Coffin-Lowry Syndrome Foundation

Frequently Asked Questions

Q: What is Coffin-Lowry syndrome?
A: 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 there is a great deal of variability in expression, especially in females. 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.  

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Q: How common is it?

The exact incidence is not known, but researchers estimate the prevalence at one in every 40-50,000 births.

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Q: What genes are related to CLS?

Coffin-Lowry syndrome is caused by mutations in the RPS6KA3 gene. More than 125 mutations in the RPS6KA3 gene have been identified in people with Coffin-Lowry syndrome. 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 use to build the protein. Other mutations change single protein building blocks (amino acids) in the RPS6KA3 protein. This gene encodes RSK2, a growth-factor-regulated protein kinase.  Some people with the features of CLS do not have the identified mutations in this gene. In these cases, the cause of the condition is unknown.

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Q: Is CLS progressive?
A: Some aspects of the syndrome are progressive. Facial coarsening and skeletal involvement become more pronounced with age. Some motor and coordination neurological problems do not express themselves until later in childhood and may result in decreased mobility. Bone degeneration may occur starting in the late teen years which can lead to a higher incidence of broken bones. This is especially problematic for those who also have drop episodes as they are prone to spine and neck injuries from the repeated falls.  Depression or behavior problems may develop. Life expectancy may be reduced in individuals who have severe cardiac problems, respiratory complications, or severe progressive kyphoscoliosis.

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Q: Is there a test for CLS?
A: Molecular genetic testing of RPS6KA3, can be used to confirm, but not to rule out, the diagnosis of CLS. Sequence analysis identifies mutations in about 35%-40% of probands. Dozens of mutations have been identified that can cause CLS characteristics.  This makes a positive diagnosis using genetic testing very difficult. Professionals trained in genetic disorders and birth defects often can make the diagnosis after performing a physical exam and observing the child's behavior.

Often a diagnosis comes after a developmental evaluation when a child appears to be delayed in reaching several developmental milestones. Parents should be prepared for the likelihood that even though a clinical diagnosis is made, they may not get a confirming positive genetic diagnosis.

For more information, see Genetic Testing - Your Questions Answered. Click here for more information on facilities that offer tests for Coffin-Lowry syndrome.

 

Additional Resources

Q: How is CLS inherited?
A: Inheritance is X-linked dominant which means it is inherited from the mother. A woman who has CLS herself has a 50% chance of having a child with CLS, depending on which of her X chromosomes are inherited by the child. However, in about 70-80% of cases, the mother does not have CLS nor is there any family history - this is known as a spontaneous mutation. In the absence of any physical signs or mental impairment, the mother of a child with CLS with no known family history is probably at low risk of having another child with CLS.  20-30% have more than one additional affected family member. There are no recorded cases of an affected male producing offspring, so the ability of CLS males to father affected children is not known. The father of an affected male will not have the mutation nor will he be a carrier of the mutation. 

In families with more than one affected individual, the mother of the affected children is an obligate carrier.

• Males with the CLS-causing mutation are always  affected
• Females with the CLS-causing mutation are carriers and are at high risk for developmental delay and mild physical signs of CLS

There have been reports of mild expression of CLS in males who had the RPS6KA3 mutation but little is known about this form of CLS at this time.

Germline mosaicism has also been reported in CLS. "Mosaicism" means that the person's body is made up of a combination of cells with and cells without a mutation, like a mosaic with some blue pieces, and some red pieces. "Germline" refers to the presence of cells with mutations in the egg or sperm cell supply only. Germline mosaicism is relatively rare, and this explanation does not apply to most families with a spontaneous mutation. The chances of a mother with germline mosaicism having another child with CLS is higher than the average population. There is no simple way to determine if the mother has germline mosaicism, and no one knows how often it occurs. Therefore, the absence of a mutation in the mother of a sporadic Coffin-Lowry patient does not rule out a recurrence risk for future pregnancies, and prenatal diagnosis should be offered.

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Q: What will my child be capable of?

There is wide variability in abilities and characteristics. Early intervention, physical and speech therapies plus the child's own genetic makeup are all factors. Even among the severely affected, most will learn to speak and are able to be toilet trained. If sensorineural deafness is present, then expressive communication may still be possible through sign language.

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