A novel mutation in the SCN9A gene associated with congenital insensitivity to pain, anhidrosis, and mild cognitive impairment.

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.

From the Destruction of Two Lumbar Segments to Thoracic-Lumbar-Pelvic Fusion: A Case Caused by Congenital Insensitivity to Pain with Anhidrosis and Literature Review.

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.

Impact of the coronavirus pandemic on families of patients with congenital insensitivity to pain with anhidrosis.

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.

Anesthetic management of a child with congenital insensitivity to pain with anhidrosis: A case report.

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.

A case report: Anesthetic management for open-heart surgery in a child with congenital insensitivity to pain with anhidrosis.

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.

Identification of novel variations in the NTRK1 gene causing congenital insensitivity to pain with anhidrosis.

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.

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 9.8 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.

Manifestaciones clínicas de la insensibilidad congénita al dolor con anhidrosis / Clinicai manifestations of congenital Insensitivity to pain with anhidrosis

RESUMEN Introducción: La insensibilidad congénita al dolor con anhidrosis (HSAN IV o CIPA) es una enfermedad rara con sintomatologia multisistémica, que impacta el funcionamiento cognitivo, y afecta negativamente la calidad de vida los pacientes y sus familias. Se estima que la mayoría de los individuos que padecen esta enfermedad mueren antes de los tres años por las complicaciones que esta genera. Objetivo: Realizar una revisión de la sintomatologia clinica de la enfermedad y las alteraciones neurocognitivas reportadas en 145 casos de pacientes con insensibilidad congénita al dolor con anhidrosis reportados en la literatura cientifica entre 2000 y 2017. Desarrollo: La revisión permitió identificar los sintomas clínicos más frecuentes en los pacientes con insensibilidad congénita al dolor con anhidrosis IV: fiebres, anhidrosis, osteomielitis, fracturas, artropatias y necrosis avascular. Conclusiones: La insensibilidad congénita al dolor con anhidrosis como enfermedad multisistémica tiene implicaciones cognitivas en pacientes que la padecen; sin embargo, se desconoce el nivel de impacto de esta enfermedad en el comportamiento y las funciones superiores de los pacientes afectados.

ABSTRACT Introduction: The congenital insensitivity to pain with anhidrosis (HSAN IV) is a rare disease, which results in different with multisystem symptoms, impacting cognitive functions that affect negatively the quality of life not only in patients but also in relatives. It is estimated that most individuals suffering from this disease die before turning three years of age due to the complications that arise from this condition. Objective: Review the clinical symptomatology of this disease and the neurocognitive alterations that occurred in 145 cases of patients with HSAN IV reported in the scientific literature between 2000 and 2017. Findings: Te review allowed to identify the most frequent clinical symptoms in patients with HSAN IV: fever, anhidrosis, osteomyelitis, fractures, arthropathies and avascular necrosis. Conclusions: There is a scientific ignorance of the impact of HSAN IV on the behavior and superior functions in patients affected by this disease.

Molecular genetic analysis in 21 Chinese families with congenital insensitivity to pain with or without anhidrosis.

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.

Postoperative redislocation of the hip in a patient with congenital insensitivity to pain with anhidrosis: A case report and review of literature.

Pelvic osteotomy is commonly used to adjust acetabula dysplasia for congenital dislocation of the hip, whereas congenital insensitivity to pain with anhidrosis (CIPA) is a rare hereditary disease that often has the characteristics of joint development deformity and easy fracture. This article reports the case involving a CIPA patient who was surgically treated by Chiari pelvic osteotomy and proximal femoral rotation osteotomy for congenital dislocation of the left hip joint and was provided long-term follow-up for redislocation and bilateral femoral head absorption.

Funcionamiento Cognitivo Global y Conducta Adaptativa en dos Niñas con Neuropatía Sensitiva Autonómica Hereditaria Tipo IV / Global cognitive and adaptive functioning in two girls with hereditary sensory and autonomic neuropathy type IV

La neuropatía sensitiva autonómica hereditaria tipo IV (HSAN-IV) es una condición neurológica de origen genético extremadamente rara que puede cursar con discapacidad intelectual, sin embargo, hay escasas publicaciones sobre las características del funcionamiento cognitivo global y la conducta adaptativa de los afectados. En este estudio se describe la capacidad cognitiva global y el funcionamiento adaptativo de dos niñas de 12 y 14 años diagnosticadas con HSANIV, incluyendo una caracterización de los procesos de comprensión verbal, razonamiento perceptual, memoria de trabajo y velocidad de procesamiento. Las menores fueron evaluadas mediante la Escala de Inteligencia para niños de Wechsler cuarta edición (WISC-IV) encontrándose en ambos casos un bajo índice de comprensión verbal, una medida del desarrollo cognitivo alcanzado a través de la historia de aprendizaje de las niñas; así como un bajo índice de razonamiento perceptivo, indicador de su capacidad para adaptarse y afrontar situaciones nuevas de forma flexible. Esto se acompaña de dificultad en la manipulación de información en la memoria para la resolución de problemas y enlentecimiento en la velocidad de procesamiento de la información. Adicionalmente, se evaluó su funcionamiento adaptativo mediante el sistema de evaluación de la conducta adaptativa ABAS-II, el cual se caracterizó por fortalezas en habilidades comunicativas, uso de recursos comunitarios y vida en el hogar; con limitaciones en habilidades académicas y de autocuidado. En conclusión, la HSAN-IV es una condición que cursa con discapacidad intelectual con necesidades de apoyo variables en intensidad. En los casos estudiados se encontró discapacidad intelectual con necesidad de apoyo limitado, es decir, los apoyos se requieren de forma regular durante un periodo de tiempo corto pero definido.

Hereditary sensory autonomic neuropathy type IV (HSAN-IV) is a neurological condition of extremely rare genetic origin that may be associated with intellectual disability; however, there are few publications about the characteristics of global cognitive functioning and adaptive behaviour of these patients. In this study we describe the global cognitive function and the adaptive behavior of two girls aged 12 and 14 diagnosed with HSAN-IV, including a characterization of the processes of verbal comprehension, perceptual reasoning, working memory and processing speed. The children were assessed using the Wechsler Intelligence Scale for Children - Fourth Edition (WISC-IV), finding in both cases a low level of verbal comprehension, a measure of cognitive development achieved through the girls' learning history; as well as a low rate of perceptual reasoning, indicator of their ability to adapt and face new situations in a flexible way. This is accompanied by difficulty in manipulating information in the memory to solve problems and slow down the speed of information processing. Additionally, its adaptive functioning was evaluated through the Adaptive Behavior Assessment System ABAS-II, which was characterized by strengths in communication skills, use of community resources and life at home; with limitations in academic and self-care skills. In conclusion, HSAN-IV is a condition related with intellectual disability with varying support needs in intensity. In the cases studied, intellectual disability was found with limited need for support, that is, supports are required on a regular basis for a short but defined period.

Office-Based Anesthetic and Oral Surgical Management of a Child With Hereditary Sensory Autonomic Neuropathy Type IV: A Case Report.

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.

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

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.

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.

Phenotypic heterogeneity of intellectual disability in patients with congenital insensitivity to pain with anhidrosis: A case report and literature review.

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive heterogeneous disorder mainly caused by mutations in the neurotrophic tyrosine receptor kinase 1 gene ( NTRK1) and characterized by insensitivity to noxious stimuli, anhidrosis, and intellectual disability. We herein report the first north Han Chinese patient with CIPA who exhibited classic phenotypic features and severe intellectual disability caused by a homozygous c.851-33T>A mutation of NTRK1, resulting in aberrant splicing and an open reading frame shift. We reviewed the literature and performed in silico analysis to determine the association between mutations and intellectual disability in patients with CIPA. We found that intellectual disability was correlated with the specific Ntrk1 protein domain that a mutation jeopardized. Mutations located peripheral to the Ntrk1 protein do not influence important functional domains and tend to cause milder symptoms without intellectual disability. Mutations that involve critical amino acids in the protein are prone to cause severe symptoms, including intellectual disability.

NGF-dependent neurons and neurobiology of emotions and feelings: Lessons from congenital insensitivity to pain with anhidrosis.

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.

Anesthesia Procedure for Congenital Insensitivity to Pain in a Child with Anhidrosis Syndrome: A Rare Case.

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.

Anesthetic management during adenotonsillectomy for twins with congenital insensitivity to pain with anhidrosis: two case reports.

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.

Exome sequencing identifies novel NTRK1 mutations in patients with HSAN-IV phenotype.

Hereditary sensory autonomic neuropathy type IV (HSAN-IV) is a rare autosomal recessive disorder that usually begins in infancy and is characterized by anhidrosis, insensitivity to noxious stimuli leading to self-mutilating behavior, and intellectual disability. HSAN-IV is caused by mutations in the neurotrophic tyrosine kinase receptor type 1 gene, NTRK1, encoding the high-affinity receptor of nerve growth factor (NGF) which maps to chromosome 1q21-q22. Patients with HSAN-IV lack all NGF-dependent neurons, the primary afferents and sympathetic postganglionic neurons leading to lack of pain sensation and the presence of anhidrosis, respectively. Herein, we report nine patients from nine unrelated families with HSAN-IV due to various mutations in NTRK1, five of which are novel. These are three missense and two nonsense mutations distributed in various domains of NTRK1 involved in binding of NGF. The affected patients had variable intellectual deficits, and some had delayed diagnosis of HSAN-IV. In addition to being the first report of HSAN-IV from the Arabian Peninsula, this report expands the mutational spectrum of patients with NTRK1 mutations and provides further insights for molecular and clinical diagnosis.

Identification of a novel nonsense mutation of the neurotrophic tyrosine kinase receptor type 1 gene in two siblings with congenital insensitivity to pain with anhidrosis.

Objective To explore the aetiology of congenital insensitivity to pain with anhidrosis (CIPA) in two Chinese siblings with typical CIPA symptoms including insensitivity to pain, inability to sweat, and self-mutilating behaviours. Methods Clinical examination and genetic testing were conducted of all available family members, and the findings were used to create a pedigree. Mutation screening using PCR amplification and DNA Sanger sequencing of the entire neurotrophic tyrosine kinase receptor type 1 gene ( NTRK1) including intron-exon boundaries was used to identify mutations associated with CIPA. Results A novel nonsense mutation (c.7C > T, p. Arg3Ter) and a known splice-site mutation (c.851-33 T > A) were detected in NTRK1 and shown to be associated with CIPA. Conclusion Our findings expand the known mutation spectrum of NTRK1 and provide insights into the aetiology of CIPA.