Clinical Quiz Answer
What is the diagnosis?
In view of the severe intellectual disability, behavioural and dysmorphic facial features, chromosome microarray (aCGH) was arranged for the child. aCGH showed a 3.39 Mb deletion in chromosome 17p11.2 (Figure 3), confirming the diagnosis of Smith Magenis syndrome.
What is Smith Magenis syndrome (SMS)?
SMS patients have distinctive physical and facial features including broad square-shaped face, brachycephaly, prominent forehead, synophrys, mildly upslanting palpebral fissures, deep-set eyes, broad nasal bridge, midfacial retrusion, short and full-tipped nose with reduced nasal height, micrognathia in infancy changing to relative prognathia with age, and fleshy everted vermilion of the upper lip. They have a hoarse and deep voice, language delay with or without associated hearing loss, variable levels of intellectual disability, signs of peripheral neuropathy, minor skeletal anomalies e.g. scoliosis, prepubertal short stature, brachydactyly and eye abnormalities. During infancy, they have feeding problems with failure to thrive, lethargy, hypotonia and hyporeflexia.1-3 The inverted diurnal circadian rhythm of melatonin is very typical in SMS.4
The behavioural problems usually appear from 18 months old, including self-mutilating behaviours by self-hitting, self-biting, skin picking, inserting foreign objects into body orifices (polyembolokoilamania) and pulling nails (onychotillomania). They also have autistic spectrum disorder, sensory integration problem, inattention, distractibility, externalising behaviours including hyperactivity, impulsivity, frequent temper outbursts and aggression. They have stereotypic behaviours with the typical spasmodic upper-body squeeze or "self-hug", which is exacerbated by happiness, excitement or overstimulation.5-8 Over 50% of patients have hypercholesterolaemia.9
Virtually all SMS occur by de novo mutation. SMS is a contiguous gene deletion syndrome diagnosed clinically and confirmed by a 3.7 Mb heterozygous interstitial deletion in chromosome 17p11.2 in 90% of cases. A routine G-banded analysis with adequate resolution should detect the common deletion with 70% having the common approximately 3.5 Mb deletion. Deletion or mutation of the gene RAI1 (retinoic acid-induced protein 1) is responsible for many of the features in SMS.10,11 Normal retinoic acid-induced protein 1 is thought to function in transcriptional regulation.12 FISH or aCGH is indicated for those strongly suspected to have SMS with previous normal results. The remaining 5-10% sequence variants can be confirmed by sequence analysis.13
Potocki-Lupski syndrome is a 17p11.2 duplication syndrome and contains the recombination reciprocal of the SMS deletion. Patients differ in their phenotypes and behaviours.14
Clinical and diagnostic implication
The following workup needs to be done at diagnosis and include immunoglobulins, fasting lipid profile for monitoring of hypercholesterolaemia, thyroid function tests, spine radiographs, echocardiogram, renal ultrasound, ophthalmologic and otolaryngologic evaluation, neurodevelopmental assessment. For surveillance purpose, annual lipid profile, thyroid function, scoliosis, eye and hearing assessment is indicated.2
Management includes early childhood intervention programs, followed by ongoing special education programs, psychiatric medications for inattention and/or hyperactivity.15 For sleep problem, there were some treatment trials but they were not well-controlled.16 Adverse drug reaction with extreme aggression and escalation of behavioural problem was noted with atomoxetine for patients with Smith Magenis syndrome.
We would like to thank the patient and her family for their contribution. Informed consent was obtained for publication.
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2. Greenberg F, Lewis RA, Potocki L, et al. Multi-disciplinary clinical study of Smith-Magenis syndrome (deletion 17p11.2). Am J Med Genet 1996;62:247-54.
3. Gropman AL, Duncan WC, Smith AC. Neurologic and developmental features of the Smith-Magenis syndrome (del 17p11.2). Pediatr Neurol 2006;34:337-50.
4. Potocki L, Glaze D, Tan DX, et al. Circadian rhythm abnormalities of melatonin in Smith-Magenis syndrome. J Med Genet 2000;37:428-33.
5. Finucane BM, Konar D, Haas-Givler B, Kurtz MB, Scott CI, Jr. The spasmodic upper-body squeeze: a characteristic behavior in Smith-Magenis syndrome. Dev Med Child Neurol 1994;36:78-83.
6. Dykens EM, Smith AC. Distinctiveness and correlates of maladaptive behaviour in children and adolescents with Smith-Magenis syndrome. J Intellect Disabil Res 1998;42(Pt 6):481-9.
7. Finucane B, Dirrigl KH, Simon EW. Characterization of self-injurious behaviors in children and adults with Smith-Magenis syndrome. Am J Ment Retard 2001;106:52-8.
8. Martin SC, Wolters PL, Smith AC. Adaptive and maladaptive behavior in children with Smith-Magenis syndrome. J Autism Dev Disord. 2006;36:541-52.
9. Smith AC, Gropman AL, Bailey-Wilson JE, et al. Hypercholesterolemia in children with Smith-Magenis syndrome: del (17) (p11.2p11.2). Genet Med 2002;4:118-25.
10. Girirajan S, Vlangos CN, Szomju BB, et al. Genotype-phenotype correlation in Smith-Magenis syndrome: evidence that multiple genes in 17p11.2 contribute to the clinical spectrum. Genet Med 2006;8:417-27.
11. Potocki L, Shaw CJ, Stankiewicz P, Lupski JR. Variability in clinical phenotype despite common chromosomal deletion in Smith-Magenis syndrome [del(17)(p11.2p11.2)]. Genet Med 2003;5:430-4.
12. Carmona-Mora P, Encina CA, Canales CP, et al. Functional and cellular characterization of human Retinoic Acid Induced 1 (RAI1) mutations associated with Smith-Magenis Syndrome. BMC Mol Biol 2010;11:63.
13. Vilboux T, Ciccone C, Blancato JK, et al. Molecular analysis of the Retinoic Acid Induced 1 gene (RAI1) in patients with suspected Smith-Magenis syndrome without the 17p11.2 deletion. PLoS One. 2011;6:e22861.
14. Potocki L, Bi W, Treadwell-Deering D, et al. Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype. Am J Hum Genet 2007;80:633-49.
15. Laje G, Bernert R, Morse R, Pao M, Smith AC. Pharmacological treatment of disruptive behavior in Smith-Magenis syndrome. Am J Med Genet C Semin Med Genet 2010;154C:463-8.
16. De Leersnyder H, Bresson JL, de Blois MC, et al. Beta 1-adrenergic antagonists and melatonin reset the clock and restore sleep in a circadian disorder, Smith-Magenis syndrome. J Med Genet 2003;40:74-8.