Review Article Neurologic and Developmental Features of the Smith-Magenis Syndrome (del 17p11.2) Andrea L. Gropman, MD*† Wallace C. Duncan, PhD‡ and Ann C. M. Smith, MA, DSc (Hon)§ʈ The Smith-Magenis syndrome is a rare, complex mul- togenetic analysis help to bring cases to clinical recog- tisystemic disorder featuring, mental retardation and nition at an earlier age, this review seeks to increase multiple congenital anomalies caused by a heterozy- clinical awareness about Smith-Magenis syndrome by gous interstitial deletion of chromosome 17p11.2. The presenting the salient features observed at different phenotype of Smith-Magenis syndrome is character- ages including descriptions of the neurologic and be- ized by a distinct pattern of features including infantile havioral features. Detailed review of the circadian hypotonia, generalized complacency and lethargy in rhythm disturbance unique to Smith-Magenis syn- infancy, minor skeletal (brachycephaly, brachydac- drome is presented. Suggestions for management of the tyly) and craniofacial features, ocular abnormalities, behavioral and sleep difficulties are discussed in the middle ear and laryngeal abnormalities including context of the authors’ personal experience in the hoarse voice, as well as marked early expressive speech setting of an ongoing Smith-Magenis syndrome natural and language delays, psychomotor and growth retar- history study. © 2006 by Elsevier Inc. All rights dation, and a 24-hour sleep disturbance. A striking reserved. neurobehavioral pattern of stereotypies, hyperactivity, polyembolokoilamania, onychotillomania, maladaptive Gropman A, Duncan W. Neurologic and Developmental and self-injurious and aggressive behavior is observed Features of the Smith-Magenis Syndrome (del 17p11.2). with increasing age. The diagnosis of Smith-Magenis Pediatr Neurol 2006;34:337-350. syndrome is based upon the clinical recognition of a constellation of physical, developmental, and behav- ioral features in combination with a sleep disorder Introduction characterized by inverted circadian rhythm of melato- nin secretion. Many of the features of Smith-Magenis The Smith-Magenis syndrome is a clinically recogniz- syndrome are subtle in infancy and early childhood, able, probable contiguous gene syndrome comprising and become more recognizable with advancing age. multiple congenital anomalies and mental retardation [1]. Infants are described as looking “cherubic” with a It is caused by an interstitial deletion of chromosome Down syndrome–like appearance, whereas with age 17p11.2 (Fig 1), first described by Smith et al. in 1982, the facial appearance is that of relative prognathism. with the full clinical spectrum delineated in additional Early diagnosis requires awareness of the often subtle patients in 1986 [2]. Smith-Magenis syndrome occurs in clinical and neurobehavioral phenotype of the infant all ethnic groups with an overall frequency estimated to be period. Speech delay with or without hearing loss is 1/25,000 [3]. The diagnosis of Smith-Magenis syndrome common. Most children are diagnosed in mid-child- is based upon clinical recognition of a unique phenotype hood when the features of the disorder are most involving physical, developmental, and behavioral as- recognizable and striking. While improvements in cy- pects. The diagnosis is confirmed cytogenetically or by From the *Departments of Pediatrics (Genetics and Metabolism) and Communications should be addressed to: Neurology, Georgetown University, Washington, DC; †Medical Dr. Gropman; Department of Pediatrics; Georgetown University Genetics Branch, National Human Genome Research Institute, Medical Center; 3800 Reservoir Road; N.W. 2PHC; National Institutes of Health, Bethesda, Maryland; ‡Mood and Anxiety Washington, DC 20007. Disorders Program, National Institute of Mental Health; §Department E-mail: [email protected] of Oncology, Georgetown University, Washington, DC; ʈOffice of the Received April 7, 2005; accepted August 11, 2005. Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland. © 2006 by Elsevier Inc. All rights reserved. Gropman et al: Smith-Magenis Syndrome 337 doi:10.1016/j.pediatrneurol.2005.08.018 ● 0887-8994/06/$—see front matter Figure 1. Smith-Magenis syndrome (SMS) deletion 17p.11.2. Schematic diagram (A) and partial G-banded karytoype (B) from male with Smith-Magenis syndrome (46,XY, del 17 (p11.2p11.2); arrows point to deleted 17 chromosome. Normal chromosome 17 (left) and deleted 17 (right). (C) Metaphase fluorescence in situ hybridization FISH analysis using RA11 FISH probe for Smith-Magenis syndrome critical region. Partial karyotype courtesy of Jeanne Meck, PhD, Director of Cytogenetics Laboratory, Georgetown University, Washington, DC. FISH analysis courtesy of Jan Blancato, PhD, Georgetown University Medical Center, Washington, DC. fluorescence in situ hybridization in the majority of cases. majority of patients with Smith-Magenis syndrome and In addition, a small cohort of patients with the Smith- represent a major challenge for parents, caregivers, and Magenis syndrome phenotype, but without a detectable professionals [13-15]. deletion by fluorescence in situ hybridization, was recently Despite increased clinical awareness of Smith-Magenis found to harbor a frame shift mutation of the RAI1 gene syndrome as well as improved cytogenetic technologies, (Retinoic acid induced-1) [4-6] contained in the critical many children are not definitively diagnosed until early region, which encodes a novel gene of unknown function childhood or even school age [9,16]. The majority of believed to play a role in neuronal differentiation [6], and children with Smith-Magenis syndrome have been identi- possibly responsible for the major features of the syn- fied in the last decade owing to improved cytogenetic drome [7,8]. techniques and the availability of fluorescence in situ Patients with Smith-Magenis syndrome present with a hybridization probes specific for the Smith-Magenis syn- clinically recognizable craniofacial appearance that in- drome critical region [7,17-20,21]. cludes brachycephaly, midface hypoplasia, a prominent With few exceptions, the deletion in Smith-Magenis forehead, upslanting palpebral fissures, epicanthal folds, syndrome occurs de novo [22,23], thus imparting a low synophyrs, and age-dependent development of relative recurrence risk. However, parental cytogenetic analysis is prognathism due to persisting midfacial hypoplasia (Table 1). The facial appearance may be quite subtle in infancy, recommended in new cases. There is no evidence to thus diagnosis may not be apparent [9]. Other common suggest either a parental age contribution, or skewed sex features of Smith-Magenis syndrome include short stature, distribution in deletion cases, and random parental origin brachydactyly, ophthalmologic problems (myopia, strabis- for the 17p deletion has been demonstrated, thus suggest- mus, microcornea, retinal detachment), hearing loss, in- ing that genomic imprinting is not a factor [3,24]. The fantile hypotonia, mental retardation, maladaptive behav- mechanism of the deletion in Smith-Magenis syndrome is iors, expressive language delay, oral motor dysfunction, due to homologous recombination of a flanking repeat peripheral neuropathy, and sleep disorder partially attrib- gene cluster, leading to mismatch pairing [25]. uted to inversion of the circadian rhythm of melatonin While the molecular cause of Smith-Magenis syndrome secretion [10-12]. Behavioral problems, including self- is uncertain, it is believed to be due to a contiguous gene injury, tantrums, and stereotypies are observed in the syndrome where haploinsufficiency of multiple genes in 338 PEDIATRIC NEUROLOGY Vol. 34 No. 5 Table 1. Clinical and behavioral aspects of Smith-Magenis syndrome across the age span Infancy Toddler/Early Childhood School Age Adolescence to Adulthood Clinical features Brachycephaly Recognizable facial appearance with Characteristic facies with persisting midface Coarser facial appearance with Mild facial dysmorphism mid-face hypoplasia; rosy cheeks hypoplasia, relative prognathia, heavy deep-set eyes, relative prognathia, Broad, square-shape face Frequent/chronic otitis media brows extending laterally; heavy brows, synophyrs Upslanting palpebral fissures Hearing loss (predominantly Hoarse voice Progressive myopia “Cherubic” appearance conductive) Progressive myopia Hearing loss (conductive and/or “Down syndrome–like” appearance Vision problems (myopia) Hearing loss (conductive vs sensorineural) sensorineural) Mid-face hypoplasia Fair hair and coloring compared with Short stature Females: premature adrenarche; Cupid-bow mouth with tented family Scoliosis irregular menses; hygiene concerns upper lip Short stature Broad-based flapping gait Tendency to obesity Open mouth posture Hoarse voice Hoarse voice Eye problems: strabismus; Unusual gait/toe walking Short stature (5–10%) microcornea; pigmented flecking High cholesterol Scoliosis of iris Broad-based flapping gait Short broad hands and feet Central nervous system: mildly enlarged ventricles Neuro- Feeding difficulties (major oral- Developmental delays; Gross/fine Cognitive delays Cognitive delays develop-mental sensorimotor dysfunction motor delays weaknesses: sequential processing and Excellent long-term memory Failure to thrive Marked speech delay (expressive Ͼ short-term memory Reports of exercise intolerance Generalized hypotonia receptive) strengths: long-term memory and Poor adaptive function Alert