with anhidrosis main article: congenital insensitivity to pain with anhidrosis congenital insensitivity to pain with anhidrosis (cipa), also known as hereditary sensory and autonomic neuropathy type iv (hsan iv), is characterized by insensitivity to pain, anhidrosis (the inability to sweat), and intellectual disability. the ability to sense all pain (including visceral pain) is absent, resulting in repeated injuries including: oral self-mutilation (biting of tongue, lips, and buccal mucosa); biting of fingertips; bruising, scarring, and infection of the skin; multiple bone fractures (many of which fail to heal properly); and recurrent joint dislocations resulting in joint deformity. sense of touch, vibration, and position are normal. anhidrosis predisposes to recurrent febrile episodes that are often the initial manifestation of cipa. hypothermia in cold environments also occurs. intellectual disability of varying degree is observed in most affected individuals; hyperactivity and emotional lability are common. hereditary sensory neuropathy type iv (hsn4) is a rare genetic disorder characterized by the loss of sensation (sensory loss), especially in the feet and legs and, less severely, in the hands and forearms. the sensory loss is due to abnormal functioning of small, unmyelinated nerve fibers and portions of the spinal cord that control responses to pain and temperature as well as other involuntary or automatic body processes. sweating is almost completely absent with this disorder. intellectual disability is usually present. type 4, congenital insensitivity to pain with anhidrosis (cipa), is an autosomal recessive condition and affected infants present with episodes of hyperthermia unrelated to environmental temperature, anhidrosis and insensitivity to pain. palmar skin is thickened and charcot joints are commonly present. ncv shows motor and sensory nerve action potentials to be normal. the histopathology of peripheral nerve biopsy reveals absent small unmyelinated fibers and mitochondria are abnormally enlarged. management of hereditary sensory and autonomic neuropathy type 4: treatment of manifestations: treatment is supportive and is best provided by specialists in pediatrics, orthopedics, dentistry, ophthalmology, and dermatology. for anhidrosis: monitoring body temperature helps to institute timely measures to prevent/manage hyperthermia or hypothermia. for insensitivity to pain: modify as much as reasonable a child's activities to prevent injuries. inability to provide proper immobilization as a treatment for orthopedic injuries often delays healing; additionally, bracing and invasive orthopedic procedures increase the risk for infection. methods used to prevent injuries to the lips, buccal mucosa, tongue, and teeth include tooth extraction, and/or filing (smoothing) of the sharp incisal edges of teeth, and/or use of a mouth guard. skin care with moisturizers can help prevent palmar and plantar hyperkeratosis and cracking and secondary risk of infection; neurotrophic keratitis is best treated with routine care for dry eyes, prevention of corneal infection, and daily observation of the ocular surface. interventions for behavioral, developmental and motor delays, as well as educational and social support for school-age children and adolescents, are recommended. prevention of secondary complications: regular dental examinations and restriction of sweets to prevent dental caries; early treatment of dental caries and periodontal disease to prevent osteomyelitis of the mandible. during and following surgical procedures, potential complications to identify and manage promptly include hyper- or hypothermia and inadequate sedation, which may trigger unexpected movement and result in secondary injuries. type 5, congenital insensitivity to pain with partial anhidrosis hereditary sensory and autonomic neuropathy type v (hsan5) is a condition that primarily affects the sensory nerve cells (sensory neurons), which transmit information about sensations such as pain, temperature, and touch. these sensations are impaired in people with hsan5. the signs and symptoms of hsan5 appear early, usually at birth or during infancy. people with hsan5 lose the ability to feel pain, heat, and cold. deep pain perception, the feeling of pain from injuries to bones, ligaments, or muscles, is especially affected in people with hsan5. because of the inability to feel deep pain, affected individuals suffer repeated severe injuries such as bone fractures and joint injuries that go unnoticed. repeated trauma can lead to a condition called charcot joints, in which the bones and tissue surrounding joints are destroyed. type 5, congenital insensitivity to pain with partial anhidrosis, also manifests with congenital insensitivity to pain & anhidrosis. there is a selective absence of small myelinated fibers differentiating it from type iv (cipa). genes related to hereditary sensory and autonomic neuropathy type 5: mutations in the ngf gene cause hsan5. the ngf gene provides instructions for making a protein called nerve growth factor beta (ngfβ) that is important in the development and survival of nerve cells (neurons), including sensory neurons. the ngfβ protein functions by attaching (binding) to its receptors, which are found on the surface of neurons. binding of the ngfβ protein to its receptor transmits signals to the cell to grow and to mature and take on specialized functions (differentiate). this binding also blocks signals in the cell that initiate the process of self-destruction (apoptosis). additionally, ngfβ signaling plays a role in pain sensation. mutation of the ngf gene leads to the production of a protein that cannot bind to the receptor and does not transmit signals properly. without the proper signaling, sensory neurons die and pain sensation is altered, resulting in the inability of people with hsan5 to feel pain. type 6 - hereditary sensory and autonomic neuropathy type 6 (hsan6) is a severe autosomal recessive disorder characterized by neonatal hypotonia, respiratory and feeding difficulties, lack of psychomotor development, and autonomic abnormalities including labile cardiovascular function, lack of corneal reflexes leading to corneal scarring, areflexia, and absent axonal flare response after intradermal histamine injection. genes related to hereditary sensory and autonomic neuropathy type 6: mutations in the dst (dystosin) gene are associated hsan6. in two separate studies of families with presentations of hsan6, the dst gene was found to be mutated, in one case with a truncating mutation, and in the other a non-sense or missense mutation. in the latter case, the authors proposed that homozygous truncating mutations result in a severe form of hsan6, with congenital defects and early lethality, while heterozygosity for a truncating or missense mutation maintains enough dystosin expression and function to allow a normal lifespan, albeit with symptoms of hsan6. dst is involved in maintaining cytoskeleton integrity and intracellular transport systems, each of which are critical to the normal function of the particularly long neurons found in the peripheral nervous system. it's believed that this disrupts the cell's internal autophagy process, in which toxic proteins and other normally-occurring debris are captured and transported to the cell center for recycling or destruction. in neurons, autophagosomes, are generated at the ends of the neuron to carry the discardable material, and they are then transported toward center. with the intracellular transport system disrupted by a mutation in dst, the autophagosomes are unable to carry away the debris, which builds up at the ends of the neuron, leading to damage. genetics associated genes typesub-typegenelocus hsan 11asptlc19q22.1-q22.3 1bunknown (omim 608088)3p24–p22 1c(= cmt2b, hmsn iib)rab7a3q21 1dunknownunknown 1ednmt1 (omim 614116)19p13.2 hsan 2hsn212p13.33 hsan 3 (familial dysautonomia)ikbkap9q31 hsan 4 (cipa)ntrk11q21-q22 trka hsan 5ngfβ1p13.1 ntrk1 hsan 6 dst hsan 7 scn11a hsan 8 prdm12 9q33.2-34.13