Cold-induced sweating syndrome - CLCF1 and CRLF1 genes.

Cold-induced sweating syndrome is characterized by problems with regulating body temperature and other abnormalities affecting many parts of the body. In infancy, the characteristics associated with known frequency as Crisponi syndrome. Originally, it was thought that the cold-induced sweating syndrome and Crisponi syndrome were different disorders, but now they are considered to represent the same condition at different times during life.

Infants with Crisponi syndrome have unusual facial features, including a flat nasal bridge, upturned nostrils, philtrum, vaulted palate, micrognathia and low-set ears. The muscles of the lower part of the face are weak, resulting in severe feeding difficulties, excessive drooling and breathing problems. Other physical abnormalities associated with Crisponi syndrome include a scaly rash, inability to fully extend their elbows, fingers and hands, feet and malformations of overlapping fingers. By six months of age, infants with Crisponi syndrome develop unexplained high fever that increase the risk of seizures and sudden death.

Many of the health problems associated with Crisponi syndrome improve with time, and affected individuals who survive the neonatal period develop other features of cold - induced sweating syndrome in early childhood. Within the first decade of life, affected people start to have episodes of hyperhidrosis. Excessive sweating is usually triggered by exposure to temperatures below 21°C or about 18°C, but it can also be triggered by nervousness or eating sugary foods. Paradoxically, those affected tend not to sweat in warmer conditions. Adolescents with sweating cold - induced syndrome often develop scoliosis, kyphosis or kyphoscoliosis. Although infants may develop deadly fevers, affected individuals who survive childhood have a normal life expectancy.

About 90% of cases of sweating cold syndrome and Crisponi syndrome result from mutations in the CRLF1 gene, located on the short arm of chromosome 19 (19p12). These cases are designated as CISS1. The remaining 10% of cases are due to mutations in the CLCF1 gene located on the long arm of chromosome 11 (11q13.3) and are designated as CISS2. The proteins encoded from the CRLF1 and CLCF1 genes (factor receptor-like 1 cytokines, cytokine factor cardiotrophin 1, respectively) work together as part of a signalling pathway that is implicated in the normal development of the nervous system. This pathway appears to be particularly important for the development and maintenance of motor neurons. In addition, it is believed that this pathway plays a role in part of the sympathetic nervous system, specifically in the regulation of sweating in response to changes in temperature and other factors. In this sense, the proteins encoded from the CRLF1 and CLCF1 genes and appear to be critical for normal development and maturation of nerve cells that control the activity of the sweat glands. It is also likely that CRLF1 and CLCF1 genes have roles outside the nervous system, including roles in the body's inflammatory response and in bone development. However, little is known about their involvement in these processes.

They have identified at least four mutations in the CLCF1 gene and 10 mutations in the CRLF1 gene in people with syndrome induced by cold sweating. These genetic changes disrupt the normal development of multiple organ systems, including the nervous system. This is because the proteins encoded by these genes are defective and cannot interact. The function of these genes in the development of the sympathetic nervous system may help to explain the abnormal sweating that is characteristic of this disease, including unusual sweating patterns and the problems associated with the regulation of body temperature. The involvement of these genes in the development of motor neurons and bone development provides clues about some of the other signs and symptoms of cold-induced sweating syndrome, including distinctive facial features, facial muscle weakness and skeletal abnormalities. However, little is known about how these genetic mutations underlie these other characteristics of the disease.

Cold-induced sweating syndrome is inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.

Tests in IVAMI: in IVAMI perform the detection of mutations associated with  Crisponi syndrome or other cold sweating syndrome by complete PCR amplification of the exons of CRLF1 and CLCF1 genes, respectively, and their subsequent sequencing.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).