SMS (MIM 182290) is a multiple congenital anomalies and mental retardation disorder associated with an interstitial deletion within chromosome 17p11.2 (10-13). Clinical characteristics include minor craniofacial and skeletal anomalies such as brachycephaly, frontal bossing, synophrys, midfacial hypoplasia, short stature, and brachydactyly, neurobehavioral abnormalities such as aggressive and self-injurious behavior and sleep disturbances, ophthalmic, otolaryngological, cardiac, and renal anomalies (13,14).
As defined by fluorescence in situ hybridization (FISH) and by a unique de novo junction fragment identified in pulsed-field gel electrophoresis, 70-80% of SMS patients harbor a common approx 4-Mb deletion within 17p11.2 (3,12,15,16). Approximately 20-25% SMS patients have either smaller or larger sized deletions (16-19). Recently, premature termination codon mutations in the retinoic acid inducible-1 gene, RAI1, which maps within the SMS critical region, have been found in five SMS-like patients without deletion (20-21), suggesting RAI1 haploinsufficiency causes SMS. Bioinformatics analyses of the dosage sensitive RAI1 gene, and comparative genomics between human and mouse orthologs, revealed a zinc finger like-PHD domain at the carboxyl terminus that is conserved in the trithorax group of chroma-tin-based transcriptional regulators, suggesting that RAI1 might be involved in chromatin remodeling (21). These findings suggest RAI1 is involved in transcriptional control through a multi-protein complex, and its function may be altered in individuals with SMS.
Interestingly, despite a common deletion size, the only constant objectively defined features among patients with SMS are sleep disturbances, low adaptive functioning, and mental retardation. There is no pathognomonic clinical feature, no characteristic cardiovascular defect, renal anomaly, otolaryngological, nor ophthalmic abnormality in SMS (22).
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