The Smith-Magenis syndrome [del(17)p11.2]: Clinical review and molecular advances

Abstract

The Smith‐Magenis syndrome (SMS) is a multiple congenital anomaly, mental retardation syndrome associated with a deletion of chromosome 17p11.2. Since the recognition of this disorder as a clinical entity in 1982, the phenotypic features of SMS have been well described. Unfortunately, the often subtle physical and chromosomal findings of SMS may preclude the diagnosis in some affected individuals. This article offers a comprehensive review of more than 100 SMS patients whose cases have been reported, including details of the more recently studied clinical aspects of SMS. SMS has been postulated to be a contiguous gene deletion syndrome. Currently, only a few genes have been mapped to the SMS critical region. Further research (including genotype‐phenotype correlation) is needed to identify the gene or genes that, when deleted, cause this disorder. Although the molecular etiology of SMS is unknown, recent investigations have identified multiple repetitive sequences within the SMS region. As described in other human disorders, repetitive sequences may be involved in homologous recombination and cause deletion. The advances in the molecular dissection of the SMS region are described, and hypotheses regarding the molecular mechanisms of SMS are offered. Parallels are made between the SMS region and other regions in the human genome where the molecular etiologies of diseases have been elucidated. © 1996 Wiley‐Liss, Inc.

Variability in clinical phenotype despite common chromosomal deletion in Smith-Magenis syndrome [del(17)(p11.2p11.2)]

“…1 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. 1,2 In the majority of patients, a common deletion size is observed. [3][4][5] This common deletion is derived from nonallelic homologous recombination (NAHR) between low-copy repeat (LCR) gene clusters (distal and proximal SMS-REPs) during either maternal or paternal gametogenesis.…”

“…Seizures occur in 10% to 20% of SMS patients, 1 although a higher percentage of patients were recognized to have EEG abnormalities in the absence of clinically evident seizures. 2 In this study, a clinical history of seizures was associated with either normal or abnormal EEGs.…”

“…Characteristic physical features include minor craniofacial 24 and skeletal anomalies, 22 ophthalmological 23 and otolaryngological abnormalities, and malformations of the heart, including tetralogy of Fallot, 25,26 and kidney. 1,2 The neurobehavioral features of SMS are perhaps the most distinctive characteristic of this microdeletion syndrome and include self-injurious, aggressive, and maladaptive behavior 3,19,27,28 and significant sleep disturbances. 3,20,29 We have previously described the clinical phenotype of SMS in 27 patients with del(17)(p11.2p11.2), 2 and herein have extensively characterized the clinical phenotype in another 31 SMS patients.…”

Genes in a Refined Smith-Magenis Syndrome Critical Deletion Interval on Chromosome 17p11.2 and the Syntenic Region of the Mouse

“…SMS patients manifest abnormalities in multiple tissues/organs including: neural (100% mental retardation, 100% self-hugging, 75% peripheral neuropathy, and 69% sleep disorder), eyes (68% iris abnormalities), ears (81% hearing impairment), hearts (29%), kidneys (28%), and skeletal (93% midface hypoplasia and 85% brachydactyly) (Chen et al 1996). The SMS-causing genes are therefore likely expressed in multiple tissues.…”

“…The clinical features of SMS patients include mental retardation, delayed speech and motor development, behavior problems, sleep disturbance, minor craniofacial abnormalities, short stature, and brachydactyly (Greenberg et al 1991). Less common features include otolaryngological abnormalities, hearing impairment, opthalmological abnormalities, and renal and cardiac abnormalities (Chen et al 1996;Greenberg et al 1996). The incidence of SMS is ∼1: 25,000 births, which is likely underestimated given the often subtle clinical features, particularly early in life (Greenberg et al 1991).…”