Paula and Bobby
Parents of Lillie
Smith-Magenis syndrome (SMS)
What is Smith-Magenis syndrome (SMS)?
Smith-Magenis syndrome is a genetic developmental disorder. Individuals usually display affectionate personalities but may also present with behavioral issues and repetitive behaviors. Delayed speech and language development, as well as issues with sleep are characteristic of the syndrome as well.
This rare disease affects multiple parts of the body and is characterized by distinct facial features. These unique facial features may be more subtle in infancy and childhood, but generally become more pronounced with age.
Chromosome 17p11.2 Deletion Syndrome
What gene changes cause Smith-Magenis syndrome (SMS)?
The syndrome is caused by a deletion of the RAI1 gene on chromosome 17. It is inherited in an autosomal dominant pattern, but in many cases is the result of a new mutation.
In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation which occurs during the reproductive process.
In the case of autosomal dominant inheritance just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.
What are the main symptoms of Smith-Magenis syndrome (SMS)?
The main symptoms of the syndrome include mild to moderate intellectual disability, delayed speech, issues with sleep and potential behavioral issues.
Self-injury and repetitive self hugging are common symptoms unique to the syndrome, as is a behavior referred to as lick and flip- compulsive licking of the fingers, and of the flipping of the pages of books and magazines.
Facial and physical characteristics include a short stature, hoarse voice, a broad and square face, deep-set eyes, full cheeks, prominent lower jaw, downward turned mouth and a flattened middle of the face and nose bridge.
Other health conditions may include dental abnormalities, scoliosis, myopia and a reduced sensitivity to pain and temperature.
Possible clinical traits/features:
Short nose, Neurological speech impairment, Myopia, Anteverted nares, Micrognathia, Morphological abnormality of the middle ear, Intellectual disability, Mandibular prognathia, Abnormal form of the vertebral bodies, Abnormal localization of kidney, Abnormal renal morphology, Autosomal dominant inheritance, Otitis media, Stereotypy, Pes planus, Toe syndactyly, Obesity, Open mouth, Hand polydactyly, Taurodontia, Seizure, Self-mutilation, Precocious puberty, Velopharyngeal insufficiency, Wide nasal bridge, Broad face, Brachycephaly, Broad palm, Cleft palate, Abnormality of the larynx, Abnormality of the immune system, Abnormality of the genital system, Abnormality of the forearm, Abnormality of the outer ear, Abnormality of the ureter, Abnormal tracheobronchial morphology, Abnormality of the tongue, Aplasia/Hypoplasia of the corpus callosum, Areflexia, Attention deficit hyperactivity disorder, Hoarse voice, Broad forehead, Hypercholesterolemia, Hyperacusis, Gait disturbance, Depressed nasal bridge, Generalized h
How does someone get tested for Smith-Magenis syndrome (SMS)?
The initial testing for Smith-Magenis syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
Medical information on Smith-Magenis Syndrome
This is a microdeletion syndrome involving chromosome 17p11.2. Greenberg et al., (1991) estimates the incidence to be 1 in 25000. Struthers et al., (2002) screened 1205 patients with mental retardation/developmental delay and found two patients with a 17p11.2 microdeletion. They estimated the prevalence of Smith Megenis syndrome in the population to between 1 in 40,000 and 1 in 60,000. The features are variable, but it is probably the behaviour pattern which might suggest the diagnosis (Smith et al., 1998). Self-destructive behaviour with exotic and unpronounceable names characterises the behaviour profile, such as onychotillomania (they pull out their nails) and polyebolokoilamania (the insertion of foreign bodies into their orifices). Some children bang their heads and bite their wrists with disturbing ferocity. Many patients have a disturbed sleep pattern, either having difficulty falling asleep or staying asleep, causing major problems for the parents (Smith et al., 1998). De Leersnyder et al., (2003) discussed the use of beta1-adrenergic antagonists and melatonin in treatment of the sleep disorders in this condition. Despite this, as infants, the children are often described as 'perfect babies' as they do not cry. Other characteristic behaviour patterns include 'self-hugging' and rapidly licking the fingers and turning the pages of a book. Expressive language is delayed and it can be very helpful for the children to be taught sign language before speech develops at a later age. Dysmorphically they sometimes resemble children with Prader-Willi syndrome, ie. short and plump, and brachydactyly is a useful sign. Barnicoat et al., (1996) reported a case with an unusual form of iris dysgenesis. Wong et al., (2003) reported a case with a large VSD and a right sided aorta with a patent ductus arteriosus. Babovic-Vuksanovic et al., (1998) reported a 20 year old man with the condition with macular disciform scars. Greenberg et al., (1996) provide a good review of the clinical features. Hearing impairment was present in 68%, scoliosis in 65%, ventriculomegaly in 52%, cardiac abnormalities 37%, renal anomalies (especially duplication of the collecting system) 37% and low immunoglobulin levels in 23%. Moyamoya disease has been reported (Girirajan et al., 2007) as has West syndrome (Hino-Fukuyo et al., 2009).
The chromosomal region involved is that duplicated in Charcot-Marie-Tooth disease type IA, and absent tendon reflexes have suggested that they have a neuropathy. Chen et al., (1996) report the eye findings in 28 cases. However, there is little EMG or nerve conduction velocity evidence for this. Zhao et al., (1995) reported that a gene for a human microfibril-associated glycoprotein is commonly involved in the deletion. Smith et al., (2002) showed that hypercholesterolaemia is more common in children with the condition and could be used as a biochemical marker.
Juyal et al., (1996) reported a case with mosaicism.
Chen et al., (1997) showed that the mechanism of deletion in many cases involves homologous recombination between flanking repeat gene clusters.
Potocki et al., (2000) reported seven unrelated patients with de novo duplications of the Smith-Magenis syndrome region. It was proposed that this was the reciprocal of the Smith-Magenis deletion, generated by unequal crossing over. This appeared to only occur on the paternal chromosome. Physical features including mild to moderate developmental delay, short stature, autistic-hyperactive, or attention deficit disorders, and in some cleft palate, and hypotonia were noted. In general, the features were milder than those seen in Smith-Magenis syndrome.
Potocki et al., (2000) presented evidence for circadian rhythm abnormalities of melatonin, perhaps explaining the disturbed sleep pattern in these patients.
Natacci et al., (2000) reported a 25 year-old female with Smith-Magenis syndrome, but in addition, with a hypoplastic cerebellar vermis, hypotonia, ataxic gait, and an abnormal respiratory pattern resembling Joubert syndrome. Molecular studies showed a larger than normal 17p11 deletion extending towards the telomere. The authors suggest a possible gene for Joubert syndrome at 17p11.2.
Slager et al., (2003) identified frameshift mutations leading to protein truncation in RAI1 in three individuals with phenotypic features but no detectable 17p11.2 deletion. This is a novel gene whose role is unclear. Further cases with RA11 point mutations, were reported by Bi et al., (2004) and Vlangos et al., (2005) and Bi et al., (2006). RA11 is the retinoic acid induced 1 gene, that is involved in transcriptional control. In a study of 52 individuals referred for a phenotype consistent with Smith-Magenes for whom no 17p11.2 deletion could be found, two cases were found to have overlapping 2q37 deletions (Williams et al., 2010). Four further patients were also found to have this and the gene involved was HDAC4. The mutation also results in reduced expression of RAI1 which causes Smith-Magenis.
There is an excellent review of the condition by Gropman et al., (2006).
Yuan et al., (2016) described six patients with Smith-Magenis syndrome, harbouring contiguous gene deletions encompassing both PMP22 and RAI1 genes. Common features included motor delay, intellectual disability, behavioural problems (seizures, sleep disturbance) and ocular abnormalities (myopia, strabismus, iris abnormalities and retinal detachment). Typical physical features included short stature, brachycephaly, midface hypoplasia, broad nasal bridge, prognathism, tented upper lip, broad and square face, synophrys, brachydactyly, scoliosis, foot deformities and abnormal gait. Additional features included feeding difficulties and hypotonia at infancy, congenital heart malformation and otolaryngologic anomalies. Two out of six patients were diagnosed with hereditary neuropathy with liability to pressure palsies. Brain MRI in one patient showed moderate hydrocephalus and in another patient the prominence of the ventricular system.
Acquaviva et al., (2016) described for the first time a familial case of Smith Magenis syndrome. They identified a frameshift mutation in RAI1 in the mother and the daughter. The mutation was de novo in the mother. The mother graduated from a professional institute with an assistant teacher. She needed constant support in the daily routine and decision-making processes.
Yeetong et al., (2016) reported a girl without deletion in the 17p11.2 and a de novo nonsense mutation in the RAI1 gene."
* This information is courtesy of the L M D.
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