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The Coffin-Lowry syndrome (CLS) is a syndromic form of X-linked mental retardation. CLS has been described in various ethnic groups and does not appear to be particularly rare, as the estimated prevalence at birth is 1/45 000. The clinical presentation of CLS may vary markedly both in severity and the expression of uncommonly associated features. Typically, male patients exhibit growth retardation, psychomotor retardation, hypotonia, and progressive skeletal deformations. Physical characteristics are usually very mild during infancy; they include characteristic facial dysmorphism (hypertelorism, bulbous nose, wide and open mouth with protruding tongue, full everted lips, and small, irregular or missing teeth) and large, soft hands with lax skin and short tapered and puffy fingers, which are diagnostic criteria. Some patients present with additional features, including sensorineural deafness (30%), seizures (30%), drop episodes (10-20%) cardiac problems, corpus callosus agenesis and/or ventricular dilatation, and myelopathy. Affected individuals tend to have a friendly temperament and, despite limited verbal abilities, have good communication skills. A majority of female carriers have only minimal manifestations. Cognitive function of female carriers may be mildly impaired or normal. CLS is an X-linked semi-dominant inherited disorder. Loss of function mutations in the gene RPS6KA3 located on chromosome Xp22.2, which encodes the growth-factor induced protein kinase RSK2 are responsible for the CLS. There is a high allelic heterogeneity with, to date, over 120 different mutations distributed throughout the gene, the vast majority being found only in individual families. About 70-80% of probands have no family history of Coffin-Lowry syndrome. Diagnosis is based on clinical examination and confirmed by mutation screening of the RSK2 gene (22 exons). Western blot analysis of patient`s derived fibroblast (from a skin biopsy) or lymphoblastoid cell lines can also be used. It is able to detect all the truncating mutations, which represent about 70% of RSK2 mutations. Differential diagnosis includes alpha-thalassemia with mental retardation syndrome, fragile X syndrome, Sotos syndrome, Williams syndrome and lysosomal storage disease. A high rate of de novo mutations is observed (over 60%) and germinal mosaicism has been reported in some families. Thus, 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. Prenatal diagnosis can be performed by mutation analysis or by Western blot analysis (on cultured amniocytes). No specific treatment is currently available. Current effective management of patients focuses on supportive and symptomatic therapy. In particular, sensorineural hearing deficit should be treated very early in order to improve the development and life quality of the patients. Progressive spine deformation (scoliosis and/or kyphosis) may require surgery in adulthood. The frequency of drop episodes seems to diminish under benzodiazepine medication. |