Smith-Magenis syndrome (SMS) is a rare, neurodevelopmental genetic disorder impacting multiple bodily systems, development, and behavior. It is categorized as a microdeletion syndrome, resulting from the loss of a small piece of genetic material from a chromosome. SMS affects an estimated 1 in 15,000 to 1 in 25,000 individuals worldwide. Due to its varied presentation, many cases may be undiagnosed or misdiagnosed. This condition requires lifelong, specialized support due to its unique physical and neurobehavioral challenges.
The Genetic Basis
The cause of SMS is a genetic change on chromosome 17, specifically at the short arm region 17p11.2. The most common cause (about 90% of cases) is a small interstitial deletion of this chromosomal segment. This deletion spans about 3.7 megabases and encompasses several genes.
The features of SMS are linked to the loss of the Retinoic Acid Induced 1 (\(RAI1\)) gene within this deleted region. About 10% of individuals have a pathogenic mutation in the \(RAI1\) gene itself, rather than the larger deletion. The \(RAI1\) gene is a transcriptional regulator that controls the expression of many other genes important for neurodevelopment, circadian rhythm, and metabolism.
In most instances, the genetic change is spontaneous and occurs de novo, meaning it is not inherited from the parents. This change happens during the formation of reproductive cells or in early fetal development. The functional loss of one copy of the \(RAI1\) gene, known as haploinsufficiency, is the molecular event responsible for the core features of the syndrome.
Physical Features and Developmental Profile
Individuals with SMS have recognizable physical characteristics that become more pronounced with age. Distinctive craniofacial features include a broad, square-shaped face, a prominent forehead, deep-set eyes, and a mouth that may turn downward. The middle of the face and nasal bridge often appear flattened, and dental abnormalities are common.
Other frequent physical concerns include skeletal abnormalities, such as scoliosis. Health issues can involve hearing loss, severe nearsightedness, and, less commonly, cardiac or renal defects. Infants often experience low muscle tone (hypotonia) and feeding difficulties, sometimes leading to lethargy in early life.
The developmental profile includes intellectual disability, typically categorized as mild to moderate. Developmental delays affect motor skills and speech and language development. Expressive language skills are often more delayed than receptive understanding. The full spectrum of symptoms often becomes clear only in later childhood.
Distinct Behavioral and Sleep Patterns
The defining aspects of SMS are pervasive behavioral and sleep disturbances. The behavioral phenotype includes a characteristic pattern of maladaptive behaviors. These include chronic attention-seeking, frequent temper tantrums, sudden mood shifts, aggression, and impulsivity.
Self-injurious behaviors are highly prevalent, often involving biting, hitting, head banging, and chronic skin-picking. Individuals frequently exhibit stereotypic behaviors, such as repetitive self-hugging. A unique behavior is “lick and flip,” which involves compulsively licking fingers and flipping pages. Polyembolokoilamania, the insertion of foreign objects into body orifices, is also associated with this syndrome.
The sleep disturbance is uniquely severe, caused by an inversion of the normal circadian rhythm of melatonin. Melatonin levels, which usually rise at night to induce sleep, are abnormally low at night and elevated during the day. This dysregulation results in severe insomnia, frequent nighttime waking, and very early morning awakening. This inverted sleep-wake cycle is a hallmark of the condition and contributes significantly to the behavioral issues.
Diagnosis and Ongoing Management
Diagnosis is initially suspected based on characteristic physical features, developmental delays, and distinct behavioral and sleep patterns. Confirmation requires specific genetic testing. Common diagnostic methods include array comparative genomic hybridization (aCGH) or Fluorescence In Situ Hybridization (FISH) to detect the 17p11.2 microdeletion. If the deletion is absent, sequencing of the \(RAI1\) gene identifies a pathogenic mutation.
There is currently no cure for SMS, so management focuses on symptomatic relief and supportive care through a multidisciplinary approach. Pharmacological interventions are often necessary, especially for regulating severe sleep disturbance. Melatonin supplements, given at specific times, are used to attempt to reset the inverted circadian rhythm.
Behavioral therapy helps address challenging behaviors, aggression, and self-injury. Comprehensive support also involves speech-language, physical, and occupational therapies to address developmental delays and sensory integration issues. Specialized educational plans and long-term supportive care are required to help individuals maximize their potential.