Smith-Magenis syndrome (SMS) is a global developmental delay disorder associated with typical behavioral and discrete external features such as brachycephaly, flat midface, broad nasal bridge, “M”-shaped curved upper lip with distinct philtrum incision, brachydactyly, and forearm constriction in infancy and early childhood. The voice is often low and hoarse. Up to 70% of patients have hearing loss, often resulting from chronic middle ear infections (80-90%). About 30% have congenital malformations of the heart and/or kidneys. Foot deformities are common. Approximately 50% have myopia and occasionally related retinal detachment. Typical in SMS are tantrums, self-harming behavior and significant sleep disorders which can be very stressful for families. Many children with SMS are described as musical and most are good with computers which can be used for support. The prevalence is reported to be 1:15,000 to 1:25,000. However, SMS is probably underdiagnosed.
SMS is caused by a microdeletion of variable size (ranging from 1.5 to 9 Mb, usually about 3.7 Mb) on the short arm of chromosome 17 (17p11.2) involving the RAI1 gene in 90%, and a pathogenic variant in the RAI1 gene in 10% of cases. The RAI1 gene is responsible for most of the symptoms of SMS. Additional 13 genes located in the deleted region modify the severity (contiguous gene syndrome). The microdeletion or variant occurs almost always de novo. Consequently, the risk of recurrence is low if a parental chromosomal structural change in chromosome 17 or a rare parental mosaicism has been ruled out for a RAI1 variant. Large deletions can be found with conventional chromosomal analysis, and the more common small ones with FISH analysis or a chromosomal microarray.
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