Diseases and Disorders

Congenital Insensitivity to Pain: An Overview

Poornima Ananthasubramanian


Introduction

Pain is a feeling of distress associated with actual or potential tissue damage [1]. It is responsible for allowing the body to react to stimuli and preventing further tissue damage. The absence of pain can make the body vulnerable to wounds and injury. This occurs in the case of “Hereditary sensory and autonomic neuropathy type V (HSAN V)”, generally called congenital insensitivity to pain (CIP). It is a condition that inhibits the ability to perceive physical pain [2]. The affected individuals never feel pain in any part of their body when injured, leading to an accumulation of wounds and fractures [3]. This article aims to explain the basic mechanism concerning this disease with a special focus on case studies to show the varying ramifications of the disease.
 

General Pathway of Pain Perception

The pathway of pain perception, which is also called nociception, is the process in which the sensory nervous system perceives pain through the nociceptors, which are specialized peripheral sensory neurons that alert the body when experiencing potentially damaging stimuli like exposure to high temperature on the skin. They transduce these stimuli into long-range electrical signals that are relayed to higher brain centers systematically [4]. When the intensity of a stimulus reaches the noxious threshold, the nociceptors depolarize to send signals to their cell bodies in the dorsal root ganglia. The dorsal root ganglia is a cluster of neurons that help in transmitting information from the periphery to the central nervous system through the spinal cord. In the dorsal root ganglia, the nociceptive neurons synapse with interneurons, which transmit the neural impulse to the thalamus and cortex in the brain for pain perception [5].

There are three main classes of nociceptors: Að mechanosensitive nociceptors, Að mechanothermal nociceptors, and C fibers. While the thin and myelinated C fibers conduct rapid, sharp, and acute pain, the thick and unmyelinated Að fibers facilitate delayed, diffused, and dull pain.

 

Molecular Mechanism

The growth and innervations of nociceptors in different parts of the body are stimulated by nerve growth factor (NGF). NGF regulates anti-apoptotic and differentiative signals associated with growth and innervation of nociceptors, by binding to receptors in a co-receptor system, consisting of the high-affinity tropomyosin receptor kinase A (TrkA) receptor and the low-affinity p75 neurotrophin (NTR) receptors. This binding triggers the phosphorylation of Ras and Extracellular signal-regulated Kinase (ERK), which are the downstream proteins that initiate the signaling pathways, which are necessary for cell growth, survival, proliferation, and differentiation [5].  Several studies on mice have shown that NGF-null mice have a severe loss of sympathetic and sensory neurons due to the absence of signaling pathways mentioned previously. In humans, mutations in the gene coding for NGF, NTRK1, manifest themselves as HSAN V. These mutations prevent normal post-translational processing of proNGF [2], therefore causing it to remain in its immature form. When this immature pro- NGF binds to the p75 NTR receptor, apoptotic pathways get initiated. Apoptosis refers to the programmed death of cells, which is usually carried out to remove potentially cancerous and virus-infected cells. In this case, the apoptotic pathway is activated due to defective genetic mechanisms. The initiated apoptotic pathways lead to the recruitment of caspases, which help in apoptosis by lysing the protein, eventually effectuating neurodegeneration [6]. This altered mechanism caused by mutations in the NTRK1 gene causes deficient development of:

 

Clinical Implications

The absence of pain in an individual has multiple clinical implications.  One of the major clinical implications of this disease is the vulnerability of the patient to wounds, injuries, and self-mutilating behavior. In extreme cases, this behavior may result in auto-amputation. Especially in the case of children, the lack of pain may make it difficult to go through the stages of teething, as they might chew through their tongues, or bite their fingers until they bleed without even feeling it.  Furthermore, Corneal abrasions and other serious eye injuries caused by scratching or rubbing the eyes too hard are also common among children with HSAN V [3]. These repeated injuries often lead to a reduced life dependency in patients with HSAN V [8].

HSAN V is often associated with anhidrosis, which is the inability to sweat. Sweating is an important physiological process that helps maintain homeostasis by regulating temperature. In certain cases of HSAN V, patients are unable to sweat due to the absence of innervation in the epidermis and the eccrine sweat glands. This inability to sweat is called anhidrosis and may lead to overheating as the body is unable to get rid of excess heat. Overheating often leads to febrile seizures (seizures brought on by fever or overheating) and even death in serious cases [3].In patients with anhidrosis, HSAN V is often referred to as CIPA ( Congenital insensitivity to pain and Anhidrosis). Even more, HSAN V is also associated with anosmia, which is the complete loss of smell. While this may not have any clinical implications, it affects the sense of taste, depreciating the aesthetics in food.

 

Case Studies

Patients diagnosed with CIP show varying physiological and psychological features. Therefore, it is essential to study multiple cases to understand the characteristic variations of CIP. Several case studies and the implicated problems are described below:

  1. The “Pediatrics'' journal reported a case of a 10-year-old child with severe burns that were misinterpreted to be self-inflicted. The child was admitted to the hospital with severe contact burns on his buttocks - he had been playing computer games while sitting on top of a central heating system. After a few hours, he noticed severe blisters on his buttocks without experiencing pain. Physical examination revealed a cooperative healthy boy with a total body surface area burn of 4%. The burns were deeply dermal, and surgery was needed to close the wounds. Further examination showed that his tongue and lips had several scars from earlier lacerations caused by tongue biting, and burns caused by drinking hot liquids.  During infancy, he had no feeding or respiratory problems, but after the first tooth eruptions, he had lingual lacerations [9]. Lingual lacerations are deep cut or tear in the mouth, which is common in children with CIP, during teething[12]. While developmental milestones in the early years and learning abilities were normal, his hyperactivity wasn’t. Due to two separate unexplained fractures of his lower extremities,  his parents were already suspected of child abuse, and hence, were under the supervision of the Child Care Board for 2 years before their son being burned. Based on his medical history, CIP was considered to be a plausible diagnosis, and later, genetic studies confirmed this possibility [9].

  2. The “Annals of Indian Academy of Neurology” reported the case of an 8-year-old boy, born to a healthy non-consanguineous South Indian couple, who was presented with a history of self-mutilation in the form of ulceration of the lower lip and tongue, starting in infancy soon after primary dentition. There were repeated episodes of high fever in summer that responded poorly to medicines to reduce the fever. However, his developmental milestones were normal, and the senses of touch, position, and vibration were intact. The IQ assessment using the Binet-Kamat test showed a normal mental development for age. However, neurological examination revealed an absence of response to temperature and painful stimuli. The bedside sweat test using pilocarpine showed the total absence of sweating.  However, a full-thickness skin biopsy showed normal sweat glands. Sural nerve biopsy findings were consistent with hereditary sensory autonomic neuropathy. All of these factors confirmed the CIPA disease in the patient [10].

 

  1. The “International Journal of Contemporary Medical Research'' reported the case of a 1-year-old girl child, who had self-mutilated injuries over her legs, hands, lips and tongue. She was also insensitive to temperature and sharp injuries. On revealing the patient’s medical history, the guardians disclosed that the child had bitten her finger, tongue, and lip; removed her teeth by herself; had not cried after fall or injuries; and had not ever sweat. On clinical examination, self-mutilated injury on her left and right legs, hands, the middle finger of the left hand was partially amputated. All vital signs and parameters appeared to be normal. Baseline investigations like complete blood picture, electromyography, and electroencephalogram showed no positive findings. Further genetic evaluation revealed that there was a genetic mutation in the gene, encoding for the NTRK1 gene [11].  The identification of this mutation led to the diagnosis of CIP in the child. 

Though all these studies indicate the same major disorder, the ramifications remain different in each case ranging from burns to fractures. Also, the time taken and the methods adopted for the diagnosis of the disease vary in each case. The social complication of the disease is seen in the first case in which the family was under suspicion of child abuse. Health care workers need to be aware of the possible presence of this disease to prevent such false accusations.

 

Treatment

Current treatments for CIP are largely support-based: they are oriented towards preventing self-mutilation and managing orthopedic problems, like fractures caused due to insensitivity towards pain. Several adaptive strategies have been developed to help patients in their daily lives. Continual monitoring for injuries, special footwear for orthopedic complications, and special protective eyewear to avoid corneal abrasions are just a few of the many strategies currently being used [5]. Each person with CIPA needs an individualized plan of care that helps with his or her symptoms. Some families with HSAN V patients find it helpful to move to cooler climates to avoid the risk of overheating [7].

 

Conclusion

Despite the general aversion to pain, this sensation is a basic physiological necessity. HSAN V patients are deprived of the sensory input necessary to navigate the dangers of their environment, leaving them vulnerable to injury. Even more, the rarity of this disease has been a source of negligence in research. To achieve a more thorough understanding of NGF/proNGF receptor distribution and function, a more accurate model for HSAN V is needed as existing mouse models lack validity. With an improved model, research may further result in the development of pharmacological treatments or genetic therapies as early interventions for HSAN V, ultimately helping prevent or better manage its harmful and long-lasting effects [5].


References


  1. (16/07/2020). IASP Announces Revised Definition of Pain. International Association for the Study of Pain. https://www.iasp-pain.org/PublicationsNews/NewsDetail.aspx?ItemNumber=10475&navItemNumber=643#:~:text=The%20definition%20is%3A%20%E2%80%9CAn%20unpleasant,pain%20for%20further%20valuable%20context. Retrieved: 31/07/2020.

  2. Daneshjou, K., Jafarieh, H., & Raaeskarami, S. R. (2012). Congenital Insensitivity to Pain and Anhydrosis (CIPA) Syndrome; A Report of 4 Cases. Iranian Journal of pediatrics, 22(3), 412–416. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3564101/. Retrieved: 19/08/2020.

  3. (2020). Congenital insensitivity to pain. Genetics Home Reference. https://ghr.nlm.nih.gov/condition/congenital-insensitivity-to-pain. Retrieved: 31/07/2020.

  4. Kundapur D, Yu S, Mohanraj S.(2018).Congenital Insensitivity to Pain. https://journals.mcmaster.ca/meducator/article/view/1791

  5. Barker, P. A., Mantyh, P., Arendt-Nielsen, L., Viktrup, L., & Tive, L. (2020). Nerve Growth Factor Signaling and Its Contribution to Pain. Journal of pain research, 13, 1223–1241. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266393/. Retrieved: 31/07/2020.

  6. (2020). Congenital insensitivity to pain with anhidrosis. Genetic and Rare Diseases Information Center (GARD). https://rarediseases.info.nih.gov/diseases/3006/congenital-insensitivity-to-pain-with-anhidrosis#:~:text=CIPA%20is%20caused%20by%20changes,problems%2C%20as%20soon%20as%20possible. Retrieved: 05/09/2020.

  7. L. M. Pérez-López, M. Cabrera-González, D. Gutiérrez-de la Iglesia, S. Ricart and G. Knörr-Giméne. (2015). Update Review and Clinical Presentation in Congenital Insensitivity to Pain and Anhidrosis. Case reports on Pediatrics. 2015, 1-7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4633556/. Retrieved: 31/07/2020.

  8. Van den Bosch, G. E., Baartmans, M. G. A., Vos, P., Dokter, J., White, T., & Tibboel, D. (2014). Pain Insensitivity Syndrome Misinterpreted as Inflicted Burns. PEDIATRICS, 133(5), e1381–e1387. https://pubmed.ncbi.nlm.nih.gov/24733875/. Retrieved: 31/07/2020.

  9. Prashanth, G. P., & Kamate, M. (2012). A case of hereditary sensory autonomic neuropathy type IV. Annals of Indian Academy of Neurology, 15(2), 134–136. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3345592/. Retrieved: 31/07/2020.

  10. Peddareddygari, L. R., Oberoi, K., & Grewal, R. P. (2014). Congenital insensitivity to pain: a case report and review of the literature. Case reports in neurological medicine, 2014, 141953. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182687/. Retrieved: 31/07/2020.

  11. Kalaskar, R., & Kalaskar, A. (2015). Hereditary sensory and autonomic neuropathy type V: Report of a rare case. Contemporary clinical dentistry, 6(1), 103–106. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4319325/. Retrieved: 19/08/2020.

  12. Derek Flaherty. (01/03/2013).Understanding the mechanisms behind acute pain in dogs and cats. The Veterinary Nurse. https://www.theveterinarynurse.com/review/article/understanding-the-mechanisms-behind-acute-pain-in-dogs-and-cats. Retrieved: 19/08/2020.

  13. Josiane Budni, Tatiani Bellettini-Santos, Francielle Mina, Michelle Lima Garcez, Alexandra Ioppi Zugno. (2015). The involvement of BDNF, NGF and GDNF in aging and Alzheimer's disease. Aging and disease. http://www.aginganddisease.org/article/2015/2152-5250/ad-6-5-331.html. Retrieved: 19/08/2020.

Poornima Ananthasubramanian

Poornima Ananthasubramanian


This author has not yet uploaded a bio.