Clinical Diagnosis

Smith-Magenis syndrome (SMS) is suspected in individuals who present with a complex pattern of findings including the following:

• A subtly distinctive facial appearance (see Clinical Description) that becomes more evident with age (see Figures 1, 2, 3)

• Mild-to-moderate infantile hypotonia with feeding difficulties and failure to thrive

• Minor skeletal anomalies

• Short stature

• Brachydactyly

• Ophthalmologic abnormalities

• Otolaryngologic abnormalities

• Early speech delays with or without associated hearing loss

• Peripheral neuropathy

• Some level of cognitive impairment and developmental delay

• A distinct neurobehavioral phenotype that includes sleep disturbance and stereotypic and maladaptive behaviors [Finucane et al 1994, Dykens & Smith 1998, Smith et al 1998a, Finucane et al 2001]. Sleep disturbance is chronic and associated with an abnormal diurnal circadian rhythm of melatonin [Potocki et al 2000b, De Leersnyder et al 2001].

Figure

Figure 1. Infants with SMS. Nine-month-old female (left) and 30-month-old male (right). Note brachycephaly, broad forehead, upslanting palpebral fissures, short upturned nose, and characteristic down-turned “tent” shaped upper lip with (more...)

Figure

Figure 2. Early school-age SMS showing 4-year-old male (left) and 5-year-old female (right); the female is also pictured at age 15 years in Fig 3. Note broad forehead, deep-set eyes, midface hypoplasia.

Figure

Figure 3. Adolescent females with Smith-Magenis syndrome caused by RAI1 mutation (left) and deletion 17p11.2 (right). Note short philtrum with relative prognathism resulting from midface hypoplasia that persists with age; down-turned upper lip is more (more...)

Renal anomalies and cleft palate occur in fewer than 25% of individuals.

The phenotypic features can be subtle in infancy and early childhood, frequently delaying diagnosis until school age when the characteristic facial appearance and behavioral phenotype may be more readily apparent.

Testing

Cytogenetic testing. Diagnosis of SMS requires detection of an interstitial deletion of 17p11.2 by G-banded cytogenetic analysis and/or by FISH analysis. Probes for FISH testing must include RAI1. A visible interstitial deletion of chromosome 17p11.2 can be detected in all individuals with the common deletion by a routine G-banded analysis provided the resolution is adequate (≥ 550 band). Studies indicate that approximately 90% of individuals with SMS have a FISH-detectable deletion, with approximately 70% having the common approximately 3.5-Mb deletion [Potocki et al 2003, Vlangos et al 2003].

Note: It is not uncommon for the deletion to be overlooked particularly when the indication for the cytogenetic study is other than SMS. Thus, repeat cytogenetic study including FISH is indicated for individuals with prior "normal" routine cytogenetic analysis in whom a diagnosis of SMS is strongly suspected.

Molecular Genetic Testing

Gene. RAI1 is the only gene in which mutation is known to account for the majority of features in Smith-Magenis syndrome (SMS) [Slager et al 2003, Bi et al 2004, Girirajan et al 2005].

Clinical testing

• FISH. Approximately 70% of individuals with SMS who have a 17p11.2 deletion have a common deletion of approximately 3.5 Mb. Other affected individuals have atypical (smaller or larger) deletions involving 17p11.2 [Potocki et al 2003, Vlangos et al 2003]. All 17p11.2 deletions associated with SMS include a deletion of RAI1 [Vlangos et al 2005]. Molecular cytogenetic analysis by FISH using a DNA probe specific for the SMS critical region (D17S258 or other probe containing RAI1) detects approximately 95% of 17p11.2 deletions. Such testing is required in cases of submicroscopic deletions and/or to resolve equivocal cases.
  
  Note: Not all commercially available FISH probes contain RAI1 [Vlangos et al 2005].

• Sequence analysis. Sequence analysis (particularly of exon 3, in which all mutations have been found to date) detects RAI1 mutations in individuals with SMS when cytogenetic and FISH studies are negative for the 17p11.2 deletion [Slager et al 2003, Bi et al 2004, Girirajan et al 2005].

• Deletion/duplication analysis. Available clinical testing for deletion/duplication analysis of RAI1 includes aGH, real-time PCR, and MLPA [Truong et al 2008].
  
  Note: Recent availability of aGH is likely to lead to increased diagnostic detection of previously unsuspected cases; for example, between 2004 and April 2008 the Signature Chip^® identified 66 individuals with deletion 17p11.2 who were originally referred for study because of “developmental delay” [Shaffer, personal communication].

Table 1. Summary of Molecular Genetic Testing Used in Smith-Magenis Syndrome

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
RAI1	FISH 2	Deletion 17p11.2 involving RAI1 3	~90%	Clinical
	Sequence analysis	Sequence variants 4	5%-10%
	Deletion/ duplication analysis 5	Deletions involving RAI1 3	~90%

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

Note: A few individuals with clinical features of SMS but without confirmed deletions and/or RAI1 mutations may represent an SMS-like syndrome yet to be defined.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. FISH probe that contains RAI1 or D17S258

3. Extent of deletion detected may vary by method and by laboratory.

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband

1.

Cytogenetic analysis at greater than 550-band resolution or deletion/duplication analysis specific for RAI1

2.

If cytogenetic testing is normal, FISH testing; the probe used must contain RAI1 or D17S258 [Vlangos et al 2005]. Some commercial probes used in the past that did not contain RAI1 or D17S258 may have given a false-negative result.

3.

If FISH testing or deletion/duplication analysis (RAI1 or D17S258 probe) does not reveal a deletion, sequencing of RAI1 should be considered.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing deletion or mutation in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Persons with larger deletions extending distally to include PMP22 are also at risk for hereditary neuropathy with liability to pressure palsies (HNPP).

Persons with duplication 17p11.2 syndrome (Potocki-Lupski syndrome) harbor the recombination reciprocal of the SMS deletion and differ phenotypically and behaviorally from those with SMS [Potocki et al 2000a, Potocki et al 2007].

Natural History

Smith-Magenis syndrome (SMS) has a clinically recognizable phenotype that includes physical, developmental, and behavioral features (Table 2). Males and females are affected equally. The facial appearance is characterized by a broad square-shaped face, brachycephaly, prominent forehead, synophrys, mildly upslanting palpebral fissures, deep-set eyes, broad nasal bridge, midfacial hypoplasia, short, full-tipped nose with reduced nasal height, micrognathia in infancy changing to relative prognathia with age, and a distinct appearance of the mouth, with fleshy everted upper lip with a "tented" appearance.

With progressing age, the facial appearance becomes more distinctive and coarse, with persisting midfacial hypoplasia, relative prognathism, and heavy brows with a "pugilistic" appearance. An increased frequency of dental anomalies, specifically tooth agenesis (especially premolars) and taurodontism, was recently reported [Tomona et al 2006].

SMS has a wide degree of variability in cognitive and adaptive functioning, with the majority of individuals with SMS functioning in the mild-to-moderate range of intellectual disability.

The behavioral phenotype, which includes sleep disturbance, stereotypies, and maladaptive and self-injurious behaviors, is generally not recognized until age 18 months or older and continues to change throughout early childhood to adulthood [Dykens & Smith 1998, Smith et al 1998a, Sarimski 2004, Gropman et al 2006]. The sleep disturbance is characterized by fragmented and shortened sleep cycles with frequent nocturnal and early morning awakenings and excessive daytime sleepiness [Greenberg et al 1996, Smith et al 1998b, Potocki et al 2000b, De Leersnyder et al 2001, Smith & Duncan 2005]. Fragmented sleep with reduced total sleep time has been documented as early as age six months [Duncan et al 2003, Gropman et al 2006] and remains a chronic issue into adulthood. Actigraphy-based sleep estimates document developmental differences in nocturnal arousal patterns by age and time of night [Gropman et al 2007].

The abnormal diurnal (inverted) circadian rhythm of melatonin appears pathognomic in SMS; it is documented in 95% (26/28) of deletion cases studied to date [Potocki et al 2000b, De Leersnyder et al 2001, Boudreau et al 2009]. New data [Boudreau et al 2009] suggest that the sleep disturbance cannot be caused solely by aberrant melatonin synthesis and/or degradation as previously suggested [Potocki et al 2000b, De Leersnyder et al 2001].

Genotype-Phenotype Correlations

Parental origin of the 17p deletion has not been documented to affect the phenotype, suggesting that imprinting does not play a role in the expression of the typical SMS phenotype.

Individuals so far reported with RAI1 mutations are obese, do not exhibit short stature, and do not have organ system involvement [Slager et al 2003, Bi et al 2004, Girirajan et al 2005]. All other features typically associated with SMS are seen in individuals with mutations in RAI1. The effects of possible modifier genes within 17p11.2 are not known.

Prevalence

The birth incidence is estimated at 1:25,000 births [Greenberg et al 1991]; the actual prevalence may be closer to 1:15,000 [Smith et al 2005]. The vast majority of individuals have been identified in the last five to ten years as a result of improved cytogenetic techniques.

The syndrome has been identified worldwide in all ethnic groups.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Smith-Magenis syndrome (SMS), the following evaluations are recommended:

• Complete review of systems at the time of diagnosis

• Physical and neurologic examination

• Renal ultrasound examination to evaluate for possible renal/urologic anomalies (~20% of individuals with SMS), including urologic workup if a history of frequent urinary tract infections exists

• Echocardiogram to evaluate for possible cardiac anomalies (<45% of individuals with SMS); follow-up depending on the severity of any cardiac anomaly identified

• Spine radiographs to evaluate for possible vertebral anomalies and scoliosis (~60%)

• Routine blood chemistries, qualitative immunoglobulins, fasting lipid profile (evaluation for hypercholesterolemia), and thyroid function studies

• Ophthalmologic evaluation with attention to evidence of strabismus, microcornea, iris anomalies, and refractive error

• Comprehensive speech/language pathology evaluation

• Assessment of caloric intake, signs and symptoms of gastroesophageal reflux disease (GERD), swallowing abilities, and oral motor skills with referral as warranted for full diagnostic evaluation

• Otolaryngologic evaluation to assess ear, nose, and throat problems, with specific attention to ear physiology and palatal abnormalities (clefting, velopharyngeal insufficiency)

• Audiologic evaluation at regular intervals to monitor for conductive and/or sensorineural hearing loss

• Multidisciplinary developmental evaluation, including assessment of motor, speech, language, personal-social, general cognitive, and vocational skills

• Early evaluation by physical and/or occupational therapists

• Sleep history with particular attention to sleep/wake schedules and respiratory function. Sleep diaries may prove helpful in documenting sleep/wake schedules. Evidence of sleep-disordered breathing warrants a polysomnogram (overnight sleep study) to evaluate for obstructive sleep apnea.

• EEG in individuals who have clinical seizures to guide the choice of antiepileptic agents. For those without overt seizures, EEG may be helpful to evaluate for possible subclinical events in which treatment may improve attention and/or behavior; a change in behavior or attention warrants reevaluation.

• Neuroimaging (MRI or CT scan) in accordance with findings such as seizures and/or motor asymmetry

• In individuals with SMS documented to have larger deletions extending into 17p12:

  • Specific screening for adrenal function

  • Detailed assessment and attention to peripheral neurologic function in individuals with SMS with large deletions involving PMP22, which is associated with hereditary neuropathy with liability to pressure palsy (HNPP)

• Assessment of family support and psychosocial and emotional needs to assist in designing family interventions

Treatment of Manifestations

The following are appropriate:

• Ongoing pediatric care with regular immunizations

• From early infancy, referrals for early childhood intervention programs, followed by ongoing special education programs and vocational training in later years

• Therapies including speech/language, physical, occupational, and especially sensory integration:

  • During early childhood, speech/language pathology services should initially focus on identifying and treating swallowing and feeding problems as well as optimizing oral sensorimotor development.

  • Therapeutic goals of increasing sensory input, fostering movement of the articulators, increasing oral motor endurance, and decreasing hypersensitivity are needed to develop skills related to swallowing and speech production.

  • The use of sign language and total communication programs as adjuncts to traditional speech/language therapy is felt to improve communication skills and also to have a positive impact on behavior. The ability to develop expressive language appears dependent on the early use of sign language and intervention by speech/language pathologists.

• Use of psychotropic medication to increase attention and/or decrease hyperactivity (No single regimen shows consistent efficacy.)

• Behavioral therapies including special education techniques that emphasize individualized instruction, structure, and routine to help minimize behavioral outbursts in the school setting

• Therapeutic management of the sleep disorder. Sleep management in SMS remains a challenge for physicians and parents. No well-controlled treatment trials have been reported:

  • Early anecdotal reports of therapeutic benefit from melatonin remain encouraging. Dosages of 2.5-5.0 mg (6 mg maximum) taken at bedtime have been tried, providing general improvement of sleep without reports of major adverse reactions. However, melatonin dispensed over the counter is not regulated by the FDA; thus, dosages may not be exact. No early and controlled melatonin treatment trials have been conducted. A monitored trial of four to six weeks on melatonin (1-5 mg) may be worth considering in affected individuals with major sleep disturbance.

  • A single uncontrolled study of nine individuals with SMS treated with oral ß-1-adrenergic antagonists (acebutolol 10 mg/kg) reported suppression of daytime melatonin peaks and subjectively improved behavior [De Leersnyder et al 2001]. This treatment, however, did not restore nocturnal plasma concentration of melatonin.

  • A second uncontrolled trial by the same group [De Leersnyder et al 2003] combined the daytime dose of acebutolol with an evening oral dose of melatonin (6 mg at 8pm) and found that nocturnal plasma concentration of melatonin was restored and nighttime sleep improved with disappearance of nocturnal awakenings. Parents also reported subjective improvement in daytime behaviors with increased concentration. Contraindications to the use of ß-1-adrenergic antagonists include asthma, pulmonary problems, cardiovascular disease, and diabetes mellitus.

  • Prior to beginning any trial, the child's medical status and baseline sleep pattern must be considered.

• Enclosed bed system for containment during sleep

• Respite care and family psychosocial support to help assure the optimal environment for the affected individual

• Monitoring of hypercholesterolemia (recognized in >50% of individuals with SMS); treatment with diet or medication as indicated

• Treatment with corrective lenses as indicated by ophthalmologic abnormalities

• Treatment of recurrent otitis media with tympanostomy tubes as needed

• Auditory amplification if hearing loss is identified

• Management of seizures in accordance with standard practice

• Treatment of cardiac and renal anomalies and scoliosis in accordance with standard medical care. While growth hormone treatment has been reported [Itoh et al 2004, Spadoni et al 2004], controlled studies have not evaluated its effectiveness.

Surveillance

Recommended annually:

• Multidisciplinary team evaluation (including physical, occupational, and speech therapy evaluations and pediatric assessment) to assist in development of an individualized educational program (IEP). Periodic neurodevelopmental assessments and/or developmental/behavioral pediatric consultation can be an important adjunct to the team evaluation.

• Thyroid function

• Fasting lipid profile

• Routine urinalysis

• Monitoring for scoliosis

• Ophthalmologic evaluation

• Otolaryngologic follow-up for assessment and management of otitis media and other sinus abnormalities

• Audiologic evaluation to monitor for conductive or sensorineural hearing loss annually or as clinically indicated

Agents/Circumstances to Avoid

In at least one case, a teenage female with SMS was documented to have a serious adverse event taking Strattera^® (atomoxetine hydrochloride) with extreme escalation of behaviors and aggression leading to hospitalization. Significant changes in her sleep pattern were also documented. Care should be taken to track sleep parameters and behavior with this medication.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Registries

Contact information for voluntary patient registries is provided by GeneReviews staff.

National Institutes of Health (NIH) SMS Research Registry and Tissue Bank
Phone: 301-435-5475
Fax: 301-496-7184
Email: acmsmith@mail.nih.gov
Web: www.prisms.org

Other

Pharmacologic intervention should be considered on an individual basis with recognition that some medications may exacerbate sleep or behavioral problems and may cause weight gain.

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Smith-Magenis syndrome (SMS) is caused by deletion or mutation of RAI1 on chromosome 17p11.2.

Risk to Family Members

Parents of a proband

• Virtually all cases of SMS occur de novo. There is no evidence to suggest an obvious parental age contribution for the deletion.

• One case reported by Zori et al [1993] identified maternal mosaicism for del(17)(p11.2). Other cases of parental mosaicism are known but not reported [Smith et al 2006].

• Complex familial chromosomal rearrangements leading to del(17)(p11.2) and SMS are rare, but have been reported [Zori et al 1993, Yang et al 1997, Park et al 1998]. Consequently, chromosome analysis of the parents should be performed for all newly diagnosed individuals.

Sibs of a proband

• The risk to sibs depends on the results of parental chromosome analysis.

• If parental chromosome analysis is normal, the risk to sibs of the proband is likely less than 1% (recurrence risk attributable to the possibility of germline mosaicism in a parent).

• If a parent has a balanced structural chromosome rearrangement, the risk to sibs is increased and is dependent on the specific chromosome rearrangement and the possibility of other variables.

Offspring of a proband

• No instances of individuals with SMS having an affected child have been reported.

• Theoretically, the offspring of an individual with SMS are at a 50% risk of having SMS.

• Fertility issues in SMS remain unstudied.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent has a chromosome abnormality, his or her family members are at risk and can be offered chromosome analysis and FISH.

Carrier Detection

If a parent of the proband has a balanced chromosome rearrangement, at-risk family members can be tested by chromosome analysis and FISH.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults from families in which a chromosome rearrangement has been identified.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

High-risk pregnancies. Because SMS usually occurs as the result of a de novo deletion of 17p11.2, virtually all individuals with SMS represent a simplex case (i.e., a single occurrence in a family). In the rare instance of a complex familial chromosomal rearrangement, prenatal testing is available for pregnancies at-risk using a combination of routine cytogenetic studies and FISH on fetal cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or amniocentesis usually performed at approximately 15 to 18 weeks' gestation. Note: It is essential to include FISH studies when performing prenatal diagnosis.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Low-risk pregnancies. Unsuspected prenatal detection of del(17)(p11.2) has been reported among women undergoing amniocentesis for other reasons. At least two cases have been detected prenatally following amniocentesis performed because of low maternal serum AFP (MSAFP) on routine screening [Thomas et al 2000, personal observation].

Preimplantation genetic diagnosis (PGD). Preimplantation genetic diagnosis may be available for families in which the disease-causing deletion or mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetics Pathogenesis

Smith-Magenis syndrome is a contiguous gene deletion syndrome. A common deletion interval spanning approximately 3.5 Mb is identified in approximately 70% of individuals [Potocki et al 2003, Vlangos et al 2003]. The SMS critical region maps to 17p11.2 and spans fewer than 650 kb [Schoumans et al 2005, Vlangos et al 2005].

Normal allelic variants. The gene has six exons. See Table 3.

Pathologic allelic variants. Dominant mutations in RAI1 have been identified in individuals with the SMS phenotype who do not have a detectable 17p11.2 deletion [Slager et al 2003, Bi et al 2004, Girirajan et al 2005]. See Table 4.

Normal gene product. The normal protein is thought to function in transcriptional regulation [Bi et al 2004]; however, additional studies are required to more fully assess protein function in the cell.

Abnormal gene product. The mechanisms by which the mutations in RAI1 affect gene/protein function are not known. The mechanism by which RAI1 is thought to result in disease phenotype is haploinsufficiency; thus it is assumed that intragenic mutations result in a nonfunctional protein product.

Literature Cited

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Suggested Reading

1. Elsea SH, Girirajan S. Smith-Magenis syndrome. Eur J Hum Genet. 2008;16:412–21. [PubMed: 18231123]
2. Williams SR, Girirajan S, Tegay D, Nowak NJ, Hatchwell E, Elsea SH. Array comparative genomic hybridization of 52 subjects with a Smith-Magenis-like phenotype: identification of dosage-sensitive loci also associated with schizophrenia, autism, and developmental delay. J Med Genet. 2009;47:223–9. [PubMed: 19752160]

Author Notes

The authors of the Smith-Magenis Syndrome GeneReview are members of the PRISMS Professional Advisory Board.

Author History

Judith E Allanson, MD; Children’s Hospital of Eastern Ottawa (2001-2009)
Albert J Allen, MD, PhD; Eli Lilly Laboratories, Inc (2001-2005)
Kerry Boyd, MD, FRCP(C) (2009-present)
Elisabeth Dykens, PhD; University of California Los Angeles (2001-2005)
Sarah H Elsea, PhD, FACMG (2001-present)
Brenda M Finucane, MS, CGC (2001-present)
Andrea Gropman, MD, FAAP, FACMG (2005-present)
Barbara Haas-Givler, MEd (2005-present)
Kyle P Johnson, MD (2004-present)
James R Lupski, MD, PhD, FAAP, FACMG, FAAAS (2001-present)
Ellen Magenis, MD, FAAP, FACMG (2001-present)
Lorraine Potocki, MD, FACMG (2001-present)
Ann CM Smith, MA, DSc (hon), CGC (2001-present)
Beth Solomon, MS (2001-present)

Revision History

• 7 January 2010 (me) Comprehensive update posted live

• 11 August 2006 (me) Comprehensive update posted to live Web site

• 26 August 2005 (cd) Revision: sequence analysis of RAI1 clinically available

• 15 March 2004 (me) Comprehensive update posted to live Web site

• 15 January 2002 (as) Author revisions

• 22 October 2001 (me) Review posted to live Web site

• 23 May 2001 (as) Original submission