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Clinical genetic studies have shown that loss of Nav1.7 function leads to the complete loss of acute pain perception. The global deletion is reported lethal in mice, however, and studies of mice with promoter-specific deletions of Nav1.7 have suggested that the role of Nav1.7 in pain transduction depends on the precise form of pain. We developed genetic and animal husbandry strategies that overcame the neonatal-lethal phenotype and enabled construction of a global Nav1.7 knockout mouse. Knockouts were anatomically normal, reached adulthood, and had phenotype wholly analogous to human congenital indifference to pain (CIP): compared to littermates, knockouts showed no defects in mechanical sensitivity or overall movement yet were completely insensitive to painful tactile, thermal, and chemical stimuli and were anosmic. Knockouts also showed no painful behaviors resulting from peripheral injection of nonselective sodium channel activators, did not develop complete Freund's adjuvant-induced thermal hyperalgesia, and were insensitive to intra-dermal histamine injection. Tetrodotoxin-sensitive sodium current recorded from cell bodies of isolated sensory neurons and the mechanically-evoked spiking of C-fibers in a skin-nerve preparation each were reduced but not eliminated in tissue from knockouts compared to littermates. Results support a role for Nav1.7 that is conserved between rodents and humans and suggest several possibly translatable biomarkers for the study of Nav1.7-targeted therapeutics. Results further suggest that Nav1.7 may retain its key role in persistent as well as acute forms of pain.

Congenital Insensitivity to pain with anhydrosis (CIPA) is a rare inherited disease. It is classified as hereditary sensory and autonomic neuropathy type IV. Pain insensitivity and autonomic deficits are present, but touch and pressure sensitivity are unimpaired. Mental retardation is usually present. We report a family case of a 5 years old girl and 2 years old boy with congenital insensitivity to pain, while discussing the clinical features and the anesthetic strategy of such patients. Patients with Congenital Insensitivity to Pain with anhydrosis may undergo surgery because of susceptibility to trauma due to absence of pain. The clinical features may intrinsically possess anesthetic challenges.

alpha(1) subunit of the voltage-dependent Ca(2+) channel is essential for channel function and determines the functional specificity of various channel types. alpha(1E) subunit was originally identified as a neuron-specific one, but the physiological function of the Ca(2+) channel containing this subunit (alpha(1E) Ca(2+) channel) was not clear compared with other types of Ca(2+) channels because of the limited availability of specific blockers. To clarify the physiological roles of the alpha(1E) Ca(2+) channel, we have generated alpha(1E) mutant (alpha(1E)-/-) mice by gene targeting. The lacZ gene was inserted in-frame and used as a marker for alpha(1E) subunit expression. alpha(1E)-/- mice showed reduced spontaneous locomotor activities and signs of timidness, but other general behaviors were apparently normal. As involvement of alpha(1E) in pain transmission was suggested by localization analyses with 5-bromo-4-chloro-3-indolyl beta-d-galactopyranoside staining, we conducted several pain-related behavioral tests using the mutant mice. Although alpha(1E)+/- and alpha(1E)-/- mice exhibited normal pain behaviors against acute mechanical, thermal, and chemical stimuli, they both showed reduced responses to somatic inflammatory pain. alpha(1E)+/- mice showed reduced response to visceral inflammatory pain, whereas alpha(1E)-/- mice showed apparently normal response compared with that of wild-type mice. Furthermore, alpha(1E)-/- mice that had been presensitized with a visceral noxious conditioning stimulus showed increased responses to a somatic inflammatory pain, in marked contrast with the wild-type mice in which long-lasting effects of descending antinociceptive pathway were predominant. These results suggest that the alpha(1E) Ca(2 +) channel controls pain behaviors by both spinal and supraspinal mechanisms.

Objective: Hereditary sensory and autonomic neuropathy type IV (congenital insensitivity to pain with anhidrosis) is a rare disorder. In this study, we investigated the oral and dental manifestations associated with hereditary sensory and autonomic neuropathy type IV., Study Design: Eighteen patients with hereditary sensory and autonomic neuropathy type IV whose ages ranged from 1 year 0 months to 22 years 3 months were examined for oral signs and symptoms of tooth abnormalities, malocclusions, soft tissue disorders, tongue papilla atrophy, and morphologic abnormalities of hands and fingers., Results: All 18 patients showed congenital insensitivity to pain and anhidrosis. Oral self-mutilations, such as autoextraction of teeth and severe biting injuries (with resultant scarring) of the finger tips and oral soft tissues (tongue, lip, and buccal mucosa), were found in most patients. In infant patients the condition was typically characterized by decubital ulcers on the ventral surface of the tongue, resulting from trauma of the incisal edge of erupting mandibular primary incisors during sucking or nursing. These ulcers led to several local and systemic problems, such as tongue bleeding, infection, malnutrition, and halitosis. A large number of missing teeth and a high incidence of dental caries were additional characteristic findings. Such oral self-mutilations were found to decrease with age and with the intellectual, social, and/or emotional development of the patients. However, not all of the mutilations were completely eliminated. Two patients had partial dentures to replace missing teeth., Conclusions: Our study suggests that early diagnosis and specific dental management for patients with hereditary sensory and autonomic neuropathy type IV are important for prevention of the characteristic oral and dental problems accompanying this disorder.

Hereditary sensory neuropathy type IV is an autosomal-recessive disorder characterized by congenital insensitivity to pain and anhidrosis and resulting in recurrent hyperpyrexia, self-mutilation, recurrent infections, chronic osteomyelitis, bone and joint deformities, and limb amputations. Described is a child with signs as well as skin and nerve biopsy results compatible with this disease, emphasizing the importance of early diagnosis and appropriate medical and educational care to prevent complications.

Hereditary sensory neuropathies are a rare group of neurological disorders manifested from early childhood by diminished or absent sensibility to pain, touch and temperature. A Kashmiri family with four members affected by congenital sensory neuropathy and its oral manifestations is described. Pain and temperature sensation was lost in various parts of the body including the orofacial region resulting in mutilating acropathy, particularly of the limbs and face. Orofacial motor function was normal. Three of the four members had corneal opacification due to scarring from keratitis. To prevent any further mutilation, any corrective surgery is best delayed until the patient is old enough. A discussion of the oral manifestations of this condition with a review of the literature is presented.

Congenital corneal anesthesia (CCA) is a rare clinical entity that presents a whole gamut of problems before lending itself to a diagnosis by the clinician. Not recognizing the history of self-inflicted corneal injuries, not evaluating the corneal sensations in a child with recurrent corneal ulceration, misdiagnosis of such cases as viral keratitis, and not ruling out all the secondary causes of corneal anesthesia, as well as the other causes of self-inflicted injuries, are some of the pitfalls in the diagnosis of congenital corneal anesthesia. Four cases representative of different aspects of CCA are presented. The problems in the diagnosis of these cases are discussed. A clinical classification of congenital corneal anesthesia is suggested and the systemic anomalies associated with this disorder are enumerated.

A 2 1/2 year old child with clinical features of Goldenhar-Gorlin syndrome showed diminished pinprick sensation over the right half of the face. After surgery for the cleft lip, the child died. Neuropathological investigations showed agenesis of the right trigeminal nerve and hypoplasia of the right trigeminal brain-stem nuclei. Nosological aspects of the Goldenhar-Gorlin syndrome and previously reported cases of congenital trigeminal anaesthesia in this disorder are discussed. It is suggested that the hypoplasia of the trigeminal nerve is responsible for the diminished facial sensation seen in some patients with this craniofacial syndrome.

A nine-year-old child presented with congenital insensitivity to pain and anhidrosis. Quantitative studies and electron microscopy of the cutaneous branch of the radial nerve revealed almost complete absence of small myelinated and unmyelinated fibers and a disproportionate number of nerve fibers with a diameter of 6-10 micrometers. A grouping of both type 1 and type 2 muscle fibers was also seen. We suggest that this disease entity is not caused by a hereditary sensory neuropathy, but rather that it derives from a developmental defect.

Two siblings are described with mutilating lesions of the feet and hands, with sensory disturbances and muscle amyotrophy. The motor and afferent nerve conduction velocities were at the lower limit of normal. The nerve action potentials disappeared, first with percutaneous stimulation of the fingers and later with more proximal direct nerve stimulation. Early in the course of the illness indolent fracture of different long bones appeared in both cases. Histology revealed severe loss of nerve fibres, especially of the thin nonmyelinated ones. Excessive proliferation of Schwann sheaths and endoneurium exceeded the amount of the usual reparation for loss of nerve fibres and could be considered as a specific feature. Obliterative vasculopathy also belongs to the picture of changes in the nerves, skin, and bones.