Re: Trisomy 17

Posted By Tracy on June 17, 1998 at 01:40:08:

In Reply to: Trisomy 17 posted by Steve on June 17, 1998 at 01:00:04:






Amniocentesis done during a friend's pregancy showed that the fetus has
trisomy 17. What are the characteristics of this genetic disorder? What is
the life expectancy?
Steve...
Smith-Magenis Syndrome (SMS)
Smith-Magenis syndrome (SMS) is a chromosomal disorder characterized by a specific pattern of physical, behavioral and developmental features. It is caused by a missing piece of genetic material from chromosome 17, referred to as deletion 17p11.2. The first group of children was described in the 1980's by Ann C.M. Smith, M.A., a genetic counselor, and Ellen Magenis, M.D., a cytogeneticist. Although the exact incidence is not known, it is estimated that SMS occurs in 1 out of 25,000 births. SMS is underdiagnosed, but as awareness of it increases, the number of people identified grows every year.

Diagnosis
Smith Magenis syndrome (SMS) is a distinct and clinically recognizable multiple congenital anomaly (MCA) and mental retardation syndrome caused by an interstitial deletion of chromosome l7 p11.2. First reported in 1982 by Smith, et al, the phenotype of SMS (spectrum of clinical features of SMS) has been well described in more than 100 patients ranging from 1 month to 72 years of age. (Smith et al, 1982; Patil and Bartley 1984; Smith et al. 1986; Stratton et al. 1986; Popp et al. 1987; Lockwood et al. 1988; Colley et al. 1990; Hamill et al. 1990; Allen et al. 1991, Greenberg et al., 1991). In all cases the 17p11.2 deletion has been associated with a distinct clinical phenotype now referred to as the Smith-Magenis syndrome (SMS).

Prevalence of SMS
Additional patients with SMS continue to be identified as a result of an increased awareness of this condition in the genetics community. The vast majority of these have been identified. in the last 5 years as result of improved cytogenetic techniques for high-resolution banding. While the number of reported cases remains small, this likely reflects under-ascertainment due a general lack of awareness of SMS and the need for cytogenetic study. Greenberg et al (1991) report a minimum prevalence of SMS of 1/25,000 births in Harris County, Texas over a 2 year period. Thus, SMS may be about as common as Prader-Willi syndrome, and more common than cri-du chat syndrome (del 5p16).

Clinical Description
The phenotype associated with SMS includes: dysmorphic facial features (brachycephaly, mid-face hypoplasia, prominent forehead, epicanthal folds, broad nasal bridge, ear anomalies, and prognathism), brachydactyly, short stature, hoarse, deep voice, history of infantile hypotonia and failure to thrive, self-hugging behaviors, speech delay with/without associated hearing loss, variable degrees of mental retardation (speech and language delay greater than motor delay), clinical signs of peripheral neuropathy, sleep disturbances and behavioral problems, including self-injurious behaviors. Several clinical findings appear to be age-dependent, including prominent forehead, prognathism, brachycephaly, and hoarse voice. Recent reports of high myopia, with/without retinal detachment, also suggest it is age-dependent (Finucane et al, 1993). Other less common findings include cleft lip and/or palate (7%); congenital heart defects (31%), seizures, hearing loss, and urinary tract anomalies (30%). The diagnosis of SMS is usually made by cytogenetic analysis.

Behavioral Aspects of SMS
Behavioral problems, some unique to SMS, are observed in more than two thirds of patients and represent a major management problem for both parents and professionals. Self-injurious behaviors include head banging, wrist biting, skin picking, onychotillomania (pulling out fingernails and toenails), and polyembolokoilamania (insertion of foreign bodies into body orifices). In general, SMS patients exhibit a relative insensitivity to pain and consequently, may cause injury to themselves by persistent picking/biting. Clinical signs or symptoms of peripheral sensory neuropathy (decreased deep tendon reflexes, decreased sensitivity to pain or temperature, pes cavus or planus) were demonstrated by 55% of 32 patients evaluated by Greenberg, et al (1991).
As expected with all children, age related differences in behavior of children with SMS have been observed (Haas-Givler, 1994, 1995) Typically the child with SMS demonstrates some degree of ongoing and severe behavioral problems at home and/or in the classroom. In addition to the self-injurious behaviors, problems with attention-seeking, explosive outbursts, and aggressive behaviors are frequently seen. Students with SMS tend to be adult-oriented, demanding an unusual amount of individualized attention from the teacher (and other adults); when this is denied, aggression toward others, tantrums, and self-injurious behavior frequently result. Children with SMS respond positively to consistency, structure and routine, especially with visual cues; changes in routine, be it at home or in the classroom can precipitate behavioral outbursts, tantrums and aggression.
There are also several positive attributes of behavior in SMS that should also be emphasized. They have engaging and endearing personalities (impish smile; self-hugging; good eye contact) and are very appreciative of attention. They enjoy interaction with adults, are eager to please, and are visual learners. Most exhibit early speech delays, yet with appropriate early intervention including sign language, they are very communicative (gestural, signing and verbally); they are able to learn and use all the names of fellow teachers and other students. Their fascination with electronics, including computers, VCR's, tape recorders, etc. is a positive "skill" that opens up new avenues for teaching using assisted technology.

Sleep Disturbance
Significant symptoms of sleep disturbance were also observed in 62% in SMS. The majority have frequent awakenings and diminished sleep cycles. More than half of SMS patients who underwent formal sleep evaluations (poly-somnography) had REM sleep abnormalities (reduced). The sleep disorder in SMS is particularly disturbing to parents, who frequently report that they have difficulty falling asleep and staying asleep themselves, due to the frequent awakenings of their SMS child during the night.
The most optimum arrangement for SMS patients to minimize self-injury and maximize sleep cycle is to "SMS-ize" the bedroom, by removing all small objects, toys, etc. from the room, insert a door peephole for parents to look in outside "locking mechanism; and "black-out" curtains for the windows. Independently, parents have reported that these changes provide them with assurance that their child will not wake and wander about and/or injure themselves if they awaken at 1-2 or 3 AM to Most SMS families have independently altered their child's

Education
Unfortunately, research into specific educational strategies and interventions beneficial to SMS has lagged behind current molecular understanding. In a previous issue of Spectrum, the official newsletter for PRISMS, the support group for parents and researchers interested in SMS, Dr. Elizabeth Dykens, reported on the intellectual strengths and weaknesses of a small number of individuals with SMS (1994). Children with SMS are very much adult-oriented, with a sometimes insatiable need for individual attention. This is a key personality feature of children with SMS and one that has important implications both at home and in the classroom. For the child with SMS, positive attention is clearly preferable, but in a pinch, negative attention may serve equally well in the quest for one-on-one adult interaction. Positive attention often encourages the child to seek more; withholding teacher attention often prompts negative behaviors, including verbal outbursts, tantrums, aggression toward peers, destruction of property, etc., which ultimately disrupt the classroom and result in "desired" attention.
Children with SMS are very sensitive to the emotions of others and benefit most from a calm, emotionally-neutral classroom atmosphere. They have difficulties making transitions from one activity to another and have a strong need for consistency in their daily routine. Unexpected changes in "routine" and/or emotional upset (or excitement) exhibited by the teacher or classmates often precipitate behavioral outbursts that can disrupt the learning process as well as the classroom, itself. Children with SMS are generally very responsive to affection, praise, and other positive emotions on the part of the teacher. In moderation, a teacher's positive emotional response can strongly motivate a child to do well, and many children with SMS are exceptionally eager to please. However, since they are also easily excitable, exaggerated positive expressions on the teacher's part may make the child overly excited.
Children with SMS are also inherently distractible and tend to do better in smaller, calmer, and more focused classroom settings. Rather than working together with their classmates, they seem to be in competition with them, seeing them as obstacles to gaining teacher attention. Ideally, children with SMS seem to do best when there are no more than five to seven other children in a classroom, with one teacher and one teacher's aide. With a class size above this ratio, the competition for teacher attention becomes greater, and the possibility of behavioral problems increases.
Although children with SMS have some degree of control over their behaviors, it is important to recognize that many of the negative behaviors seen in SMS have their origins in internally driven impulses. There is currently no universal treatment that works for all SMS patients. Current research efforts to identify effective treatment modalities are underway. While some medications may offer some or limited benefit to behavioral management (e.g. tegretol), others may cause greater problems. Until the we understand the underlying biochemistry affected in SMS, and have identified the gene(s) responsible for the condition, treatment will continue to be on an individualized basis.
We have noted, and Dr. Elisabeth Dykens at Yale has confirmed, that children with SMS seem to have difficulties in sequential processing, making counting, mathematical tasks and/or multi-step tasks difficult. They tend to be visual learners and can benefit greatly from the use of pictures, etc. to illustrate multi-step tasks, classroom schedules, etc. Use of assisted technology (computerized learning) offers an unique opportunity for SMS children, who have a special skill using the computer. Effective strategies in dealing with the SMS child in the classroom are suggested by Ms. Haas-Givler's article (1995) on educational strategies, currently in press.
Children with SMS often look for affirmation that they have completed a task correctly, even when they probably know that they have done so. Their need for positive approval throughout the day can result in a teacher spending a large amount of time confirming tasks which the SMS child; posting pictures on the wall of the different steps involved in a task provides visual reminders of what is expected.

Developmental/Cognitive Function
All individuals with SMS have some degree of mental impairment. Psychometric testing on SMS patients using a variety of test scales have yielded developmental or intelligence quotients between 20-77, with the majority falling between 50-60. Speech development is markedly delayed with expressive language is significantly lower than receptive language. The use of sign language as an adjunct to speech therapy has been shown to improve language development overall and probably helps decrease the frustration associated with expressive language problems. In fact, we hypothesize that an SMS patient's behavior may be related, in part, to frustration associated with expressive language delay.

Therapeutic Intervention
Most of the patients with SMS have been tried on a number of medications to control behavior. In the recent multi-disciplinary study of SMS conducted by Greenberg et al. (manuscript in preparation), the most common medications tried among 20 SMS patients in the study were: methylphenidate, pemoline and thioridazine. In most cases, the stimulant drugs were not particularity helpful in controlling behavior or increasing attention span. Thoridazine caused excessive sedation in some. Several SMS patients, both with and without seizures, tried on carbamazepine showed some improvement behaviorally; however, some showed only transient improvement. Adverse reactions to some medications have also been reported.