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Channelopathy-Associated Congenital Insensitivity to Pain

CIP

Congenital pain insensitivity is a rare genetic disorder characterized by the inability to perceive pain. Since affected individuals do not respond appropriately to painful situations, they engage in self-mutilating behavior such as biting of the oral mucosa and fingers and sustain injuries such as burns, fractures, and joint dislocations.


Presentation

Congenital pain insensitivity (CPI) is an autosomal recessive disorder characterized by the inability to discern physical pain although the ability to feel a stimulus is intact [1]. This rare ailment is considered to be a part of the hereditary sensory and autonomic neuropathies (HSAN) [2]. CPI is a genetically heterogeneous disease caused by mutations in the SCN9A [3], NTRK1 [4], and NGFB genes [5]. If left undetected and unaddressed, this condition can affect the patient's overall health and result in serious outcomes.

The clinical presentation reflects which gene is affected. Generally, the cases demonstrate a lack of pain perception with burns, bone fractures, joint dislocations, and other injuries [6]. Moreover, they engage in self-mutilation by biting on their tongue, lips, and digits [7] [8] resulting in laceration and ulceration of oral mucosa and scarring of the cheeks [9] [10]. Additionally, affected individuals may exhibit mental retardation and developmental delays with varying degrees. Also common are behavioral issues and emotional lability. Furthermore, patients may be prone to developing neurotrophic keratitis, corneal ulcerations and scarring, and even infection.

Depending on the mutated gene and the resultant clinical phenotype, anosmia [2] or anhidrosis [4] [10] are prominent features. The latter predisposes to recurrent febrile episodes [10].

Complications

Painless injuries induce severe consequences such as recurrent disease and repeated fractures. Specifically, sufferers are susceptible to developing osteomyelitis, acroosteolysis, and Charcot joints. Additionally, they may develop oral ulcers and other lesions, which further lead to infections, oral bleeding, and malnutrition [10]. If not treated, poor outcomes such as failure to thrive are likely [10].

Physical exam

The neurologic exam in subjects with CPI reveals normal touch, vibration, and position senses. Remarkable overall findings include joint deformities, disfiguring injuries, oral and eye abnormalities.

Oral Bleeding
  • Additionally, they may develop oral ulcers and other lesions, which further lead to infections, oral bleeding, and malnutrition. If not treated, poor outcomes such as failure to thrive are likely.[symptoma.com]
Oral Ulcers
  • Additionally, they may develop oral ulcers and other lesions, which further lead to infections, oral bleeding, and malnutrition. If not treated, poor outcomes such as failure to thrive are likely.[symptoma.com]
Decreased Lacrimation
  • They present with anhidrosis, decreased lacrimation, tongue ulcerations, recurrent gastrointestinal (GI) upset, diminished or absent deep tendon reflexes, poorly controlled temperature, a fluctuating blood pressure and an absent axon reflex.[ijoonline.com]
Decreased Sweating
  • Over time, this lack of pain awareness can lead to an accumulation of injuries and health issues that may affect life expectancy. 0000970 Anosmia Lost smell 0000458 Autosomal recessive inheritance 0000007 Hypohidrosis Decreased ability to sweat Decreased[rarediseases.info.nih.gov]
  • HSAN type IV is characterized by anhidrosis, absent or markedly decreased sweating [ 1 – 3, 12, 13, 55 – 58 ].[ojrd.biomedcentral.com]
Joint Deformity
  • Remarkable overall findings include joint deformities, disfiguring injuries, oral and eye abnormalities. Infants and young children with an impaired response to pain and repeated harmful behaviors should be evaluated for this medical entity.[symptoma.com]
  • Other features include multiple bone fractures and musculoskeletal complications, scars, osteomyelitis, joint deformities, ocular complications, and hyperpyrexia. Mental retardation and behavior problems are common.[pediatricneurologybriefs.com]
  • In this way, chronic infections of bones and joints, bone fractures, osteomyelitis and joint deformities are common in people who suffer from CIPA.[flipper.diff.org]
Joint Dislocation
  • Generally, the cases demonstrate a lack of pain perception with burns, bone fractures, joint dislocations, and other injuries.[symptoma.com]
  • dislocations, and joint deformities (Charcot joints).[e-ijd.org]
Neuropathic Arthropathy
  • Repeated trauma to joints results in progressive inflammation, damage, and deformity of the affected joints (Charcot joint or neuropathic arthropathy). The large, weight-bearing joints are especially prone to this complication.[rarediseases.org]
Phenylketonuria
  • The comparison of catecholamine metabolism in patients with phenylketonuria, Lesh-Nyham syndrome, congenital sensory neuropathy with anhydrosis and familial dysautonomia on the basis of our data and those in the literature suggests that patients with[ncbi.nlm.nih.gov]
Indifference to Pain
  • Other names for congenital insensitivity to pain include: asymbolia for pain channelopathy-associated insensitivity to pain CIP congenital analgesia congenital insensitivity to pain congenital pain indifference indifference to pain, congenital, autosomal[thinkgenetic.com]
  • […] to pain congenital pain indifference indifference to pain, congenital, autosomal recessive pain insensitivity, congenital Dabby R.[ghr.nlm.nih.gov]
  • A syndrome characterized by indifference to PAIN despite the ability to distinguish noxious from nonnoxious stimuli. Absent corneal reflexes and INTELLECTUAL DISABILITY may be associated.[connects.catalyst.harvard.edu]
  • There is indifference to pain, but this is usually far less of a problem than the autonomic dysfunction. Intelligence is usually normal, but emotions can be unstable.[contact.org.uk]
  • A twenty one year review of a case of congenital indifference to pain. J Bone Joint Surg Br 1975;57:241-3. [ PUBMED ] [ FULLTEXT ] 13. Abell JM, Hayes JT. Charcot knee due to congenital insensitivity to pain.[ijoonline.com]
Nystagmus
  • The NCS and nerve biopsy are normal. 1 Familial dysautonomia (HSAN-Type-III) also comprises of nystagmus, hypotonia, areflexia and poor coordination. 6 Asymbolia for pain usually has damaged insular cortex evident on magnetic resonance imaging of brain[apicareonline.com]
Absent Deep Tendon Reflex
  • They present with anhidrosis, decreased lacrimation, tongue ulcerations, recurrent gastrointestinal (GI) upset, diminished or absent deep tendon reflexes, poorly controlled temperature, a fluctuating blood pressure and an absent axon reflex.[ijoonline.com]
Febrile Convulsions
  • It is the anhidrosis that causes episodic fevers and extreme hyperpyrexia that is usually the earliest sign of the disorder and can cause recurrent febrile convulsions secondary to high environmental temperature [ 1, 12 ].[ojrd.biomedcentral.com]
Tonic-Clonic Seizure
  • She also had three episodes of generalized tonic-clonic seizure during afebrile period. This case report highlights the rare association of congenital insensitivity to pain and anhidrosis with seizure disorder.[content.iospress.com]

Workup

Infants and young children with an impaired response to pain and repeated harmful behaviors should be evaluated for this medical entity. The workup will include the patient's history and presentation, a complete physical exam (including a focus on neurologic, oral, and eye tests), and specialized studies.

Diagnostic tests

Biopsy of the skin and nerves can confirm the diagnosis by revealing distinctive findings [11]. Specifically, microscopic analysis of the skin may show the abnormal functioning of nerves innervating eccrine sweat glands while examination of the nerve tissue may demonstrate a diminished quantity of unmyelinated small-diameter fibers. Another exam is characterized by applying pressure with a pen onto the patient's nail bed. Note that an absent withdrawal response is a result of the lack of pain perception [11]. Clinicians may perform the axonal flare test, in which an intradermal histamine injection results in a characteristic skin response. An electromyogram (EMG) will typically yield normal results [1]. Genetic testing is not routinely done since there are many mutations associated with CPI.

Treatment

  • Treatment depends on the patient's age and intelligence, as well as the parent's attitude and cooperation.[pediatricneurosciences.com]
  • […] and prognosis No specific treatment is available for CIP 1,7.[radiopaedia.org]
  • HSAN is described additionally to be a genetic disorder created through mutations with no cure or treatment. Although there is therapy to deal with the symptoms, it does not deal with the disorder, and there is no definitive treatment to each child.[neurosciencefundamentals.unsw.wikispaces.net]
  • […] guard [ Hutton & McKaig 2010 ] Bone fractures Standard treatment Treatment w/an external fixator may lead to potentially serious infectious complications.[ncbi.nlm.nih.gov]

Prognosis

  • […] reported the following features 9 : acro-osteolysis within the first year of life (100%) limb fractures with prominent periosteal reaction and exuberant callus (100%) osteomyelitis (50%) brain volume loss with mild ventriculomegaly (50%) Treatment and prognosis[radiopaedia.org]
  • The prognosis for independent function depends on the degree of disease expression and the ability to control the secondary clinical problems. Prognosis and goals There are a number of hereditary and sensory and autonomic neuropathies (HSAN).[ojrd.biomedcentral.com]

Etiology

  • The etiology and pathogenesis of CIP depends on the specific type of HSAN. For example: HSAN2D (channelopathy-associated congenital insensitivity to pain) : patients have homozygous mutations in the SCN9A gene 4,7.[radiopaedia.org]
  • Common syndromes with unknown etiology (e.g., intercostal neuralgia). B. Painful polyneuropathies (including acute-onset and slow-onset distal symmetrical polyneuropathies) HIV (Schiffito et al. 2002; Luciano et al. 2003).[shiga-med.ac.jp]

Epidemiology

  • […] insensitivity to pain to experience it for the first time. [14] Similar effects were observed in Na v 1.7 null mice treated with naloxone. [14] As such, opioid antagonists like naloxone and naltrexone may be effective in treating the condition. [14] Epidemiology[en.wikipedia.org]
  • Epidemiology HSAN IV is extremely rare among most populations with the exception of the Japanese and Israeli-Bedouins. The prevalence is unknown, but it was seen the disorder is more diffused in cultures in which intermarriage is accepted.[flipper.diff.org]
Sex distribution
Age distribution

Pathophysiology

  • Despite the discovery of these two channels and their modes of action, the pathophysiology of pain perception is incompletely understood. To date, mutations in Nav1.7 (OMIM 603415) have been implicated in three pain-related syndromes in humans.[karger.com]

Prevention

  • Endorphins are molecules in your body that when released, prevent nerve cells from releasing more pain signals.[thetartan.org]
  • In certain extreme cases, the child's baby teeth are extracted to prevent self mutilation of tongue, lips and fingers until they grow their adult teeth. Figure 4.[neurosciencefundamentals.unsw.wikispaces.net]
  • Common practices can be: • prevention of self-mutilation by smoothing or extracting teeth; • prevention of debilitating orthopedic problems by daily evaluation for early signs of unrecognized injury; • prevention of neurotrophic keratitis with tarsorrhaphy[flipper.diff.org]
  • Tea tree oil : Tea tree oil is purported to have antiseptic properties, and has been used traditionally to prevent and treat infections.[livingnaturally.com]
  • The parents need to be educated about simple measures like avoiding excessive wrapping, preventing dehydration, and measures to reduce hyperpyrexia, which reduce lot of preventable deaths.[e-ijd.org]

References

Article

  1. Peddareddygari LR, Oberoi K, Grewal RP. Congenital Insensitivity to Pain: A Case Report and Review of the Literature. Case Rep Neurol Med. 2014;2014:141953.
  2. Genetics Home Reference (GHR). Congenital insensitivity to pain. http://ghr.nlm.nih.gov/condition/congenital-insensitivity-to-pain. Accessed May 22nd, 2017.
  3. Cox JJ, Sheynin J, Shorer Z, et al. An SCN9A channelopathy causes congenital inability to experience pain. Hum Mutat. 2010;31(9):E1670-86.
  4. Miura Y, Mardy S, Awaya Y, et al. Mutation and polymorphism analysis of the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor in congenital insensitivity to pain with anhidrosis (CIPA) families. Hum Genet. 2000;106(1):116-24.
  5. Carvalho OP, Thornton GK, Hertecant J, et al. A novel NGF mutation clarifies the molecular mechanism and extends the phenotypic spectrum of the HSAN5 neuropathy. J Med Genet. 2011;48(2):131-5.
  6. Klein CJ, Wu Y, Kilfoyle DH, et al. Infrequent SCN9A mutations in congenital insensitivity to pain and erythromelalgia. J Neurol Neurosurg Psychiatry. 2013;84(4):386-391.
  7. Nolano M, Crisci C, Santoro L, et al. Absent innervation of skin and sweat glands in congenital insensitivity to pain with anhidrosis. Clin Neurophysiol. 2000;111(9):1596–601.
  8. Kriel RL. Abnormalities of Sensory Perception in the Practice of Pediatric Neurology. Vol 1. In: Swaiman KF, Wright FS, eds. St. Louis, MO: CV Mosby CO; 1982: 222–231.
  9. Amano A, Akiyama S, Ikeda M, Morisaki I. Oral manifestations of hereditary sensory and autonomic neuropathy type IV. Congenital insensitivity to pain with anhidrosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1998;86(4):425–31.
  10. Safari A, Khaledi AA, Vojdani M. Congenital Insensitivity to Pain with Anhidrosis (CIPA): A Case Report. Iran Red Crescent Med J. 2011;13(2):134-138.
  11. Zhang S, Malik Sharif S, Chen Y-C, et al. Clinical features for diagnosis and management of patients with PRDM12 congenital insensitivity to pain. J Med Genet. 2016;53(8):533-535.

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Last updated: 2019-07-11 20:14