Coffin-Lowry phenotype in a patient with a complex chromosome rearrangement.

The eponym Coffin-Lowry syndrome has been used by clinical geneticists for over a quarter of a century now, since first proposed by Temtamy et al in 1975. The syndrome refers to a recognisable clinical condition, characterised by mental retardation, characteristic facial appearance, and skeletal abnormalities. Most geneticists would consider that the condition represents a fairly good example of “gestalt” diagnosis, the recognition of a familiar pattern on observing the face. Young has tabulated the facial features in this condition, identifying coarseness, hypertelorism, antimongoloid slant, pouting, everted lower lips, and a broad nose as the most frequently observed features. In addition, affected subjects frequently have pectus excavatum/carinatum, kyphosis or scoliosis, and broad hands, often with tapering fingers and hypothenar crease. Inherited as an X linked condition, the classical phenotype is described in affected males. However, carrier females frequently manifest clinical characteristics of the condition. Mapping of the locus indicated a location in Xp22.3-p22.1. Subsequently, disease causing mutations have been described in the ribosomal protein S6 kinase (RSK2). A wide range of different types of mutations have been described, distributed throughout the gene, many associated with premature translation termination, and most associated with predicted loss of function of the mutant allele. The application of these findings in clinical practice has served not just to expand the understanding of the mutational basis of the classical syndrome, but has also shown that atypical, mild forms of Coffin-Lowry syndrome exist. Despite these occasional clinical surprises, most patients harbouring pathogenic mutations of the RSK2 locus have shown clinical characteristics consistent with those expected in Coffin-Lowry syndrome. However, as established by a recent mutational screen in 250 patients clinically suggestive of Coffin-Lowry syndrome, mutations are found in by no means all such patients. Indeed mutations were not identified in 66% of patients included in the mutation studies. While a proportion of these cases may represent failed detection owing to the procedures used for screening, it is also very likely that many patients with clinical features suggestive of Coffin-Lowry syndrome are caused by mutations at other loci. A recent report by McCandless et al records many clinical and radiological characteristics of Coffin-Lowry syndrome in a patient with a chromosome 10q25.1-25.3 deletion. The close resemblance between the patient described with the deletion and the classical Coffin-Lowry phenotype led the authors to speculate that other molecular elements of the RSK2 mediated pathway might be disrupted in their patient and that there might be a further locus, possibly autosomal, for Coffin-Lowry syndrome. Similarly, the observation recently reported by Kondoh et al of a Coffin-Lowry syndrome phenotype in a Japanese patient with de novo 8p23 duplication raises a similar prospect, although it must be acknowledged that the dysmorphic features in the latter case were less convincing to a western eye. To this growing body of evidence, cumulatively suggestive of alternative loci for Coffin-Lowry syndrome, we now add a patient with several classical clinical features associated with a complex, apparently balanced, chromosomal rearrangement.