Smith–Magenis Syndrome

Abstract

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.

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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]