Smith–Magenis Syndrome

Abstract

AbstractSmith–Magenis syndrome (SMS) is a complex neurobehavioural disorder caused by haploinsufficiency of theRAI1gene 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 encompassingRAI1or a mutation ofRAI1. G‐banding and fluorescentin situhybridization 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 toRAI1haploinsufficiency, whereas variability and severity are modified by other genes in the 17p11.2 region. The functional role forRAI1is 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),RAI1mutationKey conceptsSmith–Magenis syndrome (SMS) is a multiple congenital anomalies disorder caused by an interstitial deletion of chromosome 17p11.2 containing theretinoic acid induced 1(RAI1) gene or by mutation ofRAI1.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 inRAI1.Haploinsufficiency ofRAI1results 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 orRAI1mutation is present in either parent. Mosaicism in a parent of an affected child is estimated at 3–5%.