Coffin–Lowry Syndrome

Abstract

Abstract The Coffin–Lowry syndrome (CLS) is a rare but well‐defined X‐linked semidominant syndrome. Cardinal features include severe mental retardation, a characteristic facial appearance, digital tapering, short stature and progressive spinal deformity. However, the clinical presentation may be markedly variable both in severity and in the expression of uncommonly associated features. In addition, a few atypical cases of the disease have been reported. Highly heterogeneous loss of function mutations in the RPS6KA3 gene encoding the protein kinase RSK2 are responsible for CLS. About two‐thirds of the mutations arise de novo . RSK2 is a member of the ribosomal S6 serine/threonine kinase family, which plays a key role in the Ras‐ERK signalling pathway. RSKs are activated by phosphorylation in response to growth factors and neurotransmitters. RSK2 substrates include transcription factors, in accordance with a major role in regulation of gene expression. RSK2 is involved in proliferation, apoptosis and in learning and memory processes. Key concepts Coffin–Lowry syndrome is an X‐linked semidominant syndrome characterized typically by severe psychomotor and growth retardation, facial dysmorphism, digit abnormalities and progressive skeletal deformations. The estimated incidence is 1 50 000–1 100 000 and approximately 70–80% of patients are sporadic cases. There is no specific treatment. Highly heterogeneous loss‐of‐function mutations in the RPS6KA3 gene, encoding RSK2, are responsible for Coffin–Lowry syndrome. Two‐thirds of cases arise from new mutations. There is no consistent phenotype/genotype correlation. RSK2 is a serine/threonine kinase that acts at the distal end of the Ras‐ERK pathway and is activated by phosphorylation in response to growth factors and neurotransmitters. Mice models for CLS have been generated that exhibit delayed bone formation as well as learning and memory deficits.