Cold-Induced Sweating Syndrome (CISS)

Cold-induced sweating syndrome (CISS) is a very rare genetic disease. It mainly affects how the body controls temperature, sweating, face muscles, and bones. Children with this condition sweat a lot when they are in cold air, but they may sweat very little in hot weather. In many babies, the first signs of this disease are called “Crisponi syndrome.” Later in childhood, the same child shows the “cold-induced sweating” phase, so doctors now think Crisponi syndrome and CISS are the same disease at different ages. The syndrome is caused by harmful changes (mutations) in two genes called CRLF1 or CLCF1. These genes help a nerve-signal pathway called the CNTFR pathway. This pathway is important for the growth and health of many nerves, including the nerves that control sweat glands and posture.

Cold-induced sweating syndrome (CISS) is a very rare genetic condition in which a person starts to sweat a lot when they are exposed to cold temperatures instead of heat. In many children, the first signs appear in babyhood as “Crisponi syndrome,” with feeding problems, strange facial muscle spasms, high fevers, and trouble controlling body temperature. Later in childhood, these children develop strong sweating attacks triggered by cold air, anxiety, or emotions.

CISS is inherited in an autosomal recessive way. This means a child gets one faulty copy of a gene from each parent. Most people with CISS have changes in a gene called CRLF1 (type 1, CISS1), and a smaller group have changes in a gene called CLCF1 (type 2, CISS2). These genes make proteins that help nerve cells and the autonomic nervous system develop and work properly, especially the pathways that control sweating and body temperature. When they do not work well, the balance of “fight-or-flight” and “rest-and-digest” signals is disturbed, leading to paradoxical sweating in the cold, abnormal pain and temperature sensation, and bone or spine problems such as kyphoscoliosis.

Because of these gene changes, the nerves that go to the sweat glands do not switch to their normal “cholinergic” type after birth. They stay in an immature “noradrenergic” state. This wrong nerve type makes sweating happen at the wrong time and place, especially as strong sweating in the cold.

CISS is an autosomal recessive disease. This means the child must receive one faulty copy of the gene from each parent. Parents usually have no symptoms, because they carry only one faulty copy and one normal copy.

Other names

Cold-induced sweating syndrome has several other names used in the medical literature. One common name is CISS, which is simply the short form of the full name.

Another name is Crisponi syndrome, especially when doctors talk about the severe baby phase with feeding problems, muscle spasms, and high fevers.

You may also see the term Crisponi/cold-induced sweating syndrome 1 (CISS1) for cases caused by CRLF1 gene mutations, and Crisponi/cold-induced sweating syndrome 2 (CISS2) for cases caused by CLCF1 gene mutations.

Some sources group this condition under CNTF receptor-related disorders, because the CRLF1–CLCF1 complex acts on the CNTF receptor pathway.

Types of cold-induced sweating syndrome

1. CISS type 1 (CISS1)
CISS1 is the form caused by harmful variants in the CRLF1 gene. It is the most common form, making up about 90% of reported cases. The gene sits on chromosome 19. Many different mutations in CRLF1 have been described, and the severity of symptoms can vary from very severe in newborns to milder problems in adults.

2. CISS type 2 (CISS2)
CISS2 is caused by mutations in the CLCF1 gene on chromosome 11. It is much rarer than CISS1. Only a small number of families with CLCF1-related disease have been reported. The clinical picture is very similar to CISS1, with early feeding problems and later cold-induced sweating.

3. Infantile “Crisponi syndrome” phase
In many patients, the first months of life are dominated by what was originally called Crisponi syndrome. Babies may have severe feeding problems, muscle spasms when they are handled, breathing difficulties, and episodes of very high fever. Many infants with the most severe form die early, while survivors later develop the typical cold-induced sweating pattern.

4. Childhood / adolescent cold-induced sweating phase
Children who survive the infant phase often develop the classic CISS picture in later childhood. They have little sweating in heat, but show strong, patchy sweating over the face, chest, and arms when exposed to cool air, during stress, or sometimes after eating sweets. Spinal curvature (kyphoscoliosis) and hand/foot deformities can become more obvious during this phase.

Causes

1. Biallelic CRLF1 gene mutations
The main direct cause of CISS1 is having two faulty copies of the CRLF1 gene (one from each parent). These mutations can stop the cell from making enough correct CRLF1 protein, which is needed to form the CRLF1–CLCF1 complex that signals through the CNTF receptor.

2. Biallelic CLCF1 gene mutations
In a minority of patients, CISS2 results from two harmful changes in the CLCF1 gene. These changes disrupt the production or stability of the CLCF1 protein, again preventing proper CNTFR signaling and leading to the same clinical syndrome.

3. Loss-of-function mutations
Many reported mutations in CRLF1 or CLCF1 are “loss-of-function.” This means they either truncate the protein or disturb its folding so much that it cannot work. Without enough functional protein, the signaling pathway fails, and nerves do not develop normally.

4. Missense mutations with misfolding
Some mutations change only a single amino acid (missense), but still cause disease. These missense changes can make the CRLF1 or CLCF1 proteins fold incorrectly, causing them to be trapped inside the cell instead of being secreted and forming a stable complex.

5. Failure of CRLF1–CLCF1 complex formation
Even when each gene makes some protein, certain mutations stop CRLF1 and CLCF1 from joining together as a heterodimer. If the complex does not form, it cannot bind to the CNTF receptor and cannot send the correct growth signals to developing neurons.

6. Impaired CNTF receptor (CNTFR) pathway signaling
The CRLF1–CLCF1 complex is a ligand for the CNTFR pathway. When this pathway is not activated properly, many types of nerve cells, including sympathetic and motor neurons, may not differentiate or survive as they should. This broad nerve problem contributes to temperature control and skeletal problems in CISS.

7. Abnormal sympathetic neuron development
Studies of the disease pathway show that sympathetic neurons, which normally change from noradrenergic to cholinergic type in sweat glands, fail to change in CISS. This abnormal development of autonomic nerves is a key cause of the paradoxical sweating pattern.

8. Failure of cholinergic switch in sweat glands
Skin biopsies from CISS patients show that sweat glands lack normal cholinergic nerve endings and instead have noradrenergic fibers. This “wrong wiring” is a direct cause of sweating in cold conditions and poor sweating in heat.

9. Autosomal recessive inheritance (two carrier parents)
The condition appears when a child inherits one mutated copy of the gene from each carrier parent. Each pregnancy between two carriers has a 25% chance of producing an affected child. Carrier parents usually have no symptoms.

10. Consanguinity (parents related by blood)
Because the disease is recessive, it is more likely to appear in families where the parents are related (for example, cousins). In such situations, both parents may carry the same rare mutation, increasing the chance of affected children.

11. Founder mutations in certain regions
Some areas, such as parts of Sardinia, Turkey, and Spain, have a higher number of CISS cases. This suggests “founder” mutations, where one ancient mutation has spread within a population, making the condition more common there than elsewhere.

12. Having an affected sibling
If one child in a family has CISS, brothers and sisters have a higher chance of having the same condition because they may inherit the same genes from carrier parents. This family pattern reflects the autosomal recessive cause.

13. Compound heterozygous mutations
Some patients have two different mutations in the same gene (for example, one mutation on each CRLF1 copy). Together, these two different faulty copies act like a biallelic loss of function and cause disease.

14. Severe truncating mutations
Children with very early, severe Crisponi-type presentations may have truncating mutations that completely remove large parts of the protein. These very severe gene changes are linked with more serious breathing and feeding problems in newborns.

15. Milder missense mutations
In some families, adults are first diagnosed because they have a milder form of CISS. These milder cases often carry missense mutations that allow some residual function of the protein, leading to less severe early symptoms but clear cold-induced sweating later in life.

16. Interaction with LIFR / related pathways (shared mechanism)
CISS shares a similar biological pathway with Stüve-Wiedemann syndrome, caused by LIFR mutations. While LIFR mutations do not cause CISS itself, this overlap in signaling pathways supports that impaired cytokine signaling to developing neurons is a main cause of the clinical picture.

17. Developmental impact on bone growth
The same pathway that affects nerves also influences bone development. When these signals are abnormal, children can develop spinal curvature and limb deformities. This skeletal involvement reflects a downstream effect of the gene mutations.

18. Developmental impact on oropharyngeal muscles
Abnormal nerve development around the mouth and throat leads to facial weakness, swallowing problems, and spasms. These problems in the infant phase are another direct result of the gene-driven nerve development defect.

19. Developmental impact on autonomic temperature control centers
The autonomic nervous system, which controls temperature and sweating, depends on correct early signaling. When this is disturbed by CRLF1/CLCF1 mutations, children cannot adjust to cold or heat normally and show mixed hyperthermia and cold-induced sweating.

20. Very rare KLHL7-related Crisponi-like conditions (overlapping spectrum)
Some patients with similar features (Crisponi/cold-induced sweating-like syndrome) have mutations in a different gene, KLHL7. These are usually classified separately, but they show how defects in related molecular networks can cause a very similar clinical picture.

Symptoms

1. Cold-induced sweating
The hallmark symptom is heavy sweating that appears when the child is in cool air rather than in heat. The sweating commonly affects the face, chest, arms, and upper trunk. Children may become wet and clammy in cold environments but sweat much less in hot weather.

2. Little sweating in hot weather and heat intolerance
Many affected people sweat very little in hot conditions and can feel overheated or flushed. They may complain of feeling very hot and may not tolerate warm rooms or exercise well, because their body cannot cool itself in a normal way.

3. Temperature regulation problems
Because sweating patterns are abnormal, the whole body has trouble keeping a steady temperature. Infants may have episodes of very high fever, while older children may have both overheating and intense cold-related sweating at different times.

4. Facial muscle weakness
Many babies and children with CISS have lower facial weakness. Their mouth may droop slightly, their smile may look weak, and they may have difficulty closing the lips tightly. This weakness is due to affected cranial motor neurons.

5. Distinctive facial features
Affected children often share certain facial traits, such as a short upturned nose, full cheeks, small mouth, and sometimes a short neck. These features can help experienced doctors recognize the syndrome.

6. Feeding and swallowing difficulties in infancy
In the first weeks and months of life, many infants cannot suck or swallow well. They may choke, cough, or seem unable to coordinate breathing and swallowing, sometimes needing feeding tubes. This problem is part of the Crisponi phase.

7. Muscle spasms and abnormal posturing in newborns
When babies with CISS are touched, moved, or upset, their face and body may suddenly stiffen. They can show opisthotonus-like posturing (arching of the back) and facial contractions with puckered lips and foamy saliva. These spasms can also affect breathing.

8. Laryngospasm and breathing problems
Some infants have sudden closing of the voice box (laryngospasm) and episodes of breathing difficulty. These events can be frightening and may require emergency or intensive care treatment.

9. Recurrent hyperthermia (high fever) in infancy
In the first year of life, many babies have repeated episodes of very high body temperature without clear infection. These hyperthermia episodes are part of the early phase of the syndrome and reflect poor autonomic control.

10. Camptodactyly and hand deformities
Camptodactyly means fixed bending of the fingers. Children with CISS often have flexed fingers and fisted hands. Over time, these contractures may limit hand use and may need physical therapy or surgery.

11. Foot deformities and misshapen feet
Misshapen feet, such as high arches, curved toes, or other deformities, are common. These changes are part of the skeletal involvement and may affect walking or require orthopedic care.

12. Spinal curvature (kyphoscoliosis)
Many older children and adolescents develop curvature of the spine (kyphoscoliosis). This can worsen with growth and may need bracing or surgery. The spinal deformity is a major cause of disability in some patients.

13. Excess startle responses
Some babies have an unusually strong startle reaction to sound or touch. They may stiffen or show exaggerated movements when startled. This feature reflects increased sensitivity of the nervous system.

14. Skin changes and rashes in infancy
A scaly, red rash has been reported in some infants with the Crisponi phase of the disease. This rash usually appears early and may improve or change as the child grows.

15. Urinary and other system involvement (in some patients)
Case reports describe CISS patients with urinary tract anomalies or other organ involvement. These features are not present in every child, but they show that the disease can affect several organ systems beyond nerves, bones, and skin.

Diagnostic tests

Physical examination

1. General physical and growth examination
The doctor will first do a full physical exam. They check height, weight, head size, and body proportions. They look for signs such as poor growth, unusual body shape, or overall weakness, which can suggest a complex genetic condition like CISS.

2. Temperature and sweating pattern assessment
The clinician observes how the child sweats in different room temperatures. In CISS, sweating is often strong in cool air and reduced in warmth. Parents’ reports about sweating at home, at school, and outdoors are also very important for diagnosis.

3. Craniofacial and facial muscle examination
The doctor closely examines facial features and facial muscle strength. They note any drooping, weak smile, puckering, or inability to close the mouth well. These signs help distinguish CISS from other conditions with abnormal sweating.

4. Musculoskeletal examination (hands, feet, spine)
Detailed examination of hands, feet, and spine is done to detect camptodactyly, fisted hands, foot deformities, and spinal curvature. These findings support the diagnosis and guide later orthopedic management.

5. Neurological examination
A full neurological exam checks muscle tone, reflexes, movement patterns, and coordination. Abnormal startle responses, posturing, and facial weakness can all be documented. The pattern of findings helps confirm that a neurodevelopmental problem is present.

Manual or bedside functional tests

6. Controlled cold exposure (“cold provocation”) test
In a safe, supervised setting, the doctor may briefly expose part of the child’s skin to cool air or a cold pack and carefully watch for sweating. Children with CISS often show rapid, strong sweating in these cold conditions. This simple bedside test can highlight the paradoxical sweating pattern.

7. Feeding and swallowing assessment in infants
For babies, speech and swallowing therapists observe feeding. They watch sucking, swallowing, breathing, and any choking or coughing. This assessment shows how severe the oropharyngeal muscle involvement is and is key for early Crisponi-phase diagnosis.

8. Joint range-of-motion testing
The clinician gently moves the child’s joints, especially fingers, wrists, elbows, and feet, to measure how far they can bend and straighten. Limited movement with fixed flexion confirms camptodactyly and other contractures, supporting the skeletal part of the diagnosis.

9. Functional hand and motor assessment
Occupational or physical therapists test how the child uses their hands, walks, and performs daily tasks. These manual assessments give a real-life picture of how muscle stiffness, deformity, and weakness affect function and help plan therapy.

Laboratory and pathological tests

10. Basic blood tests (screening and ruling out other diseases)
Doctors usually order a complete blood count, electrolytes, and other standard blood tests. These are often normal in CISS but help rule out infections, metabolic disorders, or other causes of fever, weakness, or poor growth that might mimic the syndrome.

11. Tests for other genetic or metabolic conditions (differential diagnosis)
Because other syndromes like Stüve-Wiedemann syndrome, PERCHING syndrome, and other bone or autonomic disorders can look similar, doctors may order targeted tests to exclude them. This might include specific gene tests or metabolic screens, depending on the clinical picture.

12. DNA sequencing of CRLF1
Genetic testing of the CRLF1 gene is central to confirming CISS1. Modern sequencing methods can read through the entire gene and detect many types of mutation. Finding two disease-causing variants in CRLF1 in a patient with typical signs confirms the diagnosis.

13. DNA sequencing of CLCF1
If CRLF1 testing is negative, sequencing of the CLCF1 gene can detect CISS2. Again, the diagnosis is confirmed when two harmful variants are found in a child with compatible clinical features.

14. Multigene panel or exome sequencing
In some complex cases, doctors use gene panels for autonomic or skeletal disorders, or even whole-exome sequencing, to search for CRLF1, CLCF1, or related genes at the same time. This approach is useful in rare diseases with overlapping symptoms.

15. Skin biopsy of sweat glands with nerve staining
A skin biopsy from a sweating area can be examined under the microscope. In CISS, sweat glands may show preserved structure but abnormal nerve innervation: few cholinergic fibers and many noradrenergic fibers. Special staining confirms this pattern and supports the diagnosis.

Electrodiagnostic tests

16. Nerve conduction studies (NCS)
NCS measure how fast and how well electrical signals move along peripheral nerves. In many CISS patients, sensory and motor conduction may be near normal, but testing can rule out other neuropathies that might cause muscle or sweating problems.

17. Electromyography (EMG)
EMG records electrical activity in muscles. It can show whether muscle weakness is due to a nerve or muscle problem. In CISS, EMG may be relatively normal or show subtle changes, but it is mainly used to exclude other neuromuscular diseases in the differential diagnosis.

18. Autonomic sweat testing (e.g., QSART or thermoregulatory sweat test)
Specialized autonomic labs can measure sweating responses to controlled stimuli. Tests like QSART or thermoregulatory sweat testing show abnormal sweat patterns in CISS, such as excessive sweat output in cold conditions and reduced sweating in heat. These findings match the clinical story.

Imaging tests

19. Spine X-ray
Plain X-rays of the spine are used to detect and measure scoliosis and kyphosis. Regular imaging helps track how fast the curve is growing and guide decisions about bracing or surgery. Spinal deformities are a well-described complication in older children with CISS.

20. MRI of spine and/or brain (when needed)
Magnetic resonance imaging (MRI) can be done if there are unusual signs, severe scoliosis, or concern about other brain or spinal cord problems. While MRI findings are not specific for CISS, the scan is important to rule out structural causes of symptoms and to plan orthopedic or neurosurgical care if needed.

Non-pharmacological treatments (therapies and others)

(These are supportive options. They must always be planned with your medical team. They do not replace professional care.)

1. Temperature and clothing management
   People with cold-induced sweating syndrome often sweat when exposed to cool air, especially below about 22°C. Dressing in breathable layers, using soft fabrics, and adjusting clothing quickly when moving between rooms helps reduce sudden sweating bursts. Families can learn to keep indoor temperatures stable and avoid very cold wind blowing directly on the face or trunk. This careful environment control is one of the simplest yet most powerful supports.

2. Avoiding rapid temperature shifts
   Fast changes from warm to cold, or from indoor to outdoor settings, can trigger sweating attacks and discomfort. Planning outings, warming up the car in advance, and giving the body time to adapt to new temperatures can lower the frequency and severity of episodes. This gentle pacing of environmental change supports the autonomic nervous system and reduces stress on the heart and circulation.

3. Stress-reduction and relaxation training
   Emotional stress, anxiety, and sudden fright can trigger or worsen cold-induced sweating in CISS. Relaxation breathing, guided imagery, mindfulness, and soft music can help calm the “fight-or-flight” system. Working with a psychologist to learn simple coping skills, especially for children facing school and social stress, can reduce both emotional suffering and sweat episodes linked to emotional triggers.

4. Physiotherapy for posture and spine health
   Many children with CISS develop abnormal curvature of the spine (kyphoscoliosis) and joint stiffness. A physiotherapist can teach stretching, strengthening, and posture exercises to protect the back and chest, improve breathing, and maintain mobility. Early and regular therapy may delay or reduce the need for major spine surgery and help with everyday activities like walking, sitting, and playing.

5. Occupational therapy and assistive devices
   Occupational therapists help children with CISS adapt daily tasks at home and school. They may suggest special chairs, adapted cutlery, or writing aids. Braces or supports can help with joint stability and spine posture. The goal is to promote independence and safety, reduce fatigue, and make it easier for the child to join normal activities while living with muscle weakness or contractures.

6. Speech, feeding, and orofacial therapy
   In infancy, many patients have trouble sucking, swallowing, and opening the mouth because of facial muscle spasms and trismus. Speech and feeding therapists can teach safe swallowing techniques, exercises to improve mouth opening, and strategies to reduce choking risk. Early orofacial therapy supports nutrition, helps prevent aspiration, and makes later speech development smoother.

7. Dental and oral-health care
   Children with CISS often have difficulty brushing properly, may have restricted mouth opening, and can develop dental caries and gum disease. Regular check-ups with a dentist experienced in special-needs children, fluoride use, and individualized cleaning tools (such as small-head brushes or electric brushes) reduce infection risk and protect teeth, which is important when anesthesia or surgery may be needed for spine or jaw problems.

8. Skin care and infection prevention
   Repeated episodes of sweating, even in cool environments, can irritate the skin, especially in body folds. Gentle cleansing, careful drying of sweaty areas, use of non-fragranced emollients, and breathable clothing help prevent fungal and bacterial infections. Dermatology review is helpful if rashes, odor, or recurring skin infections occur, so that topical treatments can be used early.

9. Hydration and electrolyte balance
   Because sweating attacks can be heavy, people with CISS may lose more fluid and salt than expected in cool weather. Drinking enough water, and sometimes using oral rehydration solutions recommended by a doctor, helps keep blood pressure stable and prevents dizziness or faintness. Parents should watch for signs of dehydration such as dry mouth, dark urine, or unusual fatigue.

10. School and workplace accommodations
    Teachers and employers can support people with CISS by allowing flexible clothing rules, access to fans or extra layers, and short breaks when sweating is severe. Seating away from direct air conditioning vents or near temperature-controlled zones can make a big difference. Clear communication about the condition avoids misunderstandings when a child appears flushed or sweaty even in a cool classroom.

11. Psychological support and peer groups
    Living with a rare condition can cause anxiety, sadness, or social isolation. Talking therapies, family counselling, and peer support networks for rare disease families help people share feelings, learn coping strategies, and feel less alone. This mental-health support is as important as physical treatments for long-term quality of life.

12. Genetic counselling for families
    Since CISS is autosomal recessive, parents and siblings may want to understand their own carrier status and future pregnancy risks. Genetic counsellors explain how the condition is inherited, the chance of another child being affected, and options such as prenatal testing or pre-implantation genetic testing. This helps families make informed decisions that fit their values and circumstances.

(Other non-drug supports, such as careful planning of sports, fall-prevention strategies, and safe use of heaters or air-conditioning, can be added by the care team based on each person’s needs.)

Drug treatments

Important: The medicines below are not approved specifically for “cold-induced sweating syndrome.” They are used to control symptoms such as sweating, pain, or mood problems based on small studies and experience. Doses and choices must always be made by a qualified doctor. Never start, stop, or change any medicine on your own.

1. Clonidine (Catapres and similar)
   Clonidine is a centrally acting alpha-2 agonist originally approved for high blood pressure and later for attention-deficit/hyperactivity disorder. In CISS, low-dose clonidine can reduce the release of noradrenaline in brain regions that drive cold-triggered sweating. Case reports show that clonidine alone, or combined with amitriptyline, can greatly suppress cold-induced sweating in some patients. Typical oral adult doses for hypertension range from 0.1–0.3 mg twice daily; in CISS, much lower individualized doses are used. Common side effects include low blood pressure, dry mouth, fatigue, and constipation.

2. Amitriptyline
   Amitriptyline is a tricyclic antidepressant approved for depression and used off-label for chronic pain and some neurological conditions. In CISS, small doses together with clonidine may stabilize autonomic function and improve sleep, reducing sweating linked to pain and arousal. It is usually taken at night (for example 10–25 mg to start in adults, then adjusted). Side effects include drowsiness, weight gain, dry mouth, and risk of heart rhythm changes or mood shifts, especially in young people. Close monitoring is essential.

3. Moxonidine
   Moxonidine is another centrally acting antihypertensive agent that acts on imidazoline receptors and reduces sympathetic outflow. It is not approved in all countries, but reports suggest it can help control cold-induced sweating when clonidine or clonidine–amitriptyline combinations are not tolerated. Dosing and safety data come mainly from high blood pressure treatment, where side effects include low blood pressure, dry mouth, dizziness, and fatigue. It should be prescribed only by specialists with experience in autonomic disorders.

4. Topical glycopyrronium cloth (Qbrexza)
   Topical glycopyrronium tosylate cloths are approved in the United States to treat primary axillary (underarm) hyperhidrosis in adults and children 9 years and older. They work by blocking muscarinic receptors in sweat glands, reducing sweat production in the treated area. In CISS, they may be used off-label on specific body areas (for example the face or upper trunk) to reduce localized sweating when cold. Because they can still be absorbed through the skin, side effects such as dry mouth, blurred vision, and urinary retention must be watched for.

5. Topical glycopyrrolate solutions or creams
   Dermatologists sometimes prescribe compounded topical glycopyrrolate (for example 0.5–2% solutions or creams) for craniofacial hyperhidrosis. The drug blocks cholinergic stimulation of sweat glands in the treated region. Evidence from hyperhidrosis studies suggests good effect on facial sweating with fewer systemic side effects than oral tablets. In CISS, this may be considered to reduce sweating in cold-exposed facial areas, but application sites, frequency, and monitoring must be individualized.

6. Oral glycopyrrolate
   Oral glycopyrrolate is an anticholinergic medicine approved for peptic ulcer disease and for reducing secretions during anesthesia and in some pediatric drooling conditions. Off-label, oral glycopyrrolate is widely used for generalized hyperhidrosis because it blocks acetylcholine at sweat glands throughout the body. In CISS, low doses given two or three times a day may reduce both daytime and nighttime sweating, but side effects such as dry mouth, constipation, urinary retention, and blurred vision can limit long-term use.

7. Oxybutynin (oral tablets or extended-release forms)
   Oxybutynin is approved for overactive bladder and works as an antimuscarinic agent, reducing smooth-muscle contractions and sweat production. Off-label, oral and extended-release oxybutynin can reduce generalized or focal hyperhidrosis, including in children, but the drug can also decrease normal sweating and increase the risk of overheating in hot environments. Typical adult starting doses for overactive bladder are 5 mg two or three times daily. Side effects include dry mouth, constipation, blurry vision, and sleepiness.

8. Other anticholinergics (for example sofpironium bromide)
   A number of topical and systemic anticholinergics, including newer agents such as sofpironium bromide, are being developed or have been approved in some regions specifically for primary hyperhidrosis. They act on muscarinic receptors in sweat glands, similar to glycopyrrolate. In future, these medicines may offer more targeted options for people with cold-induced sweating, but at present their use in CISS remains experimental and must be carefully supervised.

9. OnabotulinumtoxinA (BOTOX) injections
   OnabotulinumtoxinA is approved for primary axillary hyperhidrosis and works by blocking acetylcholine release at nerve endings that stimulate sweat glands. Small studies and case reports show that local injections can greatly reduce sweating for several months, including in cases of cold-induced hyperhidrosis when other treatments fail. Injections are given into the skin of the affected area (for example 50 units per axilla for axillary hyperhidrosis), and must be repeated every 4–12 months. Side effects include injection-site pain, temporary weakness, or flu-like symptoms.

10. Selective serotonin reuptake inhibitors (for associated mood or anxiety)
    Some people with CISS develop anxiety or depression, which can make sweating episodes worse. Medicines such as fluoxetine, approved for depression and anxiety disorders, have been used in single cases alongside other therapies to improve mood and possibly decrease trigger-related sweating. Any SSRI must be chosen and dosed by a psychiatrist, with attention to age, other medicines, and the risk of side effects like stomach upset, sleep changes, or mood swings.

(Many other medicines—such as pain-relieving drugs or muscle relaxants—may be used to treat specific problems in CISS, but they are not directly targeted at the sweating itself.)

Dietary molecular supplements

Important: Evidence for supplements in cold-induced sweating syndrome is very limited. Most suggestions are based on general support for nerve, bone, and immune health. Always talk with a doctor before starting any supplement, especially in children.

1. Omega-3 fatty acids (fish-oil or algae-oil)
   Omega-3 fatty acids (EPA and DHA) support heart, brain, and nerve health and may reduce low-grade inflammation. In CISS, they do not treat sweating directly, but they may promote overall cardiovascular and nervous-system resilience, which can be helpful in a condition with autonomic imbalance. Typical doses used for general health are around 250–500 mg of combined EPA and DHA per day in adults, with pediatric doses adjusted by weight under medical guidance.

2. Vitamin D with calcium
   Children with rare genetic syndromes that affect mobility and spine health often have an increased risk of low bone mineral density. Adequate vitamin D and calcium intake, from food or supplements, supports bone growth and helps prevent fractures, especially when scoliosis or reduced physical activity is present. Doses must be tailored to age and blood levels, because both deficiency and excess can harm bones and kidneys.

3. B-complex vitamins (B1, B6, B12, folate)
   B-group vitamins are essential for energy production and nerve function. In people with chronic illness, poor appetite, or malabsorption, B-vitamin supplements can correct deficiencies that may worsen fatigue or neuropathic symptoms. A balanced B-complex usually provides doses near the recommended daily intake, and is taken once daily with food. Monitoring is needed in severe kidney disease or when high-dose B6 is considered.

4. Magnesium
   Magnesium plays a key role in muscle relaxation and nerve signaling. Supplementing magnesium may help reduce muscle cramps, improve sleep quality, and support heart rhythm in people who have low levels due to poor intake or chronic illness. Typical adult doses range from 200–400 mg elemental magnesium per day, often as magnesium citrate or glycinate, but high doses can cause diarrhea and must be adjusted carefully.

5. Probiotics
   Probiotic supplements containing beneficial gut bacteria may support digestion, immune balance, and nutrient absorption in people with poor appetite or frequent antibiotic use. While they do not directly affect sweating, a healthier gut may improve overall resilience and reduce inflammation. Dose and strain vary; products are usually taken once or twice daily with food. People with severe immune compromise should use them only under medical supervision.

6. Antioxidant vitamins (for example vitamin C and vitamin E)
   Antioxidants help protect cells from oxidative stress, which can be increased in chronic illnesses and in tissues under repeated temperature and metabolic stress. Balanced doses of vitamin C and vitamin E from diet or supplements may support skin integrity and immune defenses. Very high doses are not recommended, as they may cause gastrointestinal upset or interact with other medicines such as blood thinners.

(Supplement choices should always be based on blood tests and a dietitian’s or doctor’s advice, not self-prescription.)

Regenerative and stem-cell-related drugs

At present, there are no approved regenerative or stem-cell drugs specifically for cold-induced sweating syndrome. Research into gene therapy, neurotrophic factors, and stem-cell approaches for autonomic and genetic disorders is ongoing, but these treatments remain experimental and are not available as routine care for CISS. Any offers of “stem-cell cures” outside regulated clinical trials should be viewed with extreme caution.

Doctors instead focus on early recognition, careful symptom control, and support for growth and development. In the future, better understanding of CRLF1 and CLCF1 signaling may open the door to targeted therapies, but for now the safest path is evidence-based, multidisciplinary care.

Surgeries and procedures

1. Spinal surgery for kyphoscoliosis
   Many individuals with CISS develop progressive thoracolumbar kyphoscoliosis. When bracing and physiotherapy are not enough, orthopedic surgeons may recommend spinal fusion or corrective surgery. These procedures straighten and stabilize the spine, protect lung and heart function, and reduce pain. Surgery is major and requires careful planning with anesthesiologists familiar with autonomic instability and temperature-control issues in CISS.

2. Surgery for severe joint contractures
   Some patients develop fixed joint contractures that limit walking, sitting, or self-care. Orthopedic or plastic surgeons may perform tendon lengthening, contracture release, or joint realignment surgeries to improve range of motion and function. Surgery is usually combined with intensive physiotherapy before and after the procedure to maintain the gains and prevent recurrence.

3. Dental and jaw procedures
   In severe cases of jaw restriction, dental caries, or malocclusion, patients may need dental restorations, extractions, or even corrective jaw surgery under general anesthesia. The aim is to improve chewing, swallowing, mouth opening, and oral hygiene. Because CISS patients can have difficult airways and autonomic instability, planning with anesthesiology and dentistry teams is essential for safety.

4. Endoscopic thoracic sympathectomy (rare, last resort)
   For extremely disabling focal hyperhidrosis that does not respond to medicines or botulinum toxin, some centers perform endoscopic thoracic sympathectomy (cutting or clipping the sympathetic nerves that control sweating in certain body regions). While this can greatly reduce sweating in the treated area, it carries risks such as compensatory sweating in other sites, nerve injury, or lung problems, and is rarely considered in genetic syndromes like CISS.

5. Feeding tube placement in infancy (if needed)
   For infants with very severe feeding difficulty, recurrent aspiration, or poor weight gain, surgeons may place a gastrostomy tube directly into the stomach. This procedure allows safe delivery of nutrition and medicines while protecting the lungs. As feeding improves with age, some children may later have the tube removed.

Prevention and lifestyle tips

Cold-induced sweating syndrome itself cannot be prevented because it is genetic, but several steps can help prevent complications and reduce triggers:

1. Genetic counselling before future pregnancies in affected families helps parents understand recurrence risks and available testing options.

2. Early diagnosis and referral to specialized centers allow timely support with feeding, breathing, spine monitoring, and autonomic symptoms.

3. Careful temperature and clothing management reduces sweating attacks, dehydration, and skin problems.

4. Good hydration and electrolyte balance prevent low blood pressure and fainting during heavy sweating.

5. Regular physiotherapy and posture training help prevent severe kyphoscoliosis and joint contractures.

6. Routine dental and oral-health care prevent infections and complications related to limited mouth opening and drooling.

7. Vaccinations and early treatment of infections protect fragile infants and children who may have breathing and feeding problems.

8. Psychological support and school accommodations reduce emotional stress that may trigger sweating and improve quality of life.

9. Safe, supervised physical activity maintains muscle strength and bone health while avoiding overheating or over-exertion.

10. Avoiding unproven “cures” or risky procedures protects patients from harm and focuses resources on evidence-based care.

Diet: what to eat and what to avoid

A healthy, balanced diet supports growth, bone health, and energy in people with CISS, especially those with feeding difficulties or reduced physical activity.

Helpful foods to eat
Focus on:

• High-quality proteins such as lean meat, fish, eggs, dairy, legumes, and tofu to support muscle and bone strength.

• Calcium- and vitamin-D-rich foods like dairy products, fortified plant milks, and leafy greens to help protect bones affected by kyphoscoliosis or reduced mobility.

• Fruits and vegetables of many colors to provide antioxidants, vitamins, and fiber that support immune function and skin health.

• Whole grains such as oats, brown rice, and whole-wheat bread for steady energy and digestive health.

• Healthy fats from olive oil, nuts, seeds, and oily fish to support nerve and brain function.

Foods and drinks to limit or avoid

• Very spicy foods and large amounts of caffeine (coffee, strong tea, energy drinks) can trigger or worsen sweating in some people and may be best limited, especially close to cold-exposure situations.

• Sugary drinks and ultra-processed snacks add calories without nutrients and may worsen weight control and energy swings.

• High-salt processed foods can contribute to blood-pressure problems, particularly for those on medicines like clonidine.

• Alcohol and tobacco should be avoided because they can damage nerves, heart, and liver and interact with many medicines used in CISS care.

A dietitian familiar with rare disorders can build a detailed meal plan tailored to the child’s growth, oral-motor ability, and any swallowing or chewing limitations.

When to see a doctor

You should seek medical help urgently (emergency) if a person with cold-induced sweating syndrome has:

• Trouble breathing, blue lips or fingers, or pauses in breathing.

• A very high fever, repeated vomiting, or signs of severe infection (for example extreme tiredness, confusion, or poor response).

• Chest pain, severe dizziness, or fainting, especially soon after starting or changing medicines such as clonidine, moxonidine, or anticholinergics.

You should arrange a prompt medical visit if you notice:

• New or worsening cold-induced sweating attacks.

• Rapid progression of spine curvature, posture changes, or new back pain.

• Problems with feeding, growth, chewing, or swallowing.

• New mood changes, anxiety, or school difficulties.

• Side effects from medicines such as extreme sleepiness, constipation, urinary problems, or vision changes.

Regular check-ups with a multidisciplinary team (neurology, genetics, orthopedics, cardiology, dentistry, physiotherapy, and psychology) are recommended to adjust treatment as the child grows.

Frequently asked questions (FAQs)

1. Is cold-induced sweating syndrome the same as Crisponi syndrome?
   They are different stages of the same disease spectrum. Many babies first show Crisponi syndrome features such as facial spasms, feeding problems, and high fevers. As they grow, these early symptoms often improve, and cold-induced sweating becomes the main complaint. Both stages are linked to changes in the CRLF1 or CLCF1 genes and are now grouped as CS/CISS.

2. How common is CISS?
   CISS is extremely rare. Only a small number of families have been reported worldwide in the medical literature, mainly from Europe and the Middle East. Because many cases may be misdiagnosed in infancy as other neurological or feeding disorders, the true number is not known but is certainly very low.

3. Can cold-induced sweating syndrome be cured?
   Right now there is no cure that corrects the underlying genetic change. Treatment focuses on controlling sweating, protecting the spine and joints, supporting feeding and breathing, and improving overall quality of life. Future research into gene-based therapies may offer more targeted options, but these are not yet available in routine clinical practice.

4. Will my child outgrow the condition?
   Many infants with Crisponi-like symptoms improve dramatically during the first few years of life, but cold-induced sweating and skeletal problems often persist into childhood and adulthood. The severity can vary widely: some adults have only mild sweating, while others need ongoing support. Regular follow-up helps catch issues early and adapt treatment over time.

5. Is life expectancy normal in CISS?
   Severe cases in infancy can be life-threatening because of breathing problems, feeding difficulties, and infections. However, for children who survive the early critical period and receive appropriate care, long-term survival into adulthood is possible, although they may live with chronic symptoms. Exact life-expectancy numbers are not available because the condition is so rare.

6. How is CISS diagnosed?
   Doctors first look at the clinical picture: neonatal Crisponi features, later cold-induced sweating, and typical facial and skeletal signs. They then confirm the diagnosis with genetic testing of the CRLF1 and CLCF1 genes. Additional tests such as nerve studies and temperature-sensation tests may support the diagnosis and rule out other causes.

7. What is the difference between CISS and primary hyperhidrosis?
   Primary hyperhidrosis is common and usually starts in adolescence or adulthood with excessive sweating of the hands, feet, or underarms, often in warm environments or stress. CISS is genetic, very rare, and linked to a specific pattern: severe neonatal problems followed by sweating triggered by cold temperatures and a distinctive set of facial and skeletal features. Some treatments overlap, but the underlying cause is different.

8. Can children with CISS go to school and live a normal life?
   Many can attend school and eventually work, especially when their symptoms are well managed and they receive educational and physical accommodations. Supportive care—such as temperature control, physiotherapy, and psychological help—plays a big role in achieving independence and good quality of life.

9. Is pregnancy safe for women with CISS?
   There is very little information about pregnancy in women with CISS. In general, pregnancy care would require close monitoring of blood pressure, spine and lung function, and medication safety. Genetic counselling is important to understand the risk of having an affected child and to plan prenatal testing if desired.

10. Can sports or exercise make cold-induced sweating worse?
    Mild to moderate physical activity is usually helpful for muscle and bone health. However, abrupt exposure to cold air after exercise or exercising in cold environments may trigger sweating. The best approach is supervised, gradual exercise with careful clothing choices and indoor options in very cold weather.

11. Do all patients respond to clonidine or moxonidine?
    No. Some patients show dramatic improvement with clonidine or moxonidine, while others have little benefit or cannot tolerate side effects like low blood pressure and sedation. Treatment is trial-and-error, and doctors may adjust doses, combine medicines (for example clonidine with amitriptyline), or move to other options such as topical anticholinergics or botulinum toxin.

12. Is botulinum toxin safe for long-term use in CISS?
    Botulinum toxin has been used for many years to treat primary hyperhidrosis and certain muscle disorders. When injected by experienced clinicians at recommended doses and intervals, it is generally safe, but local weakness, pain, or flu-like symptoms can occur. Because CISS is rare, long-term data specific to this condition are limited, so careful follow-up is required.

13. Are there special anesthesia risks in CISS?
    Yes. Autonomic instability, abnormal temperature control, and airway or spine problems can increase anesthesia risk. Anesthesiologists should review the patient’s history in detail, plan temperature monitoring, and be prepared for blood-pressure swings and difficult intubation, especially in those with jaw restriction or severe scoliosis. Choosing centers familiar with complex, rare disorders is advisable.

14. Should brothers and sisters be tested?
    If a disease-causing variant in CRLF1 or CLCF1 is identified in one child, parents may wish to test siblings, especially if they have subtle symptoms or if the family is planning more children. Genetic counsellors can discuss the benefits and limitations of such testing and the best timing, considering emotional, legal, and ethical aspects.

15. Where can families find reliable information and support?
    Families can ask their doctors to help them contact rare-disease networks and patient organizations that focus on autonomic disorders or syndromic hyperhidrosis. Reputable medical resources such as GeneReviews, MedlinePlus, and peer-reviewed articles are good sources; social-media groups should be used carefully and never replace professional advice.

Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, geological location, weather and previous medical  history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. Regular check-ups and awareness can help to manage and prevent complications associated with these diseases conditions. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. We always try to ensure that the content is regularly updated to reflect the latest medical research and treatment options. Thank you for giving your valuable time to read the article.

The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members

Last Updated: February 09, 2025.