Coffin-Lowry syndrome
Incidence
Coffin-Lowry syndrome is inherited in an X-linked dominant manner. About 70-80% of probands have no family history of Coffin-Lowry syndrome and 20-30% have more than one affected family member. CLS has been described in various ethnic groups and does not appear to be particularly rare, as its incidence is estimated to be 1/50,000-100,000 males/year. Transmitted as an X-linked trait. Mapped to the long arm of chromosome X (Xp22.2-p22.1).
Clinical Characteristics
Coffin-Lowry syndrome (CLS) is an X-linked semi-dominant inherited disorder. Typically male patients exhibit growth retardation, psychomotor retardation, hypotonia, and progressive skeletal deformations. In addition, they present with characteristic facial dysmorphism and proximally puffy digits, which are diagnostic criteria. A majority of female carriers have only minimal manifestations. CLS has been described in various ethnic groups and does not appear to be particularly rare, as its incidence is estimated to be 1/50,000-100,000 males/year. Loss of function mutations in the gene located on chromosome Xp22.2 which encodes the growth-factor induced protein kinase RSK2 is responsible for the CLS. There is a high allelic heterogeneity with, to date, over 80 different mutations distributed throughout the gene, the vast majority being found only in individual families. No specific treatment is currently available. In summary, Coffin-Lowry syndrome (CLS) is characterized by severe to profound mental retardation in males; intellect ranges from normal to profoundly retarded in heterozygous females. The facial appearance is characteristic in the affected, older male child or adult. The hands are short, soft, and fleshy, often with remarkably hyperextensible fingers that taper from wide (proximally) to narrow with small terminal phalanges and nails. Males consistently fall below the third centile in height. Microcephaly is common, but macrocephaly may be seen. Dental anomalies are common. Stimulus-induced drop episodes (SIDES), with onset typically from mid-childhood to the teens, may affect 10-20% of individuals; unexpected tactile or auditory stimuli or excitement triggers a brief collapse but no loss of consciousness. Progressive kyphoscoliosis is one of the most troubling aspects of long-term care. Early mortality is increased in individuals with CLS.
Precipitants
None
Provocation Tests
None
Diagnostic Procedures
The diagnosis of Coffin-Lowry syndrome is established in males with severe developmental delay and characteristic craniofacial and hand findings. Carrier females may be mildly affected. Molecular genetic testing of the RPS6KA3 gene can be used to confirm, but not to rule out, the diagnosis of CLS. Sequence analysis identifies mutations in about 65% of probands. Such testing is clinically available. Several authors have stated that the diagnosis may be difficult in the young child and it does seem that, more so than in most syndromes, the face in CLS does become more easily identifiable with normal aging. However, even in neonates, the diagnosis of CLS is most often apparent if considered. \" In vitro ribosomal S6 kinase enzyme assay can be performed on cultured fibroblasts or transformed lymphoblasts. This testing is available on a clinical basis for rapid diagnosis of affected males. It is not useful in females because of the broad range of enzyme activity resulting from X-chromosome inactivation.