Last updated:
3/9/2026
Years published: 2026
NORD gratefully acknowledges Natalie Zaba, BA, Genetic Counseling Student, University of Connecticut and Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders, for their assistance in the preparation of this report.
Summary
Cold-induced sweating syndrome (CISS) is a rare inherited condition that affects the autonomic nervous system, which controls body functions such as sweating and body temperature. It usually begins in infancy or early childhood, although symptoms of this condition become more obvious as children grow older.1
The main symptom of CISS is excessive sweating when exposed to cold temperatures, especially on the face, chest, and upper back. People with CISS also experience reduced sweating at warmer temperatures. Other symptoms of CISS include feeding problems, breathing problems, poor growth, curved spine (scoliosis), and bent fingers that cannot be completely straightened. 2, 3
CISS is caused by changes (variants) in the CRLF1 or CLCF1 genes. These genes are important for the development and function of nerves that control automatic body processes, like body temperature. The condition is inherited in an autosomal recessive pattern, meaning someone must inherit one change from each parent to be affected.1
Treatment of CISS focuses on managing symptoms that an affected person has. This may include avoiding cold temperatures, protecting the eyes, monitoring growth and feeding, and addressing bone or joint problems. The medications clonidine/amitriptyline or moxonidine can be used to help control excessive sweating. 4
Introduction
Cold-induced sweating syndrome (CISS) was first described in 1978 by Sohar and his colleagues in a report titled “Cold-induced profuse sweating on back and chest.” This publication documented two Israeli sisters who developed paradoxical, excessive sweating of the back and chest when exposed to cold temperatures, establishing CISS as a distinct clinical condition and providing the basis for its name. Independently, in 1996, Giangiorgio Crisponi was the first to describe a severe neonatal disorder in Sardinian patients, characterized by marked muscle stiffness, episodes of overheating, and other autonomic abnormalities in early life. This became known as Crisponi syndrome. Further research identified older individuals who had a history of this neonatal presentation of Crisponi syndrome who later developed cold-induced excessive sweating. These studies demonstrated that Crisponi syndrome and CISS are manifestations of the same underlying disorder. Today, the term CISS is used to refer to the condition, while Crisponi syndrome specifically refers to its early-life presentation.3-5
Signs and symptoms of CISS usually begin in early childhood and may change over time as children grow older. The timing and symptoms may differ among people with CISS. Note that not every affected person will experience all the symptoms listed below.
Some features that may be seen at birth and in early childhood include: 2, 4, 6-12
In serious cases, signs and symptoms may include: 2,6, 7-9
As children grow older, additional signs and symptoms may include: 2, 4, 6, 8, 10, 12
CISS is caused by changes (pathogenic variants) in the CRLF1 or CLCF1 genes. 11, 13 These two genes provide instructions that the body needs to produce two proteins, CRLF1 and CLCF1, that function together. The CRLF1 protein and the CLCF1 protein bind to each other and form a combined structure, CRLF1-CLCF1, which acts as a messenger that delivers signals to nerve cells through a receptor called the ciliary neurotrophic factor receptor, or CNTFR, located on the surface of certain nerve cells. This signaling pathway plays a crucial role in the proper development of the nervous system, especially the nerves responsible for muscle movement and those that regulate sweating and body temperature. 2, 11, 13
People with CISS sweat when they are cold, instead of sweating when exposed to heat. This occurs because of a disruption in the normal development of certain nerves after birth.
Normally, at birth, the nerves that connect to sweat glands release a chemical messenger called norepinephrine (or noradrenaline). Nerves that release this substance are called noradrenergic nerves. After birth, as sweat glands mature, they send signals that include the CRLF1 and CLCF1 proteins back to these nerves. When these proteins bind to the CNTFR receptor on the nerve cells, they trigger an important change inside the nerve that instructs the nerve to stop producing norepinephrine and start producing a different chemical messenger called acetylcholine. When the nerve changes, it becomes a cholinergic nerve. Mature sweat glands require cholinergic nerve signals to function properly and respond correctly to temperature changes. 2
In people with CRLF1 or CLCF1 variants, the CRLF1 and CLCF1 proteins are not produced, may not attach to each other properly, or may not function as they should. If the CRLF1–CLCF1 complex does not form correctly, then it cannot effectively bind and activate the CNTFR receptor. Without proper activation of this receptor, the nerve cell does not receive the signal telling it to switch from producing norepinephrine to producing acetylcholine. 2
As a result, the normal developmental switch fails to occur, and the sweat glands remain mainly connected to noradrenergic nerves. This can lead to sweating when exposed to cold, sweating triggered by unusual stimuli, difficulty regulating body temperature, and episodes of high fever, also called hyperthermia.
In addition to their role in sweating, the CRLF1 and CLCF1 genes are also important for the development of other parts of the nervous system and for normal bone development. This explains why CISS can affect multiple areas of the body, including facial features, muscle tone, and skeleton. 4,13
CISS can be classified into two subtypes based on the specific gene involved: CISS type 1 and CISS type 2. Both subtypes have similar symptoms and differ only by the gene involved.
CISS1 and CISS2 have the same signs and symptoms and are difficult to differentiate clinically. For this reason, the general term “CISS” is used until genetic testing confirms the specific gene involved. 2
The inheritance of CISS is autosomal recessive. Recessive genetic conditions occur when an individual inherits a pathogenic variant from each parent. If an individual receives one normal gene and one mutated gene, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
The true prevalence rate of CISS is unknown, but the condition is considered very rare. As of 2021, approximately 99 individuals have been identified worldwide with genetically confirmed cold-induced sweating syndrome. 2 It has been reported worldwide. CRLF1-associated CISS appears to be particularly prevalent in the Mediterranean region. 4, 12
Doctors suspect CISS based on a person’s medical history and key symptoms, especially sweating caused by cold temperatures. To evaluate for CISS, doctors look for common signs of the condition. These include heavy sweating in the cold and reduced sweating in warm weather. They also do a careful physical exam to check for unusual facial features, differences in the arms or legs, an abnormal startle response, and problems with body temperature control. 2
Other tests may be done based on the person’s symptoms. These can include a pulse oximetry test to check oxygen levels, a swallow study to make sure it’s safe to eat and drink, and evaluations by a neurologist or an eye doctor. A physical or occupational therapy assessment may also be needed, especially if there is significant bending of the fingers or elbows. 2
The diagnosis cannot be confirmed based on clinical features, and genetic testing is needed to confirm two changes in the CRLF1 or CLCF1 gene. 2, 12
There is no cure for CISS, treatment focuses on symptom management and supportive care. Symptom management may include avoiding cold exposure to reduce sweating, protective eye care, nutritional support, and care from a team of specialists, including neurologists, pediatricians, eye doctors, and orthopedic specialists.4
Management of symptoms may include the following: 2, 4
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ . All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
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