Coffin-Lowry syndrome is a rare genetic disorder characterized by craniofacial (head and facial) and skeletal abnormalities. Some individuals also have cardiovascular disease. The disorder affects males and females, but symptoms are usually more severe in males. Neurological complications may include:

• Severe intellectual disability and delayed development in most cases (most severe in males)
• Reduced muscle tone (hypotonia)
• Seizures (in rare instances)
• Issues with speech
• Impaired hearing
• Problems with movement coordination
• Behavioral and sensory integration issues
• Progressive muscle spasticity or leg paralysis
• Loss of ability to walk

Characteristic facial features may include an underdeveloped upper jawbone, a broad nose, an abnormally prominent brow, down-slanting eyelid folds, widely spaced eyes, and large low-set ears. Skeletal abnormalities may include a curved spine, unusual prominence of the breastbone (pigeon chest), short stature, and narrowing of the spinal canal. The disorder is caused by mutations in the RPS6KA3 gene.

There is no cure and no standard course of treatment for Coffin-Lowry syndrome, which may include physical and speech therapy and educational services. Due to cardiac and respiratory complications, life span is reduced in some individuals with Coffin-Lowry syndrome.

Coffin-Lowry syndrome is a condition that affects many parts of the body. The signs and symptoms are usually more severe in males than in females, although the features of this disorder range from very mild to severe in affected women.

Males with Coffin-Lowry syndrome typically have severe to profound intellectual disability and delayed development. Affected women may be cognitively normal, or they may have intellectual disability ranging from mild to profound. Beginning in childhood or adolescence, some people with this condition experience brief episodes of collapse when excited or startled by a loud noise. These attacks are called stimulus-induced drop episodes (SIDEs).

Most affected males and some affected females have distinctive facial features including a prominent forehead, widely spaced and downward-slanting eyes, a short nose with a wide tip, and a wide mouth with full lips. These features become more pronounced with age. Soft hands with short, tapered fingers are also characteristic of Coffin-Lowry syndrome. Additional features of this condition include short stature, an unusually small head (microcephaly), progressive abnormal curvature of the spine (kyphoscoliosis), and other skeletal abnormalities.

The incidence of this condition is uncertain, but researchers estimate that the disorder affects 1 in 40,000 to 50,000 people.

Mutations in the RPS6KA3 gene cause Coffin-Lowry syndrome. This gene provides instructions for making a protein that is involved in 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. Gene mutations result in the production of little or no RPS6KA3 protein, but it is unclear how a lack of this protein causes the signs and symptoms of Coffin-Lowry syndrome.

Some people with the features of Coffin-Lowry syndrome do not have identified mutations in the RPS6KA3 gene. In these cases, the cause of the condition is unknown.

Normal Function

The RPS6KA3 gene provides instructions for making a protein that is part of a family called ribosomal S6 kinases (RSKs). These proteins help regulate the activity of certain genes and are involved in signaling within cells. RSK proteins are thought to play a role in several important cellular processes including cell growth and division (proliferation), cell specialization (differentiation), and the self-destruction of cells (apoptosis).

The protein made by the RPS6KA3 gene appears to play 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.

Health Conditions Related to Genetic Changes

Coffin-Lowry syndrome

More than 125 mutations in the RPS6KA3 gene have been identified in people with Coffin-Lowry syndrome, a condition associated with intellectual disability and skeletal abnormalities. All of these mutations severely reduce or eliminate the activity of the RPS6KA3 protein. Some mutations insert or delete genetic material in the gene or change how the gene's instructions are used to build the protein. Other mutations change single protein building blocks (amino acids) in the RPS6KA3 protein.

Researchers do not fully understand how mutations in the RPS6KA3 gene lead to the signs and symptoms of Coffin-Lowry syndrome. A functional RPS6KA3 protein appears to be important for learning and memory, but its role in the skeleton is unknown.

Other disorders

RPS6KA3 mutations have been identified in some people who have intellectual disability, but do not have most of the other characteristic features of Coffin-Lowry syndrome (described above). Because the RPS6KA3 gene is on the X chromosome, this condition is known as X-linked intellectual disability. Researchers believe that RPS6KA3 mutations are a rare cause of intellectual disability because only a few affected families have mutations in this gene.

Other Names for This Gene

• HU-2
• HU-3
• Insulin-stimulated protein kinase 1
• ISPK-1
• KS6A3_HUMAN
• MAP kinase-activated protein kinase 1b
• MAPKAPK1B
• MRX19
• p90(rsk)
• ribosomal protein S6 kinase, 90kDa, polypeptide 3
• Ribosomal S6 kinase 2
• RSK-2
• RSK2

Genomic Location

This condition is inherited in an X-linked dominant pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes. The inheritance is dominant if one copy of the altered gene in each cell is sufficient to cause the condition. In most cases, males (who have one X chromosome in each cell) experience more severe signs and symptoms of the disorder than females (who have two X chromosomes in each cell). A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Between 70 percent and 80 percent of people with Coffin-Lowry syndrome have no history of the condition in their families. These cases are caused by new mutations in the RPS6KA3 gene. The remaining 20 percent to 30 percent of affected individuals have other family members with Coffin-Lowry syndrome.

No specific treatment for Coffin-Lowry exist. Proper management of patients with CLS, includes surveillance by performing regular hearing, dental, and vision tests; annual heart examinations; and periodic monitoring for kyphoscoliosis. Medications such as valproate, clonzapam or selective serotonin uptake inhibitors might be prescribed for drop episodes. Surgery may be performed for skeletal deformities.