Copyright © 2007 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 80, Issue 5, 971-981, 1 May 2007
doi:10.1086/516843
Report
Crisponi Syndrome Is Caused by Mutations in the CRLF1 Gene and Is Allelic to Cold-Induced Sweating Syndrome Type 1
Laura Crisponi*, a, Giangiorgio Crisponi*, b, 
, 
, Alessandra Melonia, Mohammad Reza Toliatd, e, Gudrun Nürnbergd, g, Gianluca Usalaa, Manuela Udaa, Marco Masala, Wolfgang Höhneh, Christian Beckerd, g, Mara Marongiu, Francesca Chiappec, Robert Kletaj, Anita Rauchi, Bernd Wollnikf, Friedrich Strasserk, Thomas Reese, Cornelis Jakobsm, Gerd Kurlemannn, Antonio Caoa, Peter Nürnbergd, e and Frank Rutscho
a Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato
b Casa di cura Sant’Anna Cagliari, Italy
c Università degli Studi di Cagliari Cagliari, Italy
d Cologne Center for Genomics
e Institute for Genetics Charité–Universitätsmedizin Berlin
f Center for Molecular Medicine Cologne, and Institute of Human Genetics Charité–Universitätsmedizin Berlin
g University of Cologne, Cologne; RZPD Deutsches Ressourcenzentrum für Genomforschung Charité–Universitätsmedizin Berlin
h Institute of Biochemistry, Charité–Universitätsmedizin Berlin
i Berlin; Institute of Human Genetics, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany
j Centre for Nephrology, University College London, Royal Free Hospital, London
k Pediatric Practitioner, Nabburg, Germany (F.S.)
l Klinik für Kinder- und Jugendmedizin, Mathias-Spital, Rheine, Germany
m Department of Clinical Chemistry and Pediatrics, VU University Medical Center, Amsterdam
n and Departments of Pediatric Neurology (G.K.)
o General Pediatrics University Children’s Hospital, Münster, Germany
Address for correspondence and reprints: Dr. Laura Crisponi, Istituto di Neurogenetica e Neurofarmacologia–Consiglio Nazionale delle Ricerche c/o Cittadella Universitaria di Monserrato, Strada statale 554 bivio per Sestu km 4500, 09042 Monserrato (Cagliari), Italy.* These two authors contributed equally to this work.
Abstract
Crisponi syndrome is a severe autosomal recessive condition that is phenotypically characterized by abnormal, paroxysmal muscular contractions resembling neonatal tetanus, large face, broad nose, anteverted nares, camptodactyly, hyperthermia, and sudden death in most cases. We performed homozygosity mapping in five Sardinian and three Turkish families with Crisponi syndrome, using high-density single-nucleotide polymorphism arrays, and identified a critical region on chromosome 19p12-13.1. The most prominent candidate gene was CRLF1, recently found to be involved in the pathogenesis of cold-induced sweating syndrome type 1 (CISS1). CISS1 belongs to a group of conditions with overlapping phenotypes, also including cold-induced sweating syndrome type 2 and Stüve-Wiedemann syndrome. All these syndromes are caused by mutations of genes of the ciliary neurotrophic factor (CNTF)–receptor pathway. Here, we describe the identification of four different CRLF1 mutations in eight different Crisponi-affected families, including a missense mutation, a single-nucleotide insertion, and a nonsense and an insertion/deletion (indel) mutation, all segregating with the disease trait in the families. Comparison of the mutation spectra of Crisponi syndrome and CISS1 suggests that neither the type nor the location of the CRLF1 mutations points to a phenotype/genotype correlation that would account for the most severe phenotype in Crisponi syndrome. Other, still-unknown molecular factors may be responsible for the variable phenotypic expression of the CRLF1 mutations. We suggest that the syndromes can comprise a family of “CNTF-receptor–related disorders,” of which Crisponi syndrome would be the newest member and allelic to CISS1.
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