Smith-Magenis Syndrome

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Smith-Magenis syndrome

Definition

Smith-Magenis syndrome (SMS) is a relatively rare genetic disorder characterized by a specific pattern of physical, behavioral, and developmental features. First described in 1982 by Ann C.M. Smith (a genetics counselor) and Ellen Magenis (a physician and chromosome expert), the syndrome results from a deletion on chromosome 17, specifically referred to as deletion 17p11.2.

Description

Until the mid 1990s, SMS was not a well-known disorder, even among genetics experts; the chromosome deletion is small (a microdeletion) and difficult to detect. Most individuals are not diagnosed until they receive specialized genetic tests, usually in mid-childhood or adulthood.

Smith-Magenis syndrome causes multiple birth defects (congenital abnormalities) as well as moderate to severe mental retardation. The clinical manifestations of SMS vary. However, a number of characteristic physical features, developmental delays, and behavioral problems occur in all patients with the disorder. According to some researchers, the extent of the chromosomal deletion may account for the variable severity of symptoms.

The most common and clinically recognizable features of those with SMS include mild to moderate brachycephaly (short, wide head), flat mid-face, mental retardation, and short, broad hands. Common but less consistent physical abnormalities include prominent forehead, protruding jaw, and low-set ears. The major clinical features and the specific abnormalities of SMS are the most obvious diagnostic clues to the disorder. Some experts believe that with more research on this syndrome, SMS may be determined to be a relatively common cause of mental retardation.

Genetic profile

Although SMS is caused by a deletion of genetic material from a portion of chromosome 17, the syndrome usually does not run in families. In most cases, the deletion occurs accidentally at conception when an abnormal sperm or egg from one parent unites with a normal sperm or egg from the other parent. The abnormal sperm or egg contains the missing chromosomal material. These abnormal sperm or eggs are present in everyone; however, the risk of an abnormal conception increases significantly with the parents' ages.

Research has shown a random parental origin of deletion, suggesting that SMS is likely a contiguous gene deletion syndrome. Continguous gene syndromes are conditions that occur as a result of microdeletions or microduplications involving several neighboring genes.

Demographics

Although the exact incidence of SMS is not known, the disorder is rare and estimated to occur in approximately one in 25,000-50,000 live births. Only about 150 cases have been identified worldwide from a diversity of ethnic groups. The ages of those affected ranges from neonates to individuals in their 70s. About an equal number of males and females are affected by the disorder.

Signs and symptoms

Although there are many features associated with SMS, not every individual exhibits all of these features. The following is a common list of traits that have been reported:

Distinct facial features: brachycephaly, flat mid-face area, prominent forehead, eyelid folds, broad nasal bridge, protruding jaw, and low-set ears
brachydactyly (short fingers and toes)
short stature
hoarse, deep voice
speech delay
learning disabilities
chronic ear infections
mental retardation (typically in the 50-60 range for IQ)
poor muscle tone and/or feeding problems in infancy
eye disorders
sleep disturbances
insensitivity to pain
behavioral problems: hyperactivity, head banging, hand/nail biting, skin picking, pulling off fingernails and toenails, explosive outbursts, tantrums, destructive and aggressive behavior, excitability, arm hugging/squeezing when excited
engaging and endearing personality

Less common symptoms include:

heart abnormalities
scoliosis (curvature of the spine)
seizures
urinary tract abnormalities
abnormalities of the palate, cleft lip
hearing impairment

Diagnosis

Although SMS is generally believed to be underdiagnosed, with increased professional awareness and improved methods of testing, the number of individuals identified increases annually. In diagnosing the disorder, the characteristic behavioral features of SMS are usually recognized before the facial features, often leading to a delay in diagnosis.

Phenotype (physical features) identification

Facial abnormalities evolve over time and are more subtle in early childhood. Thus, diagnosis of SMS at birth or in infancy is infrequent and is usually made by chance when abnormal facial features suggest a diagnosis of Down syndrome (a more commonly known congenital abnormality caused by an extra chromosome 21) and chromosome testing reveals the SMS 17p11.2 deletion.

The phenotypic overlap of SMS with Down syndrome, particularly in early life, can be striking. Both conditions share a number of features, including brachycephaly, upward-slanting eyes, a short and broad nose, mid-face flattening, eye disorders, short stature, small hands and feet, and poor muscle tone. However, age evolves the somewhat coarse appearance of the face, and by young adulthood, the phenotype of the disorder is well developed and striking. Familiarity with the clinical manifestations of both genetic disorders improves the likelihood of early diagnosis and intervention.

High resolution chromosome analysis

The diagnosis of SMS is often confirmed through a blood test called a high resolution chromosome analysis, which is generally performed for the evaluation of developmental delays or congenital abnormalities. In the case of microdeletions, the chromosome deletions are so small that often they cannot be detected by chromosome analysis alone. In the older child, however, the phenotype is distinctive enough for a clinical diagnosis to be made by an experienced clinician prior to the chromosome analysis.

FISH analysis

If chromosome analysis is inconclusive, FISH (fluorescence in situ hybridization) is the test of choice to document the SMS deletion because its high degree of accuracy. In FISH analysis, which has become a standard molecular test, denatured DNA (DNA altered by a process that separates the complimentary strands within the DNA double helix structure) is kept in place in the chromosome and is then hybridized (mixed) with RNA or DNA (extracted from another source) to which a fluorescent tag has been attached. The advantage of maintaining the DNA in the chromosome is that the specific chromosome (or chromosomes) containing the gene of interest can be identified by observing, under a microscope, the location of the fluorescence. Combining FISH and standard chromosome analysis can characterize the structural rearrangements and marker chromosomes.

In SMS, predictive or prenatal screening is an unlikely outcome of identifying the flawed gene because the disease is so rare and does not run in families. Instead, researchers hope to determine how the extent of the microdeletion on chromosome 17 is related to the various signs and symptoms of SMS.

Treatment and management

There is no cure for SMS because the disorder is so complex and has received relatively little research attention. Therefore, managing symptoms becomes a priority in those diagnosed with the disorder.

A child with SMS typically displays self-injurious behavior as well as attention-seeking outbursts and aggressive behavior. Medications such as carbamazapine (an anticonvulsant) may be prescribed for severe behavioral problems associated with SMS. However, in most cases, drugs to help control or modify behavior or increase attention span have been found to be minimally effective. Any pharmacologic treatment of SMS remains individual, and several drugs may need to be tested to optimize results.

In addition to behavioral problems, children with SMS tend to have speech delays. Therefore, speech therapy, starting as early as possible, is typically beneficial. Most children learn to communicate verbally, either with sign language or gestures.

Since children with SMS are often easily distracted, they tend to do better in small, focused classroom settings in which there are no more than five to seven children. If the classroom is larger, competition for the teacher's attention increases, along with the probability of behavioral problems. These children also seem to respond to consistency, structure, and routines; changes in routine can provoke behavioral outbursts and tantrums.

Children with SMS have problems with sequential processing, which makes counting, mathematical skills, and multi-step tasks especially difficult. They tend to learn best with visual cues (such as pictures illustrating tasks). Also, since they have a fascination with electronics, the use of computers and other technology may be effective teaching tools in these children. Generally very responsive to affection, praise, and other positive emotions, children with SMS usually enjoy interacting with adults. A parent or teacher's positive response can often motivate a child to learn.

More than half of children with SMS have sleep disturbances such as daytime sleepiness, difficulty falling asleep at night, nocturnal awakening, decreased sleep time, and abnormalities in REM (rapid eye movement) sleep. These disturbances are due to abnormal melatonin metabolism. Melatonin is a sleep-inducing hormone secreted by the pineal gland in the brain. Therefore, a locking mechanism on the door may be helpful in preventing the child from wandering out of his or her bedroom at night. Also, a night-time dose of melatonin has been recommended for some children and adults with SMS.

Some experts have suggested that every individual with SMS have annual examinations for thyroid function, scoliosis, and eye problems. If any of these tests is abnormal, intervention and further clinical evaluation is appropriate.

Prognosis

Although there is no medical prevention or cure for SMS, early diagnosis gives parents time to learn about and prepare for the challenges of the disease. Although there is insufficient data regarding the average life expectancy of those diagnosed with SMS, some individuals have lived well into their 70s.

Resources

BOOKS

Cohen, Michael, Jr. The Child With Multiple Birth Defects. 2nd ed. New York: Oxford University Press, 1997.

Harris, Jacqueline L. Hereditary Diseases (Bodies in Crisis). Twenty First Century Books, 1995.

PERIODICALS

Hirsch, David. "Identifying Smith-Magenis Syndrome." Exceptional Parent 27 (July 1997): 72-73.

Hodapp, R.M., D.J. Fidler, and A.C.M. Smith. "Stress and Coping in Families of Children With Smith-Magenis Syndrome." Journal of Intellectual Disability Research. 42 (October 1, 1998): 331-340.

McBride, Gail. "Melatonin Disrupts Sleep in Smith-Magenis Syndrome." Lancet 354 (November 6, 1999): 1618.

ORGANIZATIONS

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.