Smith-Magenis syndrome: what is it, symptoms, treatment, prognosis

What is Smith-Magenis Syndrome?

Smith-Magenis Syndrome (CCM) is a complex developmental disorder that affects multiple organ systems in the body. The disorder is characterized by a set of abnormalities that are present at birth (congenital) as well as behavioral and cognitive problems. Common symptoms include facial features, skeletal malformations, varying degrees of mental retardation, delayed speech and motor skills, sleep disturbances, and self-injurious behavior aimed at attracting attention. The specific symptoms present in each patient can vary greatly from one person to the next. Approximately 90% of cases of CCM are caused by the absence or removal of part of a chromosome (monosomal). This deletion of a portion on chromosome 17p11.2 turns on a gene believed to play a major role in the development of the disease. In other cases, the removed material on chromosome 17 is absent; these cases are caused by mutations in the gene 

RAI1. Other genes in the distant segment may also play a role in the variable features of Smith-Magenis syndrome, but it is not entirely clear how important they play in the development of SSM.

Smith-Magenis syndrome was first described in the medical literature in 1982 by genetic consultant Ann Smith and her colleagues. In 1986, Smith and Dr. R. Ellen Magenis identified 9 patients with the disorder, which made it possible to more accurately determine the nature of the syndrome. Since then, many additional cases have been identified, allowing doctors / clinicians to better understand this complex developmental disorder.

Signs and symptoms

The main signs of Smith-Magenis syndrome are mild to moderate mental retardation, speech delay and motor skills, facial features, sleep disorders, skeletal and dental abnormalities, and behavioral Problems.

Facial features in people with CCM may be subtle in early childhood, but usually become more apparent with age and include:

• A broad square face with deep-set eyes, chubby cheeks and a prominent lower jaw.
• A flattened appearance towards the middle of the face and the bridge of the nose.
• Mouth turned downward, with upper lip fully curved outward.

Although people with SSM are often characterized as affectionate, charming personalities, most of them also have behavioral problems. They include:

• frequent tantrums and outbursts of anger;
• aggression;
• anxiety;
• impulsiveness;
• difficulty paying attention;
• self-harm, including biting, hitting, banging the head against a wall, and scratching the skin;
• repetitive self-hugs (the feature may be unique for the CCM);
• compulsive finger-licking and flipping through the pages of books.

Additional symptoms of CCM include:

• short stature;
• scoliosis;
• decreased sensitivity to pain and temperature;
• chronic ear infections;
• obesity;
• hoarse voice.

Causes and risk factors

In about 90% of patients, part of the short arm (p) of chromosome 17 (17q11.2) is absent, which is called monosomy. Chromosomes present in the nucleus of human cells carry the genetic information of every person. The cells of the human body usually have 46 chromosomes. Pairs of human chromosomes are numbered 1 through 22, and the sex chromosomes are labeled X and Y. Men have one X and one Y chromosome, while women have two X chromosomes. Each chromosome has a short arm, denoted by the letter "p", and a long arm (arm), denoted by the letter "q". Chromosomes are further subdivided into many numbered bands. For example, "chromosome 17p11.2" refers to band 11.2 on the short arm of chromosome 17. The numbered stripes indicate the location of the thousands of genes present on each chromosome.

In patients with Smith-Magenis syndrome, the deleted part (monosomy) of chromosome 17 includes the gene RAI1. Genes provide instructions for making proteins that are critical to many bodily functions. When a gene is absent due to a monosomal chromosome abnormality, the protein product of that gene is reduced. Depending on the functions of a particular protein, it can affect many organ systems in the body, including the brain.

The exact cause of the chromosomal change in SSM is unknown. The medical literature indicates that almost all documented cases are associated with spontaneous (new) genetic changes that occur for unknown reasons.

In rare cases, CCM is the result of a mistake during very early embryonic development due to a chromosomally balanced translocation in one of the parents. A translocation is balanced if parts of two or more chromosomes break off and swap places, creating an altered but balanced set of chromosomes. If the chromosomal rearrangement is balanced, it is usually harmless to the host. However, they may be associated with a higher risk of abnormal chromosome development in the carrier's offspring. In these cases, the clinical features of children may be influenced by an additional imbalance of chromosomes other than 17. Chromosome testing can determine if a parent has a balanced translocation. Parents with a child with CCM and normal chromosome analysis have a recurrence risk in future pregnancy below 1%.

The remaining 10% of cases of Smith-Magenis syndrome are caused by mutations in the gene RAI1, which leads to an insufficient level of functional copies of the protein product normally produced by this gene.

In two families reported in the medical literature, SSM has occurred due to germline mosaicism. In germline mosaicism, some of the parental reproductive (germ) cells carry the mutation RAI1 gene or deletion of 17p chromosome, while other germ cells do not (mosaicism). In addition, other cells in the parent also do not have these chromosomal abnormalities; therefore, it does not affect the parents. However, as a result, one or more of the parents' children may inherit germ cells with a chromosomal abnormality, which will lead to the development of CCM. Germline mosaicism is suspected if apparently healthy parents have more than one child with the condition. The likelihood that a parent will pass on a mosaic chromosomal germ line abnormality to a child is depends on the percentage of the parent's germ cells that are abnormal compared to the percentage that is not It has. There are no tests for germline mutations or chromosomal abnormalities before pregnancy.

A child born to a person with Smith-Magenis syndrome has a theoretical 50% risk of inheriting a deletion or mutation RAI1that causes the disease. Fertility in the CCM as a whole is not fully understood; however, there is at least one report in the medical literature of a mother with SSM having a child with SSM.

Affected populations

Smith-Magenis syndrome affects men and women in equal numbers. The disease is found in 1 in 15,000-25,000 people in the population. However, cases may go undiagnosed or misdiagnosed, making it difficult to determine the true incidence of the disorder in the general population. CCM has been found worldwide and across all ethnic groups.

Symptomatic disorders

Symptoms of the following conditions may be similar to those of Smith-Magenis Syndrome. Comparisons can be useful for differential diagnosis.

There are many different chromosomal abnormalities, the signs and symptoms of which are similar to those seen in SSM. These disorders include:

• Down syndrome;
• Williams syndrome;
• Prader-Willi syndrome;
• Angelman syndrome;
• Sotos syndrome;
• Martin Bell Syndrome (fragile X syndrome);
• chromosome 22q11.2 deletion syndrome;
• 9q34 deletion syndrome (Kleefstra syndrome);
• 2q37 deletion syndrome;
• 2q23.1 deletion syndrome;
• 1p36 deletion syndrome.

Patients with CCM are often given a psychiatric diagnosis first, which includes obsessive compulsive disorder, general developmental disorders, or attention deficit hyperactivity disorder. Some children with CCM are initially diagnosed with autism spectrum disorders.

Diagnostics

The diagnosis of Smith-Magenis syndrome is based on the identification of characteristic symptoms, a detailed history patient and family, careful clinical evaluation and various specialized genetic tests. The diagnosis of CCM is confirmed by identification of a 17p11.2 deletion (cytogenetic analysis or DNA microarray) or mutations gene RAI1.

- Clinical examination.

In the past, a special chromosome study was used to diagnose Smith-Magenis syndrome, known as G-band analysis, which demonstrates the absence of (removed) material on the chromosome 17p. Chromosomes can be obtained from a blood sample. During this test, the chromosomes are stained to make them easier to see, and then examined under a microscope where the missing segment of chromosome 17p can be found (karyotyping). Determining the exact breakpoint may require a more sensitive test known as fluorescence in situ hybridization (FISH). During the FISH study, the probes marked with a specific color of the fluorescent dye are attach to a specific chromosome, allowing researchers to better see that specific region of the chromosome.

You can also use a newer method known as chromosomal microarray analysis. During this analysis, a person's DNA is compared to that of a person without a chromosomal abnormality (a “control” person). A chromosomal abnormality is noted when differences are detected between DNA samples. Chromosomal microarray analysis can detect very small changes (missing or duplicated segments) or changes.

Molecular genetic testing can confirm the diagnosis in individuals suspected of having CCM due to mutations gene RAI1. Molecular genetic testing can detect mutations in a gene RAI1, which are known to cause CCM in certain cases, but are only available as a diagnostic service in specialized laboratories.

Standard treatments

Treatment may require a coordinated team of specialists. Pediatricians, surgeons, cardiologists, dentists, speech therapists, audiologists, ophthalmologists, psychologists and others health care providers may need systematic and comprehensive planning and influence on treatment child. Genetic counseling is beneficial for those affected and their families. Psychosocial support is also important for the entire family.

Treatment is symptomatic and supportive. Early intervention is essential for affected children to reach their potential. Services that may be helpful include specialty therapeutic training, speech / language therapy, physical therapy, occupational therapy, and therapy sensory integration, in which certain sensory actions are taken to help regulate the child's response to sensory incentives. Additional medical, social and professional services can be recommended as needed.

Some medications are used to treat behavioral problems such as attention deficit hyperactivity disorder. Certain medications are also used to treat sleep disorders potentially associated with Smith-Magenis syndrome. Melatonin supplements to normalize melatonin levels taken before bed have been shown to be beneficial in separate reports. The use of the B-blocker acebutolol in the morning to inhibit / suppress daytime melatonin secretion showed some benefit in one French study.

Feeding problems require identification and appropriate therapy. Adjunctive treatment follows standard recommendations for the specific symptom. For example, anticonvulsants (antiepileptic drugs) can be used to treat epilepsy.

Forecast

Due to the highly variable nature of the syndrome, it is impossible to make a general prognosis for individual cases. Some of the victims were able to find work and even live semi-independently with the support of family and friends. Others, however, need constant care and may need to live with their family or in a shelter. As stated above, parents should speak with the doctor and medical team about their child's specific case and overall prognosis.