| Congenital insensitivity to pain | |
|---|---|
| Other names | Congenital analgesia |
| A patient and doctor discuss congenital insensitivity to pain | |
| Specialty | Neurology |
| Symptoms | Inability to perceive pain, self-inflicted damage to the oral cavity or fingertips, repeated bone fractures, persistent ear infections, corneal damage and infection, and sometimes inability to sweat |
| Types | HSANI, HSANII, HSANIII (familial dysautonomia), HSANIV (congenital insensitivity to pain with anhidrosis), and HSANV |
| Causes | Various genetic mutations |
| Treatment | Injury management and prevention |
Congenital insensitivity to pain (CIP), also known ascongenital analgesia, is an inability for a person to feel physicalpain due to various rare genetic conditions. CIP is caused by genetic mutations that affect the development or function ofnociceptors, the sensory neurons responsible for recognizing tissue damage. Common symptoms include damage to theoral cavity, repeatedbone fractures, and sometimes the inability tosweat. Some forms of CIP are also correlated withintellectual disabilities,learning disabilities, orattention deficit hyperactivity disorder (ADHD).Hereditary sensory autonomic neuropathies (HSAN) fall under the umbrella of CIP. Methods of treatment are still being explored. The epidemiology of CIP is unclear, given the relatively low number of reported cases.
The term congenital analgesia, also known as CIP, was first coined in the 1970s or 1980s.[1] CIP is an umbrella term that describes a collection of rare genetic disorders that affect nerve tissue in either theperipheral orautonomic nervous systems.[1] When genetic disorders interfere with nociceptors, an individual develops CIP.[1][2] A 2019 paper argues that "congenital insensitivity to pain" is a misnomer, and theorizes that patients might still feel other (non-nociceptive) forms of pain, even if they are unable to accurately classify such sensations.[1] The paper suggests "congenital nociceptor deficiency" as a possible alternative term.[1] There are 5 types of HSAN that are classified as CIP disorders.[1] As of 2025, the HSAN disorders are still classified using a system developed by Dyck P. J. in 1984.[1]
For people with this disorder,cognition andsensation are otherwise normal; for instance, patients can still feeldiscriminative touch (though not always temperature), and there are generally no detectable physical abnormalities.[1][3]Congenital insensitivity to pain with anhidrosis (CIPA) is a kind of CIP categorized by patients' inability to sweat (also known as HSAN-IV).[1][4] The inability to regulate internal temperature can lead to unexplained persistent fevers.[4]
Because children and adults with CIP cannot perceive pain, they may not respond to pain-inducing stimuli, putting them at a high risk forinfections and complications resulting from injuries.[5] Children with this condition often sustain self-inflicted damage, both in and around theoral cavity (such as having bitten off the tip of theirtongue) or fractures to bones.[5] Repeated bone fractures can lead to improper healing, potentially resulting in permanent joint damage, or in severe cases,Charcot joints.[4][6] Many young children also present with persistent ear infections and damaged fingertips due to biting.[4] Unnoticed infections andcorneal damage due to foreign objects in the eye are also common.[5][4][7] Particular strains of CIP put individuals at a higher risk for developingStaphylococcus aureus infections.[2][4] Depending on the genetic cause of CIP, individuals may be intellectually impaired and may have conditions such as ADHD.[4] The degree of the effect of CIP on the intellectual impairment of an individual has to do with the location of the mutation on the affectedgene.[6] The life expectancy of individuals with CIP is shorter than normal life expectancy.[1]
There are generally two types of CIP:
CIP is caused by extremely rare genetic disorders.[2] Roughly 50% of CIP cases are inherited from a parent with CIP.[6] Of the five HSAN disorders, HSAN II, III, IV, and V are inherited via anautosomal recessive pattern, while HSAN I is inherited via anautosomal dominant pattern.[1] The breakdown of specific genetic mutation types among those diagnosed with CIP is unknown as of 2020.[4] HSAN IV, one of the more common forms of CIP, is caused by a mutation in theNTRK1 gene (also known asTrkA).[4]
Various case studies have demonstrated how specific genetic mutations have led to CIP. In all cases, this disorder can be in thevoltage-gated sodium channelSCN9A (Nav1.7).[9] There are three mutations in SCN9A: W897X, located in the P-loop of domain 2; I767X, located in the S2 segment of domain 2; and S459X, located in the linker region between domains 1 and 2.[10] This results in a truncated non-functional protein.[10] Nav1.7 channels are expressed at high levels in nociceptive neurons of thedorsal root ganglia.[10] As these channels are likely involved in the formation and propagation ofaction potentials in such neurons, it is expected that a loss-of-function mutation in SCN9A leads to abolished nociceptive pain propagation.[10][11]
ThePRDM12 gene is normally switched on during the development of pain-sensing nerve cells.[12] People with homozygous mutations of the PRDM12 gene experience congenital insensitivity to pain (CIP).[12][13]
Another gene implicated in human pain insensitivity is ZFHX2, which encodeszinc finger homeobox 2.[14] A 2018 study analyzed six members of a family with inherited pain insensitivity and identified a "novel point mutation in ZFHX2, encoding a putative transcription factor expressed in small diameter sensory neurons" as the cause.[14] As a therapeutic application, the study further discusses how "the ZFHX2 variant and downstream regulated genes associated with a human pain-insensitive phenotype are ... potential novel targets for the development of new analgesic drugs".[14]
Jo Cameron is an example of one individual known to have congenital analgesia. She has two mutations, one in the gene encodingfatty acid amide hydrolase (FAAH) and one in thepseudogeneFAAH-OUT modulating FAAHexpression, which are theorized to be responsible for her condition.[15][16][17][18] FAAH is anenzyme involved in themetabolism ofendocannabinoids likeanandamide.[19][20][21][17][18] Cameron has high levels of anandamide and other endocannabinoids.[15][17][18]
As of 2020, there is no agreed-upon method in the medical community for treating CIP.[4] Treatment plans involve injury management and prevention.[6] In an experimental trial, anopioid antagonist,naloxone, allowed a woman with CIP to experience pain for the first time.[22] This result revealed that opioid antagonists like naloxone andnaltrexone may be effective in treating CIP in the future.[22] Additionally, the genes that cause CIP provide promising targets for novel pain medications, also known asanalgesics.[2]
A 2020 estimate places the incidence of CIP as one person in a million, based on the observation that under thirty cases are known in theUnited Kingdom.[1][4] CIP is found at an abnormally high frequency inVittangi, a village inKiruna Municipality in northernSweden, where nearly 40 cases have been reported.[23]
Finally, in the remarkable case report of a patient presenting with pain insensitivity and low fear and anxiety, the C385A polymorphism together with a microdeletion linked to decreased FAAH expression was detected as a possible causal factor. In addition, blood levels of AEA and other fatty-acid amides which are degraded by FAAH were unusually elevated in this individual.112
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