Brenda Finucane, M.S. and Elliott Simon, Ph.D.
In a previously published NADD Bulletin article, we described how the understanding of specific genetic causes of developmental and psychiatric disorders can act as a unifying concept which helps to drive treatment (Simon and Finucane, 1998). In recent years, the identification of powerful molecular tools has allowed the delineation of genetic conditions which formerly went unrecognized. Smith-Magenis syndrome (SMS) is one such disorder which, despite a highly characteristic behavioral phenotype, was only first described in the mid-1980s. Because of its strong association with self-injurious behaviors and psychiatric symptoms, SMS has particular relevance for professionals interested in dual diagnosis.
In 1986, genetic counselor Ann C.M. Smith and her colleagues, including geneticist Ellen Magenis, M.D., published a report on 9 individuals with a chromosomal finding known as deletion 17p11.2 (Smith et al, 1986). Specifically, the people described each had a small missing segment (deletion) of genetic material involving a particular region (p11.2) of chromosome number 17. Other reports confirmed the laboratory finding, and by the early 1990s, a specific physical and behavioral profile began to emerge (Greenberg et al., 1991). Over 100 reports of Smith-Magenis syndrome have now appeared in the medical literature, and the incidence of SMS is estimated at 1 in 25,000 live births. While SMS is relatively rare in the general population, it is not uncommon among people known to have developmental disabilities and coinciding behavioral disorders. For example, in a five year span we diagnosed 23 individuals with SMS among approximately 1,000 day and residential clients at our facility in southeast Pennsylvania. All 23 people with SMS had both mental retardation and at least one psychiatric diagnosis. Genetic diagnostic screening of dually diagnosed individuals would be expected to yield an even higher prevalence of SMS than 23 in 1000.
SMS is associated with a characteristic physical and behavioral phenotype (Greenberg et al., 1996; Smith, Dykens., Greenberg, 1998a; Clarke and Boer, 1998). Infants with SMS frequently have hypotonia and feeding difficulties. They may have short fingers, a slightly upward slant to their eyes, and under-developed cheekbones, features which sometimes cause physicians to question the possibility of Down syndrome in the newborn period (Thomson, Finucane, Bauer, Weinstein, 1994). A minority of infants with SMS are born with structural birth defects, such as cardiac and renal anomalies, and occasionally, cleft palate. With age, the facial characteristics of people with SMS change, and by late childhood, most have developed a prominent lower jaw and characteristic downturned mouth. While the SMS facial characteristics are distinctly recognizable to those familiar with the syndrome, they can be subtle, and many children and adults do not appear physically unusual. SMS is frequently associated with eye abnormalities including strabismus, nearsightedness, and occasionally retinal detachments (Finucane, Jaeger, Kurtz, Weinstein, Scott, 1993). Chronic ear infections are typical during childhood and contribute to significant conductive hearing loss; concurrent sensorineural loss is also commonly seen. Short stature is usual, and endocrine disorders may include precocious puberty or delayed sexual maturation.
Developmental delays are usually evident in infancy, and most older children and adults reported with SMS function within the mild to moderate range of mental retardation. As with most genetic syndromes however, there can be wide variability in intellectual and adaptive functioning. Behaviorally, children with SMS often pose severe management problems from an early age (Smith et al., 1998a; Clarke and Boer, 1998). Most have attention deficit disorders, with or without hyperactivity. Children and adults with the syndrome frequently crave attention from authority figures, such as teachers and work supervisors (Haas-Givler, 1994). Attention-seeking behaviors (i.e. calling out in class, asking the same questions over and over again, physical grabbing or forceful hugging) pose disruptions in the classroom and workplace, while failure to gain wanted attention can result in prolonged tantrums, property destruction, and self-injurious behaviors.
Sleep disturbance is an almost universal finding, and most children with SMS sleep only a few hours per night and have frequent awakenings (Smith, Dykens, Greenberg, 1998b). Understandably, their parents are also sleep deprived and consider this feature to be among the most difficult to handle. Some children and adults exhibit narcolepsy-like daytime sleep episodes from which they are difficult to rouse. Researchers have documented abnormalities in REM sleep among people with SMS; it is hypothesized that one or more genes within the 17p11.2 chromosomal region plays a role in normal sleep regulation, and deletion of those genes in people with SMS results in sleep disturbance.
A characteristic pattern of self-injurious behaviors distinguishes SMS from many other genetic syndromes. During early childhood, head banging and hand or wrist biting are very common, as they are among children with mental retardation in general. Older children and adults with SMS often pick at their fingers and/ or toenails until they bleed, sometimes removing the nail completely; this behavior, called onychotillomania, is unusual even among people with dual diagnosis. Less commonly, people with SMS exhibit polyembolokoilamania, or the insertion of foreign objects into various body orifices (Greenberg et al., 1991). Older children and adults have sometimes required surgical removal of beads, food, and other items from the ears or nose. Sexual abuse may be wrongly suspected for some girls with SMS who exhibit vaginal insertion of foreign objects. Over 65% of individuals with SMS have a history of onychotillomania and/ or polyembolokoilamania (Greenberg et al., 1991), and the presence of these distinctive behaviors in a person with developmental disabilities signals a high likelihood of SMS.
Another behavior which is more benign but highly characteristic of SMS is self-hugging (Finucane, Konar, Haas-Givler, Kurtz, Scott, 1994). During periods of excitement or happiness, children and (somewhat less commonly) adults with SMS exhibit midline tic-like movements. Most wrap their arms tightly across their chests, with hands under their upper arms, and tense their bodies in quick, tic-like spasms. In another variation, some individuals twist their hands together, quickly pulling them into their chests in fleeting movements, while tensing their bodies and making facial grimaces. These odd movements appear to be involuntary and often occur in a flurry of many successive spasms, particularly during periods of great happiness or excitement. Self-hugging does not interfere with other purposeful hand movements in people with SMS, and the behavior is benign. However, it is an important diagnostic marker which should prompt evaluation for SMS when present.
One of the most exciting aspects of research into SMS is its potential to show rational connections between physiology and behavior. As mentioned above, the biological basis for sleep disturbance in SMS is an area of intense research. Serum melatonin levels in people with SMS have been shown to be abnormally low at night (when they should be high) and relatively high during the day (Potocki, Reiter, Glaze, Lupski, 1997). This finding correlates with the observed pattern of sleep problems in these individuals. Unfortunately, melatonin supplements do not appear to simply fix the sleep problems for most people with SMS, but at least now, researchers have a logical starting point on which to focus their efforts. Because lack of sleep appears to exacerbate other psychiatric symptoms in people with SMS, the eventual discovery of effective treatments for SMS sleep disturbance may have a global positive effect on behavior.
Another example of the link between behavior and biology in SMS is seen in some of its associated self-injurious behaviors. For example, people with SMS have been found to have decreased and / or abnormal pain sensation, particularly in the extremities. As they age, the hands and feet of people with SMS often become dry and leathery, causing them to crack and develop sores. Many older children and adults have unusually thin lower legs and walk with a lurching gait. All of these symptoms appear to be related to a peripheral neuropathy (abnormalities involving the nerves going to the lower arms and legs); genes important for peripheral nerve functioning are known to be located on chromosome 17 in the very region deleted in people with SMS (Greenberg et al., 1991). Peripheral neuropathy helps to explain why people with SMS can engage in self-mutilatory behavior such as onychotillomania with no apparent discomfort; it is even plausible to suspect that the behavior itself is prompted by abnormal sensations in the fingers and toes. It is not unrealistic to speculate that future treatment of self-injurious behaviors in people with SMS will start with medications for peripheral neuropathy rather than undirected, behavior-altering drugs which only address secondary symptomatology.
At the present time, our understanding of SMS has led to many insights and the promise of new therapies; but among the most important benefits of knowing about this diagnosis are the ones which affect families. SMS is considered a sporadic genetic disorder, meaning that it almost always occurs for the first time in a child whose unaffected parents and siblings are at no increased risk for passing on this genetic trait in future pregnancies. Knowing this can be very reassuring to parents who might not otherwise have dared to plan a subsequent pregnancy with only a vague diagnosis of mental retardation to go on. But apart from genetic counseling, there are many intangible benefits as well. Almost all families of people with SMS have to contend with behavioral issues at some point. Self-injurious behaviors take a particularly hard toll on parents, who by nature want to protect their children from harm. They often feel helpless in the face of the persistent, genetically driven behaviors frequently associated with SMS. Add to this the many years of sleep deprivation that parents endure because of their childrens erratic sleep patterns, and clearly SMS families must deal with far more than an average amount of parental stress (Hodapp, Fidler, Smith, 1998). The importance of support groups such as NADD and PRISMS* in helping families come to terms with SMS cannot be overstated. Parents derive strength and support from each other, and they learn ways to effectively advocate for their disabled family member. Most importantly, such groups act as a stimulus for research into medical and therapeutic advances that will ultimately improve their quality of life.
* P.R.I.S.M.S. - Parents and Researchers Interested in Smith-Magenis Syndrome, 11875 Fawn Ridge Lane, Reston, Virginia 22094 (703-709-0568).
Clarke, D.J. and Boer, A. (1998). Problem behaviors associated with deletion Prader-Willi, Smith-Magenis, and Cri du Chat syndromes. American Journal on Mental Retardation. 103, 264-371.
Finucane B.M., Jaeger E.R., Kurtz M.B., Weinstein M., and Scott C.I. (1993). Eye abnormalities in the Smith-Magenis contiguous gene deletion syndrome. American Journal of Medical Genetics, 45, 443-446.
Finucane B.M., Konar D., Haas-Givler B., Kurtz M.B., and Scott C.I. (1994). The spasmodic upper body squeeze: a characteristic behavior in Smith-Magenis syndrome. Developmental Medicine and Child Neurology 36, 78-83.
Greenberg, F., Lewis, R.A., Potocki, L., Glaze, D., Parke, J., Killian, J., Murphy, M.A., Williamson, D., Brown, F., Dutton, R., McCluggage, C., Friedman, E., Sulek, M., & Lupski, J.R. (1996). Multi-disciplinary clinical study of Smith-Magenis syndrome (deletion 17p11.2). American Journal of Medical Genetics, 62, 247-254.
Greenberg, F., Guzzetta, V., Montes de Oca-Luna, R., Magenis, R.E., Smith, A.C.M., Richter, S.F., Kondo, T., Dobyns, W.B., Patel, P.I., & Lupski, J.R. (1991). Molecular analysis of the Smith-Magenis syndrome: A possible contiguous-gene syndrome associated with del(17)(p11.2). American Journal of Human Genetics, 49, 1207-1218.
Haas-Givler B. (1994). Observations on the behavioral and personality characteristics of children with Smith-Magenis syndrome. Spectrum (newsletter of PRISMS support group), vol.1, no.2.
Hodapp, R.M., Fidler, D.J., & Smith, A.C.M. (1998). Stress and coping in families of children with Smith-Magenis syndrome. Journal of Intellectual Disability Research, 42, 331-340.
Potocki L., Reiter R.J., Glaze D., Lupski J.R. (1997). Twenty-four hour urinary excretion of 6-sulphatoxymelatonin in Smith-Magenis syndrome. American College of Medical Genetics conference presentation, Abstract A31.
Simon, E.W. & Finucane, B. (1998). Etiology and dual diagnosis: Notes on a biologically based syndromic approach. The NADD Bulletin, 1, 63-65.
Smith, A.C.M., Dykens, E., & Greenberg F. (1998b). Sleep disturbance in Smith-Magenis syndrome. American Journal of Medical Genetics, 81, 186-191.
Smith, A.C.M., Dykens, E., & Greenberg, F. (1998a). Behavioral phenotype of Smith-Magenis syndrome (del 17p11.2). American Journal of Medical Genetics, 81, 179-185.
Smith, A.C.M., McGavran, L., Robinson, J., Waldstein, G., Macfarlane, J., Zonona, J., Lahr, M., Allen, L., & Magenis, E. (1986). Interstitial deletion of (17)(p11.2p11.2) in nine patients. American Journal of Medical Genetics, 24, 393-414.
Thomson, K.A., Finucane, B.M., Bauer, M.S., & Weinstein, M.E. (1994). Overlap of clinical features of Smith-Magenis and Down syndrome in newborns and infants: Implications for testing and diagnosis. American Journal of Human Genetics, 55, 529A.
For further information contact:
Brenda Finucane, M.S.
Genetic Services at Elwyn
Elwyn, PA 19063