From Stüve-Wiedemann syndrome to Crisponi syndrome. N. Dagoneau¹, S. Bellais¹, B. Leheup², P. Blanchet³, P. Sarda³, L.I. Al Gazali⁴, M. Di Rocco⁵, A. Munnich¹, V. Cormier-Daire¹ 1) Department of Medical Genetics and INSERM U781, Necker Hospital, Paris, France; 2) Department of Clinical Genetics, Children Hospital, Vandoeuvre les Nancy, France; 3) Department of Genetics, Arnaud de Villeneuve Hospital, Montpellier, France; 4) Department of Pediatrics, Faculty of Medicine and Health Sciences, Al Ain, United Arab Emirates; 5) Department of Pediatrics, Gaslini Institute, Genoa, Italy.

   Stüve-Wiedemann syndrome (SWS) is characterized by bowing of the long bones with internal cortical thickening and flared metaphyses, trismus in response to stimuli and camptodactyly. These last features are shared by Crisponi syndrome which is distinct from SWS by the absence of congenital limb bowing. The clinical course of both syndromes is characterized by major feeding and respiratory difficulties and temperature instability usually leading to death in the first months of life.We have collected the samples of 45 SWS families and identified mutations in the Leukemia Inhibitory Factor gene (LIFR) in 33/45 SWS families. We have then excluded the LIFR in three families with Crisponi syndrome but identified mutations in the Cytokine Receptor-like Factor 1 (CRLF1) in all. Following this initial study, we identified homozygote CRLF1 mutations (c.178TG, G60S) in two sibs from Morocco with Crisponi syndrome. We also considered CRLF1 as a candidate gene in the SWS patients without any LIFR mutation but we found no mutation. CRLF1 forms a heterodimer complex with Cardiotrophin Like Cytokine Factor 1 (CLCF1) and this heterodimer competes with Ciliary Neurotrophic Factor (CNTF) for binding to the ciliary neurotrophic factor receptor complex which is composed of CNTFR, gp 130 and LIFR. These findings suggest a key role of the CNTFR pathway in the function of the autonomic nervous system while the specific impairment of the LIFR pathway is presumably involved in the bone manifestations characteristic of SWS.