“Congenital Insensitivity to Pain” (CIPA, or congenital analgesia: CIPA hereafter) is an autosomal recessive disease (Indo, 2002) and was first observed in 1932 (Daneshjou, Jafarieh, and Raeeskarami, 2012). It is called a “congenital disorder” since it is present from birth. Since the disease is autosomal recessive, the closer the two parents are in relatedness, the more likely it is they will pass on a recessive disorder since they are more likely to have and pass on autosomal recessive mutations (Hamamy, 2012). First cousins, for example, 1.7-2.8% higher risk of having a child with an autosomal recessive disease (Teeuw et al, 2013). Consanguinity is common in North Africa (Anwar, Khyatti, and Hemminki, 2014) and the Bedouin have a high rate of this disease (Schulman et al, 2001; Lopez-Cortez et al, 2020; Singer et al, 2020). Three mutations in the TrkA (AKA NTRK1) have been shown to induce protein mis-folding which affect the function of the protein. Different mutations in the TrkA gene have been shown to have be associated with different disease outcomes (Franco et al, 2016). Since the mutated gene in question is needed for nerve growth factors, the pain signals cannot be transferred to the brain since there are hardly any of them there (Shin et al, 2016).
Individuals unfortunate enough to be inflicted with CIPA cannot feel pain. Whether it’s biting their tongues, feeling pain from extreme temperatures. People with CIPA have said that while they can feel the difference between extreme temperatures—hot and cold—they cannot feel the pain that is actually associated with the temperatures on their skin see (Schon et al, 2018). When they bump into things, they may not be aware of what happened and injuries may occur which heal incorrectly due to no medical attention and only noticing the fractures and other things that occur due to CIPA years later after they see doctors for what is possibly factors due to having the disease. People with CIPA are thought to be “dumb” because they constantly bump into things. But what is really happening is that, since they cannot feel pain, they have not learned that bumping into things could be damaging to their bodies, as pain is obviously an experience-dependent event. So these people learn, throughout their lives, to fake being in pain as to not draw suspicion to people who may not be aware of the condition. Children with the disease are thought, most of the time, to be victims of child abuse, but when it is discovered that the child who is thought to be a victim of abuse is inflicted with CIPA (van den Bosch et al, 2014; Amroh et al, 2020), treatments shift toward managing the disease.
About twenty percent of people with CIPA live until three years of age (Lear, 2011), while 20 percent of those who die at age 3 die from complications due to hyperpexia (an elevated body temperature over 106. degrees Fahrenheit) (Rosemberg, Marie, and Kliemann, 1994; Schulmann et al, 2001; Indo, 2002; Nabyev et al, 2018). Since they cannot feel the heat and get themselves to cool down, Due to a low life expectancy (many more live until about 25 years of age), this disease is really hard to study (Inoyue, 2007; Daneshjou, Jafarieh, and Raeeskarami, 2012). People hardly make it past that age since they either don’t feel the pain and do things that normal people, through experience, know not to do since we can feel pain and know to not do things that cause us pain and discomfort or they commit suicide since they have no quality of life due to damaged joints. Furthermore, since they cannot feel pain, people with this disease are more likely to self-mutilate since they cannot learn that self-mutilation causes pain (since pain is a deterrent for future action that may in fact cause pain to an individual). They also cannot sweat, meaning that control of the body temperature of one afflicted with CIPA is of utmost precedence (since they could overheat and die). Thus, these cases of deaths of individuals with CIPA do not occur due to CIPA per se, they occur due to, say, not feeling heat and then sweating while not attempting to regulate their body temperature and cool down (whether by naturally sweating due to being too hot or getting out of the extreme hot temperature causing the elevated body temperature). This is known as “hyperpyrexia” and this cause of death affects around 20 percent of CIPA patients (Sasnur, Sasnur, and Ghaus-ul, 2011). Furthermore, they are more likely to have thick, leathery skin and also show little muscular definition.
Not sweating is associated with CIPA and if one cannot sweat, one cannot have their body temperature regulated when they get too hot. So if they get too hot they cannot feel it and they will die of heat stroke. The disease, though, is rare, as only 17-60 people in America currently have it, while there are about 600 cases of the disease worldwide (Inoyue, 2007; Lear, 2011). This disease is quite hard to identify, but clinicians may be able to detect the presence of the disease through the following ways: Infants biting their lips, fingers, cheeks and not crying or showing any instance of being in pain after the event; repeated fractures in older children; a history of burns with no medical attention; observing that a child has many healed joint injuries and bone fractures without the child’s parents seeking medical care; observing that the patient does not react to hot or cold events (though they can say they can feel a difference between the two) they make errors in distinguishing in whether something is hot or cold (Indo, 2008).
Children who have this disease are at a higher risk of having certain kinds of bodily deformations, since they cannot feel the pain that would make them be hesitant to perform a certain action in the future. Due to this, people with this disease must constantly check themselves for cuts, abrasions, broken bones, etc to ensure that they cannot feel when they actually occur to them. They don’t cry, or show any discomfort, when experiencing what should be an event that would cause someone without CIPA to cry. CIPA-afflicted individuals are more likely to have bodily deformations since their joints and bones do not heal correctly after injury. This then leads to their walking and appearance to be affected. This is one of many reasons why the parents of people with CIPA must constantly check their children for signs of bodily harm or unintentional injuries. One thing that needs to be looked out for is what is termed Charcot joint—which is a degenerative joint disorder (Gucev et al, 2020).
A specific form of CIPA—called HSAN-IV—was discovered in a village in southern Finland called Vittangi, where it was traced to the founder of the village itself in the 1600s. Since the village was remote with such a small population, this meant that the only people around to marry and have children with were people who were closely related to each other. This, then, is the reason why this village in Finland has a high rate of people afflicted with this disease (Norberg, 2006; Minde, 2006). This, again, goes back to the above on consanguinity and autosomal recessive diseases—since CIPA is an autosomal recessive disease, one would reason that we would find it in populations that marry close relatives, either due to custom or population density.
Many features have been noted as showing that an individual is afflicted with CIPA: absent pain sensation from birth, the inability to sweat; and mental retardation, lower height and weight for their age (Safari, Khaledi, and Vojdani, 2011; Perez-Lopez et al, 2015). Children with CIPA have lower IQs than children without CIPA, so there is an inverse relationship between IQ and age; the older the age of the child with CIPA, the lower their IQ, while the reverse is true for individuals who are younger (Erez et al, 2010). One girl, for example. had a WISC-III IQ of 49, and she self-mutilated herself by picking at her nails until they were no longer there (Zafeirou et al, 2004). Another girl with CIPA was seen to have an IQ of 52, be afflicted with mental retardation, have a low birth weight, and was microcephalic (Nolano et al, 2000). Others were noted to have IQs in the normal range (Daneshjou, Jafarieh, and Raaeskarami, 2012). People with a specific form of this disease (HSN type II) were observed to have IQs in the normal range (though it is “caused by” a different set of genes than CIPA, HSN type IV; Kouvelas and Terzoglou, 1989). However, it has been noted that the cut-off of 70 for mental retardation is arbitrary (see Arvidsson and Granlund, 2016). While running a full gamut of tests on an individual thought to have CIPA, we can better attempt to ensure a higher quality of life in individuals afflicted with the disease. In sum, IQ scores of CIPA individuals do not reflect that the mutations in TrkA “cause” IQ scores; it is an outcome of a disrupted system (in this case, mutations on the TrkA gene).
There is currently no cure for this disease, and so, the only way to manage complications stemming from CIPA is to work on the injuries that occur to the joints that occur as they happen, to ensure that the individual has a good quality of life. Treatment for CIPA, therefore, is not actually curing the disease, but it is curing what occurs due to the disease (bone breaks, joint destruction), which would then heighten the quality of life of the person with CIPA (Nabiyev, Kara, and Aksoy, 2016). Naloxone may temporarily relieve CIPA (Rose et al, 2018), while others suggest treatments such as remifentanil (Takeuchi et al, 2018). We can treat outcomes that arise from the disease (like self-mutilation), but we cannot outright cure the disease itself (Daneshjou, Jafarieh, and Raaeskarami, 2012). The current best way to manage the disease is to identify the disease early in children and to do full-body scans of afflicted individuals to attempt to cure the by-products of the disease (such as limb/joint damage and other injuries). Maybe one day we can use gene therapy to help the afflicted, but for now, the best way forward is early identification along with frequent check-ups. By managing body temperature, having frequent check-ups, modifying the behavior of the child as to avoid injuries, wearing a mouth guard so they do not grind their teeth or bite their tongue, avoiding hot or cold environments or food, (Indo, 2008; Rose et al, 2018).
CIPA is a very rare—and very interesting—disease. By better understanding its aetiology, we can better help the extremely low number of people in the world who suffer from this disease.