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Smith-Magenis syndrome
Also known as 17p11.2 deletion · SMS
Smith-Magenis syndrome is a genetic condition affecting multiple body systems, leading to developmental delay, intellectual disability, and characteristic behavioural patterns. It is a rare disorder, often diagnosed in childhood.
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Overview
Smith-Magenis syndrome (SMS) is a rare genetic condition that affects many parts of the body. It is mainly characterised by developmental delay, intellectual disability, distinctive facial features, sleep disturbances, and a range of behavioural challenges [PMID:31971775]. Most individuals with SMS have problems with speech and language development and may experience difficulties with learning. The condition is named after Ann Smith, a genetic counsellor, and R. Ellen Magenis, a clinical geneticist, who first described it in 1986.
SMS is typically caused by a small missing piece of genetic material (a microdeletion) on chromosome 17, specifically at region 17p11.2. Less commonly, SMS can be caused by a change in a single gene called RAI1, located within this deleted region [PMID:20301789]. The exact prevalence of SMS is not well established, but estimates suggest it affects between 1 in 15,000 and 1 in 25,000 individuals in the general population.
Symptoms & clinical features
The symptoms of Smith-Magenis syndrome can vary significantly among affected individuals, though some features are commonly observed. Developmental delays are almost always present, often becoming apparent in infancy, and can include delays in reaching motor milestones like sitting and walking, as well as significant delays in speech and language acquisition. Most individuals with SMS will have some degree of intellectual disability, ranging from mild to moderate.
Behavioural characteristics are a key feature of SMS. These often include self-injurious behaviours such as head banging, hand biting, and skin picking. Other common behavioural traits are temper tantrums, hyperactivity, impulsivity, and obsessive-compulsive behaviours. Sleep disturbances are also very typical, with an inverted sleep-wake cycle being a common pattern, meaning individuals may be sleepy during the day and awake at night [PMID:31971775]. Distinctive facial features, though subtle in infancy, often become more apparent with age. These can include a broad, square-shaped face, deep-set eyes, a prominent forehead, and a full, upturned nose.
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Affected organs
Smith-Magenis syndrome affects various organ systems, with the central nervous system being prominently involved. This leads to the characteristic developmental delays, intellectual disability, and complex behavioural profile. The brain's development and function are impacted, which contributes to learning difficulties and specific challenges with executive functions.
Skeletal abnormalities can include short stature, curvature of the spine (scoliosis), and issues with the hands and feet. Eye problems, such as strabismus (crossed eyes) and sensitivity to light, are also common. Hearing impairment can occur, ranging from mild to severe, and may require interventions. Additionally, some individuals with SMS may experience heart defects, kidney problems, or issues with digestion and feeding in infancy.
Risks & severity
The severity of Smith-Magenis syndrome can vary from person to person, even within the same family if the condition is caused by a de novo (new) genetic change. While most individuals experience some degree of developmental delay and intellectual disability, the extent of these challenges can differ. Behavioural issues are a significant aspect of SMS and can have a substantial impact on daily life; these behaviours often become more challenging with age.
Individuals with SMS have an increased risk of certain medical issues, including hearing and vision problems, sleep disturbances, and sometimes heart or kidney abnormalities. Regular medical monitoring is important to detect and manage these potential complications. The prognosis for individuals with SMS largely depends on the specific range and severity of their symptoms and the support systems in place. With appropriate medical care, educational support, and behavioural interventions, individuals can often achieve significant developmental milestones and improve their quality of life.
Genetic causes
Smith-Magenis syndrome is predominantly caused by a microdeletion on the short arm of chromosome 17, specifically at band 17p11.2 [PMID:20301789]. This deletion means that a small piece of genetic material, containing several genes, is missing. The most important gene within this deleted region for the features of SMS is RAI1 (retinoic acid induced 1).
The RAI1 gene provides instructions for making a protein that acts as a transcription factor. Transcription factors are proteins that help control the activity of other genes. The RAI1 protein is highly active in neurons (nerve cells) in the brain and plays a crucial role in regulating the expression of many other genes involved in brain development, as well as the formation of the skull and facial bones. When the RAI1 gene is missing or contains a pathogenic variant, it disrupts this regulatory function, leading to the characteristic features of Smith-Magenis syndrome [PMID:31971775]. In a smaller number of cases, SMS is caused by a pathogenic variant (a change) directly within the RAI1 gene, rather than a larger deletion.
- RAI1 retinoic acid induced 1The RAI1 gene provides instructions for a protein that acts as a transcription factor, playing a critical role in brain development and regulating circadian rhythms.
Inheritance pattern
Smith-Magenis syndrome follows an autosomal dominant inheritance pattern. This means that a person only needs one altered copy of the genetic material (either a microdeletion on chromosome 17 or a pathogenic variant in the RAI1 gene) to develop the condition. In most cases, the genetic change causing SMS occurs de novo, meaning it arises spontaneously during the formation of the egg or sperm, or very early in embryonic development. This implies that the genetic change is not inherited from either parent.
When SMS is caused by a de novo event, the parents typically do not have the condition and the recurrence risk for future children is generally low, though genetic counselling is recommended to discuss specific family risks. If a parent has SMS, there is a 50% chance with each pregnancy that their child will inherit the condition. Pre-implantation genetic diagnosis (PGD) or prenatal diagnosis may be options for families with an affected parent.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
The diagnosis of Smith-Magenis syndrome is initially suspected based on a combination of characteristic clinical features, including developmental delay, intellectual disability, distinctive facial features, and specific behavioural patterns. However, a definitive diagnosis requires genetic testing.
Genetic testing for SMS typically involves a chromosomal microarray analysis (CMA), which can detect the characteristic microdeletion on chromosome 17p11.2. If CMA is normal but clinical suspicion remains high, further testing such as sequencing of the RAI1 gene can be performed to look for pathogenic variants within the gene itself. In the UK, such genetic tests are typically initiated by a clinical geneticist, paediatrician, or neurologist, and fall under specific NHS Genomic Medicine Service (GMS) 'R-codes' for diagnostic testing when SMS is suspected. Referral to a clinical genetics service is the usual pathway for diagnostic confirmation.
Management & lifestyle
Management of Smith-Magenis syndrome is multi-faceted and focuses on addressing the individual's specific symptoms and needs. There is no cure for SMS, so treatment aims to manage symptoms, support development, and improve quality of life. This typically involves a coordinated approach from a multidisciplinary team of healthcare professionals.
Early intervention therapies are crucial for developmental delays and often include speech and language therapy, occupational therapy, and physical therapy. Behavioural interventions are essential to help manage challenging behaviours and can involve strategies to reduce self-injury and improve social skills. Sleep disturbances are commonly managed with behavioural techniques and, in some cases, medication under specialist guidance. Regular medical surveillance is important to monitor for potential complications affecting hearing, vision, heart, and kidney function, as well as spinal issues. Educational support plans, tailored to the individual's learning needs, are also a key component of management.
UK care pathway
In the UK, individuals suspected of having Smith-Magenis syndrome are typically referred to an NHS clinical genetics service. This service can arrange for appropriate genetic testing, such as chromosomal microarray or targeted gene sequencing, which align with the NHS Genomic Medicine Service (GMS) testing directory and associated R-codes. Following diagnosis, individuals and their families will have access to genetic counsellors who provide information, support, and discuss inheritance patterns and recurrence risks. Care is generally coordinated through a paediatrician, with referrals to various specialist teams as needed, including neurologists, developmental paediatricians, speech and language therapists, occupational therapists, and behavioural psychologists.
Frequently asked questions
What causes Smith-Magenis syndrome?
Smith-Magenis syndrome is usually caused by a small missing piece (microdeletion) on chromosome 17. Less commonly, it is caused by a pathogenic change in a specific gene called RAI1, located within that deleted region. These genetic changes disrupt normal development.
Is Smith-Magenis syndrome inherited?
In most cases, the genetic change causing Smith-Magenis syndrome occurs spontaneously (de novo) and is not inherited from a parent. However, once an individual has SMS, there is a 50% chance with each pregnancy that their child will inherit the condition, as it follows an autosomal dominant inheritance pattern.
What are the common behavioural issues in SMS?
Individuals with SMS often experience a range of behavioural challenges, including self-injurious behaviours (like head banging or hand biting), hyperactivity, impulsivity, temper tantrums, and obsessive-compulsive traits. Sleep disturbances with an inverted sleep-wake cycle are also very typical.
How is Smith-Magenis syndrome diagnosed?
Diagnosis is confirmed through genetic testing, usually a chromosomal microarray analysis (CMA) to detect the characteristic microdeletion on chromosome 17. If CMA is normal but SMS is still suspected, specific testing for pathogenic variants in the RAI1 gene may be performed. A clinical genetics service typically arranges these tests.
What kind of support is available for individuals with SMS?
Management for SMS is multidisciplinary, involving various therapies such as speech, occupational, and physical therapy. Behavioural interventions are crucial for managing challenging behaviours. Educational support, medical monitoring for associated conditions, and genetic counselling are also vital components of care. Care in the UK is coordinated through NHS clinical genetics services and paediatric teams.
References
- Huisman S, Mulder P, Kuijk J. Self-injurious behavior. Neuroscience and biobehavioral reviews. 2018. PMID: 28694012
- Elsea SH, Girirajan S. Smith-Magenis syndrome. European journal of human genetics : EJHG. 2008. PMID: 18231123
- De Leersnyder H. Smith-Magenis syndrome. Handbook of clinical neurology. 2013. PMID: 23622179
- Rinaldi B, Villa R, Sironi A. Smith-Magenis Syndrome-Clinical Review, Biological Background and Related Disorders. Genes. 2022. PMID: 35205380
- Adam MP, Bick S, Mirzaa GM. Smith-Magenis Syndrome. 1993. PMID: 20301487
- Gropman AL, Duncan WC, Smith AC. Neurologic and developmental features of the Smith-Magenis syndrome (del 17p11.2). Pediatric neurology. 2006. PMID: 16647992
- Linders CC, van Eeghen AM, Zinkstok JR. Intellectual and Behavioral Phenotypes of Smith-Magenis Syndrome: Comparisons between Individuals with a 17p11.2 Deletion and Pathogenic RAI1 Variant. Genes. 2023. PMID: 37628566
- Finucane BM, Jaeger ER. Smith-Magenis syndrome. Ophthalmology. 1997. PMID: 9160013