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Smith-Magenis Syndrome

Smith Magenis Syndrome

Smith-Magenis syndrome is a developmental disorder which affects several organs and systems of the body.


Presentation

As previously stated, SMS signs might be very variable, especially in later life stages. Thus, each case might show a different clinical presentation and family members of affected children should discuss the details with the medical team.

Facial features appear to be very distinctive:

  • Square-shaped face
  • Broad bridge of the nose
  • Deep-set eyes which appear to be placed farther apart that normal (hypertelorism)
  • Up-slanting palpebral fissures
  • Hair growth between eyebrows to form one single long line (synophrys)
  • Upper lip clearly turning downwards
  • General underdevelopment of the middle portion of the face (midface retrusion)
  • Disproportionately short head (brachycephaly)

The jaw might appear noticeable small (micrognathia) early in life, but as the child ages the jaw begins to abnormally protrude outward (relative prognathia) together with the general progression of all SMS signs. In addition, secondary teeth, particularly premolars, might be absent while the other teeth might display enlarged pulp chambers and reduced roots (taurodauntism). These dental signs may be accompanied by an open bite posture characterized by a considerable tongue enlargement (macroglossia) and previous episodes of teeth grinding (bruxism).

SMS signs can involve other body parts as well. Muscle tone might appear diminished (hypotonia), a condition which is frequently coupled with the presence of poor reflexes (hyporeflexia). Infants may show difficulties in growing and gaining weight at the expected rate based upon gender and age, a condition known as failure to thrive. This further complication is often worsened due to feeding difficulties such as poor sucking ability. Speech delay may also be observed in this early phase, especially as infrequent crying and diminished vocalizations characterizing the infant behavior. Affected infants may also show a general state of lethargy along with the tendency of napping for prolonged periods at daytime. The digestive system may be effected too, as indicated by the repeated appearance of gastroesophageal refluxes.

Cognitive ability is cut back to a state of mild or moderate intellectual disability in affected individuals. These are strictly connected with behavioral problems such as head banging and self-hugging which appear very early in life. Other behavioral problems can be summed up as follows:

Other signs of aggression might involve behaviors such as face slapping, skin picking, and hand/wrist biting which can result in self-inflicted injuries. Fingernail and toenail yanking (onychotillomania) might appear in older children, which is frequently coupled with the tendency of inserting objects into the orifices of the body (polyembolokoilamania) [7] [8] and an unusual capability of remembering faces, things, and places. It should be noted that despite the behavioral problems, affected individuals tend to show engaging personalities and a sense of humor.

Symptoms involving the ears and eyes include chronic ear infection, together with conductive hearing loss (occurring when sound wave conductivity problems arise) or increased sensitivity to particular sounds and frequencies. In regard to eye problems progressive nearsightedness (myopia), reduced cornea and crossed eyes (strabismus) are particularly frequent.

Signs might also involve larynx and its surrounding areas. Laryngeal abnormalities like polyps, nodules, and especially swelling, which results from edema, may be observed. Affected individual may experience difficulty of the mouth palate to properly close during speech (velopharyngeal insufficiency), or the problems in controlling lip, tongue, and jaw muscle movements often resulting in tongue protrusion. All these abnormalities commonly lead to vocal cord paralysis and contribute to speech delay development.

Weight gain and obesity tend to set in during adolescence, affecting 90% of children with SMS. In addition, high cholesterol levels and chronic constipation may be present. On the other hand, height seems to be seldom affected, with the majority of the patients maintaining a proper stature.

Sleep disturbances represent a life-long problem. They appear in early childhood and tend to continue in both adolescence and adulthood. Major sleep problems include difficulty in falling asleep, inability to enter into REM phase, shortening of sleep cycles, and frequent night awakening episodes. As a consequence, this might result in drowsiness during daytime associated with an inverted melatonin circadian rhythm (reported in around 90% of all cases).

Skeletal malformations often involve the spine, especially lordosis (front-to-back spine curvature) and scoliosis (sideway spine curvature). These appear frequently along with hand and feet abnormalities causing walking problems. Vertebral abnormalities and forearm and elbow limitations are rare but still significant. Other signs may suggest problems with other body systems, like:

Peripheral neuropathy should be added to this list, usually underlined by the marked decrease in pain sensitivity and loss of sensation.

Atrial Septal Defect
  • Other features include cardiac defects (ventricular septal defect, atrial septal defect, aortic stenosis,... References 1.[link.springer.com]
Prognathism
  • Radiographic findings suggest the prognathic appearance is not caused by excessive mandibular growth.[ncbi.nlm.nih.gov]
  • Their clinical manifestations included brachycephaly, midface hypoplasia, prognathism, upper lip eversion, short and broad hands with short fingers, clinodactyly of the fifth fingers, fingertip pads, moderate mental retardation, and behavior problems.[ncbi.nlm.nih.gov]
  • Infants are described as looking "cherubic" with a Down syndrome-like appearance, whereas with age the facial appearance is that of relative prognathism.[ncbi.nlm.nih.gov]
  • For example, the girl at the top of the page has heavy eyebrows, a large forehead, jaw prognathism, and a short philtrum (the groove below the nose). The Hispanic girl below also has heavy eyebrows and a short philtrum.[forgottendiseases.org]
  • […] delay hypotonia hyporeflexia lethargy feeding difficulties Physical features facial appearance specific and changes over time square face brachycephaly full cheeks deep-set eyes heavy brows square jaw micrognathia fleshy upper lip bulky philtral pillars prognathism[en.wikibooks.org]
Ectopia Lentis
  • Ocular findings in our patient include: myopia, iris nodules, loose zonules, and ectopia lentis. To our knowledge this is the first reported case of SMS in the Caribbean basin and the first case that report ectopia lentis in SMS.[ncbi.nlm.nih.gov]
Onychotillomania
  • Behavioral disorders often include outbursts, attention deficit/hyperactivity disorders, self-injury with onychotillomania and polyembolokoilamania (insertion of objects into body orifices), etc.[ncbi.nlm.nih.gov]
  • A striking neurobehavioral pattern of stereotypies, hyperactivity, polyembolokoilamania, onychotillomania, maladaptive and self-injurious and aggressive behavior is observed with increasing age.[ncbi.nlm.nih.gov]
  • […] asleep by day Anxious Aggressive Impulsive Polyembolokoilamania or wherein the person pulls out the nails and stuffs objects into almost all bodily orifices Having difficulty to pay attention Head banging Hyporeflexia General lethargy Temper tantrums Onychotillomania[syndromespedia.com]
  • Older children may yank at fingernails and toenails (onychotillomania) or insert objects into body orifices (polyembolokoilamania). Affected children tend to be excitable and easily distracted.[rarediseases.org]
Low Set Ears
  • Craniofacial and skeletal abnormalities are common, including brachycephaly, broad nasal bridge, flat midface, tented upper lip, synophrys, hypertelorism, abnormally shaped or low-set ears, and brachydactyly.[link.springer.com]
Hearing Problem
  • Treatment for vision problems and hearing problems may be needed. Sleep therapy and/or medication may be needed to help improve sleep patterns and quality of sleep. An enclosed bed system may be necessary to keep children with SMS in bed at night.[thinkgenetic.com]
Broad Nasal Bridge
  • The main clinical features of this syndrome which is also referred to as the Smith-Magenis syndrome consist of a broad flat midface with brachycephaly, broad nasal bridge, brachydactyly, speech delay, hoarse deep voice and peripheral neuropathy.[ncbi.nlm.nih.gov]
  • The common clinical findings were: speech delay with behavioural problems associated with broad flat midface, brachycephaly, broad nasal bridge and brachydactyly.[ncbi.nlm.nih.gov]
  • The main clinical features consist of a broad flat midface with brachycefaly, broad nasal bridge, brachydactily, speech delay, hoarse deep voice and peripheral neuropathy.[ncbi.nlm.nih.gov]
  • The face is characterized by a short flat head, prominent forehead, broad square face, upslanting eye slits, deep-set eyes, underdeveloped midface, broad nasal bridge, short nose, tented upper lip, and a chin that is small in infancy and becomes relatively[medicinenet.com]
Head Banging
  • Head banging, hand, wrist or finger biting are present. Onychotyllomania is not observed. Insertion of objects in the mouth as well as excessive nose picking is very frequent, although polyembolokoilomania is not present.[ncbi.nlm.nih.gov]
  • […] frequent ear infections, and heart defects when compared with patients with deletion, while a subset of small deletion cases with deletions spanning from TNFRSF13B to MFAP4 was less likely to exhibit brachycephaly, dental anomalies, iris abnormalities, head-banging[ncbi.nlm.nih.gov]
  • When he was 8, his head-banging was severe enough to cause significant damage. "He had a retinal detachment caused by head-banging, and he ultimately lost his left eye," she said.[abcnews.go.com]
  • Aggression and self-mutilation, head-banging and hand-biting, and sleep disorders are the most typical behaviors, causing management problems.[pediatricneurologybriefs.com]
  • A common initial sign is head banging during early childhood. Frequent upper body squeezes often described as “self-hugging” is also common.[rarediseases.org]
Polyembolokoilamania
  • Behavioral disorders often include outbursts, attention deficit/hyperactivity disorders, self-injury with onychotillomania and polyembolokoilamania (insertion of objects into body orifices), etc.[ncbi.nlm.nih.gov]
  • Patients with RAI1 mutation were more likely to exhibit overeating, obesity, polyembolokoilamania, self-hugging, muscle cramping, and dry skin and less likely to have short stature, hearing loss, frequent ear infections, and heart defects when compared[ncbi.nlm.nih.gov]
  • A striking neurobehavioral pattern of stereotypies, hyperactivity, polyembolokoilamania, onychotillomania, maladaptive and self-injurious and aggressive behavior is observed with increasing age.[ncbi.nlm.nih.gov]
  • Flat appearing bridge of the nose Mouth is downward with full, outward curve of the person’s upper lip Disruption of the sleep pattern cycle or having an inverted circadian rhythm which is awake at night and asleep by day Anxious Aggressive Impulsive Polyembolokoilamania[syndromespedia.com]
Self Mutilation
  • Behavioural abnormalities include hypermotility, self mutilation and sleep disturbances.[ncbi.nlm.nih.gov]
  • Behavioural abnormalities include hypermotility, self-mutilation and sleep disturbance.[ncbi.nlm.nih.gov]
  • Aggression and self-mutilation, head-banging and hand-biting, and sleep disorders are the most typical behaviors, causing management problems.[pediatricneurologybriefs.com]
  • Deliberate self-harm Self mutilation [ more ] 0000742 Short nose Decreased length of nose Shortened nose [ more ] 0003196 Short palm 0004279 Short philtrum 0000322 Short stature Decreased body height Small stature [ more ] 0004322 Strabismus Cross-eyed[rarediseases.info.nih.gov]
  • The self-mutilation may take an unusual form such as onychotillomania, and may be related to the high tolerance of pain which accompanies this condition.[jmg.bmj.com]
Wrist Biting
  • In addition to head banging, affected children may develop other self-injurious behavior such as hand biting, face slapping, skin picking, and wrist biting.[rarediseases.org]
  • biting which can result in self-inflicted injuries.[symptoma.com]
  • During early childhood, head banging and hand or wrist biting are very common, as they are among children with mental retardation in general.[thenadd.org]
Psychomotor Retardation
  • A 3-year-old girl was referred for evaluation of moderate psychomotor retardation and several behavioral problems including self-injuring behavior, hyperactivity, and sleep disturbance.[ncbi.nlm.nih.gov]
  • The central nervous system is affected and this may be shown by psychomotor retardation, intellective deficit, electroencephalographic alterations (reduced/missing REM phase); the neuroradiological tests detect megacisterna magna, cerebellar hypoplasia[ncbi.nlm.nih.gov]
Hyperactivity
  • Clinical manifestations include brachycephaly and a flat mid-face; brachydactyly; short, broad hands; mental retardation; and aberrant behaviour, including hyperactivity.[ncbi.nlm.nih.gov]
  • In any case, efforts should focus on improving communication skills, identifying and treating attention deficit/hyperactivity, aggressiveness and anxiety.[ncbi.nlm.nih.gov]
  • […] confirm previous findings and identify new genotype-phenotype associations including differences in the frequency of short stature, hearing loss, ear infections, obesity, overeating, heart defects, self-injury, self-hugging, dry skin, seizures, and hyperactivity[ncbi.nlm.nih.gov]
  • A 3-year-old girl was referred for evaluation of moderate psychomotor retardation and several behavioral problems including self-injuring behavior, hyperactivity, and sleep disturbance.[ncbi.nlm.nih.gov]
  • The behaviour problems in the three four year olds include very demanding behaviour, severe temper tantrums, hyperactivity, aggressive behaviour, self injurious behaviour, sleeping problems and stereotypic behaviour.[ncbi.nlm.nih.gov]
Behavior Problem
  • Smith-Magenis syndrome (SMS) is a rare syndrome with multiple congenital malformations, including development and mental retardation, behavioral problems and a distinct facial appearance.[ncbi.nlm.nih.gov]
  • Behavioral problems correlated with the inverted circadian rhythm of melatonin.[ncbi.nlm.nih.gov]
  • Furthermore, we evaluated the similarities of SMS adult food-related behaviors to those with intellectual disability and found that SMS adults had more severe behavioral problems.[ncbi.nlm.nih.gov]
  • Their clinical manifestations included brachycephaly, midface hypoplasia, prognathism, upper lip eversion, short and broad hands with short fingers, clinodactyly of the fifth fingers, fingertip pads, moderate mental retardation, and behavior problems.[ncbi.nlm.nih.gov]
  • A 3-year-old girl was referred for evaluation of moderate psychomotor retardation and several behavioral problems including self-injuring behavior, hyperactivity, and sleep disturbance.[ncbi.nlm.nih.gov]

Workup

SMS can be usually diagnosed by using the following techniques:

  • Full physical examination 
  • Detailed analysis of the patient's medical history
  • Flourescence In Situ Hybridization (FISH) which is usually considered a confirmative technique
  • Examination of the chromosomes and cytogenesis of the patient (this too is considered an important confirmative technique)
  • Magnetic resonance imaging (MRI) or computed tomography (CT) scan, which are used to rule out the formation of mass lesions.

Treatment

The main goal of SMS treatment is to treat and control symptoms as far as possible [9]. SMS treatment includes:

  • Physical therapy
  • Speech therapy
  • Behavioral therapy
  • Educative Learning Therapy
  • Hearing aids

The diet plays an important role and should be based on vegetarian foods and other healthy products. Paramount is also the melatonin treatment, in the attempt of restoring the impaired circadian rhythm and avoiding aggressive behavior resulting from it. This is usually coupled with the administration of anticonvulsant and antipsychotic drugs to cope with psychological complications. All in all, SMS treatment requires the involvement of a team made up of different professionals, such as genetic counselors, psychologists, speech therapists, and molecular biologists.

Prognosis

If SMS is diagnosed early in life, prognosis for the affected patients is very good, especially in terms of life expectancy. With the proper treatment provided on a regular basis, SMS patients might live up to 60 or 70 years, just as a normal person would.

Etiology

The etiological factor of SMS is a deletion of the chromosome number 17, in a section which includes the retinoic acid-induced (RAI1) gene. RAI1 has been reported to play a pivotal role in many functions of the body, including those of the brain. Unfortunately, the precise role of this gene and its related protein has not been fully understood yet [6], while the cause of the chromosomal alteration, which appears to be spontaneous, is still unknown. The chromosome rearrangements which lead to the 7p11.2 deletion are sporadic, and this explains the rare occurrence of this disorder.

Epidemiology

SMS has been identified all over the world, with no significant difference among human races. The incidence of SMS is estimated to be around 1 every 25.000 births, even though the actual prevalence is slightly higher than that, with a rate of around 1 every 15.000 births. Therefore, the disorder is sporadic, and neither recurrence in a family or germinal mosaicism has been observed.

It is interesting to notice that a great part of affected individuals identified to date is aged between 5 to 10 years.

Sex distribution
Age distribution

Pathophysiology

The vast majority of SMS cases (around 90%) has been associated with the previously mentioned deletion of the chromosome 17 in the p11.2 position (17p11.2 deletion). Deletion is usually caused by irregularities in the chromosome recombination due to the presence of frequently repeated elements in the region concerned. In particular, the region p11.2 of the chromosome 17 is among the most recombination-prone locations, reported to be associated with other genetic diseases such as hereditary neuropathy with liability to pressure palsies and Charcot Marie Tooth disease type 1A. In around 70% of the cases, the deletion is usually caused by an unequal meiotic crossover following nonallelic recombination between the repeated elements flanking the deleted region called SMS REPs. In the remaining 30% of the cases, instead, the deletion is due to recombination between other repeated elements such as AT-rich repeats or Alu elements. Furthermore, in around 10% of all SMS cases the disorder is due to mutations occurring in the RAI1 gene.

Prevention

As SMS is a congenital disorder, no particular measure can be suggested to prevent it.

Summary

Smith-Magenis syndrome (SMS) is a complex developmental disorder which affects a series of body organs and systems. It is characterized by some major signs such as particular facial features and mild to moderate intellectual disabilities, which in turn are usually associated with impaired speech or language skills and sleep or behavior problems.

Main facial features include a broad and square-shaped face, full cheeks, deep-set eyes and a prominent lower jaw. Furthermore, the middle of the face and the bridge of the nose appear clearly flattened. Another characteristic feature presents the mouth as turned downward, forming an outward-curving upper lip, as well as dental abnormalities. In early childhood, these facial differences are usually mild, but become more distinctive in later stages of life.

An affectionate and engaging personality is characteristic in individuals with SMS. Moreover, they often display fits of temper, anxiety, aggression, and impulsiveness. Common behavioral abnormalities include episodes of self-injury (e.g. head banging, skin picking), difficulty in paying attention, compulsively licking fingers and flipping book pages (a behavior known as "lick and flip"), and repeatedly hugging oneself. Disrupted sleep patterns may frequently be observed early in life, with the affected subjects sleeping at day but experiencing problems falling asleep at night.

Other signs may be:

Heart and kidney defects are reported less often [1] [2] [3] [4] [5].

Patient Information

Smith-Magenis syndrome is a rare congenital disorder associated with a significant developmental delay. The genetic causes responsible for Smith-Magenis syndrome generally result in learning and behavioral difficulties together with characteristic disturbances in the sleep pattern.

The major features of Smith-Magenis syndrome are the characteristic developmental delay and the related learning difficulties, which might rage from a moderate to a severe level. Early in life, failure to thrive is particularly frequent, which is usually associated with the distinctive low tone of muscles, the typical feeding difficulty and the frequent ear infections. Another characteristic feature is speech delay, especially in terms of difficult language comprehension and expression, which is usually more pronounced than motor difficulty.

Typical facial features present as heavy brows, up-slanting eyes, flat and wide head linked to a prominent forehead, and a broad mouth characterized by upper lips with fleshy and inverted central portion. Key features can involve other body parts, like spine (scoliosis and lordosis), kidney, the immune system, and frequent episodes of peripheral neuropathy like decreased sensitivity to pain and temperature.

Behavioral problems represent another key feature of Smith-Magenis syndrome, which especially consist of self-injuries like self-pitching, hand biting, and scratching. These are then accompanied by psychological problems like a restless mental state, aggression, hyperactivity, frequent and prolonged tantrum episodes, and in general easy distractibility, which partially explains the learning difficulties of affected individuals. Sleep disturbances are also typical and usually tend to continue in more advanced ages. Autistic-type behaviors, like unwillingness to change, repetitive questioning and a marked preoccupation for particular topics may also be commonly observed.

Despite the behavioral and psychological difficulties, the character of affected children is often described as loving and caring, with a great sense of humor and a peculiar love for the attention and the interaction of adults.

References

Article

  1. Adams DJ, Clark DA. Common genetic and epigenetic syndromes. Pediatr Clin North Am. 2015;62(2):411-26
  2. Guérin-Moreau M, Colin E, Nguyen S, Andrieux J, de Leersnyder H, Bonneau D, Martin L. Dermatologic features of Smith-Magenis syndrome. Pediatr Dermatol. 2015;32(3):337-41.
  3. Poisson A, Nicolas A, Sanlaville D, et al. Smith-Magenis syndrome is an association of behavioral and sleep/wake circadian rhythm disorders]. Arch Pediatr. 2015;22(6):638-45.
  4. Mullegama SV, Alaimo JT, Chen L, Elsea SH. Phenotypic and molecular convergence of 2q23.1 deletion syndrome with other neurodevelopmental syndromes associated with autism spectrum disorder. Int J Mol Sci. 2015;16(4):7627-43
  5. Garayzábal Heinze E, Osório A, Lens M, Sampaio A. Concrete and relational vocabulary: comparison between Williams and Smith-Magenis syndromes. Res Dev Disabil. 2014;35(12):3365-71.
  6. Dubourg C, Bonnet-Brilhault F, Toutain A, et al. Identification of Nine New RAI1-Truncating Mutations in Smith-Magenis Syndrome Patients without 17p11.2 Deletions. Mol Syndromol. 2014;5(2):57-64
  7. Gnanavel S. Smith-Magneis syndrome: behavioural phenotype mimics ADHD. BMJ Case Rep. 2014;2014.
  8. Wilde L, Silva D, Oliver C. The nature of social preference and interactions in Smith-Magenis syndrome. Res Dev Disabil. 2013;34(12):4355-65.
  9. Grigg-Damberger M, Ralls F. Treatment strategies for complex behavioral insomnia in children with neurodevelopmental disorders. Curr Opin Pulm Med. 2013;19(6):616-25.

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Last updated: 2018-06-22 00:44