report of monozygotic twins with Smith-Magenis syndrome. Journal of Developmental and Behavioral Pediatrics 29: 42–46.
    Hodapp RM, Fidler DJ and Smith AC (1998) Stress and coping in families of children with Smith-Magenis syndrome [In: Process Citation]. Journal of Intellectual Disabilty Research 42: 331–340.
    Juyal RC, Figuera LE, Hauge X et al. (1996) Molecular analyses of 17p11.2 deletions in 62 Smith-Magenis syndrome patients. American Journal of Human Genetics 58: 998–1007.
    book Kozachek S, Foster RH, Kanotra S, Stern M and Elsea SH (2008) Depression and anxiety in caregivers of individuals with Smith-Magenis syndrome. National Society of Genetic Counseling Annual Education Conference, Los Angeles, CA, Abstract #55.
    Lee JA, Inoue K, Cheung SW et al. (2006) Role of genomic architecture in PLP1 duplication causing Pelizaeus-Merzbacher disease. Human Molecular Genetics 15: 2250–2265.
    book Levitas A, Dykens E, Finucane B and Kates WR (2007) "Behavioral phenotypes of genetic disorders" In: Fletcher EL R, Stavrakaki C and First M (eds) Diagnostic Manual – Intellectual Disability: A Textbook of Diagnosis of Mental Disorders in Persons with Intellectual Disability. Kingston, NY: NADD Press.
    Lucas RE, Vlangos CN, Das P, Patel PI and Elsea SH (2001) Genomic organisation of the approximately 1.5 Mb Smith-Magenis syndrome critical interval: transcription map, genomic contig, and candidate gene analysis. European Journal of Human Genetics 9: 892–902.
    Potocki L, Glaze D, Tan DX et al. (2000) Circadian rhythm abnormalities of melatonin in Smith-Magenis syndrome. Journal of Medical Genetics 37: 428–433.
    Seranski P, Hoff C, Radelof U et al. (2001) RAI1 is a novel polyglutamine encoding gene that is deleted in Smith-Magenis syndrome patients. Gene 270: 69–76.
    Shaw CJ, Bi W and Lupski JR (2002) Genetic proof of unequal meiotic crossovers in reciprocal deletion and duplication of 17p11.2. American Journal of Human Genetics 71: 1072–1081.
    Shaw CJ and Lupski JR (2004) Implications of human genome architecture for rearrangement-based disorders: the genomic basis of disease. Human Molecular Genetics 13(Spec No 1): R57–64.
    Shaw CJ and Lupski JR (2005) Non-recurrent 17p11.2 deletions are generated by homologous and non-homologous mechanisms. Human Genetics 116: 1–7.
    Shaw CJ, Shaw CA, Yu W et al. (2004) Comparative genomic hybridisation using a proximal 17p BAC/PAC array detects rearrangements responsible for four genomic disorders. Journal of Medical Genetics 41: 113–119.
    Slager RE, Newton TL, Vlangos CN, Finucane B and Elsea SH (2003) Mutations in RAI1 associated with Smith-Magenis syndrome. Nature Genetics 33: 466–468.
    Smith AC, Dykens E and Greenberg F (1998) Sleep disturbance in Smith-Magenis syndrome (del 17 p11.2). American Journal of Medical Genetics 81: 186–191.
    book Smith ACM, Allanson J, Elsea SH et al. (2006) Smith-Magenis syndrome. GeneTests: Medical Genetics Information Resource, vol. 2008. Seattle, WA: University of Washington.
    Smith ACM, Gropman AL, Bailey-Wilson JE et al. (2002) Hypercholesterolemia in children with Smith-Magenis syndrome: del(17) (p11.2p11.2). Genetics in Medicine 4: 118–125.
    Smith ACM, McGavran L, Robinson J et al. (1986) Interstitial deletion of (17) (p11.2p11.2) in nine patients. American Journal of Medical Genetics 24: 393–414.
    Smith ACM, McGavran L, Waldstein G and Robinson J (1982) Deletion of the 17 short arm in two patients with facial clefts and congenital heart defects. American Journal Human Genetics 34: 146A.
    Solomon B, McCullagh L, Krasnewich D and Smith ACM (2002) Oral motor, speech and voice functions in Smtih-Magenis syndrome children: A research update. American Journal of Human Genetics 71: 271.
    Toulouse A, Rochefort D, Roussel J, Joober R and Rouleau GA (2003) Molecular cloning and characterization of human RAI1, a gene associated with schizophrenia. Genomics 82: 162–171.
    Truong HT, Solaymani-Kohal S, Baker KR et al. (2008) Diagnosing Smith-Magenis syndrome and duplication 17p11.2 syndrome by RAI1 gene copy number variation using quantitative real-time PCR. Genetic Test 12: 67–73.
    Vlangos CN, Yim DK and Elsea SH (2003) Refinement of the Smith-Magenis syndrome critical region to approximately 950b and assessment of 17p11.2 deletions. Are all deletions created equally? Molecular Genetic Metabolism 79: 134–141.
 Further Reading
 Reviews
    Elsea SH and Girirajan S (2008) Smith-Magenis syndrome, European Journal of Human Genetics 16(4): 412–421. Epub 2008 Jan 30.
    Gropman AL, Elsea SH, Duncan WC Jr and Smith AC (2007) New developments in Smith-Magenis syndrome (del 17p11.2). Current Opinion in Neurology 2: 125–134.
    Smith AC, Magenis RE and Elsea SH (2005) Overview of Smith-Magenis syndrome. Journal of the Association of Genetic Technologists 31: 163–167.
 Book Chapters
    book Smith AC and Gropman AL (2005) "Smith-Magenis syndrome". In: Allanson J and Cassidy S (eds) Clinical Management of Common Genetic Syndromes, 2nd edn. New York: Wiley-Liss.
    book Smith AC and Duncan WC (2005) "Smith-Magenis syndrome: a developmental disorder of circadian dysfunction". In: Butler MG and Meaney FJ (eds) Genetics of Developmental Disabilities. Boca Raton: Taylor and Francis group.
 Useful web sites
    ePath Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/sites/entrez?db=OMIM
    ePath Gene Clinics – http://www.geneclinics.org
    ePath PRISMS – Parents and Researchers Interested in Smith-Magenis Syndrome: http://www.prisms.org
    ePath The Smith-Magenis Syndrome Foundation: http://www.smith-magenis.co.uk/

Related Sub-Topics:

Neurobiology of Disease | Neural Networks and Behaviour | Molecular Genetics of Common and Complex Disease | Genetics of Intelligence and Cognition | Specific Genetic Disorders | Techniques and Tools in Clinical Genetics
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Smith–Magenis Syndrome
 
How to Cite close
Elsea, Sarah H, and Finucane, Brenda(Mar 2009) Smith–Magenis Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021428]