The Smith-Magenis syndrome (SMS) is a multiple congenital anomaly and mental retardation syndrome (Greenberg et al. 1996). The clinical phenotype includes distinctive craniofacial and skeletal features that change with age, a history of infantile hypotonia, significant expressive language delay, mental retardation, stereotypies, behavioral problems, and a sleep disorder (Potocki et al., 2000; De Leersynder et al. 2001). Two genetic mechanisms can cause SMS: an interstitial deletion involving chromosome 17p11.2 (including the retinoic acid–induced 1 [RAI1] gene) or a mutation in the RAI1 gene (Smith et al. 1986; Seranski et al. 2001; Slager et al. 2003). First described by Smith and colleagues in 1982, in two severely impaired patients (Smith et al. 1982), the phenotypic spectrum has been expanded by the recognition of additional cases (Smith et al. 1986; Stratton et al., 1986). The estimated prevalence of SMS deletion cases was reported to be 1 in 25,000 (Greenberg et al. 1991). However, new cases identified in the last decade as a result of improved molecular cytogenetic techniques (including microarray technology) now suggest the incidence to be closer to 1 in 15,000 births (Elsea and Girirajian 2008). Despite this improvement in technology accounting for new cases identified in the last several years, clinical diagnosis based on phenotypic recognition is often delayed. The phenotype of SMS becomes more pronounced and recognizable with advancing age both in terms of the physical and dysmorphic characteristics, as well as in the behavioral features (Gropman et al. 2006). Infants with SMS present with hypotonia, weak hoarse cry, decreased vocalization, and complacency (Gropman et al. 1998; 2006; Martin et al. 2006; Wolters et al.,2009). Gross and fine motor skill development is delayed in the first year of life. Sensory integration problems are frequently noted. Social skills are often age appropriate, delaying diagnosis in some cases. In older children, developmental delay, in particular expressive language delays, as well as emerging behavioral difficulties (Gropman et al. 2006; Martin et al. 2006; Madduri et al. 2006) and sleep disturbance may bring patients to clinical attention.