Congenital Pain-Insensitivity Syndromes in Perioperative Anesthesia and Analgesic Target Identification
4 affiliations
- 1School of Medicine, St. George’s University, West Indies 11739, Grenada
- 2School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
- 3Medical School, Edward Via College of Osteopathic Medicine, Blacksburg, VA 24060, USA
- 4Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA
Abstract
Congenital insensitivity to pain (CIP) comprises rare genetic disorders characterized by the absence of perception of noxious stimuli from birth. Despite their shared clinical phenotype, CIP syndromes arise from distinct molecular defects that differentially affect nociceptor development, ion channel function, and autonomic regulation. Pathogenic variants in genes, including NTRK1, SCN9A, and PRDM12, define key mechanisms of human nociception. NTRK1-associated CIP with anhidrosis results from disrupted nerve growth factor signaling, leading to loss of small-diameter sensory fibers, impaired thermoregulation, and autonomic instability. SCN9A- and PRDM12-associated forms affect sodium channel function or nociceptor development; autonomic involvement is generally less prominent but requires assessment in each patient. This narrative review synthesizes the genetic and neurodevelopmental basis of CIP syndromes and examines their implications for perioperative management and the development of analgesics. By correlating genotype-specific mechanisms with clinical phenotypes, CIP syndromes help to identify key components of nociceptive pathways. These rare disorders highlight molecular targets for precision analgesia and demonstrate how genetic characterization may guide perioperative risk assessment and the development of targeted pain therapies.
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BibTeX
@article{mckenzie2026congenital,
title = {{Congenital Pain-Insensitivity Syndromes in Perioperative Anesthesia and Analgesic Target Identification}},
author = {Alyssa Mckenzie and Dupinder Raman and Neil Shukla and Tiffany Bittar and Nour Fransis and Rachel Dombrower and Nitchanan Theeraphapphong and Sophia M. Mckenzie and Yen Nhi Hoang and Alaa Abd-Elsayed},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = nov,
doi = {10.3390/ijms27219831},
url = {https://www.mdpi.com/1422-0067/27/21/9831},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Congenital Pain-Insensitivity Syndromes in Perioperative Anesthesia and Analgesic Target Identification
AU - Alyssa Mckenzie
AU - Dupinder Raman
AU - Neil Shukla
AU - Tiffany Bittar
AU - Nour Fransis
AU - Rachel Dombrower
AU - Nitchanan Theeraphapphong
AU - Sophia M. Mckenzie
AU - Yen Nhi Hoang
AU - Alaa Abd-Elsayed
PY - 2026
DA - 2026/11/02
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219831
UR - https://www.mdpi.com/1422-0067/27/21/9831
AB - Congenital insensitivity to pain (CIP) comprises rare genetic disorders characterized by the absence of perception of noxious stimuli from birth. Despite their shared clinical phenotype, CIP syndromes arise from distinct molecular defects that differentially affect nociceptor development, ion channel function, and autonomic regulation. Pathogenic variants in genes, including NTRK1, SCN9A, and PRDM12, define key mechanisms of human nociception. NTRK1-associated CIP with anhidrosis results from disrupted nerve growth factor signaling, leading to loss of small-diameter sensory fibers, impaired thermoregulation, and autonomic instability. SCN9A- and PRDM12-associated forms affect sodium channel function or nociceptor development; autonomic involvement is generally less prominent but requires assessment in each patient. This narrative review synthesizes the genetic and neurodevelopmental basis of CIP syndromes and examines their implications for perioperative management and the development of analgesics. By correlating genotype-specific mechanisms with clinical phenotypes, CIP syndromes help to identify key components of nociceptive pathways. These rare disorders highlight molecular targets for precision analgesia and demonstrate how genetic characterization may guide perioperative risk assessment and the development of targeted pain therapies.
SN - 1422-0067
ER -