Clinical report A new Turkish infant with clinical features of CS/CISS1 syndrome and homozygous CRLF1 mutation Stephanie Moortgat a, * , Valerie Benoit a , Marie Deprez a, b , Anne Charon c , Isabelle Maystadt a a Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Charleroi, Gosselies, Belgium b Département de Neuropédiatrie, Clinique Sainte-Elisabeth, Namur, Belgium c Département de Néonatologie, Grand Hôpital de Charleroi, Charleroi, Belgium article info Article history: Received 17 July 2013 Accepted 8 February 2014 Available online 5 March 2014 Keywords: Crisponi syndrome Cold-induced sweating syndrome type 1 CRLF1 gene Muscle contractions Hyperthermia Facial dysmorphism Camptodactyly abstract Cold-induced sweating syndrome (CISS) is a rare autosomal recessive disorder characterized by profuse sweating at cold environmental temperatures, facial dysmorphism and skeletal features. The infantile presentation of CISS, referred to as Crisponi syndrome (CS), is characterized by facial muscular con- tractures in response to slight tactile stimuli or during crying, by life-threatening feeding difficulties caused by suck and swallow inabilities, and by intermittent hyperthermia. High febrile crises can lead to death within the first months of life. In preadolescence, surviving patients develop kyphoscoliosis and abnormal sweating. CISS is a genetically heterogeneous disorder caused by mutations in CRLF1 in more than 90 percent of patients (CISS1) and by mutations in CLCF1 in the remaining patients (CISS2). It is now well demon- strated that all patients with an infantile-onset CS will develop CISS, confirming that CS and CISS are not “allelic disorders” but the same clinical entity described at different ages of affected patients. Here we report on a Turkish patient with a phenotype consistent with CS/CISS1 and a nonsense ho- mozygous mutation (c.829C>T, p.R277X) in the CRLF1 gene. This mutation has already been reported in another Turkish patient with CS/CISS1. Ó 2014 Elsevier Masson SAS. All rights reserved. 1. Introduction Crisponi syndrome (CS), the infantile presentation of cold- induced sweating syndrome (CISS; MIM #272430), is a rare auto- somal recessive disorder characterized by congenital contractures of facial muscles in response to tactile stimuli or during crying. Hypersialorrhea, trismus simulating tetanic spasms and campto- dactyly with adducted thumbs may recognizable at birth. The phenotype is complicated by respiratory and major feeding diffi- culties, and by intermittent hyperthermia. Facial dysmorphic fea- tures are described, including round face with chubby cheeks, depressed nasal bridge, broad nose with anteverted nostrils, long philtrum and micrognathia with high arched palate. In the initial description in 1996 by G. Crisponi, 15 out of 17 babies from Southern Sardinia died in the first 2 years of life following severe paroxysmal attacks or during hyperthermia episodes [Crisponi, 1996]. Since then, less then 50 patients from different ethnic origins have been reported. In the most surviving patients, hyperthermia, contractures and feeding difficulties resolve after the age of 2. Psychomotor development is usually normal [Hahn et al., 2010]. During the first decade of life, they develop profuse sweating of the face, arm and chest in response to cold temperatures [Crisponi et al., 2007; Hahn et al., 2010]. Hyperhidrosis can be treated by clonidine and amitriptyline. All of the affected patients show progressive thoraco-lumbar kypho- scoliosis often requiring surgical intervention. Mutations in the cytokine receptor-like factor 1 (CRLF1) gene have been recently discovered to be associated with CS [Crisponi et al., 2007; Dagoneau et al., 2007]. The CRLF1 gene is implicated in 90 percent of patients presenting with CISS including CS (CISS1), whereas the CLCF1 gene is mutated in the remaining patients (CISS2) [Hahn et al., 2006]. CISS1 and CISS 2 are clinically indistinguishable. It is now well demonstrated that surviving patients with an infantile-onset CS will develop CISS, demon- strating variation in clinical presentation of the disease at different ages [Hahn et al., 2010; Herholz et al., 2011; Yamazaki et al., 2010]. * Corresponding author. Institut de Pathologie et de Génétique, Avenue Georges Lemaitre 25, B-6041, Charleroi, Gosselies, Belgium. Tel.: þ32 (0)71 447 181; fax: þ32 (0)71 347 861. E-mail address: stephanie.moortgat@ipg.be (S. Moortgat). Contents lists available at ScienceDirect European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg http://dx.doi.org/10.1016/j.ejmg.2014.02.003 1769-7212/Ó 2014 Elsevier Masson SAS. All rights reserved. European Journal of Medical Genetics 57 (2014) 212e215