Crisponi Syndrome and Cold-Induced Sweating Type 1: Two Syndromes - One Genetic Entity. L. Crisponi1, A. Meloni2, M. Marongiu1, F. Chiappe2, M. Deiana1, L. Marcia1, G. Zampino3, P. Nürnberg4, G. Crisponi5, F. Rutsch6 1) INN/CNN, Cittadella Univ di Monserrato, Monserrato (CA), Italy; 2) University of Cagliari, Italy; 3) Departments of Pediatrics, Catholic University, Rome, Italy; 4) Cologne Center for Genomics, Cologne, Germany; 5) Casa di cura Sant' Anna, Cagliari, Italy; 6) General Pediatrics, University Children's Hospital, Muenster, Germany.

   Crisponi syndrome (CS) is a severe autosomal recessive condition, characterized by abnormal, paroxysmal muscular contractions, hyperthermia and sudden death in most cases. Recently we identified CRLF1 as the gene implicated in the pathogenesis of CS. We extended our cohort of patients affected by CS and up to now we detected 1 novel mutation. CRLF1 is also involved in the pathogenesis of cold-induced sweating syndrome-1 (CISS1). CS and CISS1 belong to a group of conditions with overlapping phenotypes, also including cold-induced sweating syndrome type 2 and Stüve-Wiedemann syndrome. Since genotype/phenotype correlations are not clear for CS and CISS1,we performed functional studies on mutated CRLF1 constructs for the mutations pW76G, pP238RfsX6 and pK368X found in Crisponi patients, and tested the patients with CS for the presence of cold-induced sweating. We mutagenized the wt CRLF1 with the 3 indicated mutations. After transfection of the constructs in COS-1 cell lines, the mutant proteins derived from the missense and nonsense mutations were expressed and secreted, whereas the mutant protein derived from the frame-shift mutation was produced, but not secreted. The patients phenotype did not differ from protein-secreters to non-secreters. All surviving patients with CS developed scoliosis and cold- induced sweating. The presence of many overlapping clinical features in adolescence, including cold-induced sweating and scoliosis and the association of the diseases with mutations in the same gene, point to the fact that CS and CISS1 are two variations of the same genetic entity. However, the severity in the clinical phenotype of CS vs CISS1 does not seem to depend on the type of mutation, and more studies are in progress to clarify this difference.