Introduction
People with Channelopathy-associated congenital insensitivity to pain cannot feel discomfort in any part of their body. Over time, this lack of awareness of pain might result in a buildup of illnesses and injuries that may shorten life expectancy. SCN9A gene mutations and, in rare instances, PMRD12 gene mutations are the two leading causes of congenital insensitivity to pain. It has an autosomal recessive pattern of inheritance.
Because it affects the peripheral nervous system, which links the brain and spinal cord to muscles and cells that detect sensations like touch, smell, and pain, congenital insensitivity to pain is regarded as a type of peripheral neuropathy. Hereditary sensory and autonomic neuropathies are the category in which it falls.
What Is Congenital Insensitivity to Pain?
When a person has congenital insensitivity to pain (CIP), it is highly unlikely for them to ever experience any pain in their lifetime. Over a hundred Mendelian disorders that result in congenital blindness or vision loss are known to affect the senses of hearing and sight, respectively. It has dramatically assisted comprehension of the typical mechanics of human light and sound sensing to grasp how these disorders result in blindness and deafness.
What Are the Genes Responsible for CIP?
Developmental CIP Genes: These genes result in CIP when nociceptors fail to mature.
NTRK1 (Neurotrophic Receptor Tyrosine Kinase):
NTRK1 was the first gene discovered to induce a CIP in 19965. By examining several families with the previously clinically identified disorder HSAN type 4 (HSAN4), bi-allelic mutations in this gene were discovered.NTRK1 stands for neurotrophic tyrosine kinase gene one and encodes the protein known as TRKA, also known as high-affinity nerve growth factor receptor, formerly tropomyosin receptor kinase.
NGF (Nerve Growth Factor):
NGF, for which Rita Levi-Montalcini and Stanley Cohen received the 1986 Nobel Prize, is a key ligand for the tyrosine kinase receptor TRKA. In a large Swedish family, a homozygous NGF mutation was found to cause CIP in 2004.12 Only a few additional families have since been described, each with a different missense or frame-shift NGF mutation. This delay between NGF being identified and the phenotype, its loss caused in humans, being described is probably due to the rarity of this CIP phenotype. Functional analyses of these mutations have revealed either a destabilization of NGF's cysteine knot structure (a neurotrophin structural motif made up of a pair of disulfide cysteine links).
PR Domain Zinc Finger Protein 12 (PRDM12):
In 2015, bi-allelic mutations in PRDM12 (sometimes referred to as HSAN6) were found to be the source of a novel HSAN4-like phenotype.14 PRDM12 has a role in regulating transcription. Normal cognition (or occasionally a little cognitive delay) and a reduction in A but not C fibers on nerve biopsy are the clinical characteristics that set this novel illness apart from HSAN4. The second most prevalent variety of developing CIP is this ailment. The few mutations that have been functionally characterized remove function. However, most mutations are nonsensical or mis-sensical. An extension of the C-terminal poly-Alanine tract from a normal range of 8 – 13 to >18, which causes PRDM12 aggregation, is an uncommon mutational process.
What Are the Age-Related Characteristic Findings?
The inability to feel pain causes injuries more frequently and inhibits natural recovery.
Infants and Young Children:
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The oral cavity, including loss of the tongue tip, injuries to the inside of the teeth/gums, and avulsion of teeth, are common self-mutilating injuries and injuries to the fingers (biting off the fingertips).
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There could be bruising and cuts.
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Burns can happen as a result of reduced temperature perception.
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Reduced immunity to Staphylococcus aureus may cause recurrent otitis media in some individuals.
Elderly People:
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Joint injury and painless fractures are common occurrences that might have long-lasting effects.
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Fractures from the past may cause bony abnormalities.
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Nearly everyone has Charcot joints (neuropathic arthropathy), which most frequently affect the ankles, hips, and lumbar spine.
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The Charcot spine can manifest with a growing deformity or new motor and/or sensory deficiencies.
Eyes:
Because corneal reflexes are lacking, all affected people are at risk for corneal injury. The best way to diagnose permanent corneal scarring is via a slit-lamp examination. Clinical research has shown that corneal transplants have a higher failure rate, most likely because the new cornea lacks nociceptive innervation while the old cornea lacks nociceptive innervation.
Infections: Recurrent soft tissue infections, abscesses, and osteomyelitis have been seen in some affected people because of apparent selectively decreased immunity to Staphylococcus aureus.
Temperature: Regulation of body temperature, anhidrosis, and hyperhidrosis. Anhidrosis (lack of sweating) affects thermoregulation in some people, which can cause recurrent episodes of fever without a known cause.
Intelligence and Development Intelligence: The development might be normal, delayed, or impaired. Normal intelligence is often present in people with CIP brought on by biallelic pathogenic mutations in SCN9A and PRDM12. Biallelic pathogenic mutations in NTRK1 can induce CIP in people with varying degrees of intellectual disability. Children with biallelic pathogenic mutations in NTRK1 frequently exhibit hyperactivity, impulsivity, and attention deficiency.
What Is the Basis for the Diagnosis of CIP?
The assessments should be considered to determine the severity of the condition and any needs in a person with congenital insensitivity to pain (CIPA) if they were not conducted as part of the evaluation that resulted in the diagnosis. Not all assessments must be performed in every person with CIPA depending on the underlying genetic cause and/or specific pathogenic variant; instead, the evaluations should be directed by the unique phenotypic features.
Supportive Laboratory Results
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Regular electromyograms and nerve conduction investigations are normally normal.
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For additional details on assessing autonomic function for CIP with anhidrosis.
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Clinical practice only sometimes includes doing nerve biopsies. Adults are subjected to skin biopsy in some facilities to measure the density of intra-epidermal nerve fibers and the innervation of the autonomic system.
What Are the Management Strategies for CIP?
There are no widely agreed-upon therapy or surveillance guidelines.
Pediatric, orthopedic, dental, ophthalmology, and dermatology specialists are the best doctors to treat this condition.
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Dental and Oral Lesions: Consider during treatment of a mouth guard and tooth extraction and/or filing (smoothing) of sharp incisal edges
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Broken Bones: Standard therapy with cautious and ongoing assessment, low threshold for further radiological imaging until normal, and the assumption that healing may not occur. The use of an external fixator during treatment could result in significant infection problems.
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Joint and Bone Malformation: Osteotomy corrections to prevent deformity or insufficient healing require prolonged and thorough monitoring.
Thus different specialty doctors are required for the condition at that present time.
Conclusion:
People with CIP generally become aware of other people's pain and react to it usually. They frequently develop the ability to mimic pain in context-appropriate settings, such as being tackled in football. It has been proposed that naloxone might momentarily reduce CIP analgesia. While this medication may help identify the cause of an individual's illness or injury, it may also subject the individual to widespread pain from accumulated injuries.
