© Georg Thieme Verlag KG Stuttgart · New York
Heterozygous Missense Protein S Mutation in a Young Boy with Incomplete TetraplegiaHeterozygote Missense-Protein-S-Mutation bei einem Jungen mit inkompletter Querschnittsymptomatik
12 May 2009 (online)
An otherwise healthy 12-year old boy presented with acute ascending paraesthesia and muscular weakness starting from the feet and legs and migrating to hands and arms followed by paraplegia. There was no preceding trauma. The onset of the symptoms was noticed by the boy and his family only 2–3 hours before presentation to the emergency room. The spinal MRI showed no abnormalities and the CSF revealed only slight pleocytosis with 21 Gpt/l. Cultures remained sterile. No abnormality in protein levels neither in CSF nor in the serum was detected. In suspicion of a spinal stroke high-dose methylprednisolone was administered rapidly and was continued for 5 days together with prophylactic heparin. The neurological symptoms resolved completely within the treatment period. The brain MRI was normal and a follow-up spinal MRI could not prove any arterio-venous malformation nor thromboembolic alterations. Electroneurography of the tibialis nerves as well as the examination of the optical nerves showed no pathology. Screening for thrombophilia revealed reduced protein S activity (45%) and concentration (40%) resembling type I protein S deficiency. Genetic evaluation showed a novel missense mutation in the exon 10 of the protein S gene. In the position 865 base exchange C>T lead to amino acid exchange Arg289Trp (R289W). The patient’s mother carried the respective heterozygous mutation while she had normal functional protein S values. This mutation has not been described so far. The family history was completely uneventful for thromboembolism.
Stroke and para-/tetraplegia due to vascular and thromboembolic events are very infrequent in childhood (Lynch, J et al. Pediatrics 2002; 109: 116–123). Although many hereditary thrombophilic risk factors have been identified recently, the onset of thromboembolic events remains multifactorial (Pabinger, I und Schneider, B. Arterioscler Thromb Vasc Biol 1996; 16: 742 – 748; Nowak-Göttl, U et al. Blood 1999; 94: 3678–3682). Therefore, the differential diagnosis of stroke-like events includes vascular and thrombophilic disorders as well as severe underlying diseases (Kurnik, K et al. Stroke 2003; 34: 2887–2892; Steinlin, M et al. Neuropediatrics 2005; 36: 90–97). In this case the differential diagnosis auto-immune-mediated atypical Guillain-Barré syndrome was very unlikely since the clinical, electrophysiologic and CSF features did not fit well into this hypothesis. In addition, methylprednisolone pulse treatment would not have been beneficial in Guillain-Barré syndrome. However, since the acute tetraplegia could not be explained by vascular damage or thromboembolism also the close correlation between the hereditary protein S deficiency and the stroke-like episode was questionable. Furthermore, the true procoagulant nature of this defect is of debate, since the mother had no functional protein S abnormalities as a carrier of the same genetic variant. Moreover, in relevant thrombophilia steroid treatment would have had worse impact on thrombus formation. In contrast, steroid treatment had been very successful in this patient. Therefore, the idea of long-term prophylactic anticoagulation was rejected. The patient experienced a relapse-free 19 months follow-up period ever since.