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Background: Congenital insensitivity to pain with anhidrosis (CIPA) (OMIM 256800) is a rare autosomal‐recessive condition, also known as hereditary sensory and autonomic neuropathy type IV (HSAN‐IV). The most commonly reported features include anhidrosis, intellectual disability, self‐mutilation, febrile episodes, impaired temperature perception, recurrent infections and/or autonomic nervous system impairment. Major joint destruction and joint deformity known as Charcot (neuropathic) joints are also seen in CIPA patients attributed to insensitivity to joint pain. Methods: We present a case of a 46‐year‐old female affected with CIPA with a known NTRK1 variant and previously unidentified variant. Minigene reporter constructs were generated encompassing the exon 8 to exon 13 of the NTRK1 gene using the reference sequence and one harboring c.1483 + 5G > A variant identified in our proband. Minigene constructs were transfected into HEK293T cells, and the transcript was analysed for splicing to evaluate the effect of this variant in splicing. Results: The patient (46‐year‐old female) exhibited right ankle joint deformity around 5 years of age. Patient also experienced lumbar compression and knee damage in adulthood. She had undergone a significant number of evaluations without clear diagnosis. Her presentation lacked many of the common clinical presentations of CIPA, and therefore, the focus of her evaluation was directed towards her unexplained joint deformities. Exome sequencing revealed a known pathogenic variant in NTRK1 (c.851 ‐ 33T > A:p.? [Intron 7]) and a novel NTRK1 variant (c.1483 + 5G > A:p.? [Intron 11]), which was later re‐classified as likely pathogenic. The patient was started on a biologic disease‐modifying anti‐rheumatic medication (bDMARD) due to a possible inflammatory etiology of her joint deformity. Molecular diagnosis allowed for modification of her treatment and surveillance strategies. Our minigene splicing assay demonstrated that the presence of the c.1483 + 5G > A variant has a negative effect on splicing, supporting the pathogenicity of this novel variant. [ABSTRACT FROM AUTHOR]

Pathogenic variations in the NTRK1 can cause congenital insensitivity to pain with anhidrosis (CIPA), a rare autosomal recessive inherited neuropathy. The precise diagnosis of CIPA relies on the identification of pathogenic genotypes. Therefore, it is essential to expand the NTRK1 variation spectrum and improve molecular diagnosis methods. In this study, 74 probands with typical manifestations of CIPA but unknown genotypes were recruited. A comprehensive molecular genetic analysis was performed to identify variations in the NTRK1, using techniques including Sanger and next-generation sequencing, bioinformatic analysis, quantitative polymerase chain reaction (qPCR), gap-PCR, short tandem repeat (STR) genotyping, and reverse-transcription PCR. In addition, functional assays were conducted to determine the pathogenicity of variants of uncertain significance (VUS) and further characterized changes in glycosylation and phosphorylation of 14 overexpressed mutant vectors with variants at different domains in the TrkA protein, which is encoded by NTRK1. A total of 48 variations in the NTRK1 were identified, including 22 novel ones. When combined with data from another 53 CIPA patients examined in our previous work, this study establishes the largest genotypic and phenotypic spectra of CIPA worldwide, including 127 CIPA families. Moreover, functional studies indicated that the pathogenicity of VUS mainly affected insufficient glycosylation in the extracellular domain and abnormal phosphorylation in the intracellular domain. This study not only provides important evidence for precise diagnosis of CIPA but also further enriches our understanding of the pathogenesis of this disease. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Congenital insensitivity to pain with anhidrosis (CIPA) (OMIM 256800) is a rare autosomal‐recessive condition, also known as hereditary sensory and autonomic neuropathy type IV (HSAN‐IV). The most commonly reported features include anhidrosis, intellectual disability, self‐mutilation, febrile episodes, impaired temperature perception, recurrent infections and/or autonomic nervous system impairment. Major joint destruction and joint deformity known as Charcot (neuropathic) joints are also seen in CIPA patients attributed to insensitivity to joint pain. Methods We present a case of a 46‐year‐old female affected with CIPA with a known NTRK1 variant and previously unidentified variant. Minigene reporter constructs were generated encompassing the exon 8 to exon 13 of the NTRK1 gene using the reference sequence and one harboring c.1483 + 5G > A variant identified in our proband. Minigene constructs were transfected into HEK293T cells, and the transcript was analysed for splicing to evaluate the effect of this variant in splicing. Results The patient (46‐year‐old female) exhibited right ankle joint deformity around 5 years of age. Patient also experienced lumbar compression and knee damage in adulthood. She had undergone a significant number of evaluations without clear diagnosis. Her presentation lacked many of the common clinical presentations of CIPA, and therefore, the focus of her evaluation was directed towards her unexplained joint deformities. Exome sequencing revealed a known pathogenic variant in NTRK1 (c.851 ‐ 33T > A:p.? [Intron 7]) and a novel NTRK1 variant (c.1483 + 5G > A:p.? [Intron 11]), which was later re‐classified as likely pathogenic. The patient was started on a biologic disease‐modifying anti‐rheumatic medication (bDMARD) due to a possible inflammatory etiology of her joint deformity. Molecular diagnosis allowed for modification of her treatment and surveillance strategies. Our minigene splicing assay demonstrated that the presence of the c.1483 + 5G > A variant has a negative effect on splicing, supporting the pathogenicity of this novel variant.

Background: Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive disorder caused by loss‐of‐function mutations of the NTRK1 gene, affecting the autonomic and sensory nervous system. Clinical manifestation is varied and includes recurrent fever, pain insensitivity, anhidrosis, self‐mutilating behavior, and intellectual disability. Methods: Clinical and genetic features were assessed in two males and one female with genetically confirmed CIPA using exome or genome sequencing. Results: CIPA symptoms including recurrent fever, pain insensitivity, and anhidrosis manifested at the age of 1 year (age range: 0.3–8 years). Two patients exhibited self‐mutilation tendencies, intellectual disability, and developmental delay. Four NTRK1 (NM_002529.3) mutations, c.851‐33T>A (p.?), c.2020G>T (p.Asp674Tyr), c.2303C>T (p.Pro768Leu), and c.574‐156_850+1113del (exons 5‐7 del) were identified. Two patients exhibited early onset and severe phenotype, being homozygous for c.851‐33T>A (p.?) mutations and compound heterozygous for c.851‐33T>A (p.?) and c.2020G>T (p.Asp674Tyr) mutation of NTRK1. The third patient with compound heterozygous mutations of c.2303C>T (p.Pro768Leu) and c.574‐156_850+1113del (exons 5‐7 del) displayed a late onset and milder clinical manifestation. Conclusion: All three patients exhibited variable phenotypes and disease severity. This research enriches our understanding of clinical and genetic aspects of CIPA, highlighting variable phenotypes and disease severity. [ABSTRACT FROM AUTHOR]

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal disorder. It is characterized by systemic insensitivity to pain, unexplained fever, and psychiatric manifestations. Anesthetic management of these cases is a challenge to the anesthetist due to the various implications associated with it. In this case report, we describe the anesthetic management of a 3-year-old child with CIPA and report the implications and challenges faced.

Congenital insensitivity to pain (CIP) is a rare phenotype characterized by the inability to perceive pain stimuli with subsequent self‐injuries, whereas CIP associated with anhidrosis (CIPA) is an overlapping phenotype mainly characterized by insensitivity to noxious stimuli and anhidrosis. CIP is primarily associated with pathogenetic variants in the SCN9A gene while CIPA is associated with pathogenetic variants in NGF and NRTK genes. However, in recent years, a significant overlap between these two disorders has been observed highlighting the presence of anhidrosis in SCN9A variants. We report the cases of two siblings (age 4 and 6 years) born from consanguineous parents presenting with a previously undescribed phenotype due to a novel pathogenic variant in SCN9A clinically characterized by congenital insensitivity to pain, anhidrosis, and mild cognitive impairment. [ABSTRACT FROM AUTHOR]

Abstract Background Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive disorder caused by loss‐of‐function mutations of the NTRK1 gene, affecting the autonomic and sensory nervous system. Clinical manifestation is varied and includes recurrent fever, pain insensitivity, anhidrosis, self‐mutilating behavior, and intellectual disability. Methods Clinical and genetic features were assessed in two males and one female with genetically confirmed CIPA using exome or genome sequencing. Results CIPA symptoms including recurrent fever, pain insensitivity, and anhidrosis manifested at the age of 1 year (age range: 0.3–8 years). Two patients exhibited self‐mutilation tendencies, intellectual disability, and developmental delay. Four NTRK1 (NM_002529.3) mutations, c.851‐33T>A (p.?), c.2020G>T (p.Asp674Tyr), c.2303C>T (p.Pro768Leu), and c.574‐156_850+1113del (exons 5‐7 del) were identified. Two patients exhibited early onset and severe phenotype, being homozygous for c.851‐33T>A (p.?) mutations and compound heterozygous for c.851‐33T>A (p.?) and c.2020G>T (p.Asp674Tyr) mutation of NTRK1. The third patient with compound heterozygous mutations of c.2303C>T (p.Pro768Leu) and c.574‐156_850+1113del (exons 5‐7 del) displayed a late onset and milder clinical manifestation. Conclusion All three patients exhibited variable phenotypes and disease severity. This research enriches our understanding of clinical and genetic aspects of CIPA, highlighting variable phenotypes and disease severity.

Congenital insensitivity to pain with anhidrosis (CIPA) is associated with Charcot arthropathy and is a rare clinical syndrome, with limited treatment options. Through a decade-long follow-up of a single case, we aim to provide new insights for clinicians regarding the choice of surgical strategies and postoperative complications. The diagnosed patient exhibited congenital insensitivity to pain and anhidrosis, accompanied by severe Charcot arthropathy affecting the spine. Multiple postoperative complications, including implant displacement, adjacent segment pathology, and pedicle screw loosening, occurred after surgical intervention, leading to five subsequent revision surgeries. Considering the limited experience in managing CIPA-related Charcot spinal arthropathy in the literature, surgical correction remains the preferred treatment. Among the 16 cases reviewed, common postoperative complications included implant displacement, adjacent segment pathology, and pedicle screw loosening. Based on current experience, we do not recommend extensive resection and reconstruction after removing the affected vertebral body, as this may increase the risk of implant displacement. Instead, a 360° long-segment fusion may help reduce the risk of adjacent segment degeneration. Additionally, we discuss potential reasons for revision surgery after Charcot spinal arthropathy surgery and perioperative management strategies for such cases. Meticulous care, appropriate rehabilitation exercises, and metabolic therapy for bone mineralization are crucial components of the treatment for this condition.

Background Congenital insensitivity to pain with anhidrosis (CIPA) with Charcot arthropathy is a rare combination in orthopaedic clinical practice. The experience dealing with such patients is limited. Here with this case of approximately 10 years follow‐up, we wish to shed light on the choices of strategies of surgeries and alerting clinicians with post‐surgery complications. The possible underlying reasons for the recurrent Charcot arthropathies as well as strategies for peri‐operative management for such surgical cases are also discussed. Case Presentation The patient underwent a surgery to correct her severe kyphosis caused by CIPA‐related Charcot spine. Multiple post‐surgery complications occurred during her follow‐up, including hardware migration, adjacent segment disease (ASD), and loosening pedicle screws. Five revision surgeries were conducted consequently. From the limited experience on the management of CIPA‐related Charcot spine, surgical correction is still the first‐line treatment. Conclusions Of all the 16 cases reviewed (including our case), loosening pedicle screws, hardware migration, and ASDs are the common post‐surgery complications. Large‐scale removal of damaged vertebrae and subsequent reconstruction are not recommended, which might increase the risk of hardware migration. A 360° long‐segment fusion might be of help to reduce the risk of ASDs. In the meantime, comprehensive management including careful nursing, proper rehabilitation exercises, and treatments targeting bone mineral metabolism is also critical.

Background: Congenital insensitivity to pain (CIP) is a rare genetic disorder characterized by the inability to experience pain. Unrecognized, repeated injuries may result in poorly healed fractures with hyperplastic callus formation, auto-amputation of digits, and osteomyelitis. In addition, the loss of joint proprioception leads to neuropathic osteoarthropathy (Charcot joints). Case report: A child with a progressively increasing swelling of the left proximal tibia and an aggressive bone lesion on imaging was suspected to have osteosarcoma. The diagnosis of hyperplastic callus formation was established through a multidisciplinary approach with imaging and repeat tissue biopsy. Conclusion: In the context of CIP, malignant bone tumors, including osteosarcoma are a differential diagnosis and require a review of history, examination, radiology and histology.

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal disorder. It is characterized by systemic insensitivity to pain, unexplained fever, and psychiatric manifestations. Anesthetic management of these cases is a challenge to the anesthetist due to the various implications associated with it. In this case report, we describe the anesthetic management of a 3‑year‑old child with CIPA and report the implications and challenges faced. [ABSTRACT FROM AUTHOR]

Background: Congenital insensitivity to pain with anhidrosis (CIPA) with Charcot arthropathy is a rare combination in orthopaedic clinical practice. The experience dealing with such patients is limited. Here with this case of approximately 10 years follow‐up, we wish to shed light on the choices of strategies of surgeries and alerting clinicians with post‐surgery complications. The possible underlying reasons for the recurrent Charcot arthropathies as well as strategies for peri‐operative management for such surgical cases are also discussed. Case Presentation: The patient underwent a surgery to correct her severe kyphosis caused by CIPA‐related Charcot spine. Multiple post‐surgery complications occurred during her follow‐up, including hardware migration, adjacent segment disease (ASD), and loosening pedicle screws. Five revision surgeries were conducted consequently. From the limited experience on the management of CIPA‐related Charcot spine, surgical correction is still the first‐line treatment. Conclusions: Of all the 16 cases reviewed (including our case), loosening pedicle screws, hardware migration, and ASDs are the common post‐surgery complications. Large‐scale removal of damaged vertebrae and subsequent reconstruction are not recommended, which might increase the risk of hardware migration. A 360° long‐segment fusion might be of help to reduce the risk of ASDs. In the meantime, comprehensive management including careful nursing, proper rehabilitation exercises, and treatments targeting bone mineral metabolism is also critical. [ABSTRACT FROM AUTHOR]

Background: Novel coronavirus disease (COVID‐19) outbreaks have dramatically changed lifestyles, with various effects on the physical and mental health of families and children with various childhood‐onset neurological diseases. A questionnaire survey was conducted to identify family‐specific issues and needs of patients with congenital insensitivity to pain with anhidrosis (CIPA) during major changes in their daily lives due to the COVID‐19 outbreaks. Methods: An anonymous questionnaire was sent to 56 families that were members of the Association of Patients and Families of CIPA in Japan between October and November 2020, the first 2 months of the third outbreak. Results: Thirty‐eight families (67.2% response rate) responded to the questionnaire. The current concerns of the parents were (1) difficulty in predicting the future (19 parents, 50%), (2) household and work concerns (eight parents, 21.1%), and (3) whether they would become infected (25 parents, 65.8%). Fifteen families indicated stress due to increased time together (stress + group), and 10 families had a better understanding of each other due to increased time together. New sleep disturbances and behavioral changes were observed in approximately 20% and 50% of patients with CIPA, respectively. No single factor could explain family stress. There were also free descriptions of the importance of peer support, connections with experts, and prompt responses for resolution. Conclusions: Each family has its own way of coping with multiple factors that contribute to the stress of the patient and family. A long‐established resilience to the disease proved effective during this pandemic. [ABSTRACT FROM AUTHOR]

Background: Congenital insensitivity to pain with anhidrosis (CIPA) is a very rare inherited autosomal recessive disease that has multiple clinical manifestations. Since its symptoms are related to different systems, this disorder has been investigated on a variety of topics. To better understand publications about CIPA, we conducted a bibliometric study to evaluate research publications on CIPA from 2000 to 2021, and delineate the key contributions in terms of countries, authors and sources. Methods: Quantitative analysis of publications on CIPA from 2000 to 2021 was interpreted and graphed through the Science Citation Index Expanded (SCIE) of Web of Science (WOS) Core Collection. The bibliometric package in R 4.1.1, VOSviewer 1.6.18, and GraphPad Prism 8.4 were used to conduct the bibliometric analysis. Results: From 2000 to 2021, a total of 163 publications were retrieved. China had the largest number of publications (n = 31), while Japan had the highest number of citations (621 citations). Levy J and Indo Y were perhaps the most impactful researchers in the field of CIPA. The co-authorship of authors and institutions indicated little cooperation on CIPA research between different countries. Annals of Neurology (n=5) and Nature Genetics (120 citations) were the most productive and cited journals, respectively, and the top 10 local cited references clarified the theoretical basis of the CIPA research area. Furthermore, the important topics on CIPA mainly include NTRK1 mutations and nerve growth factor (NGF). Conclusion: Based on the bibliometric analysis, we have a comprehensive view of the global status of CIPA research, and the results indicate that CIPA needs more attention and cooperation to facilitate the study of its pathological mechanisms. [ABSTRACT FROM AUTHOR]

Abstract Background In this case report, we described the past history, clinical manifestations, genetic characteristics and cognitive evaluation of a boy with congenital insensitivity to pain with anhidrosis (CIPA) who developed autism spectrum disorder (ASD). Case presentation The boy had an early onset of CIPA at the age of 48 months, and was later diagnosed with ASD at 5 years old. Developmental delays in communication, social skills and the presence of maladaptive behaviors were observed in the patient. Professional treatments significantly improved the developmental delays. Conclusions This case demonstrated that ASD may develop in children with CIPA, and pediatricians should be aware that if they suspect or identify a child with CIPA that they should also be screened for ASD using similar examination and diagnostic tools as shown in the present report. Moreover, therapeutic interventions for ASD was helpful for the remission of both diseases.

Congenital Insensitivity to Pain with Anhidrosis (CIPA) is a rare genetic disorder affecting the autonomic nervous system, leading to an inability to feel pain, temperature, or sweat1. This condition is caused by mutations in the NTRK1 gene, which encodes a receptor for nerve growth factor (NGF). The lack of NGF signaling results in the improper development and function of sensory and sympathetic neurons. Patients with CIPA often suffer from repeated injuries, infections, and hyperthermia due to their inability to sense pain and regulate body temperature. Management focuses on preventing injuries, controlling infections, and providing supportive care, as there is no definitive cure for CIPA. We present several hypotheses for treating CIPA using stem cells and modern genetic techniques. One approach involves using induced pluripotent stem cells (iPSCs) to replace defective neurons. Another hypothesis suggests in vivo gene editing of neural progenitors to restore TrkA function. Additionally, mesenchymal stem cells (MSCs) genetically modified to overexpress NGF could provide trophic support. Other strategies include epigenetic modulation of NTRK1 expression and exosome-mediated gene therapy. These innovative approaches aim to address the underlying genetic defects and restore normal cellular functions in CIPA patients., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2024.)

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare, autosomal recessive disease classified as hereditary sensory and autonomic neuropathy type VI. Patients with CIPA are characterized by insensitivity to pain, episodes of unexplained fever, anhidrosis, self-mutilating behavior, intellectual disability, and autonomic nervous system abnormalities. The clinical features may intrinsically pose anesthetic challenges. We present a case of a patient with CIPA who underwent tumor biopsy under general anesthesia using a Supreme laryngeal mask airway without any complications. The anesthetic management of this condition is discussed.

Background: In this case report, we described the past history, clinical manifestations, genetic characteristics and cognitive evaluation of a boy with congenital insensitivity to pain with anhidrosis (CIPA) who developed autism spectrum disorder (ASD).Case Presentation: The boy had an early onset of CIPA at the age of 48 months, and was later diagnosed with ASD at 5 years old. Developmental delays in communication, social skills and the presence of maladaptive behaviors were observed in the patient. Professional treatments significantly improved the developmental delays.Conclusions: This case demonstrated that ASD may develop in children with CIPA, and pediatricians should be aware that if they suspect or identify a child with CIPA that they should also be screened for ASD using similar examination and diagnostic tools as shown in the present report. Moreover, therapeutic interventions for ASD was helpful for the remission of both diseases. [ABSTRACT FROM AUTHOR]

Background: Congenital insensitivity to pain with anhidrosis (CIPA), a rare autosomal recessive sensory neuropathy, was caused mainly by biallelic mutations in the NTRK1 gene. The pathogenesis of CIPA still needs further elucidation. Methods: Here, we recruited a CIPA case and introduced whole-exome sequencing (WES) to identify the causative variation. Subsequently, an in silico molecular dynamic (MD) analysis was performed to explore the intramolecular impact of the novel missense variant. Meanwhile, in vitro functional study on the novel variant from a metabolomic perspective was conducted via the liquid chromatography–mass spectrometry (LC-MS) approach, of which the result was verified by quantitative real-time PCR (qRT-PCR). Results: A novel compound heterozygous variation in NTRK1 gene was detected, consisting of the c.851–33T > A and c.2242C > T (p.Arg748Trp) variants. MD result suggested that p.Arg748Trp could affect the intramolecular structure stability. The results of the LC-MS and metabolic pathway clustering indicated that the NTRK1Arg748Trp variant would significantly affect the purine metabolism in vitro. Further analysis showed that it induced the elevation of NT5C2 mRNA level. Conclusion: The findings in this study extended the variation spectrum of NTRK1 , provided evidence for counseling to the affected family, and offered potential clues and biomarkers to the pathogenesis of CIPA. [ABSTRACT FROM AUTHOR]

Background: Congenital insensitivity to pain with anhidrosis (CIPA), a rare autosomal recessive sensory neuropathy, was caused mainly by biallelic mutations in the NTRK1 gene. The pathogenesis of CIPA still needs further elucidation.Methods: Here, we recruited a CIPA case and introduced whole-exome sequencing (WES) to identify the causative variation. Subsequently, an in silico molecular dynamic (MD) analysis was performed to explore the intramolecular impact of the novel missense variant. Meanwhile, in vitro functional study on the novel variant from a metabolomic perspective was conducted via the liquid chromatography–mass spectrometry (LC-MS) approach, of which the result was verified by quantitative real-time PCR (qRT-PCR).Results: A novel compound heterozygous variation in NTRK1 gene was detected, consisting of the c.851–33T > A and c.2242C > T (p.Arg748Trp) variants. MD result suggested that p.Arg748Trp could affect the intramolecular structure stability. The results of the LC-MS and metabolic pathway clustering indicated that the NTRK1Arg748Trp variant would significantly affect the purine metabolism in vitro. Further analysis showed that it induced the elevation of NT5C2 mRNA level.Conclusion: The findings in this study extended the variation spectrum of NTRK1, provided evidence for counseling to the affected family, and offered potential clues and biomarkers to the pathogenesis of CIPA.

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare disease also known as hereditary sensory and autonomic neuropathy. CIPA is characterized by a lack of pain sensitivity and impaired development of sweat glands. Surgery is required for patients with self‐mutilation and skeletal developmental disorders. Due to the disease's rarity and intricacy, anesthesia poses its challenges. Although there have been a few cases of CIPA patients receiving surgery and anesthesia, the number is very limited. Here, we report a case of a child with CIPA who underwent open‐heart surgery and discuss the anesthetic considerations. We conclude that patients with CIPA undergoing open‐heart surgery require some opioids, that muscle relaxants and volatile anesthetics should be used with extreme caution, and that airway management and temperature control require special attention. [ABSTRACT FROM AUTHOR]

Background: Congenital insensitivity to pain (CIP) conditions are a group of Mendelian disorders with clinical and genetic heterogeneity. CIP with anhidrosis (CIPA) is a distinct subtype caused by biallelic variants in the NTRK1 gene. Methods: In this study, six families with CIPA were recruited and submitted to a series of clinical and genetic examinations. Whole‐exome sequencing and whole‐genome sequencing were applied to perform a comprehensive genetic analysis. Sanger sequencing was used as a validation method. Results: These patients exhibited phenotypic variability. All probands in the six families were positive for biallelic pathogenic variants in NTRK1. Five individual variants, namely NTRK1: (NM_002529.3) c.851‐33T>A, c.717+2T>C, c.1806‐2A>G, c.1251+1G>A, and c.851‐794C>G, including three novel ones, were identified, which were carried by the six patients in a homozygous or compound heterozygous way. The validation results indicated that all the parents of the six probands, except for one father and one mother, were monoallelic carriers of a single variant. Conclusions: The findings in our study extended the variation spectrum of the NTRK1 gene and highlighted the advantage of the integrated application of multiplatform genetic technologies. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence has shown that the occurrence and development of various human diseases are closely related to the gut microbiota. We compared the gut microbial communities of human subjects with congenital insensitivity to pain with anhidrosis (CIPA) and healthy controls (HCs) to assess whether fecal microbiota transplantation (FMT) into germ-free mice and mice in acute pain influenced the behaviors of the host. Methods: We utilized 16 s rRNA analysis to compare the gut microbial communities of CIPA subjects and HCs and assessed whether FMT into germ-free mice and mice in acute pain influenced the behaviors of the host. Results: In a 16 s RNA analysis, the CIPA group had significant decreases in the relative abundance of 11 bacteria, whereas 7 bacteria were significantly increased. In further animal experiments, the transplantation of fecal samples from CIPA patients to healthy mice significantly increased their scores on both the mechanical withdrawal test and the tail flick test; in an acute plantar incision model, scores were also significantly increased on the mechanical withdrawal test at 4 and 5 days after the operation. Moreover, pseudo-germ-free mice receiving fecal bacteria from patients with CIPA took significantly longer to escape and had a significantly longer path length on training days 1, 2, and 5 and also had fewer platform crossings and spent less time in the target quadrant in the probe trial. Conclusions: Our results suggest that the gut microbiota in CIPA subjects plays a key role in behaviors. Therapeutic strategies for improving the gut microbiota might alleviate CIPA symptoms. [ABSTRACT FROM AUTHOR]

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disease resulting from mutations in the NTRK1 gene encoding the neurotrophic tyrosine kinase-1 receptor. In this multicenter observational retrospective study, we investigated CIPA patients identified from French laboratories sequencing the NTRK1 gene, and seven patients were identified. Patients originated from France (2), Suriname (2), Mali (1), Kazakhstan (1), and Algeria (1). Mean age of patients was 9.8 years (4–20), four patients were female (57%), infant developmental milestones were delayed in four cases (57%), and four patients had a family history of consanguinity (57%). Mean age at diagnosis was 4.8 months (3–6), and all patients presented with pain insensitivity, anhidrosis, intellectual disability, self-mutilation, febrile episodes, impaired temperature perception, and autonomous nervous system impairment. Patients also showed an assortment of associated findings, including hyperactivity (86%), emotional lability (86%), joint deformities (71%), bone fractures (57%), abnormal sense of touch, vibration and position (50%), skin, hair and nails abnormalities (28%), and hypothermia episodes (28%). Two patients died at age 9 and 12 years from infection. In three cases, nerve conduction studies showed absent lower limbs sensory nerve action potentials. In one case, sensory nerve biopsy showed complete absence of unmyelinated fibers. Nine NTRK1 pathogenic variants were found, including three newly described mutations. This nationwide study confirms that NTRK1 gene-related CIPA is an extremely rare disorder and expands the genotypic spectrum of NTRK1 mutations. [ABSTRACT FROM AUTHOR]

Abstract Background Congenital insensitivity to pain (CIP) conditions are a group of Mendelian disorders with clinical and genetic heterogeneity. CIP with anhidrosis (CIPA) is a distinct subtype caused by biallelic variants in the NTRK1 gene. Methods In this study, six families with CIPA were recruited and submitted to a series of clinical and genetic examinations. Whole‐exome sequencing and whole‐genome sequencing were applied to perform a comprehensive genetic analysis. Sanger sequencing was used as a validation method. Results These patients exhibited phenotypic variability. All probands in the six families were positive for biallelic pathogenic variants in NTRK1. Five individual variants, namely NTRK1: (NM_002529.3) c.851‐33T>A, c.717+2T>C, c.1806‐2A>G, c.1251+1G>A, and c.851‐794C>G, including three novel ones, were identified, which were carried by the six patients in a homozygous or compound heterozygous way. The validation results indicated that all the parents of the six probands, except for one father and one mother, were monoallelic carriers of a single variant. Conclusions The findings in our study extended the variation spectrum of the NTRK1 gene and highlighted the advantage of the integrated application of multiplatform genetic technologies.

Ningbo Li,1 Shanna Guo,1 Qingli Wang,2 Guangyou Duan,3 Jiaoli Sun,1 Yi Liu,1 Jin Zhang,1 Cong Wang,1 Changmao Zhu,1 Jingyu Liu,4 Xianwei Zhang1 1Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 2Department of Anesthesiology, Wuhan General Hospital of Guangzhou Military, Wuhan, China; 3Department of Anesthesiology, Xinqiao Hospital, Third Military Medical University, Chongqing, China; 4Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China Purpose: Congenital insensitivity to pain with anhidrosis (CIPA) is a rare inherited disorder whose core clinical features consist of no response to noxious stimuli and inability to sweat under any conditions. Our goal was to characterize the details of phenotypic and genotypic features in Chinese CIPA patients.Patients and methods: Personal data and clinical information were investigated by interview and physical examination. DNA was extracted from blood samples of patients and their available familial members and subjected to genetic analysis.Results: A total of 41 Han Chinese CIPA patients from 35 unrelated families were recruited. The distribution of patients was mainly in the central and southern regions of China, with a male to female ratio of 3:1 and a mortality rate of 7.3%. Heterogeneity of clinical features, including pain insensitivity, temperature sensation, and complications, were cataloged. Interestingly, some patients had “visceral pain” sensation, and there was a significant difference in temperature perception and thermal pain between individuals. The incidence of bone and joint fractures was 49%. The characteristics of 19 mutations of NTRK1 in 41 patients, with five novel mutations, were identified. More than 63% of patients had the splice mutation, c.851–33 T>A, which strongly suggests that it may be a common pathogenic site in Han Chinese patients.Conclusion: Current findings expand our knowledge about the spectrum of phenotypic features and the racial characteristics of NTRK1 mutations of CIPA patients in the Han Chinese population. Keywords: congenital insensitivity to pain with anhidrosis, HASN IV, phenotype, NTRK1, mutation, Chinese

Abstract Background Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disease characterized by unexplained fever, systemic insensitivity to pain, anhidrosis, and mental distress. Anesthetic management is challenging because autonomic dysfunction can induce perioperative complications. Only a few reports of anesthetic management of CIPA patients have been published. We herein present a case of successful management of the same patient on two occasions using small doses of fentanyl and remifentanil. Case presentation A 37-year-old man with CIPA underwent two orthopedic operations. We were able to balance the dose of remifentanil to avoid the extremes of hyperalgesia when the dose is too low and shivering when the dose is too high. Conclusion To our knowledge, no reports have described the anesthetic management of CIPA patients with remifentanil. We consider anesthetic management with coadministration of remifentanil to be potentially useful for such patients.

Background and purpose: Hereditary sensory and autonomic neuropathies (HSANs) are a group of clinically and genetically heterogeneous neurological disorders characterized by sensory dysfunctions. Here, 21 affected Chinese families are reported, including 19 with congenital insensitivity to pain with anhidrosis (CIPA; namely HSAN IV) and two with congenital insensitivity to pain (CIP; namely HSAN IID) caused by biallelic variations in NTRK1 and SCN9A, respectively, aiming to identify causative variants in these families and compare how different variants in NTRK1 affect the function of tropomyosin receptor kinase A (TrkA). Methods: Recombinant plasmids harboring the wild‐type and six mutant alleles (p.Gln216*, p.Glu584Lys, p.Leu595Arg, p.Pro684Leu, p.Val709Leu and p.Arg765Cys) of NTRK1 cDNA were constructed and transfected into HEK293 cells. Results: The results suggested that the five missense variants only presented a subtle influence on the expression level and glycosylation of TrkA but compromised the receptor phosphorylation. Our findings also suggested that a synonymous variant c.219C>T in NTRK1 may cause aberrant splicing, indicating a potential novel pathogenic mechanism of CIPA. Furthermore, gross deletion of SCN9A was first associated with CIP. Conclusions: This study identified multiple forms of variants responsible for CIPA/CIP in the Chinese population and might provide new insights into the pathogenesis of CIPA. [ABSTRACT FROM AUTHOR]

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Abstract Background Congenital insensitivity to pain with anhidrosis is a rare autosomal recessive disorder characterized by hyperpyrexia, anhidrosis, pain insensitivity, self-inflicted injuries, and intellectual disability. The anesthetic management of these patients is challenging owing to the high risk of perioperative complications resulting from their autonomic dysfunction, such as hyperthermia, hypotension, and bradycardia, which result from autonomic nervous system dysfunction. Case presentation Two 3-year-old Han Chinese identical male twins (weighing 13.5 kg and measuring 93 cm tall) were previously diagnosed as having congenital insensitivity to pain with anhidrosis based on clinical features and genetic screening. According to the presence of loud snoring and heavy breathing during sleep and neck radiograph findings, they were diagnosed as having tonsil and adenoid hypertrophy and needed adenotonsillectomy. Because of innate analgesia, some reports suggested that patients with congenital insensitivity to pain with anhidrosis do not require perioperative pain control. Accordingly, our patients did not receive opiates. We describe the general anesthetic management of these patients using sevoflurane and propofol, but without opiates, for adenotonsillectomy. Remarkable tachycardia and hypertension occurred during airway manipulation and when the surgical stimuli increased, and their temperatures increased from 36 °C and 36.8 °C to 37.8 °C and 38.5 °C, respectively. Patients with congenital insensitivity to pain with anhidrosis lack pain sensation, but they may have tactile hyperesthesia. Surgical noxious stimuli may therefore produce a stress response and unpleasant sensations, leading to hemodynamic fluctuation and temperature increase. Conclusions On the basis of these findings, we suggest that careful intraoperative opiate titration may be justified to blunt the surgical stress response and promote hemodynamic and temperature stability in similar patients; we also recommend the preparation of warming and cooling devices and continuous temperature monitoring in these patients. Since anesthetic management of these patients is not simple, careful attention is required.

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare disease that affects the sensory and autonomic nervous system. The patients do not have the ability to sense different sensations, such as pain, which tends to lead to different injuries. In addition, the patients suffer from fluctuations in body temperature due to autonomic involvement. The present case was a five-year-old girl with a neglected distal femur fracture. X-rays taken during the follow-up showed marked callus formation and pseudarthrosis of the distal femur. She had biting injuries of the tongue, auto-amputation of the fingers, some developmental delay and a history of recurrent fever with an unknown origin. The electrodiagnostic study was normal. The quantitative sudomotor axon reflex test revealed markedly reduced postganglionic sudomotor axonal responses at all sites recorded on the left. She was diagnosed with CIPA. As the initial presentation of CIPA involves the musculoskeletal system, orthopedic surgeons should have a high index of suspicion. en [ABSTRACT FROM AUTHOR]

Abstract Introduction Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disorder resulting from NTRK1 mutation. Over 105 NTRK1 mutations have been reported in CIPA patients worldwide. The causative NTRK1 mutations lead to loss of function of the TrkA protein, an important ligand for nerve growth factor (NGF), and therefore induce various clinical phenotypes associated with neuron maturation defects. Materials and methods Three patients from unrelated families with CIPA were subjected to detailed clinical examinations. Blood samples were collected from all the patients and their available family members, as well as 200 healthy volunteers. Sanger sequencing for all the exons and splicing sites of NTRK1 was performed on all samples. The phenotype-genotype relationship and genetic epidemiology of Chinese CIPA patients were also analysed. Results A total of four different NTRK1 mutations [c.851-33T>A, c.44G>A (p.Trp15*), c.287+2dupT, c.1549G>C (p.Gly517Arg)] were identified in these families, and c.1549G>C (p.Gly517Arg) was a novel mutation that had not been reported previously. The 'mild' manifestations observed in patients with c.851-33T>A indicated this mutation as a 'mild' mutation. After reviewing studies reporting mutations in Chinese CIPA patients, we speculate the mutation c.851-33T>A is one of the founder mutations in the Chinese population. Conclusions Our research expanded the spectrum of the NTRK1 mutations associated with CIPA patients, provided additional clues relating to the phenotype-genotype relationship in CIPA, and summarized the features of the genetic epidemiology of CIPA in the Chinese ethnic group. Highlights • A novel mutation [(c.1549G>C (p.Gly517Arg)) related with CIPA was identified in the gene NTRK1. • The c.851-33C>T mutation was linked with 'mild' manifestations, indicating c.851-33C>T as a 'mild' mutation. • The study pointed out that the c.851-33C>T mutation was one of the founder mutations of Chinese CIPA patients • The study further supports the association between NTRK1 mutations and CIPA. [ABSTRACT FROM AUTHOR]

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare disease caused by a mutation in the nerve growth factor (NGF) receptor, which results in an absence of Aδ and C fibers. It can be considered that this defect may also lead to deterioration of oral sensations. The aim of the present study was to clarify the ability of CIPA patients to perceive pungent, gustatory, and olfactory stimuli, which is essential for eating function, and the impact of the defect on dietary habits. Sensitivities to capsaicin and the five basic tastes were evaluated by measuring their threshold values, and dietary habits were examined using a questionnaire. Additionally, odor identification ability was evaluated using the odor stick method. The detection threshold for capsaicin and the recognition threshold for sour taste were significantly higher in the patients than in healthy volunteers. The questionnaire responses showed that the patients consumed spicy food more often. All patients were able to identify the tested odors, except those to which they had not been well accustomed. Since the abilities of CIPA patients to perceive taste and smell were not basically impaired, despite their lower sensitivity to capsaicin, it was suggested that their dietary habits were only minimally affected, except for intake of pungent foods. [ABSTRACT FROM AUTHOR]

Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive disorder characterized by self-mutilating behavior, unexplained fever, inability to sweat and intellectual disability. CIPA pathogenesis is associated with genetic loss-of-function mutations of the NTRK1 gene, which is auto phosphorylated activating intracellular signaling transduction such as cell survival, growth and differentiation. CIPA occurs with an incidence of 1 in 125 million newborns, and only some hundreds of cases have been reported worldwide. Most of cases have been reported in Asian countries. Here, we estimate the ancestral proportions of a family with consanguinity background affected with CIPA, who carries the missense pathogenic mutations rs80356677 (Asp674Tyr) in the kinase domain of NTRK1 and rs324420 (Pro129Thr) in the FAAH gene. The ancestral proportion was calculated through 45 ancestry informative markers (AIMs) and the comparison was done through the Human Genome Diversity Project panel. The resulting allele frequencies in CIPA family indicate a prevalence of the Native American ancestral component with 87.9%, and minor proportion for the European (8.9%) and African (3%) components. In conclusion, the genetic variations expressing CIPA in a Native American Ecuadorian family could have been caused by the insertion of certain genetic characteristics, which have been passed down from common ancestors as consequence of migration towards South America. [ABSTRACT FROM AUTHOR]

Hereditary sensory and autonomic neuropathy type IV (HSAN IV), or congenital insensitivity to pain with anhidrosis, is an exceptionally rare genetic disorder that results in the complete loss of pain and temperature sensation as well as anhidrosis. Anesthetic management of these patients can be difficult because of significantly increased risks during general anesthesia. Literature on perioperative anesthetic management is typically written in the context of a hospital setting. As such, our case presents a unique report on the anesthetic management of a HSAN IV patient who presented for extraction of 2 teeth in an office-based setting. In determining how to safely manage the procedure, we decided against general anesthesia as we lacked the facilities and equipment to safely handle previously reported complications. We were successful in providing sedation with nitrous oxide in oxygen and applying 20% benzocaine topical ointment on the surgical site in lieu of administering general anesthesia. We had an anesthesiologist present and obtained intravenous access prior to the surgery to help manage any complications. This report provides support that simple dental extractions can be accomplished safely in the HSAN IV patient in the office-based setting, thereby avoiding unnecessary risk. [ABSTRACT FROM AUTHOR]

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disorder, characterized by loss of algesthesis and inability to sweat. CIPA is known to be caused by mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1). However, the details of NTRK1 mutations in Chinese CIPA patients remain unclear. In the present study, we recruited 36 CIPA patients from 34 unrelated families in mainland China. Blood samples from these patients and their available familial members were collected and subjected to genetic analysis. We identified 27 mutations in NTRK1 from this cohort, including 15 novel mutations. Interestingly, we discovered two forms of novel recurrent mutations: the first was a large intragenic deletion c.429-374_717th485del mediated by recombination between Alu elements, and the second was a deep intronic substitutions c.[851-798C>T;851-794C>G]. All probands were homozygotes or compound heterozygotes of these mutations. Current findings expand our knowledge about the mutation spectrum of NTRK1 in Chinese CIPA patients and provide more evidence for precise diagnosis of the clinically suspected patients with CIPA. [ABSTRACT FROM AUTHOR]

NGF is a well-studied neurotrophic factor, and TrkA is a receptor tyrosine kinase for NGF. The NGF–TrkA system supports the survival and maintenance of NGF-dependent neurons during development. Congenital insensitivity to pain with anhidrosis (CIPA) is an autosomal recessive genetic disorder due to loss-of-function mutations in the NTRK1 gene encoding TrkA. Individuals with CIPA lack NGF-dependent neurons, including NGF-dependent primary afferents and sympathetic postganglionic neurons, in otherwise intact systems. Thus, the pathophysiology of CIPA can provide intriguing findings to elucidate the unique functions that NGF-dependent neurons serve in humans, which might be difficult to evaluate in animal studies. Preceding studies have shown that the NGF-TrkA system plays critical roles in pain, itching and inflammation. This review focuses on the clinical and neurobiological aspects of CIPA and explains that NGF-dependent neurons in the peripheral nervous system play pivotal roles in interoception and homeostasis of our body, as well as in the stress response. Furthermore, these NGF-dependent neurons are likely requisite for neurobiological processes of ‘emotions and feelings’ in our species. [ABSTRACT FROM AUTHOR]

Pain causes a reflex withdrawal from any stimuli that can cause actual or potential tissue damage. It is frequently an early symptom of a disease process and is often the impetus for a patient to seek medical treatment. In many disorders where pain appears late, patients are at risk of developing complications without getting noticed. ′Congenital insensitivity to pain′ is a rare disorder. Traumatic injury and self-mutilation is an almost consistent feature in this disorder. Injuries most frequently involve the oral and paraoral structures such as teeth, lips, tongue, and also ears, eyes, nose, and fingers. Oral manifestations may be the presenting complaint. Thus, it is important for the clinicians to be familiar with the condition. The present article provides a brief review of the condition and its insinuation in dentistry.

Congenital insensitivity to pain with anhidrosis (CIPA) syndrome is a neuropathy characterized by insensitivity to pain, impaired thermoregulation, anhidrosis, and mental retardation. A 9-year old boy with CIPA syndrome, underwent 2 operations for a calcaneal ulcer. During the first operation standard monitorization was performed. In the second operation, Bispectral Index (BIS) monitoring was added and temperature was monitored with an esophageal probe. In the first operation, in which anesthesia induction was applied with ketamine and midazolam, extremity movements with surgical stimuli were seen. Despite pain insensitivity, as extremity movements were seen with surgical stimuli, propofol was administered in the second operation. Throughout the operation, the BIS values varied from 19-58 and body temperature was measured as 36.1°C-36.9°C. In conclusion, despite the absence of pain sensitivity in CIPA syndrome cases, there is an absolute need for the administration of anesthesia in surgical procedures because of tactile hyperesthesia. [ABSTRACT FROM AUTHOR]

Background: Congenital insensitivity to pain with anhidrosis is a rare autosomal recessive disorder characterized by hyperpyrexia, anhidrosis, pain insensitivity, self-inflicted injuries, and intellectual disability. The anesthetic management of these patients is challenging owing to the high risk of perioperative complications resulting from their autonomic dysfunction, such as hyperthermia, hypotension, and bradycardia, which result from autonomic nervous system dysfunction.Case Presentation: Two 3-year-old Han Chinese identical male twins (weighing 13.5 kg and measuring 93 cm tall) were previously diagnosed as having congenital insensitivity to pain with anhidrosis based on clinical features and genetic screening. According to the presence of loud snoring and heavy breathing during sleep and neck radiograph findings, they were diagnosed as having tonsil and adenoid hypertrophy and needed adenotonsillectomy. Because of innate analgesia, some reports suggested that patients with congenital insensitivity to pain with anhidrosis do not require perioperative pain control. Accordingly, our patients did not receive opiates. We describe the general anesthetic management of these patients using sevoflurane and propofol, but without opiates, for adenotonsillectomy. Remarkable tachycardia and hypertension occurred during airway manipulation and when the surgical stimuli increased, and their temperatures increased from 36 °C and 36.8 °C to 37.8 °C and 38.5 °C, respectively. Patients with congenital insensitivity to pain with anhidrosis lack pain sensation, but they may have tactile hyperesthesia. Surgical noxious stimuli may therefore produce a stress response and unpleasant sensations, leading to hemodynamic fluctuation and temperature increase.Conclusions: On the basis of these findings, we suggest that careful intraoperative opiate titration may be justified to blunt the surgical stress response and promote hemodynamic and temperature stability in similar patients; we also recommend the preparation of warming and cooling devices and continuous temperature monitoring in these patients. Since anesthetic management of these patients is not simple, careful attention is required. [ABSTRACT FROM AUTHOR]

Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV, features loss of pain sensation, decreased or absent sweating (anhidrosis), recurrent episodes of unexplained fever, self-mutilating behavior, and variable mental retardation. Mutations in neurotrophic receptor tyrosine kinase 1 (NTRK1) have been reported to be associated with CIPA. We identified four novel NTRK1 mutations in six Korean patients from four unrelated families. Of the four mutations, we demonstrated using a splicing assay that IVS14+3A>T causes aberrant splicing of NTRK1 mRNA, leading to introduction of a premature termination codon. An NTRK1 autophosphorylation assay showed that c.1786G>A (p.Asp596Asn) abolished autophosphorylation of NTRK1. In addition, Western blotting showed that c.704C>G (p.Ser235*) and c.2350_2363del (p.Leu784Serfs*79) blunted NTRK1 expression to undetectable levels. The four novel NTRK1 mutations we report here will expand the repertoire of NTRK1 mutations in CIPA patients, and further our understanding of CIPA pathogenesis. [ABSTRACT FROM AUTHOR]