Congenital Insensitivity to Pain (CIP)

Disease Overview

Summary

Congenital insensitivity to pain (CIP) is a term that describes a group of very rare conditions in which a person is unable to feel pain from the time they are born. Individuals with CIP do not have pain from injuries, burns, or infections, which can lead to serious health problems. People with CIP cannot detect harmful levels of heat, cold, or pressure and they may have repeated injuries and difficulty healing.¹

CIP can be categorized into two distinct groups:²

• Developmental disorders: In this group, nerve cells that detect pain (nociceptors) fail to develop or “die” early.
• Functional disorders: In this group, nociceptors are present and correctly positioned in the body, but fail to respond to tissue-damage signals, leading to an inability to perceive pain.

CIP is caused by changes (variants) in different genes. Treatment is focused on the specific symptoms that the affected person has.

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Signs & Symptoms

CIP symptoms vary by age but often include:^1,2,3

In infants and young children:

• Self-injury: Biting fingers, lips, or tongue, often leading to tissue damage
• Cuts and bruises: Due to lack of pain awareness
• Burns: Due to impaired temperature sensation
• Frequent ear infections (otitis media) that may be due to weaker immune responses
• Delayed wound healing: Injuries may take longer to heal and are prone to infection

In older children and adults:

• Painless fractures: Broken bones may go unnoticed leading to severe complications
• Joint damage (Charcot joints): Common in the ankles, hips and spine, causing deformities over time
• Eye injuries: Due to absent corneal reflexes which can lead to scarring and vision problems
• Temperature regulation issues: Some individuals have trouble sweating (anhidrosis) leading to overheating and others sweat excessively (hyperhidrosis)
• Intellectual and developmental differences: Some people with CIP have normal intelligence and others have mild to moderate learning disabilities, hyperactivity, or impulsiveness
• Chronic infections: Recurrent skin and bone infections, especially caused by the bacteria Staphylococcus aureus

Chronic anemia of unknown cause has also been observed in many people with congenital insensitivity to pain and anhidrosis.

Congenital insensitivity to pain (CIP) is categorized into two primary groups of conditions. This is based on the underlying mechanism of dysfunction of the nerve cell endings called nociceptors (noci- is derived from the Latin for “hurt”) that initiate the sensation of pain:²

• Developmental Disorders: In these conditions, nociceptors either fail to develop or die early (apoptosis) due to insufficient trophic signals. Conditions in this group are referred to as hereditary sensory and autonomic neuropathies (HSANs) and are characterized by deficits in nociceptive, sensory and autonomic functions. Peripheral sensory nerve biopsies in people with HSAN often reveal a loss of what are called “C fibers” and/or “Aδ fibers”. The most common form in this category is HSAN type IV, also known as congenital insensitivity to pain with anhidrosis (CIPA).
  • Individuals with HSAN IV may have cognitive impairments and are prone to have infections with the bacteria Staphylococcus aureus, leading to persistent skin infections, osteomyelitis and septic arthritis.^2,5
• Functional Disorders: In these conditions, nociceptors develop correctly and are positioned appropriately in the body but are unable to respond to tissue-damage signals.

There are many subtypes of congenital insensitivity to pain (CIP), each with distinct genetic causes and clinical features:^1,2,3,4

• Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type 4 (HSAN4). CIPA is caused by variants in the NTRK1 Inheritance is autosomal recessive. Signs and symptoms include inability to feel pain resulting in injuries to the fingers, tongue, lips and other areas, inability to sweat (anhidrosis), increased risk of Staphylococcus aureus infections, eye corneal damage and mild to moderate intellectual disability.
• Congenital insensitivity to pain and thermal analgesia, also referred to as hereditary sensory and autonomic neuropathy type 5 (HSAN5). This type is caused by variants in the NGF Inheritance is autosomal recessive. Signs and symptoms include inability to feel pain resulting in injuries to the fingers, tongue, lips and other areas, inability to sense temperature, variable anhidrosis and susceptibility to Staphylococcus aureus infections.
• Congenital insensitivity to pain-hypohidrosis syndrome, also known as hereditary sensory and autonomic neuropathy type 8 (HSAN8). This type is caused by variants in the PRDM12 Inheritance is autosomal recessive. Signs and symptoms include inability to feel pain resulting in injuries to the fingers, tongue, lips and other areas and sometimes, decreased sweating and tear production.
• Congenital insensitivity to pain with hyperhidrosis, also called congenital analgesia with hyperhidrosis or congenital indifference to pain with hyperhidrosis, or congenital insensitivity to pain-hyperhidrosis-absence of cutaneous sensory innervation. This type has an unknown genetic cause but follows an autosomal dominant inheritance pattern. Signs and symptoms include an inability to feel pain leading to recurrent injuries and self-inflicted wounds, excessive sweating (hyperhidrosis) and a lack of sensory nerve innervation in the skin.
• Congenital insensitivity to pain with severe intellectual disability, also referred to as congenital analgesia with severe intellectual disability, congenital analgesia with severe intellectual disability or congenital insensitivity to pain with non-progressive cognitive delay. This type is caused by variants in the CLTCL1 Inheritance is autosomal recessive. Signs and symptoms include severe intellectual disability, inability to feel pain resulting in injuries to the fingers, tongue, lips and other areas and learning and motor delays.
• Congenital insensitivity to pain with anosmia and neuropathic arthropathy, also known as autosomal recessive hereditary sensory neuropathy type IID (HSN2D) or SCN9A-related congenital insensitivity to pain or channelopathy-associated congenital insensitivity to pain. This type is caused by variants in the SCN9A Inheritance is autosomal recessive. Signs and symptoms include inability to feel pain resulting in injuries to the fingers, tongue, lips and other areas and inability to sense temperature, which may be present at birth or develop in childhood. Additional symptoms include autonomic dysfunction affecting heart rate, blood pressure and digestion, decreased sense of smell (hyposmia), hearing loss, poor sense of taste (hypogeusia) and sometimes abnormal bone development (bone dysplasia).
• Congenital insensitivity to pain with gastrointestinal dysfunction, also known as hereditary sensory and autonomic neuropathy type 7 (HSNA7) or SCN11A-CIP. This type is caused by variants in the SCN11A Inheritance is autosomal dominant. Signs and symptoms include inability to feel pain resulting in injuries to the fingers, tongue, lips and other areas and severe digestive issues due to slowed movement of food in the gastrointestinal tract (hypomotility), face and neck itching and mild muscle weakness.
• Congenital insensitivity to pain syndrome, Marsili Type, also called Marsili syndrome, is caused by variants in the ZFHX2 Inheritance is autosomal dominant. Signs and symptoms include reduced pain sensation, diminished temperature perception, episodic fever (hyperthermia), headaches and pain related to internal organs (visceral pain).

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Causes

CIP is caused by changes (variants) in genes that affect specialized nerve cells responsible for sensing pain. These variants prevent the nerves from transmitting pain signals to the brain. Several genes are associated with CIP including SCN9A, CLTCL1, SCN11A, PRDM12, ZFHX2, NTRK1 and NGF. Different variants may also affect sweating, immune function, or learning abilities.^1,2

Inheritance

Some subtypes of CIP have an autosomal dominant inheritance pattern and others have an autosomal recessive inheritance pattern.

Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.

Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, 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.

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Affected populations

CIP is extremely rare. The exact number of cases worldwide is unknown but these conditions are estimated to affect about 1 in a million people. Increased awareness and genetic research have led to more diagnoses in recent years.¹

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Disorders with Similar Symptoms

Symptoms of the following disorders may be similar to those of congenital insensitivity to pain (CIP). Comparisons may be useful for a differential diagnosis.¹ Doctors use a combination of medical history, genetic testing and clinical exams to distinguish CIP from these other conditions.

• hypohidrotic ectodermal dysplasia – People with this condition may have trouble sweating (like some people with CIP) that leads to overheating, but they do not have pain insensitivity.
• Lesch-Nyhan syndrome – This condition causes severe self-injury (like biting and hitting, but these individuals can feel pain. Other signs and symptoms include developmental delays, abnormal movements and high uric acid levels.
• osteogenesis imperfecta (brittle bone disease) – People with this condition have fragile bones that break easily but these fractures are painful. Other signs include short height, blue-tinged eyes and joint flexibility.
• familial dysautonomia (HSAN III) – Babies with this condition have reduced pain sensation, but they also have digestive issues, frequent vomiting, breathing problems and difficulty regulating body temperature.
• MPV17-related mitochondrial disease – Like CIP, this condition can cause absent pain responses from birth, but it also leads to severe neurological problems, liver failure and low blood sugar levels.
• Leprosy (Hansen disease) – This disease causes patchy areas of numbness and skin lesions, but the loss of pain sensation is limited to specific areas rather than the entire body.
• Child abuse or neglect – In some children, repeated unexplained injuries may raise concerns of abuse. Unlike CIP, these children do feel pain, even if their caregivers deny it.

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Diagnosis

Doctors may suspect a specific subtype of CIP by looking at a person’s medical history and symptoms. Diagnosis of a specific subtype can be confirmed with genetic testing that identifies one or more disease-causing variants in a gene associated with CIP.

To understand how CIP is affecting a person and determine the best care plan, doctors recommend certain evaluations. These tests help identify any related health concerns and guide treatment.  More details about these evaluations are in the Standard Therapies section below.

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Standard Therapies

There is currently no cure or specific treatment for congenital insensitivity to pain (CIP). Doctors assess how the condition affects different areas of the body in each affected person. Evaluations are tailored to the specific genetic causes and symptoms. Not all the following tests are necessary for every person with CIP.

Recommended evaluations may include:¹

• Skin evaluation: A doctor will examine the skin for dryness, cracks, or thickened areas on the hands and feet. Daily moisturizer may be recommended.
• Body temperature check-ups: Since people with congenital insensitivity to pain with anhidrosis (CIPA) may not sweat properly, doctors will ask about episodes of overheating (hyperthermia) or being too cold (hypothermia).
• Full-body exam for injuries evaluation: Because CIPA prevents pain sensation, accidental injuries are common. A full-body exam will be done to check for bruises, burns, cuts and infections.
• Bone and joint evaluation: Orthopedic specialists may examine bones and joints to check for fractures, joint damage, or other bone problems. X-rays of the spine, hips, knees and ankles may be needed.
• Dental health evaluation: Since pain is not felt in the mouth, self-biting or tooth injuries are common. Regular dental exams help prevent serious damage.
• Eye exams: An eye doctor will check for damage to the clear front part of the eyes (corneas) because people with CIP may injure their eyes without realizing it.
• Developmental and behavioral assessment: Some individuals with CIPA have developmental delays or behavioral challenges like attention-deficit/hyperactivity disorder (ADHD). Neurologists or psychologists may assess cognitive and emotional development.
• Sense of smell evaluation: Doctors may ask about the ability to smell because some people with CIP have reduced or absent sense of smell (anosmia).

Regular check-ups with different specialists can help manage CIPA over time:

• Dental exams every 6 months
• Daily checks by caregivers for signs of injury
• Annual orthopedic evaluations to monitor bone and joint health
• Yearly eye exams to detect corneal damage
• Temperature monitoring as needed

Genetic counseling is recommended for affected individuals and their family members to help them understand how CIPA is inherited and provide guidance for future medical decisions.

There is no universal treatment for CIPA, so treatment is focused on preventing injuries and managing complications. Care is typically provided by a team of specialists including pediatricians, orthopedic surgeons, dentists, dermatologists and eye doctors. Management depends on the specific problem and may include: ^1,5

• Dental injuries: Sharp edges of teeth may need to be smoothed or removed, and a mouthguard can help prevent self-biting.
• Bone fractures: Standard treatment is used but healing may be slow or incomplete. Frequent X-rays may be needed.
• Joint problems and deformities: Some people need corrective surgeries or supportive devices like shoe lifts. Long-term monitoring is important.
• Eye injuries: Lubricating eye drops help protect the eyes. Regular eye exams are essential to find eye problems early.
• Infections: Wounds should be cleaned and monitored closely because people with CIP may not notice infections. Proper hygiene and antibiotic treatment are important.
• Temperature regulation: People with CIP should avoid extreme temperatures and may need cooling blankets in hot weather or warming blankets in the cold.

Children with developmental delays may benefit from early intervention services, speech therapy, occupational therapy and individualized education plans (IEPs) in school.

Because pain normally acts as a warning signal, people with CIP need extra precautions to stay safe, including the use of safety gates on stairs, covering sharp furniture edges and closely monitoring young children in the kitchen. Regular use of artificial tears can help prevent corneal damage. Teachers and school staff should be informed about the condition so they can provide help if an injury occurs. Good hygiene, antiseptic soaps and prompt treatment of cuts or wounds reduce infection risks.¹

High-impact sports and risky activities should be avoided because injuries may go unnoticed. Activities like swimming, dancing and cycling can be safer options.

During surgeries, since pain is not a reliable indicator, extra care is needed to ensure proper sedation and post-surgery monitoring. Women with CIP can have normal pregnancies, but medical teams should be aware that labor will be painless, and fractures may go unnoticed.¹

Educating individuals about their condition and connecting with others who have CIP can be helpful.

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Clinical Trials and Studies

Researchers are studying possible treatments for CIP. Stem cell therapy and gene editing are being explored as potential treatments to restore normal nerve function for those affected by CIP with anhidrosis. These advanced techniques aim to correct the genetic variants that cause the disease and improve the quality of life.⁶

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:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

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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References

1. Schon KR, Parker APJ, Woods CG. Congenital Insensitivity to Pain Overview. 2018 Feb 8 [Updated 2020 Jun 11]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK481553/ Accessed Feb 19, 2025.
2. Drissi I, Woods WA, Woods CG. Understanding the genetic basis of congenital insensitivity to pain. Br Med Bull. 2020;133(1):65-78. doi:10.1093/bmb/ldaa003
3. Bowsher D, Geoffrey Woods C, Nicholas AK, et al. Absence of pain with hyperhidrosis: a new syndrome where vascular afferents may mediate cutaneous sensation. Pain. 2009;147(1-3):287-298. doi:10.1016/j.pain.2009.09.007
4. Congenital insensitivity to pain-hyperhidrosis-absence of cutaneous sensory innervation. Orphanet. https://www.orpha.net/en/disease/detail/217399. Accessed Feb 19, 2025.
5. Hepburn L, Prajsnar TK, Klapholz C, et al. Innate immunity. A Spaetzle-like role for nerve growth factor β in vertebrate immunity to Staphylococcus aureus. Science. 2014;346(6209):641-646. doi:10.1126/science.1258705.
6. Ikrama M, Usama M, Haider MH, Israr S, Humayon M. Congenital insensitivity to pain with anhidrosis: a literature review and the advocacy for stem cell therapeutic interventions. Ther Adv Rare Dis. 2024;5:26330040241292378. Published 2024 Oct 31. doi:10.1177/26330040241292378

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