A novel mutation in the RPS6KA3 gene in a patient with Coffin-Lowry syndrome.

Summary: A novel mutation in the RPS6KA3 gene in a patient with Coffin-Lowry syndrome: Coffin-Lowry syndrome is an X-linked disorder characterized by mental retardation, characteristic facial features, skeletal abnormalities, and tapering fingers. Herein we report a novel missense mutation in exon 7 at codon 180 in the RPS6KA3 gene in a boy with Coffin-Lowry syndrome. Key-words: Coffin Lowry syndrome - RPS6KA3 gene - New mutation. INTRODUCTION Coffin-Lowry syndrome (CLS) is an X-linked disorder characterized by mental retardation, skeletal abnormalities, delayed bone development, short stature, tapering fingers, large ears, orbital hypertelorism, anteverted nares, and a prominent frontal region (2). Mutations in the gene RPS6KA3 gene on chromosome Xp22.2, have been found to cause CLS (1). Herein we report a new mutation in the RPS6KA3 gene in a patient with Coffin Lowry syndrome which has not been described before. CASE REPORT A 6-year-old boy was referred due to mental retardation. His parents were from the same small village and possibly relatives. There was no family history of mental retardation and congenital anomalies. He was born at temi and there was no history of exposure to teratogens. Clinical evaluation revealed a happy natured boy with marked mental retardation, hypertelorism, bilateral telecanthus, relatively large ears, depressed and broad nasal bridge, long philtrum, full, slightly everted lips, oligodontia, short, broad and soft hands, broad thumb, and hyperextensible tapering fingers (Fig. 1). He had skin abnormalities due to burn scars. Ophthalmologic evaluation showed optic atrophy. Neurological, otological and cardiac examinations were normal. X-ray studies showed beated copper sign of cranium, cleft of 4th cervical vertebrae, spina bifida of 4th and 5th lumbar and Slst vertebrae (Fig. 2), and short middle and terminal phalanges of both fifth fingers. Laboratory evaluations and abdominal ultrasound revealed normal findings. Cranial magnetic resonance imaging showed thinning of the posterior corpus callosum, mild white matter loss and encephalomalacia at retrotrigonal periventricular region. Chromosome analysis revealed normal karyotype. Array CGH analysis was normal. Mutation analysis of RPS6KA3 gene revealed a novel missense mutation of exon 7 at codon 180 (Alal80Asp). His mother did not present clinical signs and we did not perform mutational analysis in the mother because we could not obtain consent from her. DISCUSSION CLS is caused by mutations in the RPS6KA3 gene located at xp22.2, which encodes RSK2, a growth-factor-regulated protein kinase. RPS6KA3 mutations are extremely heterogeneous. 71 distinct disease-associated RSK2 mutations have been identified in 86 unrelated families (1). In this report, a mutation analysis of RPS6KA3 gene revealed a novel missense mutation in exon 7 at codon 1 80 (Alai 80Asp). This codon is conserved in many animals while glycine was detected in some primitive organisms like drosophila but never aspartic acid which is chemicaly very different. Anterior beaking of the vertebrae with narrow disc spaces and related degenerative vertebral changes were reported as a feature of Coffin Lowry syndrome (2). Vertebral segmentation anomalies were not reported before in CLS. Spina bifida of 4th and 5th lumbar and lsl sacral vertebrae in our patient may be a new feature of this syndrome because novel mutations may be the cause of unexpected clinical manifestations. Small distal phalanges and tapering fingers were reported as hand anomalies in previous patients with CLS (2). Phalanges of our patient were normal in shape except middle and terminal phalanges of the 5th fingers. The other clinical difference of our patient was beated copper appearance of cranium. It was not reported in previous patients with CLS. Kesler et al. …