Coffin-Lowry syndrome (CLS) is an X-linked dominant inherited syndrome; the incidence is estimated to be between 1:50,000 and 1:100,000. The leading symptoms in males are intellecutal disability (IQ 15-60) and a characteristic appearance. The external features are a prominent forehead, wide set eyes, downward slanting eyelidfoldss, broad nose with everted nasal base, full lips with evverted lower lip, hyperextensible hand and finger joints, broad tapering fingers. In infancy and childhood, muscle hypotonia is also a prominent feature. The final height is usually below the third percentile. 80% of affected individuals develop progressive kyphoscoliosis, sometimes with cardiovascular complications, and many have a funnel (sunken) or pigeon chest. In addition, about 15% show mitral regurgitation and about 30% have sensorineural hearing loss. Seizures occur in about 5%, and drop attacks, a sudden loss of tone without loss of awareness to auditory or tactile stimuli, occur in about 20%. Females are usually more mildly affected, and the spectrum of symptoms can range from mild symptoms with normal intelligence to complete penetrance as seen in the male sex, depending on X inactivation.
CLS is caused by variants in the RPS6KA3 gene on the short arm of the X chromosome (Xp22.1-22.2). The gene encodes a serine-threonine kinase. Germ cell mosaics have been described.
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