A case of mid-face toddler excoriation syndrome (MiTES).

The term mid-face toddler excoriation syndrome (MiTES) has been proposed to describe a rare condition that arises in infancy as is characterized by self-inflicted excoriations. It is considered to be a milder variant of hereditary sensory-autonomic neuropathy (HSAN) type VIII. We present an 8-year-old boy with lesions on the mid-face that were admittedly self-induced and associated with an abnormally high pain threshold. The diagnosis and management of MiTES is reviewed.

The NGFR100W Mutation Specifically Impairs Nociception without Affecting Cognitive Performance in a Mouse Model of Hereditary Sensory and Autonomic Neuropathy Type V.

Nerve growth factor (NGF) is a key mediator of nociception, acting during the development and differentiation of dorsal root ganglion (DRG) neurons, and on adult DRG neuron sensitization to painful stimuli. NGF also has central actions in the brain, where it regulates the phenotypic maintenance of cholinergic neurons. The physiological function of NGF as a pain mediator is altered in patients with Hereditary Sensory and Autonomic Neuropathy type V (HSAN V), caused by the 661C>T transition in the Ngf gene, resulting in the R100W missense mutation in mature NGF. Homozygous HSAN V patients present with congenital pain insensitivity, but are cognitively normal. This led us to hypothesize that the R100W mutation may differentially affect the central and peripheral actions of NGF. To test this hypothesis and provide a mechanistic basis to the HSAN V phenotype, we generated transgenic mice harboring the human 661C>T mutation in the Ngf gene and studied both males and females. We demonstrate that heterozygous NGFR100W/wt mice display impaired nociception. DRG neurons of NGFR100W/wt mice are morphologically normal, with no alteration in the different DRG subpopulations, whereas skin innervation is reduced. The NGFR100W protein has reduced capability to activate pain-specific signaling, paralleling its reduced ability to induce mechanical allodynia. Surprisingly, however, NGFR100W/wt mice, unlike heterozygous mNGF+/- mice, show no learning or memory deficits, despite a reduction in secretion and brain levels of NGF. The results exclude haploinsufficiency of NGF as a mechanistic cause for heterozygous HSAN V mice and demonstrate a specific effect of the R100W mutation on nociception.SIGNIFICANCE STATEMENT The R100W mutation in nerve growth factor (NGF) causes Hereditary Sensory and Autonomic Neuropathy type V, a rare disease characterized by impaired nociception, even in apparently clinically silent heterozygotes. For the first time, we generated and characterized heterozygous knock-in mice carrying the human R100W-mutated allele (NGFR100W/wt). Mutant mice have normal nociceptor populations, which, however, display decreased activation of pain transduction pathways. NGFR100W interferes with peripheral and central NGF bioavailability, but this does not impact on CNS function, as demonstrated by normal learning and memory, in contrast with heterozygous NGF knock-out mice. Thus, a point mutation allows neurotrophic and pronociceptive functions of NGF to be split, with interesting implications for the treatment of chronic pain.

Animal models of congenital hypoalgesia: Untapped potential for assessing pain-related plasticity.

Over the last 20 years a large number of transgenic mouse models have been produced showing different degrees of congenital hypoalgesia; some of these models mimic known human conditions while others seemingly have no human counterpart. However, very little significant contributions to our understanding of pain neurobiology were obtained from this multitude of animal models; in most cases the study of these animals was limited to the characterization of its pain perception without addressing the long term consequences of their hypoalgesic condition. In this review we discuss the untapped potential that these animal models of congenital hypoalgesia hold for future studies addressing brain plasticity during permanent conditions of reduced pain perception, and that may result in important insights on the interplay between pain, emotion, and cognition. Revisiting hypoalgesia using modern techniques of functional neurophysiology in awake animals may complement the recent literature of functional clinical and preclinical studies that improve our understanding of the central malplasticity caused by pain.

Phenotypic and genotypic features of a pair of Chinese identical twins with congenital insensitivity to pain and anhidrosis: A case report.

RATIONALE: Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive genetic disorder characterized by insensitivity to noxious stimulus and the absence of sweating. Fractures and joint destruction are common complications, but detailed studies on mineral and skeletal homeostasis are not available. Mental retardation is often reported, but detailed observations during childhood are lacking. PATIENT CONCERNS: A pair of 46-month-old Chinese identical twin brothers was presented at our hospital. The brothers had the typical manifestations of insensitivity to noxious stimulus, inability to sweat, and recurrent episodes of unexplained fever. Fortunately, they did not present common complications such as self-mutilation, trauma, bruise, and repeated bone fractures. DIAGNOSES: Two novel compound heterozygous variants of NTRK1 (c.632T > A and c.1253_1254delTC) were identified. INTERVENTIONS: The patients were subjected to routine and specialist clinical examinations. Daily care and symptomatic treatment were given. OUTCOME: X-ray films of proband 2 showed a fracture in the first metatarsal. Decreased bone mineral density (BMD) and mild-to-moderate retardation of the Gesell developmental schedules (GDS), especially language and adaptability, were observed. Evaluation results for BMD and GDS in proband 2 were worse than those in his brother. LESSONS: The current findings expand our knowledge about the spectrum of phenotypic and genotypic features of CIPA, which will help facilitate future genotype-phenotype association studies. Daily care by parents promotes favorable outcomes in patients.

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.

TECPR2 mutations cause a new subtype of familial dysautonomia like hereditary sensory autonomic neuropathy with intellectual disability.

BACKGROUND: TECPR2 was first described as a disease causing gene when the c.3416delT frameshift mutation was found in five Jewish Bukharian patients with similar features. It was suggested to constitute a new subtype of complex hereditary spastic paraparesis (SPG49). RESULTS: We report here 3 additional patients from unrelated non-Bukharian families, harboring two novel mutations (c.1319delT, c.C566T) in this gene. Accumulating clinical data clarifies that in addition to intellectual disability and evolving spasticity the main disabling feature of this unique disorder is autonomic-sensory neuropathy accompanied by chronic respiratory disease and paroxysmal autonomic events. CONCLUSION: We suggest that the disease should therefore be classified as a new subtype of hereditary sensory-autonomic neuropathy. The discovery of additional mutations in non-Bukharian patients implies that this disease might be more common than previously appreciated and should therefore be considered in undiagnosed cases of intellectual disability with autonomic features and respiratory symptoms regardless of demographic origin.

Hereditary Sensory Autonomic Neuropathy II, a rare disease in a large Pakistani family.

Hereditary Sensory Autonomic Neuropathy II (HSAN II) is a rare genetic disorder, characterized by severe loss of pain, temperature and touch sensation. Injuries in these patients can progress to necrosis and shedding of digits and limbs. Here we report two cases of HSAN II belonging to a Pakistani family. Individual 1, a forty five year old man, had complete loss of pain sensation since birth. Self-mutilation and complication of injuries resulted in the shedding of all the digits and right foot and surgical amputation of left leg. Individual 2, a five year old girl,had delay in healing of wounds and self-mutilation. Examination showed a complete lack of pain sensation throughout her body and hyporeflexia. As the genetic cause of HSAN II is unknown, identification of more patients will allow further research on this disease and possibly develop a cure.

Assessment of cognitive and adaptive behaviour among individuals with congenital insensitivity to pain and anhidrosis.

AIM: Individuals with congenital insensitivity to pain with anhidrosis (CIPA) are reported to have mental retardation* but to our knowledge no detailed study on the subject has ever been published. The present study assessed and documented cognitive and adaptive behaviour among Arab Bedouin children with CIPA. METHODS: Twenty-three Arab Bedouin children (12 females, 11 males) with CIPA aged between 3 and 17 years (mean 9 y 7 mo, SD 4 y 2 mo) were assessed. They were compared with 19 healthy siblings of the affected children aged between 5 and 13 years (mean 8 y 11 mo, SD 2 y 10 m). All of the children in the comparison group, but only half of the CIPA group, were attending school. The children were evaluated using a standardized, non-verbal intelligence test, the Leiter International Performance Scale--Revised, and an adaptive behaviour questionnaire, the Vineland Adaptive Behaviour Scales, 2nd edition. RESULTS: Based on scores on the intelligence test and the adaptive behaviour scale, children with CIPA functioned in the mental retardation range (mean IQ scores: CIPA group 53.8, comparison group 83.32 [p<0.001]; adaptive behaviour: CIPA group 68.1, comparison group 104.88 [p<0.001]). IQ was significantly higher among the children with CIPA aged up to 7 years 11 months than among the older children 73.83 vs 45.21 (p<0.001). INTERPRETATION: As a group, the younger children with CIPA may be functioning above the mental retardation range. We propose that early intervention addressing these children's needs and developing an appropriate educational system, might improve their outcome.

Personalidad y afrontamiento en dolor crónico neuropático: un divorcio previsible / Personality and coping in neuropathic chronic pain: a predictable divorce

Se aborda la problemática referida a las relaciones existentes entre las dimensiones de personalidad y el empleo de las estrategias de afrontamiento en enfermos con dolor crónico. El modelo teórico más empleado en el ámbito del estrés y su relación con el dolor es el modelo transaccional, considerando que la inclusión de rasgos de personalidad mejoraría las predicciones mediante el afrontamiento en el proceso del estrés. Siguiendo el modelo de los cinco grandes se establecen las relaciones existentes entre las dimensiones de personalidad y las estrategias de afrontamiento en enfermos con dolor crónico de tipo neuropático. Los resultados arrojan relaciones débiles entre dichas dimensiones y el afrontamiento. Se obtiene un perfil de personalidad vulnerable en enfermos con dolor crónico neuropático consistente en alto neuroticismo, baja extraversión, apertura y responsabilidad y moderada amabilidad (AU)

We approach the problem about relationships between personality dimensions and the use of coping strategies in chronic pai patients. The most frequently used theoretical model in the area of stress and its relation to pain is the transactional model, taking into account that the incorporation of personality traits improves predictions via coping in the stress process. Following the Big Five model, the relationships between personality and coping strategies in patients with chronical neuropathic pain were established. The results showed slight relationships between the Big-Five dimensions and coping. A vulnerable personality profile in patients with chronic neuropathic pain was obtained, consisting of high neuroticism, low extraversion, openness to experience and responsibility, and moderate agreeableness (AU)

Treatment of life-threatening self-injurious behavior secondary to hereditary sensory and autonomic neuropathy type II: a controlled case study.

Although self-injurious behavior is present in all subtypes of hereditary sensory and autonomic neuropathy, the literature has not sufficiently addressed the issue of treatment of self-injury in this population. Therefore, the purpose of the current case study was to describe a method for assessing and treating self-injurious behavior associated with hereditary sensory and autonomic neuropathies. This study was conducted with an 11-year-old boy diagnosed with hereditary sensory and autonomic neuropathy type II admitted to an inpatient behavioral unit over a 4-month period. A simplified version of a habit reversal treatment was used, consisting of awareness training, self-monitoring, competing responses, and social support. Treatment resulted in a 98% reduction in the rate of self-injurious behavior relative to pretreatment baseline rates. This case study illustrates that behavioral interventions may be a viable option for treating self-injury secondary to hereditary sensory and autonomic neuropathies.

Psychiatric aspects of acute pandysautonomia.

Five cases of acute pandysautonomia and one case of acute autonomic and sensory neuropathy are described with special reference to psychiatric symptoms. They originally presented as psychiatric disorders, such as hysterical neurosis, epilepsy, anorexia nervosa and hypochondriacal neurosis. Psychiatric symptoms arise from their autonomic nervous dysfunction and show emotional instabilities which are often regarded as hysterical overacting.