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Smith-Magenis Syndrome—A Developmental Disorder with Circadian Dysfunction
Abstract
Smith-Magenis syndrome (SMS) is a rare complex developmental disorder with multisystem involvement that is the result of a heterozygous interstitial deletion of the p11.2 band of chromosome 17. The deletion was first identified cytogenetically in the early 1980s in two males with multiple congenital anomalies (MCA) (1). This report was followed by a clinical series of 15 patients ranging in age from 3 months to 65 years that more fully delineated the clinical aspects of this MCA=mental retardation (MR) syndrome (2,3). Comprehensive clinical reviews published in the 1990s further expanded the phenotypic spectrum and variability of features that distinguish the physical, developmental, and neurobehavioral aspects of the syndrome (4-14).
... Table 4. Self injurious behaviors in Smith-Magenis syndrome [41] ...
... Individuals with Smith-Magenis syndrome present features of both central and peripheral nervous system dysfunction [1,29]. Cognitive functioning in Smith-Magenis syndrome ranges from borderline to profound mental retardation [41]. Epileptic seizures occur in 11-30% of individuals with Smith-Magenis syndrome [1] [3] [29]. ...
The Smith-Magenis syndrome is a rare, complex multisystemic disorder featuring, mental retardation and multiple congenital anomalies caused by a heterozygous interstitial deletion of chromosome 17p11.2. The phenotype of Smith-Magenis syndrome is characterized by a distinct pattern of features including infantile hypotonia, generalized complacency and lethargy in infancy, minor skeletal (brachycephaly, brachydactyly) and craniofacial features, ocular abnormalities, middle ear and laryngeal abnormalities including hoarse voice, as well as marked early expressive speech and language delays, psychomotor and growth retardation, and a 24-hour sleep disturbance. A striking neurobehavioral pattern of stereotypies, hyperactivity, polyembolokoilamania, onychotillomania, maladaptive and self-injurious and aggressive behavior is observed with increasing age. The diagnosis of Smith-Magenis syndrome is based upon the clinical recognition of a constellation of physical, developmental, and behavioral features in combination with a sleep disorder characterized by inverted circadian rhythm of melatonin secretion. Many of the features of Smith-Magenis syndrome are subtle in infancy and early childhood, and become more recognizable with advancing age. Infants are described as looking "cherubic" with a Down syndrome-like appearance, whereas with age the facial appearance is that of relative prognathism. Early diagnosis requires awareness of the often subtle clinical and neurobehavioral phenotype of the infant period. Speech delay with or without hearing loss is common. Most children are diagnosed in mid-childhood when the features of the disorder are most recognizable and striking. While improvements in cytogenetic analysis help to bring cases to clinical recognition at an earlier age, this review seeks to increase clinical awareness about Smith-Magenis syndrome by presenting the salient features observed at different ages including descriptions of the neurologic and behavioral features. Detailed review of the circadian rhythm disturbance unique to Smith-Magenis syndrome is presented. Suggestions for management of the behavioral and sleep difficulties are discussed in the context of the authors' personal experience in the setting of an ongoing Smith-Magenis syndrome natural history study.
... The severe sleep disorder seen in this population causes significant disruption in the lives of individuals with SMS and their families. Sleep for these patients is characterized by difficulty sleeping at night and resultant excessive daytime sleepiness [9][10][11][12][13]. Individuals with SMS have decreased total night sleep, lower sleep efficiency, earlier sleep onset, final sleep offset, and increased waking after sleep onset compared to healthy individuals of the same age [14]. ...
Purpose
To assess the efficacy of tasimelteon to improve sleep in Smith–Magenis syndrome (SMS).
Methods
A 9-week, double-blind, randomized, two-period crossover study was conducted at four US clinical centers. Genetically confirmed patients with SMS, aged 3 to 39, with sleep complaints participated in the study. Patients were assigned to treatment with tasimelteon or placebo in a 4-week crossover study with a 1-week washout between treatments. Eligible patients participated in an open-label study and were followed for >3 months.
Results
Improvement of sleep quality (DDSQ50) and total sleep time (DDTST50) on the worst 50% of nights were primary endpoints. Secondary measures included actigraphy and behavioral parameters. Over three years, 52 patients were screened, and 25 patients completed the randomized portion of the study. DDSQ50 significantly improved over placebo (0.4, p = 0.0139), and DDTST50 also improved (18.5 minutes, p = 0.0556). Average sleep quality (0.3, p = 0.0155) and actigraphy-based total sleep time (21.1 minutes, p = 0.0134) improved significantly, consistent with the primary outcomes. Patients treated for ≥90 days in the open-label study showed persistent efficacy. Adverse events were similar between placebo and tasimelteon.
Conclusion
Tasimelteon safely and effectively improved sleep in SMS.
... The incidence of SMS was initially estimated at 1:25,000 births [11]. However improvements in cytogenetic techniques and molecular analyses have allowed the diagnosis of most cases, leading to a current prevalence estimate of 1:15,000 [12]. eyes, broad nasal bridge, midface hypoplasia, micrognathia in infancy, relative prognathism with age, and everted, "tented" upper lip [13]. ...
Most cases of SMS are caused by a microdeletion on 17p11.2 that encompasses multiple genes, including the retinoic acid-induced 1, RAI1, gene. This deletion is observed in 90% of the cases, although in 10% of cases a point mutation in the RAI1 gene is observed [2, 4, 6, 20, 38]. SMS microdeletions are caused by irregularities in chromosomal recombination mediated by repeat elements referred to as Low copy number repeats (LCR). Already [39] identified three copies of an LCR as being responsible for the deletion on 17p11.2. These repeats (LCRs proximal, middle, and distal - SMS REPs) form substrates for inter- and intrachromosomal recombination. In 70% of SMS cases, unequal meiotic crossovers result in nonallelic homologous recombination between the proximal and distal SMS REPs and a deletion of approximately 3.7Mb. In the remaining 30%, deletions are due to alternate SMS REPs (distal x medial). Moreover, AT-rich repeats and Alu elements may act as homologous recombination substrates, and nonhomologous mechanisms can generate deletions of atypical deletions sizes [40-42].
SMS is suspected in individuals presenting distinctive facial features, a behavioral phenotype and sleep disturbance. Initial clinical suspicion of the disorder is confirmed by the presence of a microdeletion in the p11.2 region of chromosome 17 or a mutation in the RAI1 gene. The unique SMS behavioral phenotype including sleep disturbance, a hoarse voice, characteristic hands and feet, excellent long-term memory, good ability and focus with computers, self-injury scars and typical facial features are important clues to the diagnosis. Because SMS will rarely be the only possible clinical diagnosis, exams are key to diagnosis.
Yenidoğanlarda Serum 25-OH Vitamin D, Vitamin B12 ve Folat Düzeyleri İle İlişkili Faktörler
Tekirdağ Namık Kemal Üniversitesi Tıp Fakültesi, Çocuk Sağlığı ve Hastalıkları Anabilim Dalı, Neonatoloji Bilim Dalı
Giriş: Annedeki serum vitamin düzeyleri yanı sıra, yenidoğanlardaki düşük vitamin düzeyleri de önemli sağlık sorunlarına yol açabilmektedir. Rutin olarak yenidoğanlarda serum vitamin düzeylerinin taraması yapılmamaktadır. Tam da bu noktada çalışmada, düşük serum vitamin düzeyleri ile ilişkili öngörücü anlamlı faktörlerin saptanabilmesi ve düşük serum vitamin düzeylerine sahip riskli yenidoğanların hayatın çok daha erken dönemlerinde tespitinin yapılabilmesi amaçlandı.
Gereç-Yöntem: Geç preterm, term ve postterm toplam 108 yenidoğan çalışmaya dahil edildi. Anne yaşları, gebelik sayıları, yenidoğanların gebelik haftaları, doğum ağırlığı, boyu, baş çevresi, Apgar skorlarının, postnatal 24. saatteki serum 25-OH Vitamin D, Vitamin B12 ve folat düzeylerini öngörmedeki istatistiksel ilişkilerine bakıldı.
Bulgular: Tüm yenidoğanların postnatal 24. saatteki serum 25-OH Vitamin D, Vitamin B12 ve folat düzeyleri ortalaması sırasıyla, 11,5±7,9 (ng/ml), 327,8±249,7 (pg/ml), 16,9±4,9 (ng/ml) olarak saptandı. Yenidoğanların gebelik haftası ve doğum boyu ile postnatal 24. saatteki serum vitamin B12 düzeyleri arasında istatistiksel anlamlı bir pozitif korelasyon (sırasıyla, p
0,016, p 0,043) saptandı. Geç preterm ile term yenidoğanlar arasında 25-OH Vitamin D, Vitamin B12 ve folat düzeyleri ile istatistiksel olarak anlamlı bir ilişki bulunmadı. Ayrıca her üç vitamin düzeyleri düşüklüğü arasında da bir korelasyon yoktu.
Sonuç: Yenidoğanlarda klinik bulgu olmasa bile, düşük vitamin düzeylerinin öngörücü risk faktörlerinin araştırıldığı çalışmalar arttıkça, düşük vitamin düzeylerine sahip riskli yenidoğanları öngörerek hayatın çok erken döneminde vitamin düzeyleri açısından rutin taranmalarını sağlayabilecek ilişkili faktörler belirlenebilmesi önemli olacaktır.
Anahtar Kelimeler: 25-OH Vitamin D, Vitamin B12, Folat, Yenidoğan, Anne
Smith–Magenis syndrome (SMS) is a multisystem multiple congenital anomaly/intellectual disability disorder commonly caused by de novo interstitial deletion of chromosome 17p11.2. This deletion results in haploinsufficency for the gene retinoic acid‐induced 1 (RAI1), which is responsible for the major features of the syndrome. Heterozygous mutations of RAI1 also cause the Smith–Magenis syndrome phenotype in a small subset without deletions. The diagnosis is based on the clinical recognition of a unique and complex pattern of physical, developmental, and behavioral features, many of which are subtle in early childhood, becoming more distinctive with advancing age. There are characteristic craniofacial features, which appear to coarsen with age. Other common features include dental, minor skeletal, ocular, middle ear and laryngeal abnormalities, hoarse voice, marked early expressive speech, and language delays with or without hearing loss. Infantile hypotonia with failure‐to‐thrive and short stature are common in those with deletion. The degree of intellectual functioning is quite variable, and there is a striking neurobehavioral phenotype, including a chronic sleep disturbance associated with an inverted circadian rhythm of melatonin.
Smith-Magenis syndrome is a multisystem, multiple congenital anomaly/mental retardation syndrome caused by an interstitial deletion of chromosome 17p11.2. Many cases have been identified worldwide from a diversity of ethnic groups. The diagnosis is based on the clinical recognition of a unique and complex pattern of physical, developmental, and behavioral features, many of which are subtle in early childhood, becoming more distinctive with advancing age. There is a characteristic craniofacial appearance with rather close-set, deep-set eyes under heavy brows, a square jaw, and an unusual full, everted upper lip. Speech delay with or without hearing loss is common. Ocular abnormalities are frequently found and short stature with failure to thrive is often seen. There are variable levels of intellectual handicap and the neurobehavioral phenotype includes sleep disturbance with an inverted circadian rhythm of melatonin, self-injurious behaviors, stereotypies, and sensory integration disorders.
This study systematically assessed sensory processing in 34 children, aged 3-14 years, with Smith-Magenis syndrome (SMS) using the Sensory Profile Caregiver Questionnaire. Scores for the SMS cohort were significantly different from scores of the national sample of children with and without disabilities in all Sensory Profile categories and quadrants (p < .001). No main effects of age or gender were found, but an interaction effect of age by gender was found in Modulation of Sensory Input Affecting Emotional Responses, in which older females presented with the lowest scores. A significant decline over time was found in the Seeking pattern, reflecting increased vulnerability (p < .05). Nonsignificant trends suggest more vulnerabilities for older versus younger children, especially older females. The neurobehavioral phenotype in children with SMS is expanded by this description of sensory processing. How children with SMS experience and respond to everyday sensations informs multidisciplinary team decisions.
Smith-Magenis syndrome (SMS), the result of an interstitial deletion within chromosome 17p11.2, is a disorder that may include minor dysmorphic features, brachydactyly, short stature, hypotonia, speech delays, cognitive deficits, signs of peripheral neuropathy, scoliosis, and neurobehavioral problems including sleep disturbances and maladaptive repetitive and self-injurious behaviors. Physical and occupational therapists provide services for children who have the syndrome, whose genetic disorder is frequently not identified or diagnosed before 1 year of age. A comprehensive physical and occupational therapy evaluation was completed in nonidentical twins with one having SMS, using the Sensory Profile; Brief Assessment of Motor Function (BAMF); Peabody Developmental Motor Scales, Second Edition (PDMS-2); and Pediatric Evaluation of Disability Inventory (PEDI). This provides a framework for conducting assessments to enhance early detection and interdisciplinary management with this specialized population.
Smith-Magenis syndrome (SMS) is a disorder characterized by multiple congenital anomalies and behavior problems, including abnormal sleep patterns. It is most commonly due to a 3.5 Mb interstitial deletion of chromosome 17 band p11.2. Secretion of melatonin, a hormone produced by the pineal gland, is the body's signal for nighttime darkness. Published reports of 24-hr melatonin secretion patterns in two independent SMS cohorts (US and France) document an inverted endogenous melatonin pattern in virtually all cases (96%), suggesting that this finding is pathognomic for the syndrome. We report on a woman with SMS due to an atypical large proximal deletion ( approximately 6Mb; cen<->TNFRSFproteinB) of chromosome band (17)(p11.2p11.2) who presents with typical sleep disturbances but a normal pattern of melatonin secretion. We further describe a melatonin light suppression test in this patient. This is the second reported patient with a normal endogenous melatonin rhythm in SMS associated with an atypical large deletion. These two patients are significant because they suggest that the sleep disturbances in SMS cannot be solely attributed to the abnormal diurnal melatonin secretion versus the normal nocturnal pattern.
Smith-Magenis syndrome (SMS) is a complex neurobehavioral disorder caused by haploinsufficiency of the retinoic acid-induced 1 (RAI1) gene on chromosome 17p11.2. Diagnostic strategies include molecular identification of a 17p11.2 microdeletion encompassing RAI1 or a mutation in RAI1. G-banding and fluorescent in situ hybridization (FISH) are the classical methods used to detect the SMS deletions, while multiplex ligation-dependent probe amplification (MLPA) and real-time quantitative PCR are the newer, cost-effective, and high-throughput technologies. Most SMS features are due to RAI1 haploinsufficiency, while the variability and severity of the disorder are modified by other genes in the 17p11.2 region. The functional role for RAI1 is not completely understood, but it is likely involved in transcription, based on homology and preliminary studies. Management of SMS is primarily a multidisciplinary approach and involves treatment for sleep disturbance, speech and occupational therapies, minor medical interventions, and management of behaviors.