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Smith-Magenis Syndrome
Smith-Magenis syndrome (SMS) is a complex multiple con- genital anomalies and mental retardation syndrome caused by an interstitial deletion of chromosome 17p11.2.
GENETICS/BASIC DEFECTS
1. Inheritance
a. Autosomal dominant inheritance in virtually all cases of SMS occurring de novo
b. Rare familial chromosome complex rearrangements leading to del(17)(p11.2) and SMS
2. Caused by an interstitial deletion of 17p11.2
a. A common deletion size observed in the majority of patients, derived from nonallelic homologous recom- bination between low-copy repeat gene clusters during either maternal or paternal gametogenesis
b. Either smaller or larger sized deletions in about 20–25% of patients
3. Considered a contiguous gene syndrome
a. Haploinsufficiency of multiple functionally unrelated genes located in close proximity is responsible for the phenotype
b. Deletion of a common interval spanning an estimated 4–5 Mb in majority of patients
4. Sterol regulatory element binding protein 1 (SREBP1) has been mapped to 17p11.2 within the SMS critical region.
Therefore, the patients are hemizygous for the gene encod- ing SREBP1 leading to hypercholesterolemia.
5. Rare non-deletion cases
a. Report of additional patients without a microdeletion, each harbors a mutation in RAI1, which maps within the SMS critical region
b. MYO15 clearly associated with a specific phenotypic feature (sensorineural hearing impairment) in a patient with SMS who harbored a recessive mutation on the nondeleted allele
CLINICAL FEATURES
1. Infantile hypotonia 2. Feeding difficulties 3. Failure to thrive 4. Developmental delay
5. Distinctive craniofacial features a. Brachycephaly
b. Broad square-shaped face c. Prominent forehead d. Synophrys
e. Epicanthal folds
f. Upslanted palpebral fissures g. Deep-set eyes
h. Broad nasal bridge
i. Marked mid-facial hypoplasia
j. Short full-tipped nose with reduced nasal height k. Micrognathia in infancy changing to relative prognathia
with age
l. Distinctive appearance of the mouth, with fleshy everted upper lip with a “tented” appearance
6. Otolaryngologic anomalies a. Speech delay
b. Hoarse voice
c. Velophalangeal insufficiency d. Tracheobronchial problems 7. Ocular anomalies
a. Iris anomalies b. Microcornia c. Retinal detachment 8. Skeletal abnormalities
a. Short stature b. Scoliosis c. Brachydactyly d. Flat feet
9. Characteristic neurobehavioral phenotype
a. Mental retardation (most patients in moderate range)
b. Speech delay
c. Signs of peripheral neuropathy d. Inattention
e. Hyperactivity
f. Maladaptive behaviors including frequent outbursts and temper tantrums
g. Attention seeking h. Attention deficit
i. Impulsivity j. Distractability k. Disobedience
l. Aggression
m. Toileting difficulties
n. Decreased sensitivity to pain o. Self-injurious behaviors
i. Self-hitting ii. Self-biting iii. Skin picking
iv. Inserting foreign objects into body orifices v. Yanking finger nails and/or toenails (onychotil-
lomania) p. Stereotypic behaviors
i. Specific to SMS
a) Spasmodic upper-body squeeze or “self hug”
b) Hang licking and page flipping (“lick and flip”)
ii. Additional stereotypies
a) Mouthing objects or insertion of hand in mouth
b) Teeth grinding
SMITH-MAGENIS SYNDROME 913
c) Body rocking
d) Spinning or twirling objects
q. Significant sleep disturbance potentially due to circa- dian rhythm abnormalities of melatonin
10. Other features a. Cardiac defects
b. Renal and urinary tract abnormalities c. Thyroid function abnormalities d. Cleft lip/palate
e. Hearing loss f. Seizures
g. Immune function abnormalities, especially low IgA
DIAGNOSTIC INVESTIGATIONS
1. Cytogenetic studies for detection of an interstitial deletion of 17p11.2
a. G-banded karyotype: may not detect small deletion especially when the indication of cytogenetic study is other than SMS
b. Molecular cytogenetic analysis by FISH using a DNA probe specific for the SMS critical region
2. Molecular genetic testing of RAI1, the only gene known to account for the majority of features in SMS: available on a clinical basis
3. Blood chemistry
a. Hypercholesterolemia b. Hypertriglyceridemia c. Qualitative immunoglobulins d. Thyroid function tests
4. Renal ultrasound for possible renal and urologic anom- alies
5. Echocardiogram for possible cardiac defects
6. Radiography of the spine for scoliosis and other vertebral anomalies
7. EEG for clinical seizures 8. MRI and PET imaging
a. A significant decrease of grey matter concentration in the insula and lenticular nuclei
b. A significant hypoperfusion in the same regions
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib
i. <1% if parental chromosome analysis is normal, taking account of possible presence of parental germline mosaicism
ii. An increased risk, provided a parent carries a chromosome rearrangement and dependent upon the specific chromosome rearrangement
b. Patient’s offspring
i. Unlikely to have offspring due to severe phenotype ii. Theoretically, a 50% risk of having offspring
with SMS
2. Prenatal diagnosis: available for pregnancies at risk using a combination of routine cytogenetic studies and FISH a. Amniocentesis
b. CVS
3. Management
a. Early childhood intervention programs b. Special education
i. Speech and language ii. Physical and occupational iii. Sensory integration
c. Vocational training in later years
d. Psychotropic medications to increase attention and decrease hyperactivity
e. Behavioral modification
f. Administration of β
1-adrenergic antagonist and mela- tonin helps to manage hyperactivity, enhances cogni- tive performance, and reduces sleep disorders g. Psychosocial support for the family
REFERENCES
Allanson JE, Greenberg F, Smith AC: The face of Smith-Magenis syndrome: a subjective and objective study. J Med Genet 36:394–397, 1999.
Boddaert N, De Leersnyder H, Bourgeois M, et al.: Anatomical and functional brain imaging evidence of lenticulo-insular anomalies in Smith Magenis syndrome. Neuroimage 21:1021–1025, 2004.
Chen K-S, Potocki L, Lupski JR: The Smith-Magenis syndrome (del[17][p11.2]):
clinical review and molecular advances. Ment Retard Dev Disabil Res Rev 49:1207–1218, 1996.
De Leersnyder H, De Blois MC, Claustrat B, et al.: Inversion of the circadian rhythm of melatonin in the Smith-Magenis syndrome. J Pediatr 139:111–116, 2001.
De Leersnyder H, De Blois MC, Vekemans M, et al.:β1-adrenergic antagonists improve sleep and behavioural disturbances in a circadian disorder, Smith-Magenis syndrome. J Med Genet 38:586–590, 2001.
Dykens EM, Smith AC: Distictiveness and correlates of maladaptive behaviour in children and adolescents with Smith-Magenis syndrome. J Intellect Disabil Res 42:481–489, 1998.
Dykens EM Finucane BM, Gayley C: Brief report: cognitive and behavioral profiles in persons with Smith-Magenis syndrome. J Autism Dev Disord 27:203–211, 1997.
Elsea SH, Purandare SM, Adell RA, et al.: Definition of the critical interval for Smith-Magenis syndrome. Cytogenet Cell Genet 79:276–281, 1997.
(Published erratum appears in Cytogenet Cell Genet 81:67, 1998.) Greenberg F, Guzzetta V, Montes de Oca-Luna R, et al.: Molecular analysis of
the Smith-Magenis syndrome: a possible contiguous-gene syndrome associated with (del[17][p11.2]). Am J Hum Genet 49:1207–1218, 1991.
Greenberg F, Lewis RA, Potocki L, et al.: Multidiscip0linary clinical study of Smith-Magenis syndrome (del [17q]11.2). Am J Med Genet 62:274–254, 1996.
Juyal RC, Figuera LE, Hauge X, et al.: Molecular analyses of 17p11.2 dele- tions in 62 Smith-Magenis syndrome patients. Am J Hum Genet 58:998–1007, 1996.
Liburd N, Ghosh M, Riazuddin S, et al.: Novel mutations of MYO15A associ- ated with profound deafness in consanguineous families and moderately severe hearing loss in a patient with Smith-Magenis syndrome. Hum Genet 109:535–541, 2001.
Potocki L, Glaze D, Tan DX, et al.: Circadian rhythm abnormalities of mela- tonin in Smith-Magenis syndrome. J Med Genet 37:428–433, 2000.
Potocki L, Shaw CJ, Stankiewicz P, et al.: Variability in clinical phenotype despite common chromosomal deletion in Smith-Magenis syndrome (del[17][p11.2p11.2]). Genet Med 5:430–434, 2003.
Seranski P, Hoff C, Radelof U, et al.: RAI1 is a novel polyglutamine encoding gene that is deleted in Smith-Magenis syndrome patients. Gene 270:69–76, 2001.
Slager RE, Newton TL, Vlangos CN, et al.: Mutations in RAI1 associated with Smith-Magenis syndrome. Nat Genet 33:466–468, 2003.
Smith AC, Dykens E, Greenberg F: Behavioral phenotype of Smith-Magenis syndrome (del[17p11.2]). Am J Med Genet 81:179–185, 1998.
Smith AC, Dykens E, Greenberg F: Sleep disturbance in Smith-Magenis syn- drome (del[17p11.2]). Am J Med Genet 81:186–191, 1998.
Smith ACM, MacGavran L, Waldstein G, et al.: Deletion of the 17 short arm in two patients with facial cleft. Am J Hum Genet 34:410A, 1982.
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Smith ACM, MacGravran L, Robinson J, et al.: Interstitial de (17[p11.2p11.2]) in nine patients. Am J Med Genet 24:393–414, 1986.
Smith ACM, Gropman AL, Bailey-Wilson JE, et al.: hypercholesterolemia in children with Smith-Magenis syndrome: del (17[p11.2p11.2]). Genet Med 4:118–125, 2002.
Smith ACM, Allanson JE, Allen AJ, et al.: Smith-Magenis syndrome. Gene Reviews, 2004. http://genetests.org
Spilsbury J, Mohanty K: The orthopaedic manifestations of Smith-Magenis syndrome. J Pediatr Orthop B 12:22–26, 2003.
Straton RF, Dobyns WB, Greenberg F, et al.: Interstitial del (17[p11.2p11.2]):
report of six additional patients with a new chromosome deletions syn- drome. Am J Med Genet 24:421–432, 1986.
Willekens D, De Cock P, Fryns JP: Three young children with Smith-Magenis syndrome: their distinct, recognisable behavioural phenotype as the most important clinical symptoms. Genet Couns 11:103–110, 2000.
Zori RT, Lupski JR, Heju Z, et al.: Clinical, cytogenetic, and molecular evidence for an infant with Smith-Magenis syndrome born from a mother having a mosaic 17p11.2p12 deletion. Am J Med Genet 47:504–511, 1993.
Fig. 1. An infant with Smith-Magenis syndrome showing prominent forehead, broad square-shaped face, synophrys, short full-tipped nose, and fleshy everted upper lip with a “tented” appearance. Chromosome analysis showed an interstitial deletion of 17p11.2.
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