Clinical features of seven Brazilian Smith-Magenis syndrome cases and meta-analysis of 165 cases from the literature (Gamba et al., Genet. Mol. Res. 10 : 2664-2670, 2011, Published with permission from
Smith-Magenis syndrome (SMS) is a rare developmental disorder featuring impaired intellectual and behavioral abnormalities. SMS is still not well known because it is characterized by subtle facial dysmorphology that progresses with age, and clinical features that overlap with other intellectual disability syndromes as Prader–Willi, Williams-Beuren, and Down syndromes. Due to their intellectual impairment especially their abnormal and frequently anti-social behavior, most individuals affected with SMS are institutionalized without proper diagnosis and care.
Patients with the features of SMS were first described in 1982 by Ann C.M. Smith in an abstract presented at the Annual Meeting of the American Society of Human Genetics . In 1986, Ellen Magenis together with Ann C.M. Smith and their colleagues published a clinical review of nine individuals affected by this nosologic entity. For this reason the syndrome was named after them . A deletion of chromosome 17p11.2 was identified as the cause of this condition in approximately 90% of cases, and thus this disorder belongs to the group of contiguous-gene syndromes, currently referred to as genome diseases [3-5]. SMS patients without deletions 17p11.2 may carry a point mutation in the gene
3. Clinical characteristics
SMS dysmorphysms change with age. The most common facial characteristics of the syndrome include broad square-shaped face, brachycephaly, prominent forehead, synophrys, deep-set eyes, broad nasal bridge, midface hypoplasia, micrognathia in infancy, relative prognathism with age, and everted, "tented" upper lip . Dental anomalies such as premolar agenesis and taurodontism have also been reported .
To date, nearly two hundred cases have been described in the literature. In 2011 Gamba and colleagues presented seven Brazilian cases and a meta-analysis of clinical signs in SMS reported in the literature, which are summarized in the table below .
|Broad, square-shaped face||7/7||64/82||78.0||0.3367|
|Broad Nasal Bridge||7/7||41/51||80.39||0.3356|
|Everted, "tented" upper lip||6/7||64/83||77.11||1.0000|
|Relative prognathism with age||6/7||49/62||79.03||1.0000|
|Short broad hands||7/7||n/a||n/a|
|Deep-set, close-spaced eyes||6/7||47/72||65.28||0.4156|
|Hoarse, deep voice||1/7||40/52||76.92||0.0023|
|Cognitive impairment/developmental delay||7/7||100/100||100.00||1.0000|
|Head Banging/Face Slapping||1/2||36/43||83.72||0.3273|
|Renal/urinary tract abnormalities||1/7||12/49||24.49||1.0000|
|EEG abnormal/ evident seizures||3/5||23/58||39.66||0.6687|
3.1. SMS features in infancy, childhood/adolescence and adulthood
The gestation of children with SMS is commonly uneventful. When maternal report is available, a diminution of fetal movements is described in 50% of cases. At birth all parameters (weight, length, OFC) are normal, including time of gestation.
The occurrence of generalized hypotonia and hyporeflexia promotes a marked oral motor dysfunction, with poor sucking and swallowing, and gastroesophageal reflux. Failure to thrive is attributed to feeding difficulties. During the first year of life, parents often describe SMS cases as perfect babies because they sleep very well and cry little.
Behavior disturbances can be observed as early as 4 months. Videotape analysis shows patients’ motor repertoire is significantly reduced, and fidgety general movements, which are typical of that age, are missing. Posture is abnormal and overall movements are jerky and monotonous. These findings indicate a severe motor impairment as early as 4 months of age . Beyond 18 months, signs of developmental delay become increasingly obvious, with early stages of intense crying and sleepless nights. Within 2-3 years of age patients have a clear delay in language acquisition, with lalation [24-25]. Dysmorphic signs subsequently begin to become more evident, with facial hypotonia, and relative micrognathia.
It is at this stage of life that patients with SBS have dysmorphisms, significant cognitive delays and a peculiar behavior and come to the attention of health professionals. Most patients are diagnosed at this stage of life.
Facial dysmorphisms include broad and square-shaped face, mild face hypoplasia, brachicephaly, short nasal philtrum, a tendency toward an everted upper lip, and relative prognathism. Patients may present with short stature, scoliosis, dental abnormalities, and brachydactyly with clinodactyly at 5th and digital syndactyly between the 3th and 4th toe. Ocular abnormalities may be present, such as deep-set eyes and close-spaced, synophrys, strabismus and iris abnormalities. The main otoryngological alterations are recurrent ear infections resulting in hearing loss, middle/inner ear abnormalities and deep hoarse voice.
Cognitive impairment and developmental delay are pronounced, however the most pronounced neurological alteration is sleep modifications. Patients with SMS often exchange nocturnal sleep for daytime naps, with changes of the circadian cycle and alterations in the release of melatonin [26-28].
Alterations of behavior are atypical and draw the most attention, because they are often unique to patients with SMS. Besides hyperactivity and attention seeking, patients with SMS may present agressive and self-injurious behavior, including hand biting, head banging, face slapping, self-hanging, onychotilomania and polyembolokotonia [16,19, 29-35]. Other signs reported in up to 50% of patients include obesity, cardiacs defects, seizures, cleft lip/palate and male hypogonadism .
Figures 1-7 are patients diagnosed with SMS in Genetic Counseling Service Dept Genetics. IBB/UNESP- Botucatu, Brazil, and several of these patients were published (Published with permission from
Adults with SMS have a diminution of stereotypic movements, but when frustrated, develop aggressive speech, with shouting or profanity at high volume. Little data is published regarding the life expectancy of patients with SMS. However it is believed that life expectancy is normal or similar to that of other individuals with the same level of cognitive dysfunction [36,37].
Most cases of SMS are caused by a microdeletion on 17p11.2 that encompasses multiple genes, including the retinoic acid-induced 1,
SMS is suspected in individuals presenting distinctive facial features, a behavioral phenotype and sleep disturbance. Initial clinical suspicion of the disorder is confirmed by the presence of a microdeletion in the p11.2 region of chromosome 17 or a mutation in the
SMS diagnosis is confirmed by detecting 17p11.2 deletion using classic cytogenetic analysis, molecular cytogenetic analysis, or molecular genetic methods .
Cytogenetic analysis by GTG banding at the 550 band level or higher can detect deletions of approximately 4Mb, which account for 70% of the cases. However fluorescent
Beyond these cytogenetic methods, methods that require only DNA for analysis are newer, cost-efficient, and can be used in a large number of patients at the same time. Additionally, MLPA or qPCR can identify smaller deletions at a higher resolution than FISH or G-banding .
6. Differential diagnosis
1q36 deletion syndrome
9q34 deletion syndrome
As the clinical characteristics of SMS and these syndromes overlap, specific FISH tests are required for establishing a final diagnosis
22q11.2 deletion syndrome: velopharyngeal abnormalities and facial characteristics differentiate this syndrome from SMS
Down syndrome: despite having several ovelapping features with SMS, Down syndrome can be diagnosed by simple karyotype analysis
Williams-Beuren syndrome (WBS): SMS and this syndrome show opposing behavioral characteristics. While WBS patients are overfriendly, loquacious and frequently smiling, SMS individuals are shy, aggressive and restless
Prader-Willi syndrome (PWS): although obesity may be present in both PWS and SMS, it is always of the morbid type in PWS patients:
Sotos syndrome (SS): in SS patients, bone age is advanced while in SMS it is normal.
7. Treatment of manifestations
Patients with SMS present functional disturbances (obesity, sleep disturbances) and behavioral abnormalities (aggression, self-injury) which have prompted attempts to medically treat these alterations. Due to the low frequency of SMS, classical placebo-controlled prospective clinical drug trials have not been feasible. Clinical experience to date indicates that no drug is effective in alleviating any SMS symptoms in more than 60% of cases. There are a number of anecdotal reports of successful treatments, however many of unsuccessful treatments are likely unreported.
A review of pharmacological treatments with psychotropic drugs in patients with SMS was reported . The medications were grouped into seven main categories:  stimulants;  antidepressants;  antipsychotics;  hypnotics;  mood stabilizers;  alpha 2 agonists;  and benzodiazepines. The stimulant category included methylphenidate, amphetamines, and others (e.g., pemoline). Antidepressants were subdivided into selective serotonin reuptake inhibitors (SSRIs), tricyclics (TCA), and others. The antipsychotic category was divided into typical and atypical. The hypnotic category included melatonin, diphenhydramine,and others. Mood stabilizers included ithium and anticonvulsants used for mood stabilization. Clonidine and guanfacine were grouped under alpha 2 agonists and all benzodiazepines were grouped together. The beta-blockers category was excluded due to a small number of reports. The study was conducted using medical histories of 62 patients with SMS. This study concluded that no consistent results were observed for any medicine or drug group, although the study did not exclude any of the drugs used.
Another elegant work [47,48] tested the effect of administration of B1-adrenergic antagonists together with melatonin in 10 patients with SMS, in an attempt to improve the circadian disturbances. These authors concluded that the administration of acebutolol in the morning and melatonin in the early evening allowed the biological clock reset and restore the normal rhythm of melatonin in SMS patients. The patients had improvements in sleep, diminution of naps during the day, with a higher state of attention and diminution of aggressive behavior.
Significant overlap between SMS’s clinical features with other similar syndromes does makes it very difficult establish a clinical diagnosis. However, the uniqueness of the behavioral features of this condition should lead health care providers to request specific FISH testing. Treatment for SMS is merely relies on managing the symptoms. Individuals with SMS often require several forms of support, including physical therapy, occupational therapy, speech therapy, and particularly behavioral therapy, which are most effective if started early in life. Therefore, having an early diagnosis can help guide a person’s health care through life, and open the doors to a network of information from professionals and other families dealing with the syndrome.
Smith ACMMcGavran L, Waldstein G. Deletion of the 17 short arm in two patients with facial clefts. 1982Am J Hum Genet 34 (Abstract- ASHG).
Interstitial deletion of (17)( Smith A. C Mcgavran L Robinson J Waldstein G Macfarlane J Zonona J Reiss J Lahr M Allen L Magenis E 11p11.2) in nine patients. Am J Med Genet. 1986
Variability in clinical phenotype despite common chromosomal deletion in Smith-Magenis syndrome. Genet Med. Potocki L Shaw C. J Stankiewicz P Lupski J. R 2003 5 430 4
Refinement of the Smith-Magenis syndrome critical region to approximately 950kb and assessment of 17 Vlangos C. N Yim D. K Elsea S. H 11deletions. Are all deletions created equally? Mol Genet Metab. 2003
Lupski JR: Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traitsTrends Genet 1998
Mutations in RAI1 associated with Smith-Magenis syndrome. Nat Genet. Slager R. E Newton T. L Vlangos C. N Finucane B Elsea S. H 2003 33 466 468
Mutations of RAI1, a PHD-containing protein, in nondeletion patients with Smith-Magenis syndrome. Hum Genet. Bi W Saifi G. M Shaw C. J Walz K Fonseca P Wilson M Potocki L Lupski J. R 2004 115 515 24
Elsas Ii LJ, Devriendt KH, Elsea SH. RAI1 variations in Smith-Magenis syndrome patients without 17 Girirajan S 11deletions. J Med Genet. 2005
Smith ACM, Huizing M. Molecular Analysis of the Retinoic Acid Induced 1 Gene (RAI1) in Patients with Suspected Smith-Magenis Syndrome without the 17 Vilboux T Ciccone C Blancato J. K Cox G. F Deshpande C Introne W. J Gahl W. A 11Deletion. PLoS ONE. 2011e22861.
de Rezende Duarte A, Santos SR, de Souza DH, DuPont BR, Walz K, Moretti-Ferreira D, Srivastava AK. Detection of classical 17 Vieira G. H Rodriguez J. D Carmona-mora P Cao L Gamba B. F Carvalho D. R 11deletions, an atypical deletion and RAI1 alterations in patients with features suggestive of Smith-Magenis syndrome. Eur J Hum Genet. 2012
Montes de Oca-Luna R, Magenis RE, Smith AC, Richter SF, Kondo I, Dobyns WB, Patel PI, Lupski JR. Molecular analysis of the Smith-Magenis syndrome: a possible contiguous-gene syndrome associated with del(17)( Greenberg F Guzzetta V 11Am J Hum Genet. 1991
Smith-Magenis syndrome: a developmental disorder of circadian dysfunction. In: Butler MG, Meaney FJ, eds. Genetics of Developmental Disabilities. Boca Raton, FL: Taylor and Francis Group; Smith A. C Duncan W. C 2005 2005 419 75
Smith ACMBoyd K, Elsea SH, Finucane BM, Haas-Givler B, Gropman A,Johnson KP, Lupski JR, Magenis E, Potocki L, Solomon B. 2010Smith-Magenis Syndrome. 1993 2001updated 2010 Jan 7. In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors. GeneReviews (Internet). Seattle (WA): University of Washington, Seattle.
Smith ACM, Guadagnini JP, Hart TC. Craniofacial and dental phenotype of Smith-Magenis syndrome. Am J Med Genet. Tomona N 2006 140 2556 61
and attainment in Smith-Magenis syndrome. Development Medicine and Child Neurology. Udwin O Webber C y Horn I Abilities 2001 43 823 828
Distinctiveness and correlates of maladaptive behaviour in children and adolescents with Smith-Magenis syndrome. J Intellect Disabil Res. Dykens E. M Smith A. C 1998 42 481 489
Behavioral phenotype of Smith-Magenis syndrome (del 17 Smith A. C Dykens E Greenberg F 11Am J Med Genet. 1998
Communicative competence and behavioural phenotype in children with Smith-Magenis syndrome. Genet Couns. Sarimski K 2004 15 347 355
Neurologic and developmental features of the Smith-Magenis syndrome (del 17 Gropman A. L Duncan W. C Smith A. C 11Pediatr Neurol. 2006
Smith-Magenis syndrome. Eur J Hum Genet. Elsea S. H Girirajan S 2008 16 412 421
Array comparative genomic hybridization of 52 subjects with a Smith-Magenis-like phenotype: identification of dosage-sensitive loci also associated with schizophrenia, autism, and developmental delay. J Med Genet. Williams S. R Girirajan S Tegay D Nowak N. J Hatchwell E Elsea S. H 2009 47 223 9
Smith-Magenis syndrome: clinical evaluation in seven Brazilian patients. Gamba B. F Vieira G. H Souza D. H Monteiro F. F Lorenzini J. J and Carvalho D. R Moretti-ferreira D 2011Genet. Mol. Res. 10 4 2664 2670
Einspieler C; Hirota H; Yuge M; Dejima S; Marschik PBEarly behavioural manifestation of Smith-Magenis syndrome (del 17 11in a 4-month-old boy. Developmental Neurorehabilitation. 2012
Smith ACM. Neurodevelopment of children under 3 years of age with Smith-Magenis syndrome. Pediatr Neurol Wolters P. L Gropman A. L Martin S. C Smith M. R Hildenbrand H. L Brewer C. C 2009 41 250 258
Hildenbrand HL; Smith ACAnalysis of the sensory profile in children with smith-magenis syndrome. Phys Occup Ther Pediatr. 2012 32 1 48 65
Sleep disturbance in Smith-Magenis syndrome (del 17 Smith A. C Dykens E Greenberg F 11Am J Med Genet. 1998
Abnormal circadian rhythm of melatonin in Smith-Magenis syndrome patients with RAI1 point mutations. Am J Med Genet Part A. Boone P. M Reiter R. J Glaze D. G Tan D-X Lupski J. R Potocki L 2011 155 2024 2027
Williams SR; Zies D; Mullegama SV; Grotewiel MS; Elsea SHSmith-Magenis Syndrome Results in Disruption of CLOCK Gene Transcription and Reveals an Integral Role for RAI1 in the Maintenance of Circadian Rhythmicity. Am J Hum Genet. 2012 90 941 949
The spasmodic upper-body squeeze: a characteristic behavior in Smith- Magenis syndrome. Dev Med Child Neurol. Finucane B. M Konar D Haas-givler B Kurtz M. B Scott C. I 1994 36 78 83
Brief report: cognitive and behavioral profiles in persons with Smith-Magenis syndrome. J Autism Dev Disord 1997; Dykens E. M Finucane B. M Gayley C 27 203 211Finucane, B.M. and Jaeger, E.R. Smith-Magenis syndrome. Ophthalmology, 1997
Adaptive and maladaptive behavior in children with Smith-Magenis syndrome. Journal of Autism and Developmental Disorders, Martin S. C Wolters P. L Smith A. C. M 2006 36 541 552
A case report of monozygotic twins with Smith-Magenis syndrome. J Dev Behav Pediatr. Hicks M Ferguson S Bernier F Lemay J. F 2008 29 42 46
Sensory motor and functional skills of dizygotic twins: one with Smith-Magenis syndrome and a twin control. Phys Occup Ther Pediatr. Smith M. R Hildenbrand H Smith A. C 2009 2009 239 57
Heinze EG; Villaverde ML; López EM; Magro TC; Moura LF; Fernández M; Sampaio AFuncionamiento cognitivo general y habilidades psicolingüísticas en niños con síndrome de Smith-Magenis. Psicothema 2011 23 725 731
Sloneem J; Oliver C; Udwin O; Woodcock KAPrevalence, phenomenology, aetiology and predictors of challenging behaviour in Smith-Magenis syndrome. J Intell Disab Research. 2011 55 138 151
Osório A; Cruz R; Sampaio A; Garayzábal E; Carracedo A; Fernández-Prieto MCognitive functioning in children and adults with Smith-Magenis syndrome. Eur J Med Genet. 2012 55 394 399
Elsea SH; Stephen RWilliams SR. Smith-Magenis syndrome: haploinsufficiency of RAI1 results in altered gene regulation in neurologicaland metabolic pathways. Expert Rev. Mol. Med. 2011
Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome. Nat Genet. Chen K. S Manian P Koeuth T Potocki L Zhao Q Chinault A. C Lee C. C Lupski J. R 1997 17 154 63
Implications of human genome architecture for rearrangement-based disorders: the genomic basis of disease. Hum Mol Genet. Shaw C. J Lupski J. R 2004Suppl 1):R 57R64.
Shaw CJ & Lupski JRNon-recurrent 17 11deletions are generated by homologous and non-homologous mechanisms. Hum Genet. 2005
A Turkish patient with large 17 Tug E Cine N Aydin H 11deletion presenting with Smith Magenis syndrome. Genet Couns. 2011
Diagnostic FISH probes for del(17)( Vlangos C. N Wilson M Blancato J Smith A. C Elsea S. H 11p11.2) associated with Smith-Magenis syndrome should contain the RAI1 gene. Am J Med Genet A. 2005
Differential diagnosis of Smith-Magenis syndrome: 1 Vieira G Rodriguez J. D Boy R et al 36deletion syndrome. Am J Med Genet A. 2012
Truong HT; Dudding T; Blanchard CL; Elsea SHFrameshift mutation hotspot identified in Smith-Magenis syndrome: case report and review of literature. BMC Medical Genetics 2010
Smith, ACM.2010. Pharmacological Treatment of Disruptive Behavior in Smith-Magenis Syndrome. Am J Med Genet Part C Semin Med Genet. Laje G Bernert R Morse R Pao M 2010C: 463 468
Beta 1-adrenergic antagonists and melatonin reset the clock and restore sleep in a circadian disorder, Smith-Magenis syndrome. J Med Genet. De Leersnyder H Bresson J. L De Blois M. C Souberbielle J. C Mogenet A Delhotal-landes B Salefranque F Munnich A 2003 40 74 8
Inverted rhythm of melatonin secretion in Smith-Magenis syndrome: From symptoms to treatment. Trends Endocrinol Metab, De Leersnyder H 2006 17 291 298