Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Coffin-Lowry Syndrome (CLS) [Q89.8]

OMIM numbers: 303600, 300075 (RPS6KA3)

Dr. med. Imma Rost

Scientific Background

Coffin-Lowry syndrome (CLS) is an X-linked dominant inherited disorder which in males is mainly characterized by intellectual disability (IQ 15–60) and a distinctive phenotype. The incidence is estimated to be 1 in 50,000 to 1 in 100,000. Physical characteristics include a prominent forehead, widely spaced and downward-slanting eyes, thick nasal septum with anteverted nares, thick everted lips, hyperextensible, soft and fleshy hands with lax skin and joints and tapering stubby fingers. Hypotonia is a prominent symptom during infancy. The final adult height is usually below the third percentile. Eighty percent of the affected patients develop progressive kyphoscoliosis - sometimes in combination with cardiovascular complications. The same amount of patients have a pectus excavatum or a pectus carinatum. About 15% have mitral regurgitation and 30% suffer from a sensorineural hearing defect. Seizures occur in 5% of all cases. Stimulus-induced drop attacks (sudden loss of muscle tone triggered by unexpected auditory or tactile stimuli without loss of consciousness) occur in 20% of all patients. Usually, females are affected less severely; however, the spectrum of symptoms can range from a normal phenotype with normal intelligence to the full range of symptoms as in males depending on the X-inactivation.

CLS is caused by mutations in the RPS6KA3 gene on the short arm of the X chromosome (Xp22.1–22.2) . The gene codes for a serine/threonine kinase. De novo mutations constitute approximately 60% of all cases; germline mosaicims have been reported.