Congenital Insensitivity To Pain With Anhidrosis Patients Research Articles

Living without pain: A 10-year study of congenital insensitivity to pain with anhidrosis.

Congenital Insensitivity to Pain with Anhidrosis (CIPA) is a rare hereditary neuropathy caused by NTRK1 gene mutations, predisposing patients to recurrent infections and chronic wounds. Long-term studies on microbial and clinical outcomes in CIPA are limited. This study presents analysis of infection patterns, antibiotic resistance, and clinical outcomes in CIPA patients. A comprehensive ten-year retrospective cohort study was conducted at Soroka University Medical Center, Beer Sheva, Israel, from January 2014 to January 2023. Electronic medical records were reviewed to identify 63 CIPA patients, all were of consanguineous Bedouin families. Data collection included demographic details, clinical presentations, genetic analysis, documentation of infections, wound sites, hospital duration, and surgical interventions. Staphylococcus aureus, notably methicillin-resistant, dominated, with Gram-negative bacteria common in lower limbs. The study noted reduced extended-spectrum beta-lactamase bacteria and linked demographic factors to infection traits, antibiotic resistance, and surgical needs. This study provides valuable insights into the clinical and microbial patterns of CIPA, highlighting dynamic shifts in microbial compositions and antibiotic resistance profiles over time. Staphylococcus aureus, and Gram-negative bacteria particularly in lower limb infections, pose significant challenges in patient management. The findings underscore the importance of tailored approaches to address evolving microbial profiles and optimize patient care in CIPA. Key Message: This is the largest cohort study on CIPA to date, highlighting the dominance of Staphylococcus aureus, including methicillin-resistant strains, and significant Gram-negative bacterial infections in lower limbs. Contribution to Literature: It draws parallels between infection dynamics in CIPA and diabetic foot ulcers, emphasizing similar challenges due to neuropathy and ischemia, enhancing understanding of infection susceptibility and management in neuropathic conditions. The findings inform clinical practices by detailing infection and resistance patterns, supporting the development of targeted treatment strategies to improve outcomes for CIPA and similar conditions.

Congenital Insensitivity to Pain With Anhidrosis Is Associated With Harlequin Color Change: A Survey Study.

Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy (HSAN) type IV, is an extremely rare autosomal recessive congenital condition characterized by the loss of sensation to pain and absence of sweating with one case report linking this with harlequin color change. To explore the relationship further, we developed a survey using the Research Electronic Data Capture software and distributed it to families and others with close relationships and knowledge of patients with CIPA. Our results indicate that harlequin color change, characterized by unilateral flushing of the face and/or body, was significant and noted by all respondents as being present early in the condition appearing around the same time as first symptoms and around or before diagnosis of CIPA. Future clinicians should be aware of this dermatological phenomenon and its potential association with CIPA patients, especially during early disease manifestation where diagnosis can be difficult.

Atypical Presentation of Congenital Insensitivity to Pain With Anhidrosis Leading to Diagnostic Odyssey.

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. 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. 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.

Congenital insensitivity to pain with anhidrosis: a literature review and the advocacy for stem cell therapeutic interventions.

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.

Congenital Insensitivity TO Pain: A Case Report

Congenital insensitivity to pain or more scientifically Hereditary sensory and autonomic neuropathies (HSAN) is a rare genetic disorder which associates a sensory dysfunction with a varying degree of autonomic dysfunction. Due to the peripheral neuropathy, a decreased sensitivity or even complete anesthesia may be present resulting in, on the ophthalmological level, neurotrophic ulcers. We report the case of 2 sisters (JM and KM) presenting with HSAN with recurrent corneal ulcers. Unfortunately, genetic testing couldn’t be performed due to lack of means, but the clinical presentation and features were very favourable or even pathognomonic of this syndrome. The first cases or reported individuals presenting with congenital insensitivity to pain goes back to 1930’s. Five types of hereditary sensory and autonomic neuropathy have been identified according to age of onset of symptoms, clinical features and affected gene. HSAN type IV also known as congenital insensitivity to pain with anhidrosis (CIPA) is the second most common HSAN. It is caused by mutation in the NTRK1(Neurotrophic tyrosine kinase receptor type 1) (TRKA) gene located in chromosome 1 (1q21-q22). It is characterized by repetitive hyperthermic episodes in infancy, and mental retardation is usually present, as reported in our case. Clinical symptoms of pain insensitivity manifest as tongue, lip and fingers biting, and self-inflicted injuries. Congenital insensitivity to pain is a rare genetic syndrome characterized by an absence or an altered response to pain. Individuals with this syndrome can presented self-inflicted injuries and auto-mutilation leading in some cases to severe disabilities. Long-term visual prognosis in CIPA patients is not assessed and there’s an important lack of data regarding ocular manifestation of CIP syndrome.

MOTOR NEURON DISORDERS AND NEUROPATHIES: EP.247a Debilitating oste-ochondral manifestations in a patient with congenital insensitivity to pain with anhidrosis (CIPA) due to NTRK1 mutation

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disorder, caused by mutations in NTRK1 which encodes the tropomyosin receptor kinase A (TrkA) protein. Here we report a patient suffering from debilitating osteo-chondral complications with history of bone fractures at young age, then recurrent multiple joints effusion with arthropathy since adolescent despite no major history of injury. She has CIPA due to compound heterozygous mutations of NTRK1: c.2089 G>A (p.Gly697Lys) and c.744 del. She also has the classical CIPA presentation including unexplained pyrexia, inability to sweat, insensitivity to pain with self-mutilation behaviour and mild cognitive impairment. Investigations confirmed the chronic effusion is not immune-mediated but the result of poor healing and remodelling of both the osteo-chondral elements of the involved joints with progressive deformity. We found the osteo-arthropathic complications is highly prevalent among 220 reported mut-NTRK1-related CIPA patients between 1999 and 2020, in which 102 patients (50%) had bone problems, 47 patients (21.4%) had joint problems, and 23 patients (10.5%) had both bone and joint manifestation. We then simulated the point mutations of TrkA at p.Gly697Lys (our patient), p.Arg692Cys (patient with mutation site close to our patient), p.Arg654Cys, and p.Gly599Ter (2 patients with mutation site close to our patient and had same clinical and osteo-chondral presentation like our patient) with bioinformatic tools, and predicted the affected downstream protein-protein docking. Among the known bone homeostasis related TrkA binding proteins, the docking of mut-TrkA (p. Gly697Lys and p.Arg692Cys) with PLCG1 and GRB2 were predicted to be affected. For the docking of mut-TrkA (p.Gly697Lys, p.Arg692Cys, p.Arg654Cys, and p.Gly599Ter), interactions with GRB2 were predicted to be affected. Our findings confirm that osteo-arthropathic involvement is common in patients with NTRK1-related CIPA. This osteo-chondral pathology in our patient is likely due to the mutation of TrkA at p.Glu697Lys, affecting the binding of TrkA-PLCG1 and TrkA-GRB2 related downstream signalling. Currently there is no effective treatment for NKRT1-related CIPA. Further study on the PLCG1 and GRB2 signalling, and their downstream pathways may facilitate the findings of potential treatment of the debilitating osteochondral manifestation in NKTR1-related CIPA.

NTRK1 gene-related congenital insensitivity to pain with anhidrosis: a nationwide multicenter retrospective study.

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 9.8years (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 4.8months (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 12years 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.

Pivotal role of the gut microbiota in congenital insensitivity to pain with anhidrosis.

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. We utilized 16s 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. In a 16s 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 5days 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. 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.

Perception of pungent, gustatory and olfactory stimuli in patients with congenital insensitivity to pain with anhidrosis.

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.

Heterogeneity of clinical features and mutation analysis of NTRK1 in Han Chinese patients with congenital insensitivity to pain with anhidrosis.

PurposeCongenital 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 methodsPersonal 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.ResultsA 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.ConclusionCurrent 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.

Identification of a novel mutation of the NTRK1 gene in patients with congenital insensitivity to pain with anhidrosis (CIPA)

IntroductionCongenital 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 methodsThree 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. ResultsA 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. ConclusionsOur 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.

Novel NTRK1 mutations in Chinese patients with congenital insensitivity to pain with anhidrosis.

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_717 + 485del 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.

Novel NTRK1 mutations associated with congenital insensitivity to pain with anhidrosis verified by functional studies.

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.

Skeletal complications in congenital insensitivity to pain with anhidrosis: a case series of 14 patients and review of articles published in Japanese

Background Congenital insensitivity to pain with anhidrosis (CIPA) is a rare disorder with various skeletal complications; thus, a compilation of data on affected patients could provide a valuable resource for the management of this disease. The aim of this study was to ascertain and report the frequency, location, age of onset, cause, and management of skeletal complications in Japanese patients with CIPA.Methods The medical records of 14 CIPA patients in our institute and information on 77 patients reported in Japanese articles were analyzed. Data regarding skeletal-system complications, including location, symptom, major cause and management of fractures, joint dislocations, infections, and Charcot joints, were extracted.Results Fractures occurred in 59/91 patients (65 %), 91 % of them in the lower limbs. Joint dislocations occurred in 27/91 patients (30 %), 91 % of them in the hip joint. Bone and joint infections occurred in 22 patients (24 %) and Charcot joints in 26 patients (29 %); 62 % of infections and 87 % of Charcot joints developed in the lower limbs. Most fractures occurred from 1 to 7 years of age; there was no apparent relationship between age and other complications. The major known causes of bone disorders were minor trauma such as short falls; however, most were of unknown cause. Conservative therapy was used more frequently than surgery to manage fractures, dislocations, and Charcot joints.Conclusions These data show that most CIPA patients have skeletal complications, most of which occur in the lower limbs. Fractures are frequent between 1 and 7 years of age, whereas other bone disorders have no apparent age relationship. The major known causes of bone disorders were minor trauma such as short falls. Conservative therapy was more frequently used to manage fractures, dislocations, and Charcot joints.

Old fractures in two patients with congenital insensitivity to pain with anhidrosis: radiological findings

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disease that is characterized by anhidrosis, insensitivity to noxious stimuli, and mental retardation. Patients who suffer from CIPA easily sustain injuries due to pain insensitivity. Radiological findings in two CIPA patients revealed several old fractures of which the patients were unaware of previous injury. An early diagnosis of CIPA is important for the prevention and treatment of various complications. Our data indicate that radiological findings may provide important information for the diagnosis of CIPA.

Morbidity characteristics of patients with congenital insensitivity to pain with anhidrosis (CIPA)

Congenital insensitivity to pain with anhidrosis (CIPA) is a congenital autonomic sensory neuropathy. In southern Israel, there are many patients with this disease. We here tried to characterize the different infections acquired by children with CIPA. We collected all the available data about CIPA patients in southern Israel in the year 1991-2005, including the lesion types, area in the body where the infection occurs, and the treatment given. The current study included 30 children with CIPA, out of 44 known CIPA patients in southern Israel (68.2%). A total of 382 different episodes of infections, fever, orthopedic lesions, and jaw and mouth lesions led our patients to our outpatient clinic or resulted in hospitalization. We found that children with CIPA mainly have infections of the skin and skeleton, and that the most frequent pathogen is Staphylococcus aureus. We also found that a fair amount of these pathogens are resistant to conventional treatment regimens.

Pathological fracture of the mandible in a paediatric patient with congenital insensitivity to pain with anhidrosis (CIPA)

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare hereditary sensory and autonomic neuropathy (HSAN) characterized by pain, self-mutilating behaviour, anhidrosis and recurrent hyperthermia. CIPA has a multisystem involvement, including fractures of the extremities with slow healing, immunologic abnormalities, and a chronic inflammatory state. The mandible is reported to have a higher incidence of osteomyelitis, though mandibular fracture among CIPA patients, is very rare, with to our knowledge no reports in children.A case of pathological fracture of the mandible in a 6-year-old child with CIPA treated by ORIF is reported. In contrast to the slow healing reported in long bones, the mandible healed very quickly, possibly indicating that the osteoporotic mandible in this group of patients is different from that seen in the elderly. Furthermore, the standard ORIF technique can be safely used in this rare group.

Osteomyelitis of the mandible in a group of 33 pediatric patients with congenital insensitivity to pain with anhidrosis

ObjectiveTo determine the frequency of mandibular osteomyelitis (OM) in patients with congenital insensitivity to pain with anhidrosis (CIPA) and to relate its appearance to possible risk factors. MethodsThe records of 33 patients were reviewed for data concerning events of jaw OM, oral trauma, maxillofacial interventions, or OM of long bones. ResultsEighteen percent of the patients had mandibular OM. Of the six patients, preceding oral laceration was documented in one and tooth extraction in two. Seventy percent of the patients had OM of the limbs, but only 15% overlapped, having both jaw and limb OM. Half of the patients with mandibular OM had also OM of the limbs during the following year. There seems to be a correlation between high frequency of limb OM (at least 5 events per patient) and appearance of mandibular OM. ConclusionThe incidence of mandibular OM is very high among patients with CIPA and can result in pathologic fracture and the need for open reduction and internal fixation. The reason for this phenomenon is presently not clear. Preventive and therapeutic strategy for CIPA patients should be undertaken to minimize this severe complication.

Evaluation of nonnociceptive sensation in patients with congenital insensitivity to pain with anhidrosis

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare, autosomal recessive disorder characterized by lack of pain and thermal sensation, anhidrosis, thermodysregulation, and mental retardation. Although nonnociceptive sensation, which is mediated by large-caliber myelinated Abeta fibers, is reported to be normal in CIPA patients, precise clinical assessments of this type of sensation have yet to be performed. The aim of this study was to evaluate peripheral sensory nerve function, including senses of touch/pressure, vibration, joint position, and two-point discrimination, in patients with CIPA by basic clinical neurological examination. We examined touch/pressure sense, deep senses (vibration, joint proprioception), and two-point discrimination in 12 patients with CIPA (six males and six females aged 11-44) and 12 age- and sex-matched healthy controls. Touch/pressure sense was examined with Semmes-Weinstein monofilaments, vibration sense with a tuning fork, and two-point discrimination with a vernier caliper. Joint proprioception was assessed through subject recognition of passive movement of the great toe. Perception thresholds of touch/pressure, vibration, and two-point discrimination were significantly higher (p < 0.05), and proprioception sensitivity was significantly lower (p < 0.05) in CIPA patients than in the healthy controls. Our findings suggest that CIPA patients suffer from more widespread disturbances of sensation than has been previously recognized. Impairment may not be restricted to the types of sensation conducted by peripheral sensory Adelta and C fibers.

Abnormal neutrophil chemotactic activity in children with congenital insensitivity to pain with anhidrosis (CIPA): The role of nerve growth factor

A 1926-ins-T mutation in the TrkA gene encoding the tyrosine kinase receptor for nerve growth factor (NGF) was previously documented in patients with congenital insensitivity to pain with anhidrosis (CIPA). These patients suffer from skin lacerations which often evolve into deep tissue infections. Abnormality in neutrophil functions may explain this high rate of severe infections. In this study we show that chemotaxis was significantly (P < 0.001) suppressed in patients' neutrophils, compared to healthy controls. Although NGF alone did not exert a chemotactic effect, its presence enhanced both migration toward fMLP and phosphorylation of MAP kinases (ERK and JNK) in neutrophils from healthy controls, but not in neutrophils from CIPA patients. The significantly impaired chemotactic activity of neutrophils from a CIPA patient, which has been attributed to the molecular defect in the TrkA receptor, may contribute to the high rate of infection.