Синдром Коффина-Лоури: генетика, симптомы и диагностика.

Coffin–Lowry syndrome is a genetic disorder that is X linked dominant and which causes severe mental problems sometimes associated with abnormalities of growth, cardiac abnormalities, kyphoscoliosis, as well as auditory and visual abnormalities.

Symptoms of disease are more severe in males, who are generally diagnosed in early childhood. Children with CLS display cognitive disabilities of varying severity. Additional neuromuscular features include sleep apnea, muscular spasticity, progressive loss of muscle strength and tone leading to paraplegia or partial paralysis. Affected individuals are at elevated risk of stroke. Some patients experience stimulus induced drop attacks (SIDAs, temporary paralytic episodes without loss of consciousness), triggered by unpredictable environmental stimuli (touch, scents, sounds, etc.). SIDA episodes become more frequent as the disease progresses, and become frequent around adolescence in males. Additional clinical physical features include small, soft hands with tapered fingers. Distinct facial architecture such as a flattened nose, widely separated and downward sloping eyes, a prominent forehead, and a wide mouth with large lips are reported as coincident facial features in patients with the disorder. Some individuals experience hearing loss. Others display kyphoscoliosis (multidirectional curvature of the spine) which can lead to difficulty with breathing and/or pulmonary hypertension. Cardiorespiratory complications may arise, which is why it is recommended that CLS patients undergo regular monitoring for spinal irregularities. Physical exams, CT imaging and X ray imaging are standard methods of assessment.

The syndrome is caused by mutations in the RPS6KA3 gene. This gene is located on the short arm of the X chromosome (Xp22.2). The RPS6KA3 gene makes a protein that is involved with signaling within cells. Researchers believe that this protein helps control the activity of other genes and plays an important role in the brain. The protein is involved in cell signaling pathways that are required for learning, the formation of long term memories, and the survival of nerve cells. The protein RSK2 which is encoded by the RPS6KA3 gene is a kinase which phosphorylates some substrates like CREB and histone H3. RSK2 is involved at the distal end of the Ras/MAPK signaling pathway. Mutations in the RPS6KA3 disturb the function of the protein, but it is unclear how a lack of this protein causes the signs and symptoms of Coffin–Lowry syndrome. At this time more than 120 mutations have been found.

X ray and neuroimaging studies may be helpful in confirming a diagnosis of Coffin–Lowry syndrome. Decreased ribosomal S6 kinase activity in cultured fibroblast or transformed lymphoblast cells from a male indicates Coffin–Lowry syndrome. Studies of enzyme activity can not be used to diagnose an affected female. Molecular genetic testing on a blood specimen or cells from a cheek swab is available to identify mutations in the RSK2 gene. This testing can be used to confirm but not rule out the diagnosis of Coffin–Lowry syndrome because not all affected individuals have a detectable mutation.

There is no cure for Coffin–Lowry syndrome. Clinical objectives are centered on symptom management. Because stimulus induced drop attacks (SIDAs) can result in physical harm to patients with the disorder, the use of medication to prevent or reduce the number of SIDA episodes is a safety priority. Physical precautionary measures have also been used to protect patients from injury, including the use of a helmet or a wheelchair. Because sudden excitement or fright can trigger a SIDA episode it is important to minimize exposure to startling stimuli. Medications prescribed include benzodiazepines (tranquilizers used to treat anxiety), valproate (used to manage epilepsy and bipolar disorder), and selective serotonin reuptake inhibitors (SSRIs) (used to treat major depression). When affected individuals display aggressive or destructive behavior that could harm themselves or others, the antipsychotic medication risperidone may eventually be prescribed. It is recommended that spinal development be monitored regularly by X ray and physical exams. Echocardiograms are recommended every 5–10 years to assess cardiac function and development. Families are encouraged to receive genetic counseling in order to understand and prepare to provide care for children affected by Coffin–Lowry syndrome. Dr. Temtamy showed that the cases represented a single syndrome in 1975. In 1972, Peter G. Procopis and B. Turner published a case study on a family of four brothers with Coffin Lowry Syndrome, with female relatives, specifically sisters, only possessing some mild deformities and abnormalities. In 1975, Samia Temtamy reported eight patients from three different families displaying symptoms of Coffin Lowry Syndrome, suggesting that the disorder is more common than believed and often goes underdiagnosed. On the basis of these reports, AG Hunter, Simone Gilgenkrantz, and ID Young established Coffin Lowry Syndrome as a novel medical diagnosis and named it for the two doctors to originally describe its clinical symptoms. Additional case studies have since expanded the original list of clinical signs and symptoms. In 2002, Helen Fryssira and RJ Simensen identified a 3 base pair deletion in the gene encoding RSK2, which was the first report of the gene responsible for Coffin Lowry.

The Coffin–Lowry Syndrome Foundation acts as a clearinghouse for information on Coffin–Lowry syndrome and hosts a forum for affected families. The family matching program facilitates community building and resource sharing for recent diagnoses. The Coffin Lowry Syndrome Foundation was created in 1991. The mission of the Foundation is to provide informational links, resources, and databases to families and patients dealing with the disease and enables them to communicate with one another. Families and patients can share their experiences and retrieve advice on the foundation's online site as well as locate helpful services, telephone support, and day to day news on medical progress into understanding and treating those affected by Coffin Lowry Syndrome. The symbol of the foundation is an apple, chosen for its representation of knowledge, feminine beauty, immortality, rebirth, and peace. The foundation provides a support network and source of hope for the families of patients with Coffin Lowry Syndrome.